record_id,pubmedID,title,authors,abstract,year,label_included,label_abstract_screening 1,10023901,Effect of statins on C-reactive protein in patients with coronary artery disease.,T E Strandberg; H Vanhanen; M J Tikkanen,,1999.0,0,0 2,10024335,Distinct and combined vascular effects of ACE blockade and HMG-CoA reductase inhibition in hypertensive subjects.,P Nazzaro; M Manzari; M Merlo; R Triggiani; A Scarano; L Ciancio; A Pirrelli,"Hypercholesterolemia and hypertension are frequently associated with elevated sympathetic activity. Both are independent cardiovascular risk factors and both affect endothelium-mediated vasodilation. To identify the effects of cholesterol-lowering and antihypertensive treatments on vascular reactivity and vasodilative capacity, we studied 30 hypercholesterolemic hypertensive subjects. They received placebo for 4 weeks, either enalapril or simvastatin for 14 weeks, and, finally, both medications for an additional 14 weeks. Postischemic forearm blood flow (MFBF) and minimal vascular resistance (mFVR) were used as indices of vasodilative capacity and structural vascular damage, respectively. Total (resting-stress-recovery phases) cardiovascular (blood pressure [BP] and heart rate [HR]) and regional hemodynamic (FBF and FVR) reactivity to stressful stimuli were calculated as area-under-the-curve (auc) (valuextime). Compared with baseline levels, simvastatin reduced total (TOT-C) and LDL cholesterol (LDL-C) (1.27 mmol/L, P<0.001 and 1.33 mmol/L, P<0.001, respectively). Enalapril also reduced TOT-C and LDL-C (0.6 mmol/L, P<0.001 and 0.58 mmol/L, P<0.05, respectively). MFBF was increased substantially by both treatments (P<0.001). Enalapril had a greater effect (-1.7 arbitrary units (AU), P<0.001) than simvastatin (-0.6 AU, P<0.05) on mFVR. During stress, FBF increased more with enalapril (4.4 FBFxminutes, P<0.001) than with simvastatin (1.8 FBFxminutes, P<0.01). Conversely, FVR stress response was reduced more with enalapril (9.1 FVRxminutes, P<0.001) than with simvastatin (2.9 FVRxminutes, P<0.01). During combination treatment, a significant (0.001>P<0.05) additive effect on hypercholesterolemia, structural vascular damage, BP, and FVR was shown. The findings suggest that angiotensin-converting enzyme (ACE) inhibition induces a larger reduction than HMG-CoA reductase blockade in vascular reactivity and structural damage in hypercholesterolemic hypertensive subjects.",1999.0,0,0 3,10026704,Coronary artery disease and diabetes.,N J Bohannon,"The increased risk of cardiovascular disease in diabetic patients is well documented. A greater appreciation for the importance of this fact and regular use of secondary prevention strategies, including aggressive use of HMG-CoA reductase inhibitors or other lipid-lowering agents to reduce cholesterol levels, are clearly indicated for diabetic patients with CAD. If no contraindications exist, ACE inhibitors, beta blockers, and aspirin also should be considered for these high-risk patients.",1999.0,0,0 4,10027660,Effect of itraconazole on cerivastatin pharmacokinetics.,T Kantola; K T Kivistö; P J Neuvonen,"To determine the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of cerivastatin, a competitive 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. A randomized, double-blind, cross-over study design with two phases, which were separated by a washout period of 4 weeks, was used. In each phase ten healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days according to a randomization schedule. On day 4, 0.3 mg cerivastatin was administered orally. Serum concentrations of cerivastatin, its major metabolites, active and total HMG-CoA reductase inhibitors, itraconazole and hydroxyitraconazole were measured up to 24 h. Itraconazole increased the area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) of the parent cerivastatin by 15% (P < 0.05). The mean peak serum concentration (Cmax) of cerivastatin lactone was increased 1.8-fold (range 1.1-fold to 2.4-fold, P < 0.001) and the AUC(0-24h) 2.6-fold (range 2.0-fold to 3.6-fold, P < 0.001) by itraconazole. The elimination half-life (t1/2) of cerivastatin lactone was increased 3.2-fold (P < 0.001). Itraconazole decreased the AUC(0-24h) of the active M-1 metabolite of cerivastatin by 28% (P < 0.05), whereas the AUC(0- 24h) of the more active metabolite, M-23, was increased by 36% (P < 0.05). The AUC(0-24h) and t1/2 of active HMG-CoA reductase inhibitors were increased by 27% (P < 0.05) and 40% (P < 0.05), respectively, by itraconazole. Itraconazole has a modest interaction with cerivastatin. Inhibition of the CYP3A4-mediated M-1 metabolic pathway leads to elevated serum concentrations of cerivastatin, cerivastatin lactone and metabolite M-23, resulting in increased concentrations of active HMG-CoA reductase inhibitors.",1999.0,0,0 5,10037456,"Protective effect of fluvastatin sodium (XU-62-320), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on oxidative modification of human low-density lipoprotein in vitro.",K Suzumura; M Yasuhara; K Tanaka; T Suzuki,"We investigated the protective effect of fluvastatin sodium on the oxidation of low-density lipoprotein (LDL) induced in vitro by copper ions. The extent of lipid peroxidation was assessed by monitoring the increase of UV absorbance at 234 nm, which is the peak absorbance of a conjugated diene. Fluvastatin sodium (1-30 microM) not only prolonged the lag time of oxidation in the initiation step, but also decreased the rate of oxidation in the propagation step, both concentration dependently. Fluvastatin sodium and alpha-tocopherol showed an additive effect when both compounds were added before oxidation. However, when the lag time was prolonged initially by alpha-tocopherol, and fluvastatin sodium and alpha-tocopherol, were further added into the reaction mixture at the end point of the lag phase, fluvastatin sodium still showed an antioxidative effect, whereas alpha-tocopherol showed a pro-oxidative effect. Therefore, the antioxidative property of fluvastatin sodium differs from that of alpha-tocopherol. In this experiment, as neither the double bond-reduced derivative of fluvastatin sodium nor pravastatin sodium showed any protective effect, we concluded that the antioxidative effect of fluvastatin sodium is not a common property of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, but may be derived from its unique chemical structure. Since the oxidative modification of LDL plays an important role in the genesis of atherosclerosis, fluvastatin sodium may help reduce the risk of atherosclerosis, not only by reducing plasma LDL levels but also by protecting LDL from oxidative modification.",1999.0,0,0 6,10037537,Treating average cholesterol levels in patients with coronary heart disease.,E J Lindbloom,,1999.0,0,0 7,10047626,Comparative efficacy and tolerability of low-dose pravastatin versus lovastatin in patients with hypercholesterolemia.,W E Strauss; D Lapsley; J M Gaziano,"The HMG CoA reductase inhibitors have quickly become the most widely prescribed family of agents for the treatment of patients with elevated low-density lipoprotein (LDL) cholesterol. The incidence of side effects with these agents increases as the dose increases within the recommended dosage range. A lower dosage presumably would have a lower incidence of adverse effects. In addition, lower doses should translate into reduced drug costs. We compared the efficacy of 10 mg of pravastatin and 10 mg of lovastatin in a randomized, crossover design trial among 30 patients with hypercholesterolemia. At baseline, their total cholesterol and LDL cholesterol levels were 249.0 +/- 27.3 and 185.1 +/- 25.5 mg/dL. After 4 weeks of treatment with lovastatin, the total cholesterol and LDL cholesterol levels fell to 202.8 +/- 29.6 and 141.0 +/- 25.3 mg/dL, decreases of 19% and 24%, respectively. Four weeks of pravastatin treatment resulted in levels of 212.6 +/- 30.8 and 150.5 +/- 25.5 mg/dL, or 15% and 19%, respectively. There were highly significant changes in total cholesterol and LDL cholesterol levels with each agent and no differences in effect between the 2 agents. In 13 (43%) of the 30 patients, LDL levels were reduced to 40% (+1.8%). Finally, the numbers of akinetic or hypokinetic segments at rest and during exercise were not different in the two groups before and after treatment. Mean maximal exercise load (113+/-23 watts in F vs. 104+/-27 W in S before treatment) was not modified by the treatment (111+/-21 and 104+/-27 W). Thus a 12-week lipid-lowering treatment with either S or F did not negatively alter left ventricular function during exercise in dyslipidemic patients with established coronary heart disease and did not affect their ability to exercise. The improvement in left ventricular function at rest after simvastatin in patients with left ventricular dysfunction warrants confirmation in further studies with large sample size.",1999.0,0,0 10,10073746,"A comparison of the use, effectiveness and safety of bezafibrate, gemfibrozil and simvastatin in normal clinical practice using the New Zealand Intensive Medicines Monitoring Programme (IMMP).",P W Beggs; D W Clark; S M Williams; D M Coulter,"Because of the importance of treating dyslipidaemia in the prevention of ischaemic heart disease and because patient selection criteria and outcomes in clinical trials do not necessarily reflect what happens in normal clinical practice, we compared outcomes from bezafibrate, gemfibrozil and simvastatin therapy under conditions of normal use. A random sample of 200 patients was selected from the New Zealand Intensive Medicines Monitoring Programme's (IMMP) patient cohorts for each drug. Questionnaires sent to prescribers requested information on indications, risk factors for ischaemic heart disease, lipid profiles with changes during treatment and reasons for stopping therapy. 80% of prescribers replied and 83% of these contained useful information. The three groups were similar for age, sex and geographical region, but significantly more patients on bezafibrate had diabetes and/or hypertension than those on gemfibrozil or simvastatin. After treatment and taking the initial measure into account, the changes in serum lipid values were consistent with those generally observed, but with gemfibrozil being significantly less effective than expected. More patients (15.8%S) stopped gemfibrozil because of an inadequate response compared with bezafibrate (5.4%) and simvastatin (1.6%). Gemfibrozil treatment was also withdrawn significantly more frequently due to a possible adverse reaction compared with the other two drugs. In normal clinical practice in New Zealand gemfibrozil appears less effective and more frequently causes adverse effects leading to withdrawal of treatment than either bezafibrate or simvastatin.",1999.0,0,0 11,10073863,Rationale and design of the Arterial Disease Multiple Intervention Trial (ADMIT) pilot study.,D A Egan; R Garg; T J Wilt; M B Pettinger; K B Davis; J Crouse; J A Herd; D B Hunninghake; D S Sheps; J B Kostis; J Probstfield; M A Waclawiw; W Applegate; M B Elam,"The primary objectives of the pilot study were to: (1) evaluate the feasibility of recruiting patients with peripheral arterial disease (PAD); (2) measure the efficacy and safety of high-density lipoprotein (HDL)-raising treatment, low-density lipoprotein (LDL)-lowering therapy, antioxidant therapy, antithrombotic therapy, and their combinations; and (3) assess adherence to a complex multiple drug regimen. Secondary objectives included measurement of the effect of the interventions on prespecified biochemical markers, maintenance of therapy masking (in particular with niacin), and measurement of the intervention's impact on functional status and on quality of life. To date, no secondary prevention trial has been conducted specifically among patients with PAD. Intermittent claudication affects about 0.5% to 1.0% of persons aged >35 years. There is a striking increase in incidence of PAD with age, particularly among those aged >50 years in both sexes, although men are twice as likely as women to develop PAD. The Arterial Disease Multiple Intervention Trial was a double-blind randomized pilot trial of 468 participants with documented PAD. A 2 x 2 x 2 factorial design was used to evaluate the effect of 3 interventions. The pilot incorporated several major novel design features: first, the use of a simple noninvasive method (measurement of ankle brachial index) to identify a population with either symptomatic or asymptomatic PAD; and second, a lipid modifying strategy to increase HDL with nicotinic acid in the intervention group while lowering LDL levels equally with an hydroxymethylglutaryl-coenzyme A reductase inhibitor as needed in the intervention and control group. Two other arms, the antioxidant arm (consisting of beta-carotene and vitamins E and C) and the antithrombotic arm (using warfarin) were also added. Adherence to therapy was measured by pill count, and success in treatment was measured by the proportion of values in target range for HDL, LDL, and the international normalized ratio.",1999.0,0,0 12,10075142,A randomized placebo-controlled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty; final results of the fluvastatin angiographic restenosis (FLARE) trial.,P W Serruys; D P Foley; G Jackson; H Bonnier; C Macaya; M Vrolix; A Branzi; J Shepherd; H Suryapranata; P J de Feyter; R Melkert; G A van Es; P J Pfister,"The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors competitively inhibit biosynthesis of mevalonate, a precursor of non-sterol compounds involved in cell proliferation. Experimental evidence suggests that fluvastatin may, independent of any lipid lowering action, exert a greater direct inhibitory effect on proliferating vascular myocytes than other statins. The FLARE (Fluvastatin Angioplasty Restenosis) Trial was conceived to evaluate the ability of fluvastatin 40 mg twice daily to reduce restenosis after successful coronary balloon angioplasty (PTCA). Patients were randomized to either placebo or fluvastatin 40 mg twice daily beginning 2-4 weeks prior to planned PTCA and continuing after a successful PTCA (without the use of a stent), to follow-up angiography at 26+/-2 weeks. Clinical follow-up was completed at 40 weeks. The primary end-point was angiographic restenosis, measured by quantitative coronary angiography at a core laboratory, as the loss in minimal luminal diameter during follow-up. Clinical end-points were death, myocardial infarction, coronary artery bypass graft surgery or re-intervention, up to 40 weeks after PTCA. Of 1054 patients randomized, 526 were allocated to fluvastatin and 528 to placebo. Among these, 409 in the fluvastatin group and 427 in the placebo group were included in the intention-to-treat analysis, having undergone a successful PTCA after a minimum of 2 weeks of pre-treatment. At the time of PTCA, fluvastatin had reduced LDL cholesterol by 37% and this was maintained at 33% at 26 weeks. There was no difference in the primary end-point between the treatment groups (fluvastatin 0.23+/-0.49 mm vs placebo 0.23+/-0.52 mm, P=0.95) or in the angiographic restenosis rate (fluvastatin 28%, placebo 31%, chi-square P=0.42), or in the incidence of the composite clinical end-point at 40 weeks (22.4% vs 23.3%; logrank P=0.74). However, a significantly lower incidence of total death and myocardial infarction was observed in six patients (1.4%) in the fluvastatin group and 17 (4.0%) in the placebo group (log rank P=0.025). Treatment with fluvastatin 80 mg daily did not affect the process of restenosis and is therefore not indicated for this purpose. However, the observed reduction in mortality and myocardial infarction 40 weeks after PTCA in the fluvastatin treated group has not been previously reported with statin therapy. Accordingly, a priori investigation of this finding is indicated and a new clinical trial with this intention is already underway.",1999.0,1,1 13,10075395,The role of dietary calcium in hypertension: a hierarchical overview.,L M Resnick,"The role of calcium in clinical hypertension can be best understood by a hierarchical model in which the blood pressure effects of a dietary signal depend on alterations of hormonal systems specific for that signal. These alterations mediate both the cellular recognition of these signals as well as the resultant clinical responses to them. In the case of both dietary calcium and dietary salt, these systems appear to include calcium regulating hormones having direct, calcium-dependent vasoactive properties, and which are linked to the activity of the renin-angiotensin system. Altered salt and calcium intake exert reciprocal linked effects on these hormone systems and on blood pressure. These reflect altered cellular calcium uptake from the extracellular space, salt-induced calcium hormones stimulating and calcium-induced suppression of these hormones inhibiting extracellular calcium uptake. Among normotensive individuals, this is associated with a reciprocal calcium-dependent suppression or stimulation of renin secretion, respectively, resulting in an offsetting decreased or increased angiotensin II-mediated release of calcium into the cytoplasm from intracellular stores. Hence, no significant change in cytosolic free calcium or, consequently, in blood pressure usually results from increasing or decreasing dietary salt or calcium intake. However, whether due to genetic or other environmental factors as yet undefined, the metabolic ""set point"" of plasma renin activity in some subjects is already suppressed, or, alternatively, is unresponsive to the above hormonally mediated dietary mineral variations. Under these circumstances, increases in dietary salt will cause cytosolic free calcium and thus blood pressure to rise, whereas increased dietary calcium in these very same ""salt-sensitive"" subjects will offset the effect of salt, and lower pressure in these individuals. This analysis suggests that although increasing oral calcium intake to achieve at least current nutritional standards is entirely appropriate, uniform recommendations for all hypertensives to further increase or decrease dietary calcium or salt may be inappropriate and will obscure those for whom these maneuvers are particularly relevant.",1999.0,0,0 14,10075964,Effect of long term simvastatin administration as an adjunct to ursodeoxycholic acid: evidence for a synergistic effect on biliary bile acid composition but not on serum lipids in humans.,F Lanzarotto; B Panarotto; R Sorbara; M Panteghini; F Pagani; S Sosta; A Lanzini,"Stimulated bile acid synthesis preferentially utilises newly synthesised cholesterol, raising the possibility that combination of simvastatin (an inhibitor of cholesterol synthesis) with ursodeoxycholic acid (UDCA; a stimulator of bile acid synthesis) may result in reduced bile acid synthesis and greater enrichment of the pool with UDCA than that achieved with UDCA treatment alone. To investigate the effect of simvastatin and UDCA given alone and in combination on serum and biliary lipid and biliary bile acid composition. Eighteen patients with primary non-familial hypercholesterolaemia were studied during treatment with simvastatin 20 mg/day, UDCA 10 mg/kg/day, and a combination of the two drugs. Each regimen was given in random order for three months following a three month lead in period. Simvastatin significantly reduced serum low density lipoprotein (LDL) cholesterol but biliary cholesterol concentration remained unchanged. Combination of the two drugs had no synergistic effect on serum cholesterol concentration, but significantly increased the proportion of UDCA in the bile acid pool from 35% during UDCA to 48% during combination treatment (p<0.04). Results showed that: (1) simvastatin reduces serum LDL cholesterol but has no effect on biliary cholesterol concentration, supporting the concept that newly synthesised cholesterol is not the preferential source for biliary cholesterol; and (2) combination of simvastatin with UDCA has the predicted effect of enhancing the proportion of UDCA in the pool. This effect may be of benefit in the treatment of cholestatic liver diseases.",1999.0,0,0 15,10080498,"""Care,"" cancer and coenzyme Q10.",S T Sinatra,,1999.0,0,0 16,10081301,"[Clinical study of the month. The LIPID study: ""long-term intervention with pravastatin in ischaemic disease""].",A J Scheen,"The LIPID study is a placebo-controlled, double-bind, randomized trial, performed in 9014 patients with coronary heart disease and total cholesterol levels of 155 to 271 mg/dl. After a mean follow-up of 6.1 years, patients receiving pravastatin (40 mg/day) had significantly (p < 0.001) lower death rate from coronary heart disease (24%), lower overall mortality (22%) and lower incidence of all cardiovascular outcomes (20 to 29% depending on the event). Interestingly enough, the reduction in death from coronary heart disease or nonfatal myocardial infarction was observed whatever the initial cholesterol concentration, and already significant if total cholesterol was < 213 mg/dl and LDL cholesterol was < 135 mg/dl. Thus, in secondary prevention, the favourable effect of the statin on the coronary heart disease outcomes is observed even in case of initial cholesterol levels yet considered as ""normal"".",1999.0,0,0 17,10082999,The HLA adventure.,J Dausset,,1999.0,0,0 18,10083575,Prevention of chronic heart allograft rejection.,H A Valantine-von Kaeppler,,1999.0,0,0 19,10083765,Effects of lovastatin and gemfibrozil in subjects with high ratios of total cholesterol to high-density lipoprotein cholesterol.,Y J Hung; D Pei; D A Wu; S W Kuo; M M Fuh; C Jeng,"Insulin resistance is associated with hypertriglyceridemia, low serum high-density lipoprotein cholesterol (HDL-C) concentrations and high serum total cholesterol (TC) to HDL-C ratios. Several reports have demonstrated that either lovastatin or gemfibrozil may favorably lower serum lipid concentrations. However, their effects on insulin sensitivity are unknown. The primary aim of this study was to compare the effects of lovastatin and gemfibrozil on insulin sensitivity and serum leptin concentrations in subjects with high TC/HDL-C ratios. We enrolled 25 nondiabetic patients, similar in terms of age and weight with TC/HDL-C ratios greater than 5. Thirteen subjects were treated with lovastatin 20 mg per day, and 12 received gemfibrozil 300 mg twice per day. Plasma lipids, glucose, and leptin were measured, and a 75-g oral glucose tolerance test (OGTT) and a modified insulin suppression test were performed before and after 3 months of treatment. The study showed the mean plasma TC, low-density lipoprotein cholesterol (LDL-C) concentrations, and TC/HDL-C ratio were significantly reduced in the lovastatin-treated group, but no obvious effects on plasma triglyceride (TG) and HDL-C were noted. In the gemfibrozil group, plasma TG and HDL-C were markedly lowered, but no significantly different effects in other plasma lipids were found. Gemfibrozil did not affect steady-state plasma glucose (SSPG) concentrations, whereas lovastatin significantly increased SSPG concentrations. Neither drug affected the serum leptin concentration during the OGTT. We conclude that lovastatin significantly lowers plasma TC and LDL-C ratio, and TC/HDL-C concentrations and adversely affects insulin sensitivity, while gemfibrozil markedly reduces plasma TG concentrations without altering insulin sensitivity in subjects with high TC/HDL-C ratios.",1999.0,0,0 20,10085441,"Oral and intravenous itraconazole for systemic fungal infections in neutropenic haematological patients: meeting report. London, United Kingdom, 20 June 1998.",H G Prentice; D Caillot; B Dupont; F Menichetti; U Schuler,"Effective prevention, or treatment, of invasive fungal infection in the neutropenic patient has hitherto been unsatisfactory because of either an inadequate anti-fungal spectrum of the agent or important toxicity. Itraconazole is effective against a broad spectrum of the opportunistic pathogens seen in Europe and North America. Prior problems with absorption, e.g. in the marrow transplant recipient, have been overcome with the introduction of an oral solution and an i.v. preparation. The deliberations of an expert meeting held in June, 1998 include recommendations on which patient requires one of these new preparations based on clinical trials, the dose and route. Important drug interactions are also detailed.",2000.0,0,0 21,10090113,Forecasting patient outcomes in the management of hyperlipidemia.,K L Brier; J J Tornow; A J Ries; M P Weber; J R Downs,"To forecast adult patient outcomes in the management of hyperlipidemia using adult National Health and Examination Survey III (NHANES III) population statistics and National Cholesterol Education Program (NCEP) guidelines for goals of therapy. Review of the hyperlipidemia drug therapy English-language medical literature with emphasis on randomized controlled trials of more than 6 weeks' duration published in the last 7 years, product package inserts, US Food and Drug Administration submission information, and NHANES III population statistics. Data were extracted from studies of lipid-lowering therapy to modify low-density lipoprotein (LDL) levels for primary and secondary prevention of coronary heart disease. The data that were evaluated included sample size, study design, therapeutic intervention, length of study, percentage change in LDL levels, and patient demographics. Cumulative frequency curves of the LDL distribution among the US adult population were constructed. The mean efficacy of drug therapy from qualified studies was used to extrapolate the percentage of the population expected to respond to the intervention and to forecast the patient outcome. A useful tool for clinicians was constructed to approximate the percentage of patients, based on risk stratification, who would reach NCEP target goal after a given pharmacotherapeutic intervention to decrease LDL levels.",1999.0,0,0 22,10090116,Cost-effectiveness of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the secondary prevention of cardiovascular disease: forecasting the incremental benefits of preventing coronary and cerebrovascular events.,S A Grover; L Coupal; S Paquet; H Zowall,"To forecast the long-term benefits and cost-effectiveness of lipid modification in the secondary prevention of cardiovascular disease. A validated model based on data from the Lipid Research Clinics cohort was used to estimate the benefits and cost-effectiveness of lipid modification with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) based on results from the Scandinavian Simvastatin Survival Study (4S), including a 35% decrease in low-density-lipoprotein (LDL)-cholesterol levels and an 8% increase in high-density-lipoprotein (HDL)-cholesterol levels. After comparing the short-term outcomes predicted for the 4S with the results actually observed, we forecast the long-term risk of recurrent myocardial infarction, congestive heart failure, transient ischemic attacks, arrhythmias, and strokes and the need for surgical procedures such as coronary artery bypass grafting, catheterization, angioplasty, and pacemaker insertions. Outpatient follow-up care costs were estimated, as were the costs of hospital care and drug therapy. All costs were expressed in 1996 US dollars. The short-term outcomes predicted for the 4S were consistent with the observed results. The long-term benefits of lipid modification among low-risk subjects (normotensive nonsmokers) with a baseline LDL/ HDL ratio of 5 but no other risk factors ranged from $5424 to $9548 per year of life saved for men and $8389 to $13747 per year of life saved for women. In high-risk subjects (hypertensive smokers) with an LDL/HDL ratio of 5, the estimated costs ranged from $4487 to $8532 per year of life saved in men and $5138 to $8389 per year of life saved in women. Assuming that lipid modification has no effect on the risk of stroke, cost-effectiveness increased by as much as 100%. These long-term cost estimates are consistent with the short-term economic analyses of the published 4S results. The long-term treatment of hyperlipidemia in secondary prevention is forecasted to be cost-effective across a broad range of patients between 40 and 70 years of age. Recognizing the additional effects of lipid changes on cerebrovascular events can substantially improve the cost-effectiveness of treating hyperlipidemia.",1999.0,0,0 23,10091815,The effects of pravastatin on hospital admission in hypercholesterolemic middle-aged men: West of Scotland Coronary Prevention Study.,,"The purpose of the study was to assess the effect of lipid reduction with pravastatin on hospital admissions in middle-aged men with hypercholesterolemia in the West of Scotland Coronary Prevention Study. A prospective, randomized controlled trial was undertaken in primary care centers in the West of Scotland. A total of 6,595 participants randomized to receive pravastatin 40 mg or placebo daily were followed up for a mean of 4.9 years (range 3.5 to 6.1 years). Analysis of hospital admissions was undertaken according to the ""intention to treat"" principle both for cardiovascular diseases and noncardiovascular diseases (including malignant neoplasms, psychiatric diagnoses, trauma and other causes). A secondary analysis of hospitalization in patients who were > or = 75% compliant was performed. During the trial, 2,198 (33%) of the 6,595 men were admitted to hospital on 4,333 occasions, of which 1,234 (28%) were for cardiovascular causes. Pravastatin reduced the number of subjects requiring hospital admission for cardiovascular causes by 21% (95% CI [confidence interval] 9 to 31, p = 0.0008) overall, and by 27% (95% CI 15 to 38) in compliant participants. The number of admissions per 1,000 subject-years for cardiovascular disease was reduced by 10.8 (95% CI 4 to 17.4, p = 0.0013) in all subjects, and by 15.6 (95% CI 8.3 to 23, p < 0.0001) in compliant participants. Pravastatin had no significant influence on hospital admission for any noncardiovascular diagnostic category. There were 13.4 fewer admissions per 1,000 subject-years for all causes in the pravastatin-treated group (95% CI -0.4 to 27.3, p = 0.076). No significant difference in duration of hospital stay was found between the pravastatin and placebo patients in any diagnostic group. Pravastatin therapy reduced the burden of hospital admissions for cardiovascular disease, without any adverse effect on noncardiovascular hospitalization.",1999.0,0,1 24,10093013,Lipid lowering and beyond: results from the CARE study on lipoproteins and inflammation. Cholesterol and Recurrent Events.,F M Sacks; P M Ridker,"The plasma LDL concentration in firmly established as a cause of coronary heart disease. However, the efficacy of LDL lowering may reach a limit when it is brought well below average during treatment. The Cholesterol and Recurrent Events (CARE) trial compared pravastatin and placebo in patients who had experienced myocardial infarction who had average concentrations of total cholesterol < 240 mg/dl (baseline mean 209 mg/dl) and LDL cholesterol (LDL) 115 to 174 mg/dl (mean 139 mg/dl). Pravastatin reduced coronary death or recurrent myocardial infarction by 24%. In multivariate analysis, the LDL concentration achieved during follow-up was a significant predictor of the coronary event rate. The relationship was nonlinear since the coronary event rate declined as LDL decreased during follow-up from 174 to approximately 125 mg/dl, but no further decline was seen in the LDL range from 125 to 71 mg/dl. A major ongoing effort in the CARE trial concerns the identification of non-LDL mediated mechanisms of coronary events. Chronic low-grade inflammation has recently been identified as an important new risk factor for coronary artery disease. Two markers of inflammation, C-reactive protein (CRP) and serum amyloid A (SAA), were measured in patients in the CARE trial who suffered a recurrent myocardial infarction or coronary death and in those who did not have these recurrent events. Levels of both inflammatory markers were significantly higher among post-myocardial infarction patients who subsequently developed recurrent coronary events. This association was significant in the patients who were treated with placebo but not in those in the pravastatin group. In conclusion, attaining an LDL of < 125 mg/dl may be sufficient treatment of LDL concentrations, removing the adverse effect of LDL on coronary events. These findings also raise the possibility that the efficacy of pravastatin may partly result from anti-inflammatory as well as lipid lowering properties.",1999.0,0,0 25,10095181,HMG-CoA reductase inhibitors and apoptosis.,M Senatore; M Buemi,,2000.0,0,0 26,10095800,Effects of atorvastatin on serum lipids of patients with familial hypercholesterolaemia.,N Hoogerbrugge,"The effects of atorvastatin, a new synthetic HMG-CoA reductase inhibitor, were investigated in patients with familial hypercholesterolaemia (FH), with high LDLc levels whilst on standard treatment. Open treatment with 40 mg atorvastatin daily for 6 weeks, followed by another 6 weeks with 80 mg atorvastatin. Outpatient lipid clinic of a tertiary referral centre. FH was diagnosed when the untreated LDLc concentration was higher than 6 mmol L-1, tendon xanthomas were present at the participant or a first degree relative, and the family history for hypercholesterolaemia was positive. The FH patients were selected for an LDLc above 5.0 mmol L-1 whilst on standard therapy for at least 3 months. Standard therapy consisted of a diet and 40 mg simvastatin, either alone (n = 17), or in combination with 8-12 g colestyramin (n = 12), or 1800 mg nicotinic acid (n = 12). Effects on LDLc concentration. LDLc concentration significantly decreased during treatment with 80 mg atorvastatin as compared to LDLc levels on 40 mg simvastatin alone or in combination with 8-12 g colestyramin, by 24 +/- 14% (P < 0.01) and 19 +/- 22% (P < 0.01), respectively. LDLc concentration was comparable during treatment with 80 mg atorvastatin or 40 mg simvastatin in combination with 1800 mg nicotinic acid. Atorvastatin was tolerated well, no side-effects were observed. Atorvastatin is a valuable addition to the treatment possibilities of patients with serious hypercholesterolaemia, like FH.",1999.0,0,0 27,10095816,Atorvastatin compared with simvastatin in patients with severe LDL hypercholesterolaemia treated by regular LDL apheresis.,H C Geiss; K G Parhofer; P Schwandt,"Atorvastatin is a new potent HMG-CoA reductase inhibitor. We evaluated whether patients with coronary heart disease and severe hypercholesterolaemia showing insufficient LDL (low-density lipoprotein) cholesterol reduction despite combined therapy with simvastatin and regular LDL apheresis will benefit from atorvastatin therapy. Tertiary care centre, university hospital. In 21 patients treated by LDL apheresis, concomitant simvastatin therapy (40 mg day-1) was replaced by atorvastatin (40 mg day-1) and increased to 60 and 80 mg day-1 (each for 3 months) if no side-effects were reported and NCEP treatment goals were not reached. In 20 of 21 patients (95%), atorvastatin resulted in significant reduction of LDL cholesterol compared with simvastatin (by 10%, additional 8% and additional 1%, with 40, 60 and 80 mg day-1, respectively). In four patients, NCEP treatment goals were reached (in three by atorvastatin alone, and in one by atorvastatin and apheresis). Patients with little reduction in LDL cholesterol to 40 mg day-1 atorvastatin benefited most by increasing the dose to 60 mg day-1 (additional 13% reduction), whilst those responding to atorvastatin 40 mg day-1 benefited less (additional 1.9% reduction). During atorvastatin therapy, significantly less plasma had to be treated during apheresis resulting in shorter apheresis time. Eight patients (38%) reported side-effects, resulting in discontinuation of atorvastatin in three (14%) and dose reduction in five patients (24%), whilst no elevation of biochemical markers was observed. Concomitant atorvastatin therapy is superior to simvastatin therapy in patients with severe hypercholesterolaemia treated with regular LDL apheresis, but is associated with a high rate of subjective side-effects.",1999.0,0,0 28,10099070,Fluvastatin titrate-to-goal clinical practice study.,R J Weiss,"The efficacy and safety of fluvastatin in patients with moderate hypercholesterolemia was evaluated in this open-label, multicenter trial. Patients whose cholesterol did not meet National Cholesterol Education Program guidelines after an 8-week dietary stabilization period underwent a 12-week treatment period. The study population was 1776 patients ranging in age from 18 to 75 years with an average low-density lipoprotein cholesterol level for two visits of 160 to 200 mg/dL. For all patients, the mean serum level of low-density lipoprotein cholesterol showed a decrease of 21% between baseline and week 12 (177.8 +/- 19.0 to 141.0 +/- 22.7 mg/dL). Total cholesterol decreased 14% (263.3 +/- 24.3 to 224.2 +/- 12.9 mg/dL). Triglycerides decreased 14% (183.7 +/- 82.3 to 158.0 +/- 70.1 mg/dL). High-density lipoprotein cholesterol levels increased only slightly (49.7 +/- 12.1 to 51.8 +/- 12.9 mg/dL). Therapy with fluvastatin resulted in few adverse effects. No patient terminated the study prematurely because of laboratory abnormalities, although laboratory values of concern occurred in 0.3% of patients regarding serum glutamic oxaloacetic transaminase and in 0.07% regarding creatine phosphokinase. Fluvastatin is confirmed as effective and safe for the treatment of moderate hypercholesterolemia in the general-practice patient.",1999.0,0,0 29,10146336,LDL-apheresis: clinical experience and indications in the treatment of severe hypercholesterolemia.,J Thiery; D Seidel,"LDL-cholesterol is the leading risk factor which influences the clinical outcome of patients with preexisting coronary heart disease. Clinical trials show that plasma LDL-cholesterol below 100 mg/dL decrease the rate of recurrent myocardial infarction and can induce regression in patients with coronary heart disease. However, in most cases of severe hypercholesterolemia with plasma LDL-cholesterol concentrations above 220 mg/dL LDL cannot be sufficiently decreased by maximal dietary and pharmacological therapy alone. Today this group of high risk CHD patients can be treated in addition with an extracorporeal procedure to eliminate LDL from the plasma circulation, the H.E.L.P.--LDL-apheresis. This method for selective removal of LDL, lipoprotein(a) and fibrinogen from plasma has been shown to be a clinically safe and very efficient method for the treatment of patients with homozygous familial hypercholesterolemia or CHD patients with severe hypercholesterolemia. Treatments with 1 week H.E.L.P. intervals revealed a mean reduction of minus 51% for LDL, of minus 45% for Lp(a) and of minus 46% for apo B, while HDL was increased by +12%. Fibrinogen was decreased by minus 46%. Besides the marked reduction of LDL and fibrinogen plasma concentrations the H.E.L.P. treatment significantly improves hemorheological parameters and increases the oxygen tension in the tissue. We have also investigated the efficiency of a combined therapy, using HMG-CoA reductase inhibitors together with the H.E.L.P.--apheresis. Under this combined treatment, a reduction of the interval LDL-cholesterol levels of 70-80% has been achieved, while Lp(a) and fibrinogen were not further affected. We now report about our long-term clinical experience with the H.E.L.P. system in treating patients with different lipoprotein disorders: (1) Homozygous form of familial hypercholesterolemia; (2) CHD patients with familial and non-familial hypercholesterolemia; (3) CHD patients with very high concentrations of lipoprotein(a); and (4) Hypercholesterolemic patients after heart transplantation. Based on present experience guidelines for secondary prevention of coronary heart disease indications for the H.E.L.P.--LDL-apheresis treatment are discussed.",1993.0,0,0 30,10146648,,,,,0,0 31,10147032,Cost-effectiveness of simvastatin versus cholestyramine: results for Sweden.,K Hjalte; B Lindgren; U Persson,"Cost-effectiveness ratios were estimated for each of 2 plasma cholesterol-lowering drug therapies, the HMG-CoA reductase inhibitor simvastatin and the well established cholestyramine, in comparison with a nonpreventive drug treatment alternative. The study was confined to Swedish men (aged 37 to 64 years at start of therapy) with total serum cholesterol levels above 6.2 mmol/L who were free of coronary artery disease (CAD). Costs included expected direct costs of plasma cholesterol-lowering treatment less expected savings resulting from preventing CAD. Effects were defined as changes in life expectancy. A discount rate of 5% and Swedish kronor (SEK) 1988 prices were used. The impact on CAD risks was calculated using multivariate logistic risk estimates from the Framingham Heart Study; Swedish estimates were used to calculate intervention costs and changes in healthcare costs. Over the range of cholesterol levels examined (6.2 to 9.8 mmol/L), simvastatin was consistently more cost-effective than cholestyramine.",1992.0,0,0 32,10155198,Results of recent trials on the progression of coronary artery disease and recurrent ischemic events: implications for interventional cardiology.,B Pitt,,1994.0,0,0 33,10170450,Cost effectiveness in the treatment of heart failure with ramipril. A Swedish substudy of the AIRE study. Acute Infarction Ramipril Efficacy.,L Erhardt; S Ball; F Andersson; P Bergentoft; C Martinez,"We estimated the cost effectiveness of adding the ACE inhibitor ramipril to conventional treatment in patients with heart failure after acute myocardial infarction. These estimates were based on the Acute Infarction Ramipril Efficacy (AIRE) study and on complementary Swedish healthcare resource use data for a subset of patients. The average follow-up period was 15 months (minimum 6 months, maximum 3.8 years). The perspective of the analysis was that of the county councils (third-party payers), and we focused on the cost of drugs and hospitalisation. The marginal cost effectiveness of the treatment was estimated over 3 treatment periods: 1, 2 and 3.8 years. The cost-effectiveness ratios varied between SEK14,148 and SEK33,033 per life-year gained ($US1 = SEK7.70. Pounds 1 = SEK12.40) for the 3 treatment periods. Adding ramipril to conventional treatment for heart failure after acute myocardial infarction is therefore cost effective, and compares favourably with the cost effectiveness of other common medical therapies in the cardiovascular field.",1997.0,0,0 34,10170452,Cost effectiveness of treatment to National Cholesterol Education Panel (NCEP) targets with HMG-CoA reductase inhibitors. Trial design.,D Black; M Davidson; M Koren; R Bakker-Arkema; P Tresh; R McLain; D Smith; D Hunninghake,"HMG-CoA reductase inhibitors effectively reduce cholesterol levels, and this is associated with a lower rate of cardiovascular events. Some HMG-CoA reductase inhibitors are more effective than others in reducing low density lipoprotein (LDL) cholesterol, and such drugs should help patients achieve LDL cholesterol targets prescribed by the National Cholesterol Education Panel (NCEP). This paper describes the design of a trial comparing the clinical efficacy and cost effectiveness of four HMG-CoA reductase inhibitors in reducing LDL cholesterol to specified targets. This trial is being conducted in 30 physicians' practices in the USA. Its primary aim is to assess the resource use required to achieve and maintain NCEP targets by all patients randomised and followed up for one year.",1997.0,0,1 35,10172696,The 4S study and its pharmacoeconomic implications.,J P Reckless,,1996.0,0,0 36,10172918,Simvastatin. A reappraisal of its cost effectiveness in dyslipidaemia and coronary heart disease.,K L Goa; L B Barradell; D McTavish,"The Scandinavian Simvastatin Survival Study (4S) has confirmed the link between the cholesterol-reducing effects of simvastatin and improved survival in patients with hypercholesterolaemia and pre-existing coronary heart disease (CHD). Pharmacoeconomic analyses of the 4S trial, using prospectively collected data for cost-generating events, demonstrate that the cost per year of life saved for simvastatin in such patients falls within the range considered cost effective. Reductions in resource utilisation costs (numbers of hospitalisations and revascularisation procedures) largely offset the acquisition cost of long term simvastatin treatment in the US. Models of primary prevention incorporating epidemiological data to predict CHD events generally suffer from deficiencies in the methods and assumptions used, and no firm conclusions can be made at present regarding relative cost effectiveness of the drugs studied, including simvastatin. It is generally agreed that cost effectiveness will improve in patients with higher absolute risk of CHD. In summary, simvastatin has been shown in a major clinical trial and its companion economic analyses to reduce mortality and to be cost effective in patients with hypercholesterolaemia and existing CHD. As is the case for others of its class, its cost-effectiveness ratio in primary prevention remains to be ascertained. This issue aside, simvastatin is a rational choice of cholesterol-lowering agent in secondary prevention whose use can be justified on an economic basis.",1996.0,0,1 37,10173046,"When the vessel is bad, lowering cholesterol may save the ship.",K H Bachman,,1997.0,0,0 38,10173126,Cost effectiveness of micronised fenofibrate and simvastatin in the short-term treatment of type IIa and type IIb hyperlipidaemia.,K U Kirchgässler; J Schiffner-Rohe; U Stahlheber,"The aim of this study was to compare the cost effectiveness of micronised fenofibrate 200 mg and simvastatin 20 mg in the treatment of type IIa and IIb hyperlipidaemia. In a retrospective analysis, data from 2 randomised controlled clinical trials were evaluated. The results show that micronised fenofibrate has a better short term cost effectiveness than simvastatin. The costs per successfully treated patient with hyperlipidaemia over a 12-week period were [in Deutschmarks (DM); DMI = $US0.66, April 1995] DM537 for fenofibrate and DM809 for simvastatin. When the data were analysed according to type of hyperlipidaemia (classification of Frederickson), there were only small differences between both test drugs (DM450 for fenofibrate, DM517 for simvastatin) in patients with type IIa because simvastatin had higher response rates which, in part, compensated for the higher acquisition cost. However, response rates in patients with type IIb hyperlipidaemia were higher for fenofibrate, which led to a substantial cost advantage for this agent (DM768 for fenofibrate, DM2080 for simvastatin). These results were confirmed by various sensitivity analyses, including the assessment of drug monitoring programmes (postmarketing surveillance) to validate response rates and the total costs of the therapy. In this study, we evaluated the total costs of a 12-week period of therapy, not the costs per day. The results are based on actual clinical data and not just on theoretical models. The study underlines the necessity to differentiate between the types of hyperlipidaemia when performing a pharmacoeconomic analysis of lipid-lowering treatments.",1997.0,0,0 39,10178490,The impact of a simulated immunization registry on perceived childhood immunization status.,B P Yawn; L Edmonson; L Huber; G A Poland; R M Jacobson; S J Jacobsen,"We developed a simulated immunization registry to assess the impact on the perceived immunization status in a population-based sample of 2-year-olds living in Olmsted County, MN, in 1995. We compiled records of all immunizations by abstracting immunization data from all medical care facilities in the county. The data collected from each facility were analyzed separately to provide the immunization rate as perceived by each facility. This perceived rate was compared to the rate obtained by combining all recorded immunizations from all facilities (simulated registry). Information on children not receiving any carefrom facilities in Olmsted County was compiled from birth certificate data and community school lists. Data from the simulated registry indicated that 69.1% of all children in Olmsted County with medical records were up-to-date on their immunizations by 20 months of age. By 24 months, this increased to 74.2%. The immunization rate of 24-month-old children recorded at individual healthcare facilities in Olmsted County ranged from 24.3% to 79.5%. The addition of data from the simulated registry increased the immunization rate at each site: a 27.7% relative increase in the site with the lowest recorded immunization rate, a 14.0% increase in the site with the intermediate immunization rate, and a 6.9% increase in the site with the highest internally perceived immunization rate. The registry also identified excess immunizations in 5% of the county's 2-year-olds. Each healthcare facility in this community gained an immediate benefit from the development of a simulated immunization registry. This immediate improvement in one quality-of-care measure (up-to-date immunization rate) should be factored into the cost/benefit assessment of immunization registries.",1998.0,0,0 40,10179907,Economic benefits of aggressive lipid lowering: a managed care perspective.,J M McKenney; B Kinosian,"Coronary heart disease (CHD) has high prevalence in the United States and is associated with significant mortality as well as costs to society. Hyperlipidemia is a major and common modifiable risk factor for CHD. In clinical trials, cholesterol-lowering strategies have a dramatic impact on CHD risk, cardiovascular events, and mortality. Cost-effectiveness data have established that clinical and economic benefits are gained by instituting early and aggressive lipid-lowering therapy. We present new evidence for the clinical benefits and cost effectiveness of aggressive lipid-lowering therapy as primary or secondary prevention of CHD and describe strategies that managed care organizations can take to benefit from a lipid management program.",1997.0,0,0 41,10182195,"The cost of reaching National Cholesterol Education Program (NCEP) goals in hypercholesterolaemic patients. A comparison of atorvastatin, simvastatin, lovastatin and fluvastatin.",M J Koren; D G Smith; D B Hunninghake; M H Davidson; J M McKenney; S R Weiss; H G Schrott; R W Henley; P Tresh; R W McLain; R G Bakker-Arkema; D M Black,"Recognising the importance of treating hyperlipidaemia, the National Cholesterol Education Program (NCEP) has established widely accepted treatment goals for low density lipoprotein cholesterol (LDL-C). Medications used most commonly to achieve these LDL-C goals are HMG-CoA reductase inhibitors. The relative resource utilisation and cost associated with the use of reductase inhibitors of different LDL-C lowering efficacy are unknown, but are major health and economic concerns. The objective of this study was to determine the mean total cost of care to reach NCEP goals with various reductase inhibitors. In a randomised, 54-week, 30-centre controlled trial we compared resources used and costs associated with treating patients to achieve NCEP goals using 4 reductase inhibitors: atorvastatin, simvastatin, lovastatin and fluvastatin. The trial studied 662 patients; 318 had known atherosclerotic disease. Reductase inhibitor therapy was initiated at recommended starting doses and increased according to NCEP guidelines and package insert information. For patients who did not reach the goal at the highest recommended dose of each reductase inhibitor, the resin colestipol was added. Patients treated with atorvastatin, compared-with other reductase inhibitors, were more likely to reach NCEP goals during treatment (p < 0.05), required fewer office visits (p < 0.001) and less adjuvant colestipol therapy (p = 0.001). Consequently, the mean total cost of care (1996 values) to reach NCEP goals was lower with atorvastatin [$US1064; 95% confidence interval (CI): $US953 to $US1176] compared with simvastatin ($US1471, 95% CI: $US1304 to $US1648), lovastatin ($US1972; 95% CI: $US1758 to $US2186) and fluvastatin ($US1542; 95% CI: $US1384 to $US1710). Results were similar for patients with or without known atherosclerotic disease. In patients requiring drug therapy for hypercholesterolaemia, NCEP LDL-C goals are achieved significantly more often using fewer resources with atorvastatin compared with simvastatin, lovastatin or fluvastatin.",2001.0,0,0 42,10182252,Strategies for the management of hypercholesterolaemia: a systematic review of the cost-effectiveness literature.,S Morris; A McGuire; J Caro; D Pettitt,"To review research addressing the management of cholesterol in the prevention of coronary heart disease in order to assess the cost-effectiveness of such interventions. A systematic review of economic evaluations identified through searches of MEDLINE and the Social Sciences Citation Index revealed 38 studies addressing the cost-effectiveness of cholesterol management. They were distinguished according to screening approaches, dietary advice and drug treatment. Most studies were not associated directly with clinical trial results, but adopted economic modelling approaches. Whilst there is general agreement among the majority of analyses, studies of cholesterol management concerned with screening strategies were extremely sensitive to changes in their assumptions; so much so that only a limited emphasis may be placed on specific cost-effectiveness ratios and the conclusions drawn from them. All studies considered direct costs, though many were limited to drug costs. The cost-effectiveness of primary prevention by cholesterol-lowering drugs is highly variable, depending on age at initiation of treatment and cardiovascular risk profile. Pharmacological intervention is least cost-effective in the young and the elderly. The cost-effectiveness of cholesterol-reducing agents improves when they are targeted at those at high risk. HMG-CoA reductase inhibitors are generally more effective and more cost-effective at reducing cholesterol-related coronary events than other medications. The methods and economic data upon which these studies are based need to be improved if robust policy conclusions are to be formulated.",1997.0,0,0 43,10186462,Pravastatin. A pharmacoeconomic review of its use in primary and secondary prevention of coronary heart disease.,A J Coukell; M I Wilde,"Coronary heart disease (CHD) is a major cause of death and illness in industrialised countries. Like other hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, pravastatin reduces total and low density lipoprotein (LDL)-cholesterol levels and increases high density lipoprotein (HDL)-cholesterol levels. Cholesterol modification with pravastatin in middle-aged hypercholesterolaemic men without CHD (i.e. primary prevention) was shown in the West of Scotland Coronary Prevention Study (WOSCOPS) to reduce the incidence of fatal and nonfatal coronary events. In several other large studies, pravastatin reduced the incidence of CHD events in patients with prior CHD (secondary prevention). Large, long term studies of the relationship between cholesterol modification and CHD event rate have been conducted for some, but not all, other HMG-CoA reductase inhibitors. A UK pharmacoeconomic analysis of the WOSCOPS data indicated that primary prevention with pravastatin was associated with a cost of 20,375 Pounds per year of life gained (YLG) [discounted]. Treatment of men at high risk for CHD resulted in a lower cost estimate (13,995 Pounds/YLG). A US economic analysis based on secondary prevention with pravastatin in large plaque regression studies suggested a net cost of drug therapy of $US7124 to $US12,665 per YLG. A number of projected-risk models have attempted to calculate the cost effectiveness of primary or secondary prevention with pravastatin compared with other lipid-modifying interventions. These comparisons indicated that pravastatin was economically superior to intensive lifestyle counselling without drug therapy. Pravastatin generally appeared to be less cost effective than other HMG-CoA reductase inhibitors, although the relative effectiveness of the various drugs depended on the model considered. Risk-projection economic models are subject to methodological limitations, principally the necessity of estimating clinical effectiveness from epidemiological data (often derived from the Framingham Heart Study). An increased absolute risk of CHD improves the cost effectiveness of lipid-lowering therapy. Thus, the cost per YLG of pravastatin in secondary prevention is, in general, lower than that of primary prevention, reflecting the higher absolute risk of second versus first CHD events. However, it is important to note that individual absolute risk rates may overlap between patients receiving primary and secondary prevention. Similarly, treatment of selected individual patients at high risk for CHD events is associated with a lower cost per YLG than unselected treatment. In large clinical studies, pravastatin effectively reduced the risk of primary and secondary CHD events. These benefits come at a substantial economic cost, but one that is in line with accepted costs for other medical interventions. Selective treatment of patients or populations at high risk of CHD events improves the cost effectiveness of pravastatin therapy.",1998.0,0,0 44,10190398,Effect of the stromelysin-1 promoter on efficacy of pravastatin in coronary atherosclerosis and restenosis.,M P de Maat; J W Jukema; S Ye; A H Zwinderman; P H Moghaddam; M Beekman; J J Kastelein; A J van Boven; A V Bruschke; S E Humphries; C Kluft; A M Henney,"It has proved difficult to identify high-risk patients for atherosclerosis and to determine how they might respond to medication. Recently, a common promoter variant of the human stromelysin-1 gene has been reported, which has been shown to affect the transcription. We investigated whether this polymorphism had any impact on the risk of events, especially restenosis and progression of coronary artery disease and whether the effect was modulated by treatment with pravastatin. The stromelysin-1 genotype was determined for 496 men with coronary artery disease and cholesterol levels between 4.0 and 8.0 mmol/L, participating in the Regression Growth Evaluation Statin Study (REGRESS) study, a clinical trial assessing the effect of the lipid-lowering drug pravastatin on the progression of atherosclerosis. Patients in the placebo group with 5A6A or 6A6A genotypes had more clinical events than patients with the 5A5A genotype (26% and 12%, respectively, p = 0.03). In the pravastatin group, the risk of clinical events in patients with 5A6A or 6A6A genotypes was lower, compared with placebo, whereas it was unchanged in those with a 5A5A genotype (p value for interaction: 0.038). Also, the incidence of repeat angioplasty in the placebo group was greater in patients with the 6A6A or 5A6A genotypes, compared with 5A homozygotes (38% and 40%, respectively, vs 11%, p = 0.09). Again, treatment substantially reduced the incidence in heterozygotes and 6A homozygotes (0% and 15%, respectively), whereas it was unchanged in 5A homozygotes (28%, p for interaction: 0.002). These effects were independent of the effects of pravastatin on the lipid levels. Thus, this study suggests that the stomelysin-1 promoter polymorphism confers a genotype-specific response to medication in determining clinical event-free survival and the risk for symptom-driven repeat angioplasty. This variant may therefore act as a predictor, not only of disease progression, but also of response to therapy and risk of restenosis.",1999.0,0,0 45,10190536,Effectiveness and safety of alternate-day simvastatin and fenofibrate on mixed hyperlipidemia.,M Kayikçioğlu; F Ozerkan; I Soydan,"This randomized prospective clinical study evaluated the lipid-lowering effects and safety of a new combination regimen in patients with mixed hyperlipidemia. The data show that alternate-day simvastatin and fenofibrate therapy was as effective as the standard daily combination of the same drugs at the same doses, and it was safer, less expensive, and more tolerable.",1999.0,0,0 46,10191973,Impact of intravascular ultrasound in understanding transplant coronary artery disease.,S R Kapadia; S E Nissen; E M Tuzcu,"Intravascular ultrasound imaging has been recognized as a sensitive tool to study early transplant vasculopathy lesions. An early examination performed soon after transplantation allows one to study donor atherosclerosis. Further, serial follow-up imaging with meticulous site matching provides important information regarding the progression of donor atherosclerosis and the development of transplant vasculopathy lesions. This review highlights the contribution of intravascular imaging in understanding the transplant coronary artery disease. This review also outlines various methodologies employed by different investigators, and stresses the strengths and weaknesses of these methodologies for correct interpretation as well as comparison of data from different studies.",1999.0,0,0 47,10191975,Current therapies for secondary prevention after myocardial infarction.,C E Cannon; S C Smith,"Compelling evidence from clinical trials confirms the benefits of secondary prevention for patients with known coronary disease. Preventive therapies initiated after myocardial infarction can extend overall survival, reduce subsequent myocardial infarction, decrease the need for revascularization, and improve quality of life. All patients with atherosclerotic cardiovascular disease should be considered for lipid lowering therapy, antiplatelet agents, beta-blockers, and control of hypertension. Long-term therapy with angiotensin-converting enzyme inhibitors should be continued in patients with systolic dysfunction. Hormone replacement therapy has not been shown to benefit postmenopausal women when initiated after myocardial infarction. Smoking cessation, weight control, exercise, and appropriate diet represent important behavioral modifications.",2001.0,0,0 48,10192685,Coenzyme Q10.,J Pepping,,1999.0,0,0 49,10192749,"The effect of the apolipoprotein E phenotype on cholesteryl ester transfer protein activity, plasma lipids and apolipoprotein A I levels in hypercholesterolaemic patients on colestipol and lovastatin treatment.",T Korhonen; M L Hannuksela; S Seppänen; K Kervinen; Y A Kesäniemi; M J Savolainen,"Apolipoprotein E (apo E) allele E 4 is associated with high atherogenic lipid levels and coronary heart disease. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from (high density lipoprotein) HDL to other lipoproteins. CETP gene expression is enhanced in hypercholesterolaemia and correlates with plasma apo E concentration. The effect of the apo E phenotype on plasma CETP activity and the hypolipidaemic efficacy of colestipol and lovastatin was studied in patients with type II a or II b hypercholesterolaemia. The baseline mean plasma total, low density lipoprotein (LDL) and HDL cholesterol, triglyceride, apolipoprotein A I (apo A I) concentrations and CETP activity were 8.89 mmol x l(-1), 6.78 mmol x l(-1), 1.39 mmol x l(-1), 1.59 mmol x l(-1), 1.49 g x l(-1) and 114 nmol x h(-1) x ml(-1), respectively. The colestipol-induced changes were -26%, -36%, +5%, + 12%, -1% and -17%, and the lovastatin-induced changes -34%, -44%, +6%, -18%, +1% and -19%. The lipid and apo A I concentrations or the CETP activity did not differ statistically significantly according to the apo E phenotype, although the HDL cholesterol and apo A I levels were lowered in patients with apo E 4/4 but elevated in patients with the other phenotypes. The CETP activity correlated with the LDL cholesterol concentration (r = 0.52, P = 0.01) and the change in the LDL cholesterol during colestipol (r = 0.51, P = 0.02) and lovastatin (r = 0.65, P = 0.001) treatment, but only in patients without the apo E 4 allele. Colestipol and lovastatin reduced CETP activity to the same amount, regardless of the apo E phenotype. The apo E phenotype seems to modify the interaction between CETP activity and LDL cholesterol in hypercholesterolaemia and during pharmacological lowering of cholesterol.",1999.0,0,0 50,10193729,Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia.,A Szczeklik; J Musiał; A Undas; P Gajewski; P Góra; J Swadźba; M Jankowski,"To assess the effects of aspirin compared with simvastatin on thrombin generation in hypercholesterolemic men, and to establish whether the reduction of elevated blood cholesterol by simvastatin would affect the action of aspirin on thrombin formation. Aspirin inhibits thrombin formation, but its performance is blunted in hypercholesterolemia. By virtue of altering lipid profile, statins could be expected to influence thrombin generation. Thirty-three men, aged 34 to 61 years, with minimal or no clinical symptoms, serum total cholesterol >6.5 mmol/liter and serum triglycerides <4.6 mmol/liter, completed the study consisting of three treatment phases. First, they received 300 mg of aspirin daily for two weeks (phase I), which was then replaced by simvastatin at the average dose of 24 mg/d for three months (phase II). In phase III, aspirin, 300 mg/day, was added for two weeks to simvastatin, the dose of which remained unchanged. Thrombin generation was assessed: 1) in vivo, by measuring levels of fibrinopeptide A (FPA) and prothrombin fragment 1+2 (F1+2) in venous blood; and 2) ex vivo, by monitoring the rates of increase of FPA and F1+2 in blood emerging from standardized skin incisions of a forearm. A mathematical model was used to describe the kinetics of thrombin formation at the site of microvascular injury. Two-week treatment with aspirin had no effect on thrombin markers in vivo, while ex vivo it depressed the total amount of thrombin formed, though not the reaction rate. After simvastatin treatment, serum cholesterol decreased by 31% and LDL cholesterol by 42%, while thrombin generation became markedly depressed. In venous blood, FPA was significantly reduced. Concomitantly, the initial thrombin concentration and total amount of thrombin generated decreased significantly. Addition of aspirin to simvastatin (phase III) had no further effect on any of these parameters. In men with hypercholesterolemia, lowering serum cholesterol level by a three-month simvastatin treatment is accompanied by a marked reduction of thrombin generation both at basal conditions in venous blood and after activation of hemostasis by microvascular injury. Once blood cholesterol became reduced, adding aspirin to simvastatin did not enhance dampening of thrombin formation.",1999.0,0,0 51,10193730,Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile.,G Dangas; J J Badimon; D A Smith; A H Unger; D Levine; J H Shao; P Meraj; C Fier; J T Fallon; J A Ambrose,"The study sought to determine the effects of lipid-lowering with pravastatin on the systemic fibrinolytic profile and on thrombus formation under dynamic flow conditions. Lowering cholesterol (C) decreases clinical events in coronary artery disease (CAD) patients, but an analysis of the effects of lipid-lowering on the entire hemostatic and thrombotic profile has not been conducted. We prospectively studied 93 stable patients with untreated low-density lipoprotein cholesterol (LDL-C) >145 mg/dl. The CAD patients received pravastatin, and non-CAD patients were randomized to pravastatin versus placebo (double-blind). Thrombus formation upon an injured vascular surface was assessed in a substudy of 40 patients with a previously validated ex vivo perfusion chamber system. Systemic hemostatic markers and thrombus formation were evaluated at baseline, three and six months. Placebo produced no changes in either the lipid profile, any of the hemostatic markers, or the ex vivo thrombus formation. Both pravastatin groups (CAD and non-CAD) showed decreased LDL-C by 30% within 6 weeks (188 to 126 mg/dl, p < 0.001 vs. baseline), and decreased plasminogen activator inhibitor-1 at 3- and 6-month follow-up compared to baseline (15% to 18% decrease at 3 months and 21% to 23% at 6 months). For the tissue plasminogen activator antigen, CAD and non-CAD groups showed significant decreases at 6 months compared to baseline (10% and 13%, respectively). No significant changes were observed with treatment in d-dimer, fibrinopeptide A, prothrombin fragment F1.2, factor VIIa, von Willebrand factor, or C-reactive protein. Fibrinogen levels were significantly increased at 6 months compared to baseline, though still below the upper normal limit. In the perfusion chamber substudy, there was a decrease in thrombus area in non-CAD patients treated with pravastatin at both 3 and 6 months compared to baseline (by 21% and 34%, respectively). The CAD patients showed decreases in thrombus formation by 13% at 3 months, and by 16% at 6 months. The change in LDL-C- correlated modestly with the change in thrombus formation (r = 0.49; p < 0.01). Pravastatin therapy significantly decreased thrombus formation and improved the fibrinolytic profile in patients with and without CAD. These early effects may, in part, explain the benefit rendered in primary and secondary prevention of CAD.",1999.0,0,0 52,10193731,The anti-thrombotic effects of statins.,D Kearney; D Fitzgerald,,1999.0,0,0 53,10197299,Electronic monitoring of compliance to lipid-lowering therapy in clinical practice.,A Schwed; C L Fallab; M Burnier; B Waeber; L Kappenberger; B Burnand; R Darioli,"Nonadherence to treatment is a common problem in the clinical management of hypercholesterolemic patients. This study was carried out with the aim of monitoring the daily compliance to a 6-month course of lipid-lowering therapy, using a microelectronic device, the Medication Event Monitoring System (MEMS), versus pill count. Forty men with primary hypercholesterolemia were prescribed fluvastatin 1 x 40 mg daily, provided in a MEMS package to record the date and time of each opening of the pillbox. Thirty-nine of 40 patients (98%) completed the study. Total cholesterol and LDL cholesterol levels decreased significantly (18% and 25%, p < 0.001) during the 6-month therapy period. A high mean rate of compliance was achieved by MEMS using the following three indexes--compliance to total prescribed dose (88.8% +/- 13.5%), compliance to prescribed days (82.4% +/- 19.5%), and compliance to prescribed time of day (81.86% +/- 19.5%)--and by pill count (93.4% +/- 9.5%). In addition, the MEMS provided some patterns of nonadherence to medication, undetectable by pill count alone, such as a drug holiday in 38% of cases, a drug omission for more than 7 consecutive days in 9% of cases, and, conversely, use of more than the one prescribed daily dose in 47% of cases. A significant correlation between the rate of compliance and the decrease in LDL cholesterol was observed only when the compliance was assessed by MEMS. The results indicate that MEMS is a useful tool for monitoring compliance in clinical practice and may possibly increase adherence to long-term lipid-lowering therapy.",1999.0,0,0 54,10197301,"The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers.",A M Meadowcroft; K M Williamson; J H Patterson; A L Hinderliter; J A Pieper,"Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady-state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A prospective, open-label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phase was 7 days of losartan (50 mg QAM), and the inhibition phase was 14 total days of fluvastatin (40 mg QHS), with the final 7 days including losartan. The authors found that fluvastatin did not significantly change the steady-state AUC0-24 or half-life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolism appears to require both CYP2C9 and CYP3A4 inhibition.",1999.0,0,0 55,10198923,Impact of cholesterol on cardiovascular morbidity and mortality in older adults.,Y T Chen; H M Krumholz,,1999.0,0,0 56,10206830,Pravastatin and coronary heart disease.,F P Meyer,,1999.0,0,0 57,10208500,Atorvastatin in the management of an index patient with complete hepatic lipase deficiency.,R A Hegele; J A Little; P W Connelly,,1999.0,0,0 58,10208998,Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density.,A Zambon; J E Hokanson; B G Brown; J D Brunzell,"Small, dense LDL particles are associated with coronary artery disease (CAD) and predict angiographic changes in response to lipid-lowering therapy. Intensive lipid-lowering therapy in the Familial Atherosclerosis Treatment Study (FATS) resulted in significant improvement in CAD. This study examines the relationship among LDL density, hepatic lipase (HL), and CAD progression, identifying a new biological mechanism for the favorable effects of lipid-altering therapy. Eighty-eight of the subjects in FATS with documented coronary disease, apolipoprotein B levels >/=125 mg/dL, and family history of CAD were selected for this study. They were randomly assigned to receive lovastatin (40 mg/d) and colestipol (30 g/d), niacin (4 g/d) and colestipol, or conventional therapy with placebo alone or with colestipol in those with elevated LDL cholesterol levels. Plasma hepatic lipase (HL), lipoprotein lipase, and LDL density were measured when subjects were and were not receiving lipid-lowering therapy. LDL buoyancy increased with lovastatin-colestipol therapy (7.7%; P<0.01) and niacin-colestipol therapy (10.3%; P<0.01), whereas HL decreased in both groups (-14% [P<0.01] and -17% [P<0.01] with lovastatin-colestipol and niacin-colestipol, respectively). Changes in LDL buoyancy and HL activity were associated with changes in disease severity (P<0.001). In a multivariate analysis, an increase in LDL buoyancy was most strongly associated with CAD regression, accounting for 37% of the variance of change in coronary stenosis (P<0.01), followed by reduction in apolipoprotein Bl (5% of variance; P<0.05). These studies support the hypothesis that therapy-associated changes in HL alter LDL density, which favorably influences CAD progression. This is a new and potentially clinically relevant mechanism linking lipid-altering therapy to CAD improvement.",1999.0,0,0 59,10211353,The use of HMG Co-A reductase inhibitors following acute myocardial infarction in hospital practice.,T K Khong; C G Missouris; M Murda'h; G A MacGregor,"Treatment with a HMG-CoA reductase inhibitor (statin) following a myocardial infarction has been shown to reduce the incidence of subsequent coronary revascularisation, myocardial infarction and cardiovascular death. The majority (89%) of patients admitted to the coronary care unit of our hospital received a fasting cholesterol check as part of a routine coronary care unit protocol. However, our survey shows that only 26% of patients surviving an acute myocardial infarction were on treatment with a statin at follow-up. Furthermore, those receiving statins were given smaller doses than those used in clinical trials. One way to ensure patients receive adequate treatment with statins, may be to include it as part of a coronary care unit protocol.",2000.0,0,0 60,10211536,Efficacy of three statins at lower maintenance doses.,S Carr-Lopez; T Exstrum; T Morse; M Shepherd; A C Bush,"The purpose of this study was to determine whether patients who are receiving lovastatin 20 mg daily can be switched to daily regimens of lovastatin 10 mg, pravastatin 10 mg, or simvastatin 5 mg without loss of lipid control or an increase in side effects. One hundred five patients were identified whose lipid levels were clinically stable on a regimen of lovastatin 20 mg/d; these patients were randomly allocated to a group that continued to receive lovastatin 20 mg/d (the control group) or a group receiving 1 of the 3 alternative regimens. Patients were evaluated after 6 and 12 weeks of treatment for side effects and changes in liver and muscle enzymes and lipid levels compared with baseline. Of the 105 patients enrolled, 5 withdrew because of side effects, 4 did not return for follow up, and 3 were excluded. Ninety-three patients completed the 12-week study. When baseline values were compared to those at week 12 for each group, the proportions of patients meeting treatment goals for LDL cholesterol, as defined by the National Cholesterol Education Program, were as follows: control group, 30.8% improved; lovastatin 10 mg, 16.7% worsened; pravastatin 10 mg, 27.3% improved; and simvastatin 5 mg, no change. Patients who were switched from lovastatin 20 mg daily to pravastatin 10 mg or simvastatin 5 mg daily did not experience statistically significant changes in mean total cholesterol levels. Patients who were switched from 20 to 10 mg/d of lovastatin experienced increases in mean total cholesterol levels (from 195 mg/dL +/-5 mg/dL at baseline to 200 mg/dL +/-5 mg/dL at 12 weeks; P<0.05). There were no differences in side effects or in elevations in liver or muscle enzymes. Thus patients who are stable on 20 mg/d lovastatin can be switched to a regimen of 10 mg/d pravastatin or 5 mg/d simvastatin.",1999.0,0,0 61,10212010,The outcome of very low dosages of simvastatin in patients with hypercholesterolemia.,J P Rindone,"A retrospective study evaluated the success of dosages of simvastatin lower than the 10-20 mg/day recommended by the manufacturer in patients with hypercholesterolemia. Records of 95 patients enrolled in a pharmacist-managed lipid clinic receiving stable dosages of simvastatin were reviewed. Data collected were demographics, number of simvastatin refills, dosage distribution, baseline and posttreatment lipid profiles, and proportion of patients with low-density lipoprotein (LDL) levels below target as recommended by the National Cholesterol and Education Program. Dosages for 62% of patients were less than 20 mg/day. Percentages of patients at goal LDL were 98%, 89%, and 83% for patients taking 2.5, 5, and 10 mg/day, respectively. Patients taking 40 mg/day were least likely to be below the goal. There was an even distribution of patients taking each dosage. No statistical difference in compliance was noted among dosages based on prescription refills. Most patients taking less than the recommended initial dosage of the agent had satisfactory lipid control.",1999.0,0,0 62,10215754,Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations.,T Prueksaritanont; B Ma; C Tang; Y Meng; C Assang; P Lu; P J Reider; J H Lin; T A Baillie,"To determine the effects of mibefradil on the nletabolism in human liver microsomal preparations of the HMG-CoA reductase inhibitors simvastatin, lovastatin, atorvastatin, cerivastatin and fluvastatin. Metabolism of the above five statins (0.5, 5 or 10 microM), as well as of specific CYP3A4/5 and CYP2C8/9 marker substrates, was examined in human liver microsomal preparations in the presence and absence of mibefradil (0.1-50 microM). Mibefradil inhibited, in a concentration-dependent fashion, the metabolism of the four statins (simvastatin, lovastatin, atorvastatin and cerivastatin) known to be substrates for CYP3A. The potency of inhibition was such that the IC50 values (<1 microM) for inhibition of all of the CYP3A substrates fell within the therapeutic plasma concentrations of mibefradil, and was comparable with that of ketoconazole. However, the inhibition by mibefradil, unlike that of ketoconazole, was at least in part mechanism-based. Based on the kinetics of its inhibition of hepatic testosterone 6beta-hydroxylase activity, mibefradil was judged to be a powerful mechanism-based inhibitor of CYP3A4/5, with values for Kinactivation, Ki and partition ratio (moles of mibefradil metabolized per moles of enzyme inactivated) of 0.4 min(-1), 2.3 microM and 1.7, respectively. In contrast to the results with substrates of CYP3A, metabolism of fluvastatin, a substrate of CYP2C8/9, and the hydroxylation of tolbutamide, a functional probe for CYP2C8/9, were not inhibited by mibefradil. Mibefradil, at therapeutically relevant concentrations, strongly suppressed the metabolism in human liver microsomes of simvastatin, lovastatin, atorvastatin and cerivastatin through its inhibitory effects on CYP3A4/5, while the effects of mibefradil on fluvastatin, a substrate for CYP2C8/9, were minimal in this system. Since mibefradil is a potent mechanism-based inhibitor of CYP3A4/5, it is anticipated that clinically significant drug-drug interactions will likely ensue when mibefradil is coadministered with agents which are cleared primarily by CYP3A-mediated pathways.",2000.0,0,0 63,10215758,Is reporting rate a good predictor of risks associated with drugs?,C Pierfitte; B Bégaud; R Lagnaoui; N D Moore,"Uncertainty as to relative under-reporting plagues the comparisons of spontaneous reporting rates as a tool for decision-making in pharmacovigilance. However, it is generally accepted that under-reporting should be reasonably similar for similar drugs sharing the same indication, country and period of marketing. To test this, we compared the adverse drug reaction reporting rates to the French regional pharmacovigilance centres for six pairs of identical drug marketed at the same time by different companies under different brand names (co-marketing). All reaction reports were related to sales, to compute reporting rate; within each pair, the reporting rate ratio and its confidence interval were calculated. The rate ratios were all between 0.76 and 1.33. Two of them were significantly different from 1 (1.28; 95% C.I. [1.01; 1.60] and 1.33; 95% C.I. [1.06; 1.74]). These small differences in reporting rates would not warrant regulatory action and support the usual assumption of similar reporting for similar drugs.",1999.0,0,0 64,10217372,Plasma lipoprotein distribution and lipid transfer activities in patients with type IIb hyperlipidemia treated with simvastatin.,L Lagrost; A Athias; N Lemort; J L Richard; C Desrumaux; L Châtenet-Duchêne; M Courtois; M Farnier; B Jacotot; S Braschi; P Gambert,"The aim of the present study was to search in type IIb hyperlipidemic patients for putative concomitant effects of simvastatin on the physicochemical characteristics of low density lipoproteins (LDL) and high density lipoproteins (HDL), as well as on the activities of the cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP) that were determined in both endogenous lipoprotein-dependent and endogenous lipoprotein-independent assays. In a double-blind, randomized trial, patients received either placebo (one tablet/day; n = 12) or simvastatin (20 mg/day; n = 12) for a period of 8 weeks after a 5-week run-in period. Simvastatin, unlike placebo, reduced the lipid and apolipoprotein B contents of the most abundant LDL-1, LDL-2, and LDL-3 subfractions without inducing significant changes in the overall size distribution of LDL and HDL. Whereas simvastatin significantly increased PLTP activity in an endogenous lipoprotein-dependent assay (P < 0.01), no variation was observed in a lipoprotein-independent assay. Simvastatin significantly decreased plasma CETP activity in an endogenous lipoprotein-dependent assay (P < 0.01), and the reduction in plasma cholesteryl ester transfer rates was explained by a 16% drop in CETP mass concentration (P < 0.01). In contrast, the specific activity of CETP was unaffected by the simvastatin treatment reflecting at least in part the lack of significant alteration in plasma triglyceride-rich lipoprotein acceptors. The simvastatin-induced changes in plasma CETP mass levels correlated positively with changes in plasma CETP activity (r = 0.483, P = 0.0561), in total cholesterol levels (r = 0.769; P < 0.01), and in LDL-cholesterol levels (r = 0.736; P < 0.01). Whereas the observations suggest that simvastatin might exert concomitant beneficial effects on plasma CETP and LDL levels, neither plasma cholesteryl ester transfer activity nor plasma phospholipid transfer activity appeared as the main determinants of the LDL and HDL distribution profiles in type IIb hyperlipidemic patients.",1999.0,0,0 65,10217377,More on the effect of atorvastatin on plasma fibrinogen levels in primary hypercholesterolemia.,A Bertolotto; S Bandinelli; L Ruocco; A Lo Faro; G Penno; R Navalesi,,1999.0,0,0 66,10221321,Relative importance of various risk factors for asymptomatic carotid atherosclerosis versus coronary heart disease incidence: the Atherosclerosis Risk in Communities Study.,A R Sharrett; P D Sorlie; L E Chambless; A R Folsom; R G Hutchinson; G Heiss; M Szklo,"Major risk factors for coronary heart disease are also associated with early carotid artery thickening, but no studies have yet examined patterns of risk factors to see whether they differ for the two outcomes. Assuming similar pathogenesis for both coronary and carotid atherosclerosis, one could interpret risk factor pattern differences as relating to differences in staging, i.e., early atheroma versus later stenotic or occlusive atherothrombosis. This study included 12,193 Atherosclerosis Risk in Communities Study participants aged 45-64 years who were free of clinical cardiovascular disease in 1987-1989, in whom 420 myocardial infarctions or coronary heart disease deaths occurred over the next 6 years. Plasma low density lipoprotein cholesterol, systolic blood pressure, and smoking were major risk factors for both outcomes. Compared with these factors, triglycerides and high density lipoprotein (HDL) cholesterol were associated only weakly with carotid atherosclerosis but were associated strongly with coronary heart disease incidence. No other risk factors, including those associated with diabetes mellitus, hemostasis, and inflammation, differed in their relative contribution to the two outcomes. These results suggest that the high triglyceride-low HDL cholesterol pattern is involved in the transition from atheroma to atherothrombosis, and that control of this pattern may be important in persons with detectable subclinical disease.",1999.0,0,0 67,10221367,"HIV protease inhibitors: advances in therapy and adverse reactions, including metabolic complications.",D R Kaul; S K Cinti; P L Carver; P H Kazanjian,"Protease inhibitors (PIs) effectively inhibit replication of the human immunodeficiency virus (HIV), and reduce mortality and prolong survival in patients with HIV infection. Newer PIs saquinavir (soft gelatin capsule) and amprenavir, as well as other PIs, may be effective when administered twice/day. Adverse reactions may occur, as well as metabolic complications and interactions between PIs and other drugs, including other PIs. The strategy of combining PIs is based on specific pharmacologic interactions among the agents.",1999.0,0,0 68,10225769,The familial hypercholesterolemia regression study: a randomized comparison of therapeutic reduction of both low-density lipoprotein and lipoprotein(a) versus low-density lipoprotein alone.,Y Kitano; G R Thompson,"Lipoprotein (a) [Lp (a)] is a risk factor for coronary heart disease (CHD), especially in the presence of a raised low-density lipoprotein (LDL)-cholesterol (LDL-C). To ascertain whether reduction of both LDL and Lp(a) is more advantageous than reduction of LDL alone, patients with heterozygous FH and CHD were selected randomly to receive either LDL apheresis fortnightly plus simvastatin 40 mg/day or colestipol 20 g plus simvastatin 40 mg/day. Quantitative coronary angiography was undertaken before and after 2.1 years. Changes in serum lipids were similar in both groups except for the greater reduction of LDL-C and Lp(a) by apheresis. There were no significant differences in primary angiographic endpoints, and none of the angiographic changes correlated with Lp(a). Although LDL apheresis plus simvastatin was more effective than colestipol plus simvastatin in reducing LDL-C and Lp(a), it was not more beneficial in influencing coronary atherosclerosis. Decreasing Lp(a) seems unnecessary if LDL-C is reduced below 130 mg/dl.",1999.0,0,0 69,10225774,The role of low density lipoprotein apheresis in the treatment of familial hypercholesterolemia.,G R Thompson; Y Kitano,"The chief indication for low density lipoprotein (LDL) apheresis is the treatment of homozygous familial hypercholesterolemia (FH), a potentially fatal condition that responds poorly to conventional therapy. Dextran sulfate/cellulose adsorption columns (Kaneka) and on-line heparin precipitation (HELP) are the most popular systems used in LDL apheresis. Weekly or biweekly procedures plus concomitant drug therapy enable LDL cholesterol to be maintained at 30-50% of its untreated level, with regression of xanthomas, arrest of progression of coronary atherosclerosis, and improved life expectancy. However, aortic stenosis may progress despite apheresis and necessitate valve replacement. Better control of hypercholesterolemia results from combining apheresis with a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, atorvastatin. LDL apheresis can also be useful in treating drug-resistant FH heterozygotes with coronary disease. However, the FH Regression Study showed no evidence that reduction by apheresis of both LDL and lipoprotein(a), was more advantageous than reduction by combination drug therapy of LDL alone.",1999.0,0,0 70,10226769,"Mibefradil, a potent CYP3A inhibitor, does not alter pravastatin pharmacokinetics.",L Becquemont; C Funck-Brentano; P Jaillon,"Dramatic drug-drug interactions have been observed between several HMG-CoA reductase inhibitors and cytochrome P450 3A (CYP3A) inhibitors. The aim of the present study was to investigate the effects of mibefradil, a potent CYP3A inhibitor, on pravastatin pharmacokinetics. 12 healthy volunteers were included in this open-label one-period study. Pravastatin pharmacokinetics (following a single oral dose of 40 mg) was studied in the absence of mibefradil (day 1) and after repeated doses (100 mg/day) of mibefradil (day 8). Pravastatin pharmacokinetics after repeated doses of 40 mg/day was also studied in association with repeated doses (100 mg/day) of mibefradil (day 16). Pravastatin area under the plasma concentration vs. time curve (AUC0-infinity) and Cmax in the absence of mibefradil on day 1 (170 [117 to 395] ng h/mL and 91 [72 to 200] ng/mL respectively, geometric mean [95% confidence intervals]) were not significantly altered in the presence of mibefradil on day 8 (224 [174 to 381] ng h/mL and 124 [72 to 200] ng/mL) and on day 16 (200 [137 to 555] ng h/mL and 91 [74 to 184] ng/mL). Tmax of pravastatin in the absence of mibefradil (0.9 +/- 0.1 h, arithmetic mean +/- SD) was slightly delayed in the presence of mibefradil on day 8 and 16 (1.1 +/- 0.3 and 1.2 +/- 0.3 h respectively, p < 0.01 for both comparisons). The results of the present study confirm the lack of pharmacokinetic interactions between mibefradil and pravastatin and indicate that pravastatin may be safely prescribed in the presence of potent CYP3A inhibitors.",1999.0,0,0 71,10227772,Can aggressive lipid lowering using low-density lipoprotein apheresis prevent restenosis after percutaneous transluminal coronary angioplasty in patients with normocholesterolemia?,K Yamashita; H Tasaki; Y Tsuda; E Himeno; Y Nakashima,"We examined whether aggressive lipid lowering using low-density lipoprotein (LDL) apheresis could prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA). Fifteen patients with 17 lesions underwent LDL apheresis once within a week before and after PTCA and thereafter every 2 or 3 weeks (apheresis group) for about 4 months. The control group consisted of 17 patients with 17 lesions. No patients received additional lipid lowering drugs after PTCA. In the apheresis group, the time interval means of the total and LDL cholesterol levels were significantly lower than those in the control group whereas no significant differences were found between the 2 groups regarding the mean percent diameter stenosis or minimal lumen diameter before and after PTCA and at follow-up. The restenosis rate was 29.4% in the apheresis group and 47.1% in the control group. The restenosis rate tended to be slightly lower in the apheresis group. The overall results, however, indicated that aggressive lipid lowering does not prevent restenosis.",1999.0,0,0 72,10227773,The effect of selective low-density lipoprotein apheresis on plasma lipoperoxides and antioxidant vitamins in familial hypercholesterolemic patients.,R Baricchi; R Pizzala; G Cacciavillani; P Rivasi; A Tomasi,"Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by a lifelong elevation in the concentration of low-density lipoprotein (LDL) bound cholesterol in blood by cholesterol deposits and by early coronary artery disease. The LDL apheresis technique has been introduced with the goal of reducing LDL cholesterol levels, thereby preventing the development of atherosclerosis. The literature on LDL apheresis reports 2 different facets, the therapeutic aspect associated with the lessening of LDL concentration and the initiation of a peroxidation process associated with the biocompatibility of the artificial membrane. Lipid and protein peroxidation gives rise to toxic and atherogenic hydroperoxide, mostly lipid hydroperoxides, and derivative compounds, which may offset the benefit of the procedure. In this paper, plasma hydroperoxide levels are determined along with the elevation of the serum and LDL antioxidant status in hypercholesterolemic patients before and following repeated LDL apheresis sessions. Hydroperoxide concentration has been expressed both in terms of plasma volume and LDL concentration. A highly significant increase in LDL lipid hydroperoxides is demonstrated when expressed in terms of LDL concentration and is associated with the LDL apheresis procedure. The usefulness of antioxidant supplementation in LDL apheresis is discussed.",1999.0,0,0 73,10227774,Double filtration plasmapheresis maintains normal adhesion molecule levels.,S Yamane; T Matsugane; K Motohashi; T Nobuto; N Azuma; T Nishide; M Suzuki,"Levels of plasma soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), and von Willebrand factor (vWF) increase in patients with peripheral vascular or ischemic heart disease. These factors are related to the progression of atherosclerosis. Furthermore, these substances and thrombomodulin (TM) are indicators for assessing the degree of damage to the endothelium. To evaluate the effect of double filtration plasmapheresis (DFPP) on these molecules, the plasma levels of vWF, sICAM-1, sVCAM-1, and TM were measured in 4 familial hypercholesterolemia (FH) patients who underwent treatment with DFPP at 2 week intervals for more than 3 years. The levels of sVCAM-1 and sICAM-1 in hypercholesterolemia patients with ischemic heart disease as a control was 773 +/- 109 and 334 +/- 82 ng/ml. These values were higher than the normal value. In the FH patients who underwent DFPP treatment, the average sICAM-1 levels were 221 +/- 47 and 197 +/- 36 ng/ml before and after, respectively. The average sVCAM-1 levels were 601 +/- 87 and 486 +/- 60 ng/ml. There were no significant differences between the pre- and post-DFPP values. The activities of plasma vWF before and after DFPP treatment were 158 +/- 23 and 45 +/- 9%. The levels of plasma TM before and after treatment were 3.0 +/- 0.3 and 3.4 +/- 0.5 FU/ml. From these results, it is suggested that DFPP treatment does not damage the endothelium and may prevent the progression of atherosclerosis by removing the substances that induce the production of sICAM-1 and sVCAM-1 due to long-term treatment.",1999.0,0,0 74,10230580,A risk-benefit assessment of HIV protease inhibitors.,G J Moyle; B G Gazzard,"The use of triple regimens, often called highly active antiretroviral therapy (HAART), generally involving 2 nucleoside analogues and an HIV protease inhibitor, have been endorsed as the standard of care for persons with HIV initiating therapy by a number of sets of international guidelines. The widespread availability of protease inhibitor-containing regimens has been associated with a dramatic drop in the incidence of new AIDS events and mortality throughout the developed world. Use of HAART regimens, particularly in treatment-naïve individuals, is also associated with dramatic reductions in HIV RNA load, rises in CD4+ cell numbers and improvements in some aspects of immune function. However, protease inhibitor therapy is associated with a range of adverse effects, which varies between agents, and regimens frequently involve inconvenient administration schedules and disruption to patient's lives. Thus, the undoubted benefits of antiretroviral therapy come at some cost in terms of both physical and psychological morbidity to the recipient. In assessing an individual for therapy, consideration of the risk of disease events and the benefit of therapy in reducing or preventing these events must be weighed against the potential of therapy to cause morbidity. Using these criteria, we suggest that an individual with a 3 year risk of disease progression of less than 10% (based on CD4+ cell count and HIV RNA load) is more likely to a experience a morbidity if treated with HAART than if left untreated and monitored. For individuals with higher risks of HIV progression the risk versus benefit of initiating therapy may, in many cases, still be in favour of no therapy and continued observation. This will vary depending on the individuals risks (such as family and past medical history) and on the choice of agents in the regimen, some regimens having greater risks than others.",1999.0,0,0 75,10235694,Fluvastatin: a review of its use in lipid disorders.,H D Langtry; A Markham,"Fluvastatin is an HMG-CoA reductase inhibitor used to treat patients with hypercholesterolaemia. Since fluvastatin was last reviewed in Drugs, trials have shown its efficacy in the secondary prevention of coronary heart disease (CHD) events and death and have expanded knowledge of its effects in primary CHD prevention and its mechanisms of activity. In addition to reducing total (TC) and low density lipoprotein (LDL-C) cholesterol, fluvastatin has antiatherogenic, antithrombotic and antioxidant effects, can improve vascular function, and may have immunomodulatory effects. Although fluvastatin interacts with bile acid sequestrants (requiring separation of doses), its pharmacokinetics permit oral administration to most patient groups. Fluvastatin is well tolerated, with adverse effects usually mild and transient. Use of fluvastatin to reduce lipids in patients with primary hypercholesterolaemia is well established. Its effects are similar in most patient groups, with 20 to 80 mg/day reducing LDL-C by 22 to 36%, triglycerides (TG) by 12 to 18% and apolipoprotein B by 19 to 28% and increasing high density lipoprotein cholesterol by 3.3 to 5.6%. Attempts to find fluvastatin dosages with efficacy equivalent to that of other HMG-CoA reductase inhibitors produce variable results, but larger per-milligram fluvastatin dosages are needed when patients switch from other HMG-CoA reductase inhibitors. Combinations of fluvastatin with fibric acid derivatives and bile acid sequestrants produce additive effects. Small noncomparative studies suggest fluvastatin reduces LDL-C in patients with hypercholesterolaemia secondary to kidney disorders by < or = 40.5% and with type 2 diabetes mellitus by < or = 32%. Three large randomised, double-blind trials show fluvastatin can help prevent CHD events or death and slow disease progression in patients with CHD with or without hypercholesterolaemia. In the Fluvastatin Angiographic Restenosis trial in patients undergoing balloon angioplasty, fluvastatin 80 mg/day for 40 weeks reduced the postangioplasty rate of deaths plus myocardial infarctions (1.5% vs 4% with placebo, p < 0.025) without altering vessel luminal diameters. In the Lipoprotein and Coronary Atherosclerosis Study in patients with coronary artery stenosis, luminal diameter reduced to a significantly lesser extent after fluvastatin 20 mg twice daily than placebo after 2.5 years (-0.028 vs -0.01 mm, p < 0.005). The Lescol in Symptomatic Angina study found reductions in all cardiac events or cardiac death in patients after 1 year of fluvastatin 40 mg/day (1.6% vs 5.6% for placebo, p < 0.05). An evolving pattern of data suggests that, in addition to its well established efficacy and cost effectiveness in reducing hypercholesterolaemia, fluvastatin may now also be considered for use in the secondary prevention of CHD.",1999.0,0,0 76,10321422,A population-based treat-to-target pharmacoeconomic analysis of HMG-CoA reductase inhibitors in hypercholesterolemia.,D E Hilleman; J O Phillips; S M Mohiuddin; K L Ryschon; C A Pedersen,"The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have become the drugs of choice for the treatment of patients with hypercholesterolemia. However, one of the major concerns with these drugs is cost. In an attempt to develop a cost-effective treatment strategy for patients referred to our lipid clinic, we conducted a meta-analysis to estimate the lipid-lowering efficacy of the various HMG-CoA reductase inhibitors alone or in combination with niacin or cholestyramine. Based on cholesterol-lowering efficacy estimates derived from a literature-based meta-analysis, we performed a population-based treat-to-target analysis. Fifty-six trials with 101 monotherapy cohorts and 20 trials with 31 combination-therapy cohorts (573 patients) were included in the meta-analysis. Based on reduction in low-density lipoprotein cholesterol (LDL-C), the most effective monotherapy was atorvastatin and the least effective monotherapy was fluvastatin. Combination therapy was more effective in reducing LDL-C than monotherapy with the respective HMG-CoA reductase inhibitor. However, on the basis of dollars spent per percentage of LDL-C reduction, combination therapy was frequently less cost-effective than monotherapy. In addition, combination therapy was associated with a higher rate of noncompliance and a greater risk of drug-drug interactions. As a result, we based our treat-to-target analysis on the use of monotherapy as first-line treatment, with combination therapy reserved for patients failing to achieve the target LDL-C levels of the US National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP-II) with monotherapy. In the population-based treat-to-target analysis, atorvastatin was the most cost-effective drug for high-risk patients (those with coronary heart disease [CHD]), whereas fluvastatin was the most cost-effective agent for low-risk patients (<2 risk factors for CHD) and moderate-risk patients (> or =2 risk factors for CHD). If 1 drug is chosen to treat all patients (i.e., in cases of formulary restriction), atorvastatin would be the most cost-effective agent. In adapting the findings on cholesterol-lowering efficacy from this analysis to our lipid clinic, we concluded that the most cost-effective treatment approach is to individualize the selection of an HMG-CoA reductase inhibitor based on both coronary risk and the LDL-C reduction required to achieve NCEP ATP-II goals. Based on our results, 2 agents--atorvastatin and fluvastatin--should be available on the formulary.",1999.0,0,0 77,10323355,Stroke: part I. A clinical update on prevention.,R G Hart; O Benavente,"Clinical trials conducted during the past five years have yielded important results that have allowed us to refine our approach to stroke prevention. Treatment of isolated systolic hypertension prevents stroke and is generally well tolerated. New antiplatelet agents (clopidogrel and the combination of aspirin plus high-dose dipyridamole) have been shown to be effective in reducing vascular events in survivors of ischemic stroke, although aspirin remains the mainstay of antiplatelet therapy for stroke prevention. Several clinical trials support the benefit of lipid-lowering agents (""statins"") in reducing stroke. Warfarin reduces stroke for high-risk patients with atrial fibrillation. Carotid endarterectomy is highly beneficial in reducing stroke for symptomatic patients with severe carotid stenosis (greater than 70 percent), but the benefit is less for symptomatic patients with a moderate degree of stenosis (50 to 69 percent) and for patients with asymptomatic carotid disease of any severity.",1999.0,0,0 78,10327772,Statin therapy for prevention of coronary artery disease with average cholesterol levels.,D S Gambhir,,1999.0,0,0 79,10329064,MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience.,,"In observational studies, prolonged lower blood total cholesterol levels - down at least to 3 mmol. l-1 - are associated with lower risks of coronary heart disease. Cholesterol-lowering therapy may, therefore, be worthwhile for individuals at high risk of coronary heart disease events irrespective of their presenting cholesterol levels. Observational studies also suggest that increased dietary intake of antioxidant vitamins may be associated with lower risks of coronary heart disease. The present randomized trial aims to assess reliably the effects on mortality and major morbidity of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of different categories of high-risk patients. Men and women aged 40 to 80 years were eligible provided they were considered to be at elevated risk of coronary heart disease death because of past history of myocardial infarction or other coronary heart disease, occlusive disease of non-coronary arteries, diabetes mellitus or treated hypertension; had baseline blood total cholesterol of 3.5 mmol. l-1 or greater; and no clear indications for, or contraindications to, either of the study treatments. Eligible patients who completed a pre-randomization run-in phase on active treatment were randomly allocated to receive simvastatin (40 mg daily) or matching placebo tablets and, in a '2x2 factorial' design, antioxidant vitamins (600 mg vitamin E, 250 mg vitamin C and 20 mg beta-carotene daily) or matching placebo capsules. Follow-up visits after randomization are scheduled at 4, 8 and 12 months, and then 6-monthly, for at least 5 years. Between July 1994 and May 1997, 15 454 men and 5082 women were randomized, with 9515 aged over 65 years at entry. Diagnostic criteria overlapped, with 8510 (41%) having had myocardial infarction (most of whom were either female, or elderly or with low blood cholesterol), 4869 (24%) some other history of coronary heart disease, 3288 (16%) cerebrovascular disease, 6748 (33%) peripheral vascular disease, 5963 (29%) diabetes mellitus (of whom 3985 had no history of coronary heart disease) and 8455 (41%) treated hypertension. Baseline non-fasting total cholesterol levels were less than 5.5 mmol. l-1 in 7882 (38%) participants, and LDL (low density lipoprotein) cholesterol less than 3.0 mmol. l-1 in 6888 (34%). During a mean follow-up of 25 months (range: 13 to 47 months), no significant differences had been observed between the treatment groups in the numbers of patients with muscle symptoms, other possible side-effects leading to termination of study treatment, or elevated liver and muscle enzymes. After 30 months of follow-up, 81% of randomized patients remained compliant with taking their study simvastatin or placebo tablets, and allocation to simvastatin produced average reductions in non-fasting blood total and LDL cholesterol of about 1.5-1.6 mmol. l-1 and 1.1-1.2 mmol. l-1 respectively. Eighty-seven per cent of patients remained compliant with taking their vitamin or placebo capsules, and allocation to the vitamin supplement produced an average increase in plasma vitamin E levels of about 24 micromol. l-1. Based on this initial follow-up period, the estimated annual rate of non-fatal myocardial infarction or fatal coronary heart disease is 2.4%, annual stroke rate is 1.3%, and annual all-cause mortality rate is 2. 2%. The Heart Protection Study is large, it has included a wide range of patients at high risk of vascular events, and the treatment regimens being studied are well-tolerated and produce substantial effects on blood lipid and vitamin levels. The study should, therefore, provide reliable evidence about the effects of cholesterol-lowering therapy and of antioxidant vitamin supplements on all-cause or cause-specific mortality and major morbidity in a range of different categories of individuals for whom uncertainty remains about the balance of benefits and risks of these treatments. Copyrig",1999.0,1,1 80,10335757,"Pharmacodynamics, safety, tolerability, and pharmacokinetics of the 0.8-mg dose of cerivastatin in patients with primary hypercholesterolemia.",E Stein; J Isaacsohn; R Stoltz; A Mazzu; M C Liu; C Lane; A H Heller,"Cerivastatin is a third generation hydroxy-methyl-glutaryl-Co-enzyme A (HMG-CoA) reductase inhibitor proven to lower low-density lipoprotein (LDL) cholesterol 28% to 31% in patients with primary hypercholesterolemia when given at 0.3 mg/day. This study evaluates the safety, tolerability, pharmacodynamics, and pharmacokinetics of cerivastatin 0.8 mg once daily for 4 weeks. In this randomized, double-blind, placebo-controlled parallel group trial conducted at 2 study centers, 41 patients (63% women) with primary hypercholesterolemia were placed on an American Heart Association Step 1 diet for 4 weeks. Single-blind placebo was administered for the final 2 weeks, before randomization. Patients received cerivastatin 0.8 mg (n = 28) or placebo (n = 13) once each evening for 28 days. Cerivastatin at 0.8 mg daily was well tolerated. No discontinuations occurred during the study. Adverse events were mild and transient. One cerivastatin-treated patient experienced asymptomatic creatinine kinase, 8x the upper limit of normal (ULN) elevation on the last day of the study, which resolved 6 days after the completion of the study. Cerivastatin 0.8 mg daily significantly reduced LDL cholesterol compared with placebo (-44.0 +/- 2.0% vs 2.2 +/- 2.8%, p <0.0001); total cholesterol (-30.8 +/- 1.4% vs 2.6 +/- 2.1%, p <0.0001), triglycerides (-11.2 +/- 5.9% vs 15.9 +/- 8.6%, p <0.02), but did not significantly alter high-density lipoprotein (HDL) cholesterol (3.2 +/- 2.1% vs -1.2 +/- 3.1%, p = NS). The pharmacokinetics of the 0.8-mg dose revealed dose proportional elevations in the 24-hour area under the curve and maximum plasma concentration relative to 0.3- and 0.4-mg doses with no change in time to maximum concentration or the elimination half-life in plasma. The increased efficacy and lack of clinically significant laboratory abnormalities or adverse events demonstrates a need for a large long-term study to confirm the safety and efficacy of this dose of cerivastatin.",1999.0,0,0 81,10335764,Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I.,J R Crouse; J Frohlich; L Ose; M Mercuri; J A Tobert,"A randomized, blinded, multicenter clinical trial was performed comparing low- and high-dose simvastatin (40 and 80 mg) with comparable doses of atorvastatin (20 and 40 mg) for effects on plasma concentrations of lipoproteins and apolipoprotein A-I over 12 weeks in 842 patients with elevated low-density lipoprotein cholesterol. The 2 agents reduced low-density lipoprotein cholesterol and triglycerides to a comparable degree, but simvastatin raised high-density lipoprotein cholesterol and apolipoprotein A-I more than atorvastatin, suggesting differences in metabolic effects of the 2 agents on plasma lipids and lipoproteins.",2001.0,1,1 82,10335771,Additional reduction in blood pressure after cholesterol-lowering treatment by statins (lovastatin or pravastatin) in hypercholesterolemic patients using angiotensin-converting enzyme inhibitors (enalapril or lisinopril).,A C Spósito; A P Mansur; O R Coelho; J C Nicolau; J A Ramires,"Blood pressure (BP) reduction was compared between patients receiving angiotensin-converting enzyme inhibitors alone and patients receiving these medications plus statins after 3 months of dietary intervention. Although BP was similarly reduced at week 4, the statin-treated group had a greater reduction in BP and total cholesterol levels at week 16, suggesting a synergistic effect between cholesterol lowering with statins and angiotensin-converting enzyme inhibitor treatment for hypertensive patients.",1999.0,0,0 83,10337451,Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum coenzyme Q10 in diabetic patients.,Y Miyake; A Shouzu; M Nishikawa; T Yonemoto; H Shimizu; S Omoto; T Hayakawa; M Inada,"Serum coenzyme Q10 (CoQ10: 2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34 ,38 -tetracontadecaenyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone, CAS 303-98-0) and cholesterol levels were measured to assess the effect of cholesterol-lowering therapy in patients with non-insulin-dependent diabetes mellitus (NIDDM). Twenty healthy volunteers, 97 NIDDM patients and 2 patients with familial hypercholesterolemia were studied. None had overt heart failure or any other heart disease. Mean serum CoQ10 concentrations were significantly (p < 0.01) lower in diabetic patients with normal serum cholesterol concentrations, either with or without administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) including simvastatin (normal: 0.91 +/- 0.26 (mean +/- SD) mumol 1(-1); diabetic with HMG-CoA RI: 0.63 +/- 0.19; diabetic without HMG-CoA RI: 0.66 +/- 0.21). CoQ10 concentrations were higher (1.37 +/- 0.48, p < 0.001) in diabetic patients with hypercholesterolemia. Simvastatin or low density lipoprotein apheresis decreased serum CoQ10 concentrations along with decreasing serum cholesterol. Oral CoQ10 supplementation in diabetic patients receiving HMG-CoA RI significantly (p < 0.001) increased serum CoQ10 from 0.81 +/- 0.24 to 1.47 +/- 0.44 mumol 1(-1), without affecting cholesterol levels. It significantly (p < 0.03) decreased cardiothoracic ratios from 51.4 +/- 5.1 to 49.2 +/- 4.7%. In conclusion, serum CoQ10 levels in NIDDM patients are decreased and may be associated with subclinical diabetic cardiomyopathy reversible by CoQ10 supplementation.",1999.0,0,0 84,10337501,Diet only and diet plus simvastatin in the treatment of heterozygous familial hypercholesterolemia in childhood.,C Stefanutti; G Lucani; A Vivenzio; S Di Giacomo,"This study was a 1-year clinical study on 16 (7 males and 9 females) pediatric patients with heterozygous familial hypercholesterolemia treated with hypocholesterolemic diet only, or with diet plus drug (simvastatin 10 mg/day). According to the study protocol, the children were submitted to a 3-month washout (free diet). Then they were given a diet (American Heart Association, step 2) for 6 months. After 6 months they were divided into two groups matched for sex, age and body mass index (BMI). Diet only was given to group A (n = 8); simvastatin (10 mg/daily) was given to group B, for 1 year. All patients were examined at baseline, and monitored for safety during the study by pediatricians. All patients were submitted to noninvasive cardiovascular examinations (exercise electrocardiogram, echocardiography). After 12 months of treatment with simvastatin, total cholesterol (TC) and low density lipoprotein cholesterol (LDLC) showed a statistically significant reduction (group B). The decrease of TC and LDLC in patients on diet only was 4% and 3% (all) and 17% and 4% (group A) after 6 and 12 months, respectively.",1999.0,0,0 85,10339027,Cholesterol and coronary heart disease: screening and treatment.,S Ebrahim; G D Smith; C McCabe; N Payne; M Pickin; T A Sheldon; F Lampe; F Sampson; S Ward; G Wannamthee,,1999.0,0,0 86,10342343,Effect of pravastatin on erythrocyte rheological and biochemical properties in poorly controlled Type 2 diabetic patients.,P Miossec; F Zkhiri; J Pariès; M David-Dufilho; M A Devynck; P E Valensi,"The rheological properties of erythrocytes are impaired in diabetes mellitus, especially because of changes in their membrane lipid composition. In hypercholesterolaemic patients, lowering plasma cholesterol is associated with an improvement of the erythrocyte rheological parameters. The aim of this study was to investigate the relationship between erythrocyte deformability, plasma lipids, lipid membrane composition and cytosolic cations in poorly controlled Type 2 diabetic patients and to test the effects of a cholesterol-lowering treatment on these parameters. We compared 37 poorly controlled Type 2 diabetic patients with 26 controls. In 22 of the diabetic patients who showed an impairment in erythrocyte deformability (filtration index >10.5 on the Hanss' haemorheometer), a double-blind randomized trial compared the effect of the inhibitor of HMG CoA reductase pravastatin 20 mg per day for 4 months vs. placebo on the erythrocyte parameters. Compared with controls, diabetic patients had higher filtration index (FI), erythrocyte sodium and calcium contents and lower free cholesterol-phospholipids ratio in erythrocyte membranes. Erythrocyte sodium content correlated positively with the FI and the membrane free cholesterol-phospholipids ratio. In the pravastatin-treated group (11 patients), fibrinogen decreased significantly, FI reached a normal value (<10) in six patients. Four of the five other patients who still had abnormal FI after 4 months of treatment had either a high plasma triglycerides (> or =4.60 mmol/l) or a high plasma fibrinogen (> or =4 g/l) level at baseline. Only two of the 11 placebo-treated patients achieved a normal FI. These data suggest that in poorly controlled Type 2 diabetic patients there is a link between the chemical composition and the rheological properties of erythrocytes. Erythrocyte deformability may be improved by lowering plasma cholesterol with a statin.",1999.0,0,0 87,10342818,Effects of aggressive cholesterol lowering and low-dose anticoagulation on clinical and angiographic outcomes in patients with diabetes: the Post Coronary Artery Bypass Graft Trial.,B J Hoogwerf; A Waness; M Cressman; J Canner; L Campeau; M Domanski; N Geller; A Herd; A Hickey; D B Hunninghake; G L Knatterud; C White,"Diabetic patients have greater risk for coronary heart disease (CHD) events after coronary artery bypass graft (CABG) surgery than nondiabetic patients. The Post CABG trial studied the effects of aggressive cholesterol lowering and low-dose anticoagulation in diabetic patients compared with nondiabetic patients. A double-blind, randomized clinical trial in 1,351 patients (1-11 years after CABG), the Post CABG trial consisted of two interventions (aggressive cholesterol-lowering versus moderate lowering and low-dose warfarin versus placebo) on angiographic end points. Angiographic changes in saphenous vein graft conduits 4.3 years after entry were compared in 116 diabetic and 1,235 nondiabetic patients. Seven clinical centers participated in the trial, as well as the National Institutes of Health project office (National Heart, Lung, and Blood Institute), the coordinating center (Maryland Medical Research Institute), and the Angiogram Reading Center (University of Minnesota). Baseline characteristics of the diabetic patients differed from the nondiabetic patients in the following ways: percentage of women participants, 15 vs. 7%, P = 0.002; mean baseline weight, 87.4 vs. 82.8 kg, P = 0.006; mean BMI, 29.5 vs. 27.6 kg/m2, P = 0.0002; mean systolic blood pressure, 141.7 vs. 133.6, P < 0.0001; mean triglyceride concentrations, 2.09 vs. 1.77 mmol/l, P < 0.0001; and mean HDL cholesterol concentrations, 0.93 vs. 1.02 mmol, P = 0.0001. The percentage of clinical events was higher in diabetic than nondiabetic patients (20.6 vs. 13.4, P = 0.033) and angiographic outcomes were not different. The benefits of aggressive cholesterol lowering were comparable in diabetic and nondiabetic patients for the angiographic end points. Warfarin use was not associated with clinical or angiographic benefit. Diabetic patients in the Post CABG trial had more CHD risk factors at study entry and higher clinical event rates during the study than nondiabetic patients. The benefits of aggressive cholesterol lowering in diabetic patients were comparable to those in nondiabetic patients for both angiographic and clinical end points. The small number of diabetic patients provided limited power to detect significant differences between diabetic and nondiabetic patients or between diabetic patients in the aggressive versus moderate cholesterol treatment strategies.",1999.0,0,0 88,10344068,The role of lipid lowering in transplantation.,A S Wierzbicki,"Transplantation is an increasingly common procedure. Yet the contribution of accelerated atherosclerosis to the reduction of graft life is often underestimated. This review examines the evidence for the involvement of hyperlipidaemia and other cardiovascular disease risk factors in the aetiology of chronic graft failure in renal, cardiac, liver and pancreatic transplantation. The evidence for the role of lipid lowering therapy in the prevention of accelerated atheroma in these patients is reviewed.",1999.0,0,0 89,10344609,Management of toenail onychomycosis.,C M Tom; M P Kane,"The treatment of toenail onychomycosis is reviewed. Onychomycosis contributes to 40% of all nail disorders and appears to be increasing in frequency. Mycotic nail infections are usually caused by dermatophytes, yeasts, and nondermatophyte molds. Most cases of toenail onychomycosis are caused by dermatophytes. Mycotic nail infections do not always resolve spontaneously and may have a substantial impact on the patient's quality of life. Current treatment modalities for onychomycosis include surgery, topical antifungals, and oral antifungals. Surgery is generally not recommended as first-line therapy. Broad-spectrum topical and oral antifungal agents are the most frequently used treatments. Topical treatment is well tolerated but is usually not effective because of poor patient compliance and inadequate penetration of the nail. Oral antifungals are more successful but carry greater risks. Griseofulvin and ketoconazole have been oral antifungals traditionally used for onychomycosis, but these agents are associated with relatively low cure rates. Itraconazole and terbinafine are both safe and effective first-line agents, with reported overall cure rates of 50-90% for dermatophyte-related onychomycosis. Intermittent oral antifungal therapy may reduce the risk of systemic adverse effects and the cost of therapy; more study of this approach is needed. Oral antifungal agents offer patients with toenail onychomycosis greater likelihood of a cure than topical antifungals, but oral therapy carries greater risks and requires closer monitoring.",1999.0,0,0 90,10345158,Pharmacoeconomics of lipid-lowering agents for primary and secondary prevention of coronary artery disease.,J W Hay; W M Yu; T Ashraf,"Cardiovascular disease is the leading cause of death and the leading source of healthcare expenditure in the US and most other industrialised countries. Cholesterol lowering by pharmacological means prevents atherosclerotic plaque progression and has been shown to reduce both fatal and nonfatal coronary events in patients with or without coronary artery disease (CAD). Because of their excellent efficacy and safety profiles, the introduction of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known an 'statins') in 1987 raised hopes for demonstrating the survival benefit of cholesterol reduction. In the past decade, several large-scale placebo-controlled trials with statin therapy have revisited the relationship between cholesterol reduction, cardiovascular disease and mortality. The West of Scotland Coronary Prevention Study (WOSCOPS) [pravastatin] and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) [lovastatin] have shown significant cardiovascular disease reduction in primary prevention trials of patients with elevated and normal cholesterol levels, respectively. The Scandinavian Simvastatin Survival Study (4S), the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study and the Cholesterol and Recurrent Events (CARE) trial [pravastatin] have shown significant cardiovascular disease reduction in patients with a previous history of CAD with high, moderate and normal cholesterol levels, respectively. Three of these studies (4S, WOSCOPS and LIPID) have shown significant reduction in all-cause mortality, while all the statin secondary prevention trials (4S, CARE and LIPID) have demonstrated significant reduction in cerebrovascular disease/ Earlier cholesterol reduction cost-effectiveness studies with nonstatin treatments (bile acid resins, fibrates, niacin and diet) suggested that only patients at extremely high risk could be treated with lipid therapy in a cost-effective manner. More recently, rigorous outcomes evidence demonstrates that statins, particularly for simvastatin for secondary prevention and lovastatin for primary prevention, have a broadly favourable cost-effectiveness profile. Based on US medical price levels and the available clinical trial data on statins, it would be cost effective [e.g. cost less than $US50,000/year of life saved] to intervene with statin therapy in any patient with an annual CAD risk exceeding 1%. This includes all patients with pre-existing CAD or diabetes mellitus, and many more primary prevention patients than are currently contemplated by the US National Cholesterol Education Panel treatment guidelines. Achieving such a goal will require enormous changes in patient education, clinical perspective, healthcare practice and healthcare finances. But any proven opportunity for saving the lives of 25% of those dying from cardiovascular disease each year deserves to be considered with the utmost seriousness and urgency.",1999.0,0,0 91,10346426,Clinical positioning of HMG-CoA reductase inhibitors in lipid management protocols.,M Cziraky,"Drug treatment of dyslipidaemia has progressed dramatically over the past decade. Of the available drugs, HMG-CoA reductase inhibitors (statins) have emerged as very effective and important treatments for dyslipidaemia. These agents potently reduce low density lipoprotein (LDL) cholesterol levels (the main lipid target in management protocols and treatment guidelines) and have produced significant reductions in coronary heart disease (CHD) related morbidity and mortality, as well as overall mortality, in large intervention studies. They have also been shown to reduce progression and increase regression of coronary atherosclerosis. Statins are generally well tolerated and are thus associated with high patient compliance in comparison with the other classes of medications used for dyslipidaemia. There are minimal studies to date with these agents in patients with elevated triglycerides, either with or without accompanying elevated cholesterol levels. Preliminary results with statins in patients with hypertriglyceridaemia are promising, with reductions in triglycerides of 26 and 46%, respectively, having been reported following treatment with simvastatin and atorvastatin. Therefore, statins can be considered first-line drugs in many patients with elevated total and/or LDL-cholesterol levels according to treatment guidelines.",1999.0,0,0 92,10350664,Efficacy and safety of cerivastatin in primary hypercholesterolemia: a long term comparative titration study with simvastatin.,L A Leiter; K Hanna,"To compare cerivastatin with simvastatin in their long term safety and efficacy in reducing low density lipoprotein cholesterol (LDL-C). Multicentre, randomized, double-blind, parallel group study. Thirteen Canadian centres. A total of 387 patients with primary hypercholesterolemia received treatment with either cerivastatin (0. 05 to 0.3 mg/day) or simvastatin (5 to 40 mg/day) to achieve plasma LDL-C levels below 3.36 mmol/L (130 mg/dL) for an initial 32-week dose-titration phase and a subsequent 72-week extension phase. Cerivastatin and simvastatin produced clinically significant reductions in LDL-C of 28.4% and 35.4%, respectively, at the end point for the 32-week study, and reductions of 32.8% and 35. 0%, respectively, at the end of the extension phase of the study. Response rates (a greater than 15% drop in LDL-C) were comparable for the two treatments (88.9% cerivastatin versus 93.2% simvastatin) at the 32-week end point. Response rates were 100% for both treatments at the end of the 72-week extension phase. Both treatments also reduced total cholesterol, apolipoprotein B and very low density lipoprotein cholesterol levels. Cerivastatin and simvastatin increased HDL-C levels significantly by 8.8% and 11.0%, respectively, at the end point for the 32-week study, and by 8.6% and 12.1%, respectively, at the end of the extension phase of the study. Treatments were well tolerated, and the incidence of adverse effects was similar in both groups. This forced titration study demonstrates that cerivastatin, given once daily at doses up to 0.3 mg/day, is effective and well tolerated. The results of this study support further investigation of higher doses of cerivastatin given the excellent safety profile at doses up to 0.3 mg.",1999.0,0,0 93,10353071,Comparison of the efficacy of atorvastatin and micronized fenofibrate in the treatment of mixed hyperlipidemia.,E T Bairaktari; C S Tzallas; V K Tsimihodimos; E N Liberopoulos; G A Miltiadous; M S Elisaf,"To evaluate and compare the influences of micronized fenofibrate and atorvastatin on serum lipid profile, including lipoprotein(a) levels, and on fibrinogen levels in a large group of patients with primary mixed hyperlipidemia (serum total and low-density lipoprotein cholesterol levels > 240 and 160 mg/dl, respectively, and serum triglyceride level > 200 mg/dl). This was a 16-week, open-label, parallel-design study conducted in our lipid clinic. After a 6-week dietary baseline phase, we implemented a treatment phase, during which patients received 10 mg/day atorvastatin (n = 45) or 200 mg/day micronized fenofibrate (n = 46) for 16 weeks. Patients were assigned to one of the drugs in sequential orders. Serum lipid profiles, including levels of lipoprotein(a) and fibrinogen, as well as muscle and liver enzymes, were measured during screening, and during weeks -4, -2, 0, 8, and 16 of the treatment period. Atorvastatin was more effective than was micronized fenofibrate at lowering levels of total and low-density lipoprotein cholesterol, whereas fenofibrate was more effective at lowering levels of triglycerides, and raising levels of high-density lipoprotein cholesterol and apolipoprotein A1. However, micronized fenofibrate could significantly decrease plasma fibrinogen levels, whereas atorvastatin evoked a small increase. Both atorvastatin in small doses and micronized fenofibrate are effective for improving serum lipid profiles of patients with mixed hyperlipidemia. However, there are considerable differences between the two drugs concerning their influences on plasma fibrinogen levels.",1999.0,0,0 94,10354197,"Effect of inhibiting HMG-CoA reductase on 7 alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis: contrasting findings in patients with and without prior up-regulation of the latter pathway.",R P Naoumova; F H O'Neill; S Dunn; C K Neuwirth; G W Taylor; M Axelson; G R Thompson,"Atorvastatin is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, but its effect on bile acid synthesis is unknown. The objectives of the study were to determine the effect of atorvastatin on bile acid synthesis in patients in whom this process had not been or had been previously up-regulated by pharmacological or surgical means. Four patients with heterozygous familial hypercholesterolaemia (FH) and partial ileal bypass (PIB) and 19 FH heterozygotes without PIB were treated with placebo, atorvastatin 10 mg and atorvastatin 40 mg daily, each regimen for 4 weeks. The non-PIB group was subsequently treated with bile acid (BA) sequestrant 8-16 g daily followed by co-administration of atorvastatin 10 mg, each for 4 weeks. Plasma 7 alpha-hydroxy-4-cholesten-3-one (7 alpha-HCO), a well-validated marker of BA synthesis was measured using high-performance liquid chromatography with UV detection. The plasma 7 alpha-HCO concentration was tenfold higher with placebo in the PIB than in the non-PIB group (418.5 ng mL-1 vs. 39.6 ng mL-1 p = 0.0001). Levels decreased in PIB patients treated with atorvastatin 10 mg and 40 mg daily (350.1 ng mL-1 and 174.0 ng mL-1, P = 0.007 respectively) but did not change significantly in the non-PIB group (44.7 ng mL-1 and 28.3 ng mL-1 respectively). Administration of BA sequestrant to non-PIB patients increased 7 alpha-HCO to 197.4 ng mL-1; this decreased to 106.0 ng mL-1 during co-administration of atorvastatin 10 mg daily (P = 0.0001). Atorvastatin decreases the rate of BA synthesis only if the latter is up-regulated by PIB or BA sequestrants, presumably by limiting the supply of newly synthesized free cholesterol.",1999.0,0,0 95,10355866,Decrease in P-selectin levels in patients with hypercholesterolaemia and peripheral arterial occlusive disease after lipid-lowering treatment.,G Kirk; M McLaren; A H Muir; P A Stonebridge; J J Belch,"At sites of thrombosis and vascular injury, interactions occur among platelets, leucocytes and endothelial cells. Patients with peripheral arterial occlusive disease (PAOD) have been shown to have raised total serum cholesterol and serum triglycerides and increased sP-selectin levels when compared with controls. A total of 31 patients with PAOD and hypercholesterolaemia took part in this three-staged study. Soluble P-selectin (sP-selectin) levels were significantly lowered after 12 weeks of fluvastatin treatment (157.0 ng/ml versus 113.77 ng/ml, p = 0.01), whereas 12 weeks of placebo treatment had no statistically significant effect on sP-selectin levels (150.0 ng/ml versus 139.4 ng/ml). An unpaired t-test almost reached statistical significance (p = 0.051) when the levels by which sP-selectin fell after 12 weeks of active or placebo treatment were compared. The placebo group was then put onto long-term, active treatment and sP-selectin levels were significantly lowered by fluvastatin when compared to pre-treatment levels (150.0 ng/ml versus 110.0 ng/ml, p = 0.03). By lowering the levels of P-selectin, fluvastatin may not only attenuate atherosclerotic progression but may also decrease the platelet activation associated with PAOD.",1999.0,0,0 96,10356659,Joint effects of HMG-CoA reductase inhibitors and eicosapentaenoic acids on serum lipid profile and plasma fatty acid concentrations in patients with hyperlipidemia.,N Nakamura; T Hamazaki; M Ohta; K Okuda; M Urakaze; S Sawazaki; K Yamazaki; A Satoh; R Temaru; Y Ishikura; M Takata; M Kishida; M Kobayashi,"HMG-CoA reductase inhibitors reduce serum total cholesterol concentrations and the risk of coronary heart disease in patients with hypercholesterolemia. Recently, it has been reported that patients with combined hyperlipidemia are also at risk of coronary heart disease. However, HMG-CoA reductase inhibitor therapy alone does not sufficiently reduce serum triglyceride concentrations. Epidemiological and clinical evidence has shown that fish oil can lower plasma lipid levels, especially triglycerides. Consequently, we investigated the effects of the combination of HMG-CoA reductase inhibitors and eicosapentaenoic acid, a major component of fish oil, on hyperlipidemia. We administered 900-1,800 mg/day of the ethyl ester of eicosapentaenoic acid to patients with hyperlipidemia who had been treated with HMG-CoA reductase inhibitors for 30 +/- 6 months (means +/- SE). Serum total cholesterol and triglyceride concentrations were significantly decreased 3 months after the administration of eicosapentaenoic acid (from 5.63 +/- 0.23 mmol/l to 5.02 +/- 0.20 mmol/l, P < 0.05; from 2.07 +/- 0.41 mmol/l to 1.08 +/- 0.17 mmol/l, P < 0.01, respectively). Serum high-density lipoprotein-cholesterol concentrations were significantly increased after the treatment (from 1.23 +/- 0.12 mmol/l to 1.34 +/- 0.13 mmol/l, P < 0.05). Plasma eicosapentaenoic acid concentrations and the ratio to arachidonic acid in plasma were also significantly increased 3 months after the treatment (from 101.9 +/- 8.1 mg/l to 181.8 +/- 23.9 mg/l, P < 0.001; from 0.640 +/- 0.075 to 1.211 +/- 0.170, P < 0.001, respectively). These results suggested that the combination therapy of HMG-CoA reductase inhibitors and eicosapentaenoic acid was effective for patients with hyperlipidemia.",1999.0,0,0 97,10359730,Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis.,D Baller; G Notohamiprodjo; U Gleichmann; J Holzinger; R Weise; J Lehmann,"Early stages of coronary atherosclerosis are characterized by a mainly functional impairment of coronary vasodilator capacity under the impact of such risk factors as hypercholesterolemia. The goal of this study was to determine whether 6-month cholesterol-lowering therapy improves coronary flow reserve in patients with angina, reduced flow reserve despite minimally diseased coronary vessels or even normal angiogram, and mild to moderately elevated LDL levels on average. We noninvasively investigated 23 consecutive patients (18 men, 5 women; mean age, 56+/-7.6 years) with a mean LDL level of 165+/-34 mg/dL at baseline by PET for myocardial blood flow measurement with [13N]ammonia at rest and under dipyridamole stress (0.56 mg/kg) before and after lipid-lowering therapy with simvastatin for 6 months. Between baseline and the 6-month follow-up, total cholesterol concentration fell from 241+/-44 to 168+/-34 mg/dL, and the LDL level decreased from 165+/-34 to 95+/-26 mg/dL (P<0.001). Overall, coronary flow reserve increased from 2.2+/-0.6 to 2.64+/-0.6 (P<0.01). Maximal coronary flow increased significantly from 182+/-36 to 238+/-58 mL/minx100 g (P<0.001) at follow-up. Minimum coronary resistance declined significantly from 0. 51+/-0.12 to 0.40+/-0.14 mm Hg. mL-1. minx100 g (P<0.001). Concomitantly, a regression of anginal symptoms was observed in most patients. Our results suggest that cholesterol-lowering therapy with simvastatin may improve overall coronary vasodilator capacity assessed noninvasively by PET in patients with mild to moderate hypercholesterolemia. Consequently, intensive lipid-lowering therapy is considered a vasoprotective treatment for selected patients in very early stages of coronary atherosclerosis with the potential of preventing further disease progression.",1999.0,0,1 98,10360474,Lovastatin-induced apoptosis of human medulloblastoma cell lines in vitro.,R J Macaulay; W Wang; J Dimitroulakos; L E Becker; H Yeger,"Medulloblastoma is a malignant paediatric central nervous system tumor with a poor prognosis, stimulating the evaluation of improved treatment strategies. Lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, is currently used to treat patients with hypercholesterolemia. This compound also inhibits the production of non-steroidal mevalonate derivatives that are implicated in the control of cellular proliferation, and can induce cell-cycle arrest in vitro. We recently showed that lovastatin inhibited growth and promoted apoptosis of neuroblastoma, the peripheral nervous system 'cousin' of medulloblastoma. Therefore the potential of lovastatin as a possible anticancer drug against medulloblastoma was evaluated in vitro. Four medulloblastoma cell lines, Daoy, UW228, D341 Med and D283 Med, were treated with 1-40 microM of lovastatin in vitro. Analysis of cell morphologic changes, cell viability, DNA fragmentation and flow cytometry in all four cell lines showed growth inhibition and induction of apoptosis with lovastatin treatment. As little as 10 microM of lovastatin was sufficient to cause a marked reduction in cell numbers, and more than 20 microM of lovastatin induced >90% cells to undergo apoptosis, after intervals ranging between 36 and 96 h, depending on the cell line. Lovastatin induced apoptosis in these cell lines was concomitant with cell cycle arrest in G1. The attached cell lines UW228 and Daoy were more sensitive to lovastatin than D283 Med and D341 Med. Daoy cells which survived several cycles of lovastatin treatment could still be induced to undergo apoptosis after longer treatment times. The efficient induction of apoptosis by lovastatin favours this drug as a potential new avenue of therapeutic intervention for medulloablastoma.",1999.0,0,0 99,10361905,Secondary prevention with lipid lowering therapy in familial hypercholesterolemia: a correlation between new evolution of stenotic lesion and achieved cholesterol levels after revascularization procedures.,S Fukuzawa; S Ozawa; M Inagaki; S Morooka; T Inoue,"To assess the value of secondary prevention with lipid lowering therapy following either balloon angioplasty (PTCA) or bypass surgery (CABG) in familial hypercholesterolemia patients, the correlation of the new evolution of stenotic lesions and therapeutically achieved cholesterol levels was studied in 50 patients. All surviving patients were followed angiographically after 5 years, and findings were correlated with the annually determined total serum cholesterol (TC) levels. New coronary atherosclerotic plaques were not observed in 18 patients in whom the TC was controlled to <220 mg/dl but in 19 of 32 patients in whom the TC was >220 mg/dl, a new evolution of stenotic lesions was observed angiographically. The new evolution of stenotic lesions following revascularization in patients with FH can be controlled significantly by lipid lowering therapy to maintain a TC level of <220 mg/dl, and if diet alone can not achieve it, aggressive medication and even LDL apheresis might be justified.",1999.0,0,0 100,10362210,Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease.,D M Herrington; B L Werbel; W A Riley; B E Pusser; T M Morgan,"We sought to examine the individual and combined effects of estrogen/progestin therapy versus lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with heart disease. Little information is available regarding the relative benefits of estrogen replacement therapy versus reductase inhibitors and the potential utility of their combination as lipid-lowering therapy for postmenopausal women. We conducted a randomized, double-blind, crossover trial in 24 postmenopausal women, each of whom received the following drug regimens during three consecutive six-week treatment periods: 1) hormone replacement (oral dose of 0.625 mg/day conjugated equine estrogens and 2.5 mg/day medroxyprogesterone acetate); 2) 20 mg lovastatin/day and 3) hormone replacement plus lovastatin. Total and low density lipoprotein (LDL) cholesterol were significantly lowered and high density lipoprotein (HDL) cholesterol was significantly increased by all three regimens compared with baseline (p < 0.05). Lovastatin was more effective than estrogen/progestin in reducing LDL (p < 0.001), but estrogen/progestin was slightly more effective in increasing HDL. The hormone replacement and lovastatin regimen blocked the estrogen-associated increase in triglycerides. Hormone replacement (alone and with lovastatin) resulted in increases in brachial artery flow-mediated vasodilator capacity (p = 0.01 for both regimens) and the area under the curve (p = 0.016 and p = 0.005, respectively) compared with baseline. Percent dilation was greatest after the hormone replacement regimen, whereas the area under the curve was greatest after hormone replacement plus lovastatin (69% improvement vs. baseline). In postmenopausal women with coronary disease and hyperlipidemia, conjugated equine estrogen produced significant improvements in lipids and vasodilator responses despite the concurrent administration of low dose medroxyprogesterone acetate. Low dose lovastatin produced greater reductions in LDL, but less dramatic improvements in vasodilator responses. Estrogen/progestin plus lovastatin may provide additional benefits via a greater reduction in the LDL/HDL ratio and attenuation of estrogen-associated hypertriglyceridemia. More information is needed about the safety and efficacy of such combinations of hormone replacement and reductase inhibitor therapy.",1999.0,0,0 101,10366279,,,,,0,0 102,10368773,Alternatives to the use of estrogen in postmenopausal women.,J V Pinkerton; R Santen,,1999.0,0,0 103,10368879,Effect of fluvastatin in combination with moderate endurance training on parameters of lipid metabolism.,R Wittke,"To establish whether patients receiving the cholesterol synthesis enzyme inhibitor fluvastatin 20 mg/day could obtain an additional improvement in their lipid pattern as a result of physical endurance training. This was an observational study using a before- and after-treatment comparison of fitness and lipid parameters in outpatients with dyslipidaemia who undertook an exercise programme with or without treatment with a lipid-lowering drug. Participants were 18 sedentary [maximum oxygen uptake (VO2max) < 30 ml/kg bodyweight per minute] men (age range 38 to 65 years) with dyslipidaemia but without overt cardiovascular disease. All participants undertook a 1-hour bout of endurance training twice a week for 3 months. The training involved a circuit using various ergometers, with continuous monitoring of pulse rate, at an exercise intensity of 2 to 3 mmol/L lactate. The control group (n = 6) received no drug treatment; they completed the training programme only. The pretreatment group (n = 6) comprised participants who had already been treated with fluvastatin 20 mg/day for at least 3 months before beginning the training programme. The treatment group (n = 6) received fluvastatin 20 mg/day from the beginning of the training programme. All participants were required to comply with the exercise programme and with a standardised carbohydrate-loaded diet together with restriction of alcohol consumption to a maximum of 20 ml/day. In the control group, increased physical activity alone reduced serum triglyceride (TG) levels (-24.7%) and increased serum high density lipoprotein-cholesterol (HDL-C) levels (+19.3%). There was a smaller effect on serum low density lipoprotein-cholesterol (LDL-C) levels (-12.8%). Similar but smaller effects were observed in the pretreatment group (i.e. patients previously treated with fluvastatin): TG -12.88%, HDL-C +13.81%, LDL-C -8.7%. Marked changes were observed in the treatment group: TG -33.1%, HDL-C +34.7%, LDL-C -40.5%, total cholesterol -30.5%. A reduction of serum LDL-C level in the target range of -30 to -40% cannot be achieved by this intensity of training alone. In combination with fluvastatin 20 mg/day, however, the positive effects on lipid metabolism are potentiated. Thus, treatment with fluvastatin combined with moderate endurance training is a rational mode of therapy, particularly in patients with a highly pathological lipid profile.",1999.0,0,0 104,10370746,Effect of atorvastatin on low-density lipoprotein subfraction profile.,M J Landray; A Hartland; D Hubscher; M J Kendall; R Cramb,,1999.0,0,0 105,10370979,Treatment for carotid atherosclerosis--who should have it and who should not?,R S MacWalter,,1999.0,0,0 106,10371111,Preoperative lipid-control with simvastatin reduces the risk of postoperative thrombocytosis and thrombotic complications following CABG.,J T Christenson,"It has earlier been suggested that postoperative thrombocytosis frequently occur after coronary artery bypass grafting (CABG) and may be linked to lipid disturbances. A prospective randomized study was undertaken to evaluate if preoperative lipid-control, using HMG-CoA-reductase inhibitor (Zocor), simvastatin, reduces the risk of postoperative thrombocytosis. Seventy-seven patients with symptomatic coronary artery disease and hypercholesterolemia (total cholesterol > or =6.2 mmol/l), planned for CABG where randomly assigned to; undergo CABG without preoperation lipid control (group I, n = 37) or undergo simvastatin-treatment (20 mg daily) to control their lipids (4 weeks) prior to CABG (group II, n = 40). Patient characteristics and operation data did not differ between the groups. Serum-cholesterol, cholesterol/HDL-cholesterol, LDL-cholesterol, Apolipoprotein A1 and Plasminogen were all significantly higher in group I patients compared with group II just prior to surgery. Other laboratory parameters did not differ. In group II, total cholesterol and cholesterol/HDL-cholesterol quota were significantly lowered by simvaststin (-2 and -29%, respectively). Postoperative thrombocytosis (platelet counts > or =400000/microl) occurred significantly more frequently in group I 81% (30/37) compared with 3% (1/40) in group II, P<0.0001. Myocardial infarction after the 7th postoperative day was more often diagnosed in group I, 14 vs. 0% in group II. Postoperative transient renal failure occurred also more frequently in group I, 24% compared with 8% in group II. Other postoperative complications and laboratory data did not differ. This study once again underlines the importance of lipid control using HMG-CoA-reductase inhibitors (e.g. Zocor) in patients with established coronary artery disease. For the first time it is shown that lipid-control with simvastatin prior to CABG reduces the risk of postoperative thrombocytosis, thus lowers the risk for thrombotic complications.",2000.0,0,0 107,10372447,Security and maximal tolerated doses of fluvastatin in pediatric cancer patients.,E López-Aguilar; A C Sepúlveda-Vildósola; H Rivera-Márquez; F Cerecedo-Diaz; M Valdez-Sánchez; M A Villasis-Keever,"The role of cholesterol in neoplasic cell growth and its inhibition by drugs has recently been studied. Cholesterol biosynthesis inhibitors have been used as adjuvants in the treatment of cancer and possibly as prophylactic in carcinogenesis. The objective of the study was to determine the maximal tolerated doses (MTD) and toxic effects of fluvastatin in pediatric cancer patients. This study was carried out in a third level Social Security Hospital in Mexico City. We included pediatric patients from April 1996 to May 1997. All were terminal cancer patients who did not respond to conventional therapies. Fluvastatin was given p.o. at doses of 2 mg/kg/day for 14 days every 4 weeks in three patients. Subsequent cohorts of three patients each had increments of 2 mg/kg/day of the drug until maximal tolerated doses were found. Toxic effects of the drug were evaluated by physical exploration, laboratory assays and a questionnaire given to each patient. Twelve patients were included. Diagnoses included two osteosarcomas, eight central nervous system tumors, one lung tumor, and one Ewing's sarcoma. Ten patients died within 1 to 18 months. Two are alive 22 months after inclusion into the study, both with anaplasic astrocytoma. A total of 27 courses were administered. The MTD was 8 mg/kg/day. Toxic effects were insomnia, nausea, vomiting, abdominal distention and myalgias. Toxicity was dose-dependent. Laboratory assays demonstrated no significant changes during treatment. Fluvastatin can be safely used at doses of 8 mg/kg/day in pediatric patients with cancer. This dose should be used in additional trials.",1999.0,0,0 108,10381291,Metabolic basis of high density lipoproteins and apolipoprotein A-I increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease.,J R Schaefer; H Schweer; K Ikewaki; H Stracke; H J Seyberth; H Kaffarnik; B Maisch; A Steinmetz,"HMG-CoA reductase inhibitors, such as pravastatin, are widely used as lipid lowering drugs in hypercholesterolemia. Pravastatin does not only reduce the atherogenic low density lipoprotein (LDL)-cholesterol, but is also increasing high density lipoprotein (HDL)-cholesterol. However, the mechanism leading to an increase of HDL are unclear. Therefore, the effects of pravastatin on the in vivo kinetics of apolipoprotein (apo) A-I were studied in six normolipidemic subjects and in a patient with coronary artery disease (CAD) utilizing stable isotope tracer techniques. Two turnover studies were performed. The first turnover study was carried out before any drug treatment, the second study after 6 weeks of 40 mg pravastatin/day. Three times deuterium labeled L-leucine (3D-leucine) was given as a primed bolus constant infusion (bolus: 1340 microg/kg; infusion: 22 microg/kg per h), and tracer uptake into HDL apoA-I was determined by gas chromatography (GC)-mass-spectrometry (MS). In the healthy subjects HDL-cholesterol increased by 13% and apoA-I increased by 12% under pravastatin treatment. The HDL in the CAD patient decreased by 3% and apoA-I increased by 2%. Prior to drug treatment the mean apoA-I fractional synthetic rate (FSR) was 0.194 per day (S.D. +/- 0.02) and apoA-I production rate (PR) was 10.8 mg/kg per day (S.D. +/- 2.1). The CAD patient had a FSR of 0.219 per day and a PR of 10.6 mg/kg per day. After treatment with pravastatin the mean apoA-I FSR was 0.204 per day (S.D. +/- 0.02) and apoA-I PR was 12.5 mg/kg per day (S.D. +/- 1.5) in the healthy subjects. Despite only minor changes of HDL and apoA-I in the CAD patient, there were significant changes of FSR (0.267 per day) and PR (13.1 mg/kg per day) with pravastatin treatment. The in vivo kinetic data demonstrate an increased FSR of apoA-I. The increase in apoA-I is due to an increased PR of apoA-I. This study demonstrates increased production of HDL apoA-I as the metabolic cause of the increase in HDL and apoA-I levels under inhibition of HMG-CoA reductase in man.",1999.0,0,0 109,10381298,A more mature phenotype of blood mononuclear phagocytes is induced by fluvastatin treatment in hypercholesterolemic patients with coronary heart disease.,G Rothe; A S Herr; J Stöhr; C Abletshauser; G Weidinger; G Schmitz,"Monocytes are recruited as the principal inflammatory cells into the atherosclerotic lesion. In a previous study we demonstrated that a low HDL-cholesterol and the apo E4 allele are associated with an increased proportion of blood monocytes that are characterized by a high expression of Fcgamma-RIIIa (CD16), a dim expression of the lipopolysaccharide (LPS) receptor (CD14) and a high expression of beta1- and beta2-integrins (Rothe et al. Arterioscler Thromb Vasc Cell Biol 1996;16:1437-1447). In this study, 79 hypercholesterolemic patients were treated either with the HMG CoA reductase inhibitor fluvastatin in combination with diet or with placebo and diet in a double-blind and randomized multicenter study, and monitored for the potential effects on the phenotype of peripheral blood monocytes. At baseline, in the whole group of hypercholesterolemic patients the population size of these more mature monocytes (CD14dimCD16+) was positively correlated to triglyceride (P = 0.003) and total serum cholesterol levels (P = 0.012) confirming our previous study. Fluvastatin treatment for 52 weeks was associated with a 24.2% reduction in LDL-cholesterol (P < 0.001) as well as a 40.7% decrease in the expression density of CD14 on all monocytes (P = 0.027). A 24.5% decrease (P < 0.001) of the population of less differentiated CD14brightCD16- monocytes and an 83.1% increase (P = 0.029) of the population of more differentiated CD14dimCD16+ monocytes further confirmed this modification of the phenotype of peripheral blood monocytes. The positive pre-study correlation of the CD14dimCD16+ monocyte subset to the serum cholesterol concentration, but inverse changes of both parameters under fluvastatin therapy, in conclusion indicate that fluvastatin exerts an as yet uncharacterized immunomodulatory effect on either monocyte maturation and differentiation, or extravasation which may also depend on the endothelial phenotype that is independent of the change in serum lipids.",1999.0,0,0 110,10381299,The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment.,G Riegger; C Abletshauser; M Ludwig; P Schwandt; J Widimsky; G Weidinger; D Welzel,"The primary objective of the present study was to investigate the cholesterol-lowering effect of fluvastatin on the incidence of cardiac events in hyperlipidaemic patients with symptomatic, clinically-diagnosed (exercise-ECG) coronary heart disease (CHD) during 1 year of treatment. Exercise tolerance, incidence of angina pectoris episodes, use of anti-anginal medication and intimal-medial-thickness (IMT subgroup) of the A. carotis were secondary endpoints. In the double-blind trial a total of 365 male and female patients with stable symptomatic CHD and a low-density lipoprotein cholesterol (LDL-C) above 160 mg/dl on a lipid-lowering diet were randomised to fluvastatin 40 mg (o.a.d. or b.i.d.) or placebo for 1 year. Fluvastatin lowered total cholesterol by 17% and LDL-C by 27%. There was a significantly lower incidence of cardiac events (cardiac death, nonfatal myocardial infarction, unstable angina pectoris) in the fluvastatin group (3 events) as compared to the placebo group (10 events) (P < 0.05). Exercise tolerance improved and the incidence of angina pectoris episodes decreased in both groups, but more pronounced on fluvastatin (n.s.). Exercise-ECG discontinuation due to angina pectoris and ST-segment depression decreased in the fluvastatin group by 55.6 and 70.9%, respectively, and in the placebo group by 39.6 and 46.5% (n.s.). At baseline, a subgroup of 76 patients showed a mean IMT value of 0.73 mm which remained uninfluenced in the fluvastatin and the placebo groups. Fluvastatin was safe and well tolerated. In conclusion, patients with symptomatic CHD get cardiovascular benefit from lipid-lowering therapy with fluvastatin even during the first year of treatment.",1999.0,1,1 111,10381854,"Despite good compliance, very low fat diet alone does not achieve recommended cholesterol goals in outpatients with coronary heart disease.",R Aquilani; R Tramarin; R F Pedretti; G Bertolotti; M Sommaruga; P Mariani; L Ruffato; M Catapano; F Boschi; M Dossena; O Pastoris,"A low-saturated, low-cholesterol diet is important in the treatment of hypercholesterolaemia in patients with coronary heart disease. The aim of this study was to investigate the efficacy of a very low fat diet to achieve a targeted serum low density lipoprotein (LDL) cholesterol level (3.37mmol x l-1 were investigated 12-14 weeks after an acute coronary event. After overnight fasting each patient had (a) his resting energy expenditure measured (indirect calorimetry using standard protocol) and (b) venous blood sampled from a forearm vein to determine lipid profile. All the patients were randomly allocated to four groups of treatment: Group A on a very low fat diet (resting energy expenditure-fat diet, where fat intake was /=5.2 mmol/L or LDL >/=3.4 mmol/L were randomized to placebo (n=30) or pravastatin 40 mg daily (n=30) for 6 weeks. Brachial ultrasound was used to measure endothelium-dependent flow-mediated dilatation (FMD) and response to endothelium-independent nitroglycerin. Changes in the levels of markers of platelet activation, coagulation factors, and plasma endothelin levels were also assessed. Total and LDL cholesterol levels were similar at admission and before randomization in both groups. With pravastatin, but not with placebo, they decreased by 23% (P<0.05) and 33% (P<0.01), respectively. FMD was unchanged with placebo, 5.43+/-0.74% (mean+/-SEM) to 5.84+/-0.81%, but increased with pravastatin, 4.93+/-0.81% to 7.0+/-0.79% (P=0.02), representing a 42% relative increase. Responses to nitroglycerin were similar during the time course of the study in the 2 groups. Markers of platelet activity, coagulation factors, and endothelin levels were not affected by pravastatin. Cholesterol reduction with pravastatin initiated early after acute coronary syndromes rapidly improves endothelial function after 6 weeks of therapy.",1999.0,0,1 116,10385497,"Aggressive cholesterol lowering delays saphenous vein graft atherosclerosis in women, the elderly, and patients with associated risk factors. NHLBI post coronary artery bypass graft clinical trial. Post CABG Trial Investigators.",L Campeau; D B Hunninghake; G L Knatterud; C W White; M Domanski; S A Forman; J S Forrester; N L Geller; F L Gobel; J A Herd; B J Hoogwerf; Y Rosenberg,"The NHLBI Post Coronary Artery Bypass Graft trial (Post CABG) showed that aggressive compared with moderate lowering of low-density lipoprotein-cholesterol (LDL-C) decreased obstructive changes in saphenous vein grafts (SVGs) by 31%.1 Using lovastatin and cholestyramine when necessary, the annually determined mean LDL-C level ranged from 93 to 97 mg/dL in aggressively treated patients and from 132 to 136 mg/dL in the others (P<0.001). The present study evaluated the treatment effect in subgroups defined by age, gender, and selected coronary heart disease (CHD) risk factors, ie, smoking, hypertension, diabetes mellitus, high-density lipoprotein cholesterol (HDL-C) <35 mg/dL, and triglyceride serum levels >/=200 mg/dL at baseline. As evidenced by similar odds ratio estimates of progression (lumen diameter decrease >/=0.6 mm) and lack of interactions with treatment, a similar beneficial effect of aggressive lowering was observed in elderly and young patients, in women and men, in patients with and without smoking, hypertension, or diabetes mellitus, and those with and without borderline high-risk triglyceride serum levels. The change in minimum lumen diameter was in the same direction for all subgroup categories, without significant interactions with treatment. Aggressive LDL-C lowering delays progression of atherosclerosis in SVGs irrespective of gender, age, and certain risk factors for CHD.",1999.0,0,1 117,10385633,The pravastatin-induced decrease of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis in humans.,G Kallien; K Lange; E F Stange; J Scheibner,"3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to suppress biliary cholesterol secretion and saturation. It remains unproven whether this is mediated by inhibition of cholesterol synthesis. Therefore, the effect of a long-term administration of pravastatin on cholesterogenesis and on biliary lipid secretion was investigated in seven healthy volunteers. Placebo or 40 mg of pravastatin were taken daily at bedtime for 5 weeks using a double-blind crossover design. During the last week, 12 hours after the last drug intake 0.04 mmol [1-13C]acetate/kg. h and 0.5 g polyethylene glycol 4,000/h were infused intraduodenally for 15 hours. Plasma and duodenal bile samples were collected hourly. Thereafter, the decay of [13C]labeled plasma cholesterol was measured during the following 3 days. The fractional and absolute syntheses of plasma and biliary cholesterol were determined by gas chromatography mass spectrometry using mass isotopomer distribution analysis. At the end of the pravastatin period plasma total and low-density lipoprotein (LDL) cholesterol had decreased by 20% and 24%, respectively. Similarly, pravastatin suppressed biliary secretion rates of cholesterol, total bile acids and phospholipids (P <.05) by 46%, 36%, and 51%. As a consequence, cholesterol saturation index remained unchanged. However, fractional syntheses of cholesterol were comparable (P >.05) on placebo compared with pravastatin with 3.1% versus 4.0% in plasma and 4.3% versus 5.2% in bile after 15 hours, respectively. The mean absolute synthesis rates amounted to 0.3 mg/kg/h on placebo versus 0.4 on pravastatin (P >. 05). In conclusion, the pravastatin-induced reduction of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis.",1999.0,0,0 118,10385779,Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders.,D K Murdock; A K Murdock; R W Murdock; K J Olson; A M Frane; M E Kersten; D M Joyce; S E Gantner,"Combinations of gemfibrozil and a 3-hydroxy-3-methylglutaryl (HMG) coenzyme A reductase inhibitor show promise in treating mixed lipid abnormalities. However, concern regarding the risk of myopathy and hepatic toxicity has limited the use of this combination. To determine the long-term safety and efficacy of this combination, we prospectively identified all patients placed on a combination of gemfibrozil and any HMG reductase inhibitor. Pravastatin, simvastatin, fluvastatin, lovastatin, or atorvastatin at incremental doses was combined with gemfibrozil (600 mg twice daily). Lipid profiles, creatine kinase levels, and aminotransferase levels were monitored. Two hundred fifty-two patients with established atherosclerosis receiving combination therapy for a mean of 2.36 +/- 1.52 years spanning a total of 593.6 patient-years were monitored. In 148 patients, gemfibrozil was started before an HMG was added. The pretreatment total cholesterol level fell from 222 +/- 34 mg/dL to 181 +/- 26 mg/dL (P <.001) on combination therapy. HDL cholesterol level rose from 30 +/- 5 mg/dL to 36 +/- 7 mg/dL (P <.01), triglyceride level fell from 361 +/- 141 mg/dL to 212 +/- 101 mg/dL (P <.03). The ratio of total cholesterol to HDL fell from 7.6 +/- 1. 7 to 5.3 +/- 1.6 (P <.001). In 104 patients an HMG was begun before gemfibrozil was added. Pretreatment total cholesterol level fell from 246 +/- 54 mg/dL to 192 +/- 40 mg/dL on combination therapy (P <.01). HDL level rose from 33 +/- 9 mg/dL to 38 +/- 9 mg/dL (P <.03) and triglyceride level fell from 314 +/- 183 mg/dL to 183 +/- 93 mg/dL (P <.001). The ratio of total cholesterol to HDL fell from 7.9 +/- 3.6 to 5.2 +/- 1.4 (P <.001). In both groups the lipid profile on combination therapy was significantly better than that obtained on single-agent therapy. One episode of myopathy (0.4%) and one episode of aminotransferase level elevation (0.4%) of greater than 3 times upper limit of normal occurred. Both resolved with cessation of therapy without consequence. Combinations of gemfibrozil and an HMG, compared with either agent alone, results in improved long-term control of lipid abnormalities in mixed lipid disorders. The low incidence of toxicity permits the use of combination therapy in patients at high risk of atherosclerotic complications.",1999.0,0,0 119,10385780,Comparison of the hypolipidemic effect of gemfibrozil versus simvastatin in patients with type III hyperlipoproteinemia.,F Civeira; A Cenarro; J Ferrando; J Puzo; A L Garcia-Otín; P Mozas; M Pocoví,"Type III hyperlipoproteinemia is characterized by the accumulation of chylomicron and very low density lipoprotein (VLDL) remnants. Individuals with this disorder have a high risk of premature atherosclerosis, and hypolipidemic drugs are useful in their management. We compared, in a double-blind, placebo-controlled, randomized crossed study, the effects of gemfibrozil (1200 mg/day) and simvastatin (20 mg/day) on lipids, apolipoprotein AI, apolipoprotein B, and apolipoprotein E and on lipids and apolipoprotein B content in VLDL, intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in 10 patients with type III hyperlipoproteinemia. Levels of total cholesterol, VLDL cholesterol, IDL cholesterol, and apolipoprotein B decreased with both drugs. Larger reductions in triglycerides (109 +/- 28.2 mg/dL, P =.005), VLDL cholesterol (24.7 +/- 10.9 mg/dL, P =.05), and VLDL triglycerides (86.3 +/- 20.2 mg/dL, P =.003) were obtained with gemfibrozil compared with simvastatin. LDL cholesterol reduction was more effective with simvastatin than with gemfibrozil (44.3 +/- 17.1 mg/dL, P =.03). HDL cholesterol after gemfibrozil was 5.71 +/- 2.37 mg/dL higher than after simvastatin. In patients with type III hyperlipoproteinemia gemfibrozil is more effective in reducing total triglyceride and VLDL lipid levels than simvastatin, and simvastatin is better in reducing LDL cholesterol than gemfibrozil is. IDL and apolipoprotein E levels were reduced similarly with both drugs.",1999.0,0,0 120,10386503,Antioxidant therapy for coronary artery disease: don't paint the walls without treating the termites!,G A Ewy,,1999.0,0,0 121,10387386,Impact of therapeutic interchange from pravastatin to lovastatin in a Veterans Affairs Medical Center.,R J Patel; D R Gray; R Pierce; M Jafari,"To evaluate the impact of a therapeutic interchange from pravastatin to lovastatin on treatment outcomes, quality of life, patient satisfaction, and costs. A prospective cohort study of 170 patients switched from pravastatin to lovastatin from September 1997 through November 1997. The therapeutic interchange program promoting lovastatin as the preferred agent went into effect June 2, 1997 after Merck & Co. was awarded the Veterans Health Administration national contract for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Patients were switched to lovastatin by either their primary care physician during routine clinic visits or the pharmacist by mail. The following outcomes were measured before and after conversion to lovastatin: lipid values, liver function tests, National Cholesterol Education Program (NCEP) low-density cholesterol (LDL-C) goals achieved, quality of life (QOL) (measured by the Medical Outcomes Study 36-item short-form health survey [SF-36]), medication tolerance (measured with a global symptom survey), patient satisfaction, and cost-minimization analysis. Lipid values and liver function test results were similar for pravastatin and lovastatin treatment. Forty percent of patients achieved NCEP LDL-C goals before and after formulary conversion. There were no significant differences between pravastatin and lovastatin in QOL, medication tolerance, and patient satisfaction. The projected cost savings from this therapeutic interchange was approximately $211,000 annually. Therapeutic interchange from pravastatin to lovastatin resulted in substantial cost savings. QOL, patient satisfaction, and achievement of NCEP LDL-C goals were maintained.",1999.0,0,0 122,10389000,Endothelial dysfunction is not reversed by simvastatin treatment in type 2 diabetic patients with hypercholesterolemia.,W H Sheu; B L Juang; Y T Chen; W J Lee,,1999.0,0,0 123,10391399,Intensive lipid-lowering strategy in patients with diabetes mellitus.,S D Kanters; A Algra; T W de Bruint; D W Erkelens; J D Banga,"To assess the feasibility of an intensive lipid-lowering strategy in diabetic subjects pursuing target plasma lipid levels. Patients with diabetes mellitus (DM), Type 1 or 2, with plasma lipid levels exceeding target values (LDL-cholesterol <2.6 mmol/l, triglycerides < 1.7 mmol/l, HDL-cholesterol > 0.9 mmol/l for men and > 1.1 mmol/l for women) were eligible. After 6-12 weeks of diet and glycaemic control, lipid-lowering medication (simvastatin/gemfibrozil/acipimox) was prescribed in steps of incremental dosages and combinations for 30 weeks. Of all eligible clinic patients, 25% initially responded and finally 12% were entered. Thirty-six patients with Type 1 and 59 with Type 2 DM were studied. Mean baseline lipid levels in Type 1 and Type 2 diabetic subjects were: LDL-cholesterol 3.6 and 3.7 mmol/l, triglycerides 1.7 and 2.2 mmol/l, HDL-cholesterol for men 1.1 and 1.0 mmol/l, and for women 1.4 and 1.2 mmol/l, respectively. All three target values were reached in 66% of the patients. LDL-cholesterol was reduced by 1.2 mmol/l in Type 1 and 1.3 mmol/l in Type 2 diabetic patients and triglycerides by 0.7 mmol/l and 1.1 mmol/l, respectively. HDL-cholesterol increased by 0.15 mmol/l and 0.34 mmol/l in men and women with Type 1 diabetes mellitus, respectively. The cholesterol-triglyceride ratio decreased significantly in VLDL in Type 1 diabetes and in IDL in Type 2 diabetes and increased significantly in HDL in Type 2 DM. A minority of subjects eligible for intensive lipid lowering agreed to participate in a feasibility study, suggesting a potentially large compliance problem for a general lipid-lowering programme in a diabetes clinic. Nevertheless, intensive lipid lowering with drug combinations can attain the recommended target lipid levels in 66% of subjects with diabetes. With this strategy the plasma lipoprotein composition shifts towards a less atherogenic profile. Subjects with diabetes should therefore receive lipid-lowering therapy tailored to reach target levels, rather than standard dosages, in order to reduce atherogenic risk.",1999.0,0,0 124,10391420,,,,,0,0 125,10393380,Effects of simvastatin and pravastatin on hyperlipidemia and cyclosporin blood levels in renal transplant recipients.,D Capone; P Stanziale; A Gentile; P Imperatore; T Pellegrino; V Basile,"Thirty-one renal transplant recipients, submitted to treatment with cyclosporin in association with other immunosuppressive agents, were also treated for 9 months with two hydroxymethylglutaryl coenzyme A reductase inhibitors, simvastatin (10 mg/day) or pravastatin (20 mg/day), for concomitant hypercholesterolemia and hypertriglyceridemia. Both drugs significantly decreased total cholesterol and triglyceride serum levels, but they did not modify whole-blood trough concentrations of polyclonal and monoclonal cyclosporin or polyclonal/monoclonal cyclosporin ratio. No alterations of the clinical and laboratory parameters investigated were found. The results of this study show the efficacy and safety of hydroxymethylglutaryl coenzyme A reductase inhibitors in the treatment of hyperlipidemia in kidney transplant patients.",1999.0,0,1 126,10393675,Relationship between delay in performing direct coronary angioplasty and early clinical outcome in patients with acute myocardial infarction: results from the global use of strategies to open occluded arteries in Acute Coronary Syndromes (GUSTO-IIb) trial.,P B Berger; S G Ellis; D R Holmes; C B Granger; D A Criger; A Betriu; E J Topol; R M Califf,"Time to treatment with thrombolytic therapy is a critical determinant of mortality in acute myocardial infarction. Little is known about the relationship between the time to treatment with direct coronary angioplasty and clinical outcome. The objectives of this study were to determine both the time required to perform direct coronary angioplasty in the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) trial and its relationship to clinical outcome. Patients randomized to direct coronary angioplasty (n=565) were divided into groups based on the time between study enrollment and first balloon inflation. Patients randomized to angioplasty who did not undergo the procedure were also analyzed. The median time from study enrollment to first balloon inflation was 76 minutes; 19% of patients assigned to angioplasty did not undergo an angioplasty procedure. The 30-day mortality rate of patients who underwent balloon inflation /=91 minutes after enrollment, 6.4%. The mortality rate of patients assigned to angioplasty who never underwent the procedure was 14.1% (P=0.001). Logistic regression analysis revealed that the time from enrollment to first balloon inflation was a significant predictor of mortality within 30 days; after adjustment for differences in baseline characteristics, the odds of death increased 1.6 times (P=0.008) for a movement from each time interval to the next. The time to treatment with direct PTCA, as with thrombolytic therapy, is a critical determinant of mortality.",2001.0,0,1 127,10395630,Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators.,B Pitt; D Waters; W V Brown; A J van Boven; L Schwartz; L M Title; D Eisenberg; L Shurzinske; L S McCormick,"Percutaneous coronary revascularization is widely used in improving symptoms and exercise performance in patients with ischemic heart disease and stable angina pectoris. In this study, we compared percutaneous coronary revascularization with lipid-lowering treatment for reducing the incidence of ischemic events. We studied 341 patients with stable coronary artery disease, relatively normal left ventricular function, asymptomatic or mild-to-moderate angina, and a serum level of low-density lipoprotein (LDL) cholesterol of at least 115 mg per deciliter (3.0 mmol per liter) who were referred for percutaneous revascularization. We randomly assigned the patients either to receive medical treatment with atorvastatin, at 80 mg per day (164 patients), or to undergo the recommended percutaneous revascularization procedure (angioplasty) followed by usual care, which could include lipid-lowering treatment (177 patients). The follow-up period was 18 months. Twenty-two (13 percent) of the patients who received aggressive lipid-lowering treatment with atorvastatin (resulting in a 46 percent reduction in the mean serum LDL cholesterol level, to 77 mg per deciliter [2.0 mmol per liter]) had ischemic events, as compared with 37 (21 percent) of the patients who underwent angioplasty (who had an 18 percent reduction in the mean serum LDL cholesterol level, to 119 mg per deciliter [3.0 mmol per liter]). The incidence of ischemic events was thus 36 percent lower in the atorvastatin group over an 18-month period (P=0.048, which was not statistically significant after adjustment for interim analyses). This reduction in events was due to a smaller number of angioplasty procedures, coronary-artery bypass operations, and hospitalizations for worsening angina. As compared with the patients who were treated with angioplasty and usual care, the patients who received atorvastatin had a significantly longer time to the first ischemic event (P=0.03). In low-risk patients with stable coronary artery disease, aggressive lipid-lowering therapy is at least as effective as angioplasty and usual care in reducing the incidence of ischemic events.",2000.0,1,1 128,10399983,Results from late-breaking clinical trials sessions at ACCIS '99 and ACC '99. American College of Cardiology.,D C Morris,,1999.0,0,0 129,10399998,Pravastatin prevents clinical events in revascularized patients with average cholesterol concentrations. Cholesterol and Recurrent Events CARE Investigators.,G C Flaker; J W Warnica; F M Sacks; L A Moyé; B R Davis; J L Rouleau; R R Webel; M A Pfeffer; E Braunwald,"This analysis was carried out to determine if revascularized patients derive benefit from the 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin. The HMG-CoA reductase inhibitors result in substantial reductions in serum cholesterol and stabilization of atherosclerotic plaques in patients with coronary artery disease. Pravastatin was found to reduce clinical cardiovascular events in the Cholesterol and Recurrent Events (CARE) trial consisting of 4,159 patients with a documented myocardial infarction and an average cholesterol level (mean 209 mg/dl and all <240 mg/dl). A total of 2,245 patients underwent coronary revascularization before randomization including 1,154 patients with percutaneous transluminal coronary angioplasty (PTCA) alone, 876 patients with coronary artery bypass graft (CABG) alone, and 215 patients with both procedures. Clinical events in revascularized patients were compared between patients on placebo and on pravastatin. In the 2,245 patients who had undergone revascularization, the primary endpoint of coronary heart disease death or nonfatal myocardial infarction (MI) was reduced by 4.1% with pravastatin (relative risk [RR] reduction 36%, 95% confidence interval [CI] 17 to 51, p = 0.001). Fatal or nonfatal MI was reduced by 3.3% (RR reduction 39%, 95% CI 16 to 55, p = 0.002), postrandomization repeat revascularization was reduced by 2.6% (RR reduction 18%, 95% CI 1 to 33, p = 0.068) and stroke was reduced by 1.5% (RR reduction 39%, 95% CI 3 to 62, p = 0.037) with pravastatin. Pravastatin was beneficial in both the 1,154 PTCA patients and in the 1,091 CABG patients who had undergone revascularization before randomization. Pravastatin reduced clinical events in revascularized postinfarction patients with average cholesterol levels. This therapy was well tolerated and its use should be considered in most patients following coronary revascularization.",1999.0,1,1 130,10404843,Safety of low-density lipoprotein cholestrol reduction with atorvastatin versus simvastatin in a coronary heart disease population (the TARGET TANGIBLE trial).,W März; H Wollschläger; G Klein; A Neiss; M Wehling,"Reduction in plasma lipids has been recognized as one of the primary cardiovascular risk reduction strategies in the secondary prevention of coronary heart disease (CHD). The primary end points of TARGET TANGIBLE were the safety (adverse events and laboratory measurements) and efficacy (responder rates) of therapy with atorvastatin versus simvastatin with the aim of achieving low-density lipoprotein (LDL) cholesterol lowering to < or =100 mg/dl (2.6 mmol/L). A total of 3,748 CHD patients with LDL cholesterol levels > or =130 mg/dl (3.4 mmol/L) entered a run-in diet phase of 6 weeks without any lipid-lowering drug therapy. At the end of the diet phase, 2,856 patients met the lipid criteria and were randomized to active treatment for 14 weeks. Patients received 10 to 40 mg of either drug in an optional titration design at 2:1 randomization for atorvastatin versus simvastatin. Adverse event rates were statistically equivalent (p<0.01) for simvastatin (35.7%) and for atorvastatin patients (36.3%). Both drugs were well tolerated; <5% of patients in both groups were withdrawn due to adverse events. In all, 37 atorvastatin patients (2%) and 27 simvastatin patients (3%) had serious adverse events. Drug-related side effects (elevations in creatine kinase, liver enzymes) occurred in both groups at similar rates with 10 atorvastatin patients (0.5%) and 5 simvastatin patients (0.5%) presenting confirmed transaminase elevations >3 x the upper limit of the normal range. Significantly fewer patients in the atorvastatin group (n = 724) required titration to 40 mg compared with the simvastatin group (n = 514) (38% vs. 54%, respectively; p<0.001). Atorvastatin resulted in a significantly greater number of patients reaching the LDL cholesterol goal than those treated with simvastatin, with 67% of atorvastatin patients and 53% of simvastatin patients reaching the target LDL cholesterol level of < or =100 mg/dl (2.6 mmol/L) (p<0.001). Both atorvastatin and simvastatin are safe for use by patients in the secondary prevention of CHD, with patients in both drug groups having similar adverse event rates. Despite the use of concomitant medications there was no drug-induced rhabdomyolysis with either atorvastatin or simvastatin.",1999.0,1,1 131,10404924,The treatment and prevention of coronary heart disease in Canada: do older patients receive efficacious therapies? The Clinical Quality Improvement Network (CQIN) Investigators.,F A McAlister; L Taylor; K K Teo; R T Tsuyuki; M L Ackman; R Yim; T J Montague,"To review the evidence for clinical efficacy and cost-effectiveness of proven medications in the treatment and prevention of myocardial infarction (MI) in older patients; to summarize Canadian data on treatment patterns and clinical outcomes for younger and older patients with coronary heart disease; to explore the reasons for gaps between best care, based on the evidence of efficacy from trials, and usual care, based on the population effectiveness audits; and to explore potential approaches to closing the care gaps. Review of the recent clinical trial literature on the management of MI, highlighting results in older patients. Review of medication utilization and outcomes data from a series of large, consecutively enrolled patient cohorts with acute MI (N = 7070) in a variety of cardiac care settings (10 centers in five Canadian provinces, including university-based teaching hospitals, community hospitals, cardiologist and family physician out-patient clinics) from 1987 to 1996. There is no qualitative interaction of cardiac therapies: thrombolytics, beta-blockers, acetylsalicylic acid (ASA), and statins are efficacious in all clinically relevant patient subgroups, including older people. However, there are consistent gaps between usual care and best care, particularly among older patients (in whom there is also a concomitantly higher mortality risk). Repeated multivariate analyses confirm older age to be an independent contributor to increased risk. Use of efficacious medications is, in contrast, consistently associated with increased survival. Analysis of temporal trends suggests beneficial changes in practice patterns and outcomes are possible to achieve. However, ""best care"" has not been rapidly or completely achieved. Review of strategies to close these care gaps suggests that audit and feedback, critical pathways, and multifactorial interventions involving patients and other members of the healthcare team as well as physicians may be the most efficacious strategies for change. Despite equal or enhanced efficacy, there is consistently less prescription of proven drugs among older cardiac patients. These care patterns may contribute to their enhanced risk. The causes underlying these practice patterns are complex, and their population impact may be undervalued by clinicians and managers. Improvement of these patterns is difficult, but ultimately it would be beneficial for this presently disadvantaged, readily identified, high risk patient population.",1999.0,0,0 132,10407502,Effects of intensive lipid lowering by low-density lipoprotein apheresis on regression of coronary atherosclerosis in patients with familial hypercholesterolemia: Japan Low-density Lipoprotein Apheresis Coronary Atherosclerosis Prospective Study (L-CAPS).,S Nishimura; M Sekiguchi; T Kano; S Ishiwata; F Nagasaki; T Nishide; T Okimoto; Y Kutsumi; Y Kuwabara; F Takatsu; H Nishikawa; H Daida; H Yamaguchi,"Twenty-five heterozygous familial hypercholesterolemic patients treated with LDL-apheresis and drugs and 11 patients treated with drugs underwent follow-up angiography 2.3 years later. One-hundred thirteen lesions were measured by quantitative angiography. Mean LDL-cholesterol levels during the trial were 140 +/- 34 mg/dl in the apheresis group and 170 +/- 58 mg/dl (P < 0.05) in the control group. The mean changes in minimal lumen diameter of lesions were +0.19 +/- 0.30 mm (improved) in the apheresis group (n = 76) and -0.44 +/- 0.40 mm (worsened) in the control group (n = 37) (P < 0.0001). When progression and regression were defined as a change in minimal lumen diameter of +/- 0.67 mm, in the apheresis group, two (8%) patients had progression, 19 (76%) stayed unchanged and four (16%) had regression, but in the control group seven (64%) patients had progression and four (36%) stayed unchanged. The frequency of regression or no change was significantly higher in the apheresis group than in the control group (P < 0.004). Intensive cholesterol lowering therapy with LDL-apheresis and lipid lowering drugs can achieve a substantial decrease in LDL-cholesterol levels to induce regression of coronary lesions in familial hypercholesterolemic patients with advanced coronary artery disease.",1999.0,0,0 133,10407505,"Lipoprotein lipase gene mutations, plasma lipid levels, progression/regression of coronary atherosclerosis, response to therapy, and future clinical events. Lipoproteins and Coronary Atherosclerosis Study.",K Sing; C M Ballantyne; L Ferlic; R Brugada; I Cushman; J K Dunn; J A Herd; H J Pownall; A M Gotto; A J Marian,"Mutations in human lipoprotein lipase (LPL) gene are potential risk factors for susceptibility to coronary artery disease (CAD). The objectives of this study were to determine the influence LPL mutations Asn291Ser and Ser447Ter on plasma lipid levels, regression and progression of CAD, clinical events rate, and response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. LCAS is a double blind, randomized, placebo-controlled study designed to test the influence of fluvastatin on progression or regression of CAD. The Asn291Ser and Ser447Ter genotypes were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. Fasting plasma lipid profiles were measured and quantitative coronary angiography was performed at baseline and 2.5 years following randomization. Fatal and non-fatal cardiovascular events during the follow-up period were recorded. A total of 4% (14/363) and 18% (62/352) of the subjects had the Asn291Ser and Ser447Ter mutations, respectively. Overall, there was no statistically association between the Asn291Ser and Ser447Ter mutations and the baseline or final mean plasma levels of lipids, number of coronary lesions, total occlusions, the mean minimal lumen diameter (MLD) stenoses and the clinical events rate. However, patients with the Ser447Ter variant had a slightly higher baseline high density lipoprotein-cholesterol (HDL-C) level (46.2 +/- 12 vs 43.2 +/- 11, P = 0.057), less increase in plasma HDL levels in response to fluvastatin therapy (3 vs 11%, P = 0.056) and a higher cardiovascular events rate (23 vs 13%, P = 0.056). Thus, the Ser447Ter variant had a modest influence on plasma HDL levels and the rate of cardiovascular events. These changes were of borderline statistical significance. Neither the Ser447Ter nor the Asn291Ser mutation had a major impact on susceptibility to CAD, progression or regression of CAD, clinical events rate or response to fluvastatin therapy in LCAS population.",1999.0,0,0 134,10408031,[Lipid intervention and coronary heart disease in men less than 56 years of age. The Coronary Intervention Study: CIS].,U F Rensing; H P Bestehorn; H Roskamm; J Petersen; P Betz; M Spinder; L Benesch; K Schemeitat; G Blümchen; J Claus; H Wieland; J F Böcker; A Neiss; E Stiepel; P Mathes; L Kappenberger; K Braunagel; K Peters; G Meister; L Samek; J Schuon; B Leimenstoll; H Kiefer,"The CIS was undertaken with the aim to evaluate the effects of lipid modifications on angiographic progression and regression of CAD in patients with CAD and hypercholesterolemia. The design included a multicenter randomized, double-blind, parallel, placebo-controlled comparison, with target and safety limits for adjusting the trial medication depending on the LDL cholesterol level (LDL-C) achieved, i.e., up to 40 mg of simvastatin (S) or placebo (P) daily, add-on medication (up to 3 x 4 g Colestyramin), and diet counselling. Male patients, average age 49 (< or = 56) years, were included with angiographic CAD and a screening total cholesterol of 207-350 mg/dl, who were not due to undergo coronary bypass surgery or PTCA, who did not suffer from serious other disease (e.g., diabetes mellitus), and who had not undergone coronary bypass surgery previously. All baseline variables were comparable in the treatment groups, with 129 patients taking S and 125 taking P. Of these 254 patients 217 had their final study visit and 207 underwent a second angiography after an average treatment time of 2.3 years under an average daily dose of 37 mg S. 205 pairs of films were available for analysis. Vital information was obtained of all patients until closure of the data bank, half a year after the last study angiography. Five deaths occurred within the study period, 12 through March 15, 1995 (S: 1/6, P: 4/6). 37 patients (S: 18, P: 19) discontinued trial drug and protocol. Concomitant CAD medication was comparable in both groups, except lipid-lowering add-on medication which was significantly higher in the P group (38% versus 13%). Significant changes in lipid levels, on treatment, were observed in the S group amounting to a mean difference in LDL-C of -35%, in Apo-Protein B (ApoB) of -30%, in VLDL-C of -37%, and in triglycerides (TG) of -27%, and in HDL-C of +6%, in comparison to the control group; these differences were even greater in 137 fully compliant patients: -41, -36, -39, -31, and +7%, respectively. Progression in the S group was significantly less, as defined by the two primary target criteria: 1) the minimum obstruction diameter (MOD), determined by quantitative coronary angiography (QCA), decreased about five times less in comparison to the control group (S: by -0.017; P: -0.0954 mm), and 2) the standardized visual global change score (GCS) deteriorated almost three times less in the S group (by +0.20) than in the P group (+0.58). Of the secondary target criteria, the mean lumen diameter (QCA) also developed a significant difference (S: -0.20; P: +0.23 mm; p = 0.0006) with a trend toward regression in the S group. The QCA-%-stenosis deteriorated three- to four-times less in the S group as compared to the control group (S: by 0.69%; P: by 2.73%; p = 0.0022), and the number of patients with angiographic progression was nearly halved (S: 30%; P: 56%; p < 0.0000). These differences were determined by intention to treat analysis (ITT), and they were obtained in spite of lipid lowering add-on medication in 38% of the P patients; they turned out to be more pronounced in 137 fully compliant patients, in an analysis ""as treated"". The mean decrease in LDL-C serum level caused by S was significantly correlated to the decrease in progression, and multivariate regression analysis of both treatment groups identified LDL-C (or ApoB) and TG as independent predictors of progression. Progression appeared to be most pronounced in low and medium sized lesions, and the beneficial effect of lipid intervention dominated in lesions with 12-56% QCA stenosis severity. A small fraction of patients who suffered from exercise-induced angina, with ST-segment-depression at the beginning of the study, experienced a significant improvement under S as compared to P treatment. Although the study was not designed to show differences in clinical events, the combined number of all major cardiovascular events tended to be less frequent in the S than in the C gr",1999.0,0,0 135,10408999,Compliance with fluvastatin treatment characterization of the noncompliant population within a population of 3845 patients with hyperlipidemia. CREOLE Study Team.,E Bruckert; C Simonetta; P Giral,"The objectives of the study were to analyze 1) compliance with an HMG-CoA reductase inhibitor, 2) the relationship between treatment compliance and sociodemographic, clinical, and psychological criteria, and 3) the effect of raising patients' awareness through distribution of an information notice. The results analyzed in this article compare the noncompliant and compliant population independently of awareness. This open-label study was conducted in two randomized parallel groups: a control group that received the information normally given by the practitioners, and an awareness group that received specific informational brochures on diet and cardiovascular risk factors and the reasons for the treatment. Male and female patients (n = 3845) aged 18 to 75 years with primary hypercholesterolemia (type IIa and IIb), not taking a cholesterol-lowering drug or for whom an ongoing treatment was poorly tolerated or ineffective, were to be included. Cholesterol levels had to be greater than 250 mg/dL (or 200 mg/dL if previous coronary history) and triglyceride levels less than 350 mg/dL. A total of 2888 subjects (75%) were defined as compliant (taking more than 90% of the prescription) and 957 (25%) noncompliant. Both populations are identical for age, sex ratio, and different risk factors, with the exception of diabetes. The adverse effects in noncompliant subjects were very clearly different, with an overrepresentation of gastrointestinal and neurologic effects and the noncompliant patients more frequently having more than one adverse effect. Noncompliant patients had an identical duration of follow-up, and the number of patients claiming to have a symptom related to hypercholesterolemia, self-evaluation of cardiovascular risk level, and source of knowledge about cholesterol and diet was similar in both groups. In contrast, in the noncompliant group, there were a larger number of symptomatic patients who thought the drug did not improve the symptoms. In practice, these results show that physicians should systematically evaluate compliance by looking for and analyzing adverse effects and by reassuring the patient when these effects are minor or probably unrelated to the treatment. Diabetics and polymedicated patients deserve special attention in this regard.",1999.0,0,0 136,10411845,Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators.,P M Ridker; N Rifai; M A Pfeffer; F Sacks; E Braunwald,"Elevated plasma concentrations of C-reactive protein (CRP) are associated with increased cardiovascular risk. We evaluated whether long-term therapy with pravastatin, an agent that reduces cardiovascular risk, might alter levels of this inflammatory parameter. CRP levels were measured at baseline and at 5 years in 472 randomly selected participants in the Cholesterol and Recurrent Events (CARE) trial who remained free of recurrent coronary events during follow-up. Overall, CRP levels at baseline and at 5 years were highly correlated (r=0.60, P<0.001). However, among those allocated to placebo, median CRP levels and the mean change in CRP tended to increase over time (median change, +4. 2%; P=0.2 and mean change, +0.07 mg/dL; P=0.04). By contrast, median CRP levels and the mean change in CRP decreased over time among those allocated to pravastatin (median change, -17.4%; P=0.004 and mean change, -0.07 mg/dL; P=0.002). Thus, statistically significant differences were observed at 5 years between the pravastatin and placebo groups in terms of median CRP levels (difference, -21.6%; P=0.007), mean CRP levels (difference, -37.8%; P=0.002), and absolute mean change in CRP (difference, -0.137 mg/dL; P=0.003). These effects persisted in analyses stratified by age, body mass index, smoking status, blood pressure, and baseline lipid levels. Attempts to relate the magnitude of change in CRP to the magnitude of change in lipids in both the pravastatin and placebo groups did not reveal any obvious relationships. Among survivors of myocardial infarction on standard therapy plus placebo, CRP levels tended to increase over 5 years of follow-up. In contrast, randomization to pravastatin resulted in significant reductions in this inflammatory marker that were not related to the magnitude of lipid alterations observed. Thus, these data further support the potential for nonlipid effects of this agent.",1999.0,0,0 137,10414931,Diabetes management: shared care or shared neglect.,J Overland; M Mira; D K Yue,"Shared care is increasingly being advocated as a way of managing patients with diabetes. While this approach has been supported by clinical trials, the success of shared care in 'real life' is not well established. If health care professionals leave undone what they think is done by others, shared care can become neglected care. Follow up of 200 'shared care' patients who had been referred to the Royal Prince Alfred Diabetes Centre, Sydney, Australia on two or more occasions between October 1995 and September 1998 showed that the majority of specialist recommendations regarding metabolic control (76%), referral to an ophthalmologist (73%) and blood pressure treatment (76%) had been implemented by the primary care physician; however, they were less likely to implement recommendations regarding lipid treatment (55%). The median HbA1c (7.6% vs. 8.4%; P = 0.04), cholesterol (5.6 vs. 6.8 mmol/l; P = 0.0005) and triglyceride (2.0 vs. 2.8 mmol/l; P = 0.05) levels for patients in whom recommendations had been implemented were significantly lower at the time of second referral. Doctors registered with the Diabetes Shared Care Programme and those who wrote longer letters were more likely to implement recommendations than their counterparts (87.2%, versus 70.9%; chi2 = 4.12, 1 df; P = 0.04 and 56 words (inter-quartile range (IQR): 36-71) versus 45 words (IQR: 23-59); P = 0.02, respectively). It therefore appears that diabetes care can be well provided by a shared care approach. However, further monitoring of different shared care models is warranted.",1999.0,0,0 138,10419438,Cholesterol lowering in older patients.,K S Bannerman,,2000.0,0,0 139,10422491,"[Serum leptin, early atherosclerosis and hypolipidemia (a new, previously undescribed effect of pravastatin, a hypolipemic agent)].",D Stejskal; V Růzicka; J Bartek,"Hyperleptinemia is considered to be one of predictors of early atherosklerosis complications. This stimulated us to investigate differences between leptinemia in persons with accelerated atherosclerosis and leptinemia in probands without atherosclerosis complications. The study also verified whether leptinemia and its relationship to other anthropometric and biochemical parameters can differ in hypolipemic-treated probands and hypolipemic-untreated individuals. We examined 89 probands with accelerated atherosclerosis. The controls were 20 persons without any signs of accelerated atherosclerosis. Probands with accelerated atherosclerosis had a slight hyperglycemia and were slightly obese, but they did not meet criteria of metabolic cardiovascular syndrome. No significant differences between both groups under study were found in terms of anthropometric and biochemical parameters (BMI, % body fat, glycemia, insulin, C-peptide, intact proinsulin, total proinsulin cholesterol, HDL, triglycerides, LDL, homeostatic model of insulin secretion and resistance). Leptin concentration was not different as well. Stratification into males and females showed that women had a significantly higher leptinemia and fat tissue mass. Other biochemical parameters were similar in both groups. We suppose that in individuals without signs of metabolic syndrome, leptinemia does not belong among predictors of accelerated atherosclerosis. The accelerated atherosclerosis persons were then divided into subgroups according to medication (28 probands--pravastatin Lipostat 20, 15 probands--phenofibrate Lipanthyl 200M, 9 probands--simvastatin Zocor 20, 47 probands--no hypolipemic medication). No significant differences between the groups were found in terms of the analysed anthropometric and biochemical parameters, except leptinemia. The pravastatin-medicated probands had a significantly lower leptinemia (significant at 99% significance level) which was evidently sex-related than other patients. The pravastatin-administered persons showed no correlation between leptinemia and body fat mass (in contrast to other groups where such a correlation was highly statistically significant). These findings can be explained by a still unclear effect of pravastatin on insulin metabolism and on other factors involved in leptin synthesis and elimination. Thus, a new therapeutic effect of pravastatin can be supposed. This may account for a highly favourable effect of pravastatin on reduced manifestations of atherosclerosis complications event at a low LDL cholesterol decrease (particularly in persons with metabolic cardiovascular syndrome).",1999.0,0,0 140,10423597,A crossover comparison of the efficacy and safety of lovastatin and gemfibrozil in the treatment of hyperlipidemic organ transplant recipients.,D S Hanes; P G Nicholson; D D Raval; F L Hooper; M T Behrens; M R Weir,"Hypercholesterolemia is associated with accelerated atherosclerosis in transplant recipients. It has been notoriously difficult to treat pharmacologically due to the complex interactions that occur with lipid-lowering drugs and immunosuppressive therapies. The purpose of the current study was to compare the efficacy and safety of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (lovastatin, 20 mg/d) with a fibric acid derivative (gemfibrozil, 600 mg twice a day). We used a randomized, crossover design in 18 solid organ transplant recipients who followed the National Cholesterol Education Program Adult Treatment Guidelines diet for 8 weeks and had persistent elevations of total cholesterol (>240 mg/dL). Each patient received each therapy for a minimum of 8 weeks (mean 14.2 +/- 2.4, range 8-20 weeks). The participants had stable allograft function and were treated with a standard immunosuppressive regimen containing cyclosporine, prednisone, and azathioprine. Lovastatin therapy reduced the mean total cholesterol by 15.5% (271.9 mg/dL to 229.9 mg/dL; p = 0.02) and the mean low-density lipoprotein (LDL) cholesterol by 22.7% (178.2 mg/dL to 137.8 mg/dL; p = 0.07). There were no significant changes in high-density lipoprotein (HDL) cholesterol or triglycerides. Conversely, when these same patients were treated with gemfibrozil, the mean total cholesterol decreased by 7.9% (271.9 mg/dL to 250.5 mg/dL; p = NS) and the LDL cholesterol decreased by 5.1% (178.2 mg/dL to 169.1 mg/dL; p = NS). In addition, the mean triglyceride concentration decreased significantly by 46.1% (234.0 mg/dL to 126.3 mg/dL; p = 0.002) and the mean HDL cholesterol increased 15.4% (48.8 mg/dL to 56.3 mg/dL; p = 0.09). In all patients, the serum creatinine, hepatocellular enzymes, and creatinine phosphokinase remained stable. Lovastatin was discontinued in three patients for myalgias, one patient with unexplained anemia, and one patient with parasthesias. These results suggest that lovastatin and gemfibrozil are both safe and efficacious in transplant patients. However, neither therapy alone completely corrects abnormalities of high LDL cholesterol and low HDL cholesterol in transplant recipients.",2000.0,0,0 141,10423661,Advances in cardiovascular pharmacology: protocol design and methodology--the US regulatory process.,J C Somberg; J S Borer,,1999.0,0,0 142,10428291,Triglyceride-rich lipoproteins: are links with atherosclerosis mediated by a procoagulant and proinflammatory phenotype?,C D Byrne,"Specific treatment that primarily reduces low density lipoprotein cholesterol (LDLc) levels improves survival of patients with pre-existing vascular disease by 20-30%. Failure to produce a more marked improvement in outcome is most likely explained by: (1) the observation from angiographic studies that established atherosclerotic vascular disease (AVD) is largely irreversible with current therapy and (2) other important factors cause AVD besides LDLc. One such risk factor predicting development of AVD is the atherogenic lipoprotein phenotype (ALP), comprising abnormalities of triglyceride enriched lipoproteins, high density lipoprotein cholesterol (HDLc) and small dense LDL particles. Despite strong links between the ALP and AVD, the mechanism(s) linking these relatively subtle lipoprotein abnormalities to vascular disease is poorly understood. Recent evidence suggests that a procoagulant and proinflammatory state develops within the vasculature, perhaps mediating a link between the ALP and AVD. The purpose of this review is to discuss mechanisms by which the ALP, and specifically, certain triglyceride-rich lipoproteins, may cause AVD by adverse affects on platelet function, coagulation and vascular inflammation. All rights reserved.",1999.0,0,0 143,10428737,,,,,0,0 144,10431658,"Less heat, more light.",A Rees,,1999.0,0,0 145,10431661,"Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis.",J C Fruchart; P Duriez; B Staels,"The peroxisome proliferator-activated receptors (PPARs) [alpha, delta (beta) and gamma] form a subfamily of the nuclear receptor gene family. All PPARs are, albeit to different extents, activated by fatty acids and derivatives; PPAR-alpha binds the hypolipidemic fibrates whereas antidiabetic glitazones are ligands for PPAR-gamma. PPAR-alpha activation mediates pleiotropic effects such as stimulation of lipid oxidation, alteration in lipoprotein metabolism and inhibition of vascular inflammation. PPAR-alpha activators increase hepatic uptake and the esterification of free fatty acids by stimulating the fatty acid transport protein and acyl-CoA synthetase expression. In skeletal muscle and heart, PPAR-alpha increases mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation through stimulating the muscle-type carnitine palmitoyltransferase-I. The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha dependent stimulation of lipoprotein lipase and an inhibition of apolipoprotein C-III expressions, whereas the increase in plasma HDL cholesterol depends on an overexpression of apolipoprotein A-I and apolipoprotein A-II. PPARs are also expressed in atherosclerotic lesions. PPAR-alpha is present in endothelial and smooth muscle cells, monocytes and monocyte-derived macrophages. It inhibits inducible nitric oxide synthase in macrophages and prevents the IL-1-induced expression of IL-6 and cyclooxygenase-2, as well as thrombin-induced endothelin-1 expression, as a result of a negative transcriptional regulation of the nuclear factor-kappa B and activator protein-1 signalling pathways. PPAR activation also induces apoptosis in human monocyte-derived macrophages most likely through inhibition of nuclear factor-kappa B activity. Therefore, the pleiotropic effects of PPAR-alpha activators on the plasma lipid profile and vascular wall inflammation certainly participate in the inhibition of atherosclerosis development observed in angiographically documented intervention trials with fibrates.",1999.0,0,0 146,10436251,"Changes in serum amylase, lipase and leukocyte elastase during diabetic ketoacidosis and poorly controlled diabetes.",M C Vantyghem; S Haye; M Balduyck; C Hober; P M Degand; J Lefebvre,"Diabetic ketoacidosis (DKA) is frequently associated with pancreatic enzyme abnormalities. In order to determine the main factors that lead to this increase, serum total amylase (TA), pancreatic amylase (PA), lipase (L) and leukocyte elastase (LE), an early predictor of acute pancreatitis, were measured in four groups of patients on admission. Group 1 consisted of 52 patients with DKA (age: 41.9 +/- 19.2 years; blood glucose (Glc): 27.4 +/- 11.5 mmol/L; pH: 7.20 +/- 0.16; plasma bicarbonate: 10.5 +/- 6.2 mmol/L; blood urea nitrogen (BUN): 0.60 +/- 0.44 g/L; HbA(1C): 12.5% +/- 2.8%). Group 2 consisted of 90 patients with poorly controlled non-ketotic diabetes (age: 53.4 +/- 16.0; Glc: 14.3 +/- 0.6; HCO(3)(-): 26.6 +/- 3.2; BUN: 0.38 +/- 0.20; HbA(1C): 11.3 +/- 2.1). Group 3 consisted of 22 patients with well-controlled diabetes (age: 53.7 +/- 12.8; Glc: 10. 1 +/- 5.2; HCO(3)(-): 27.4 +/- 3.8; BUN: 0.36 +/- 0.19; HbA(1C): 6.8 +/- 0.8). Group 4 (controls) comprised 27 non-diabetic patients (age: 46.0 +/- 15.0; Glc: 4.9 +/- 0.5; HCO(3)(-): 28.4 +/- 2.5; BUN: 0.30 +/- 0.16; HbA(1C): 5.2 +/- 0.7) (means +/- SD). Increased enzyme activities were more frequent in group 1 (TA: 30.7; PA: 27.0; L: 36.5; LE: 73%) than in groups 2 (TA: 8.9; PA: 7.1; L: 8.9; LE: 45. 5%), 3 (TA: 13.6; PA: 9.0; L: 18.1; LE: 31.8%) and 4 (TA: 7.0; PA: 3. 0; L: 0.0; LE: 29.6%). Mean serum enzyme activities were significantly different in the 4 groups (ANOVA, P < 0.01) and were higher in group 1 than in groups 2, 3 and 4 (Student's t-test; group 1 vs 2 or 3 or 4: P < 0.001). In groups 1 + 2 + 3 + 4 (all patients), the four enzymes correlated with one another and also with Glc, BUN and HCO(3)(-) (P < 0.001). In group 1, TA correlated negatively with HCO(3)(-) (P < 0.001) and pH (P < 0.05); PA and L correlated positively with Glc and BUN (P < 0.01) and negatively with HCO(3)(-) (respectively, p < 0.01 and 0.05). PA correlated positively with pH (P < 0.01); LE correlated with Glc (P < 0.05) and BUN (P < 0.01). In conclusion, this study suggests that the serum levels of pancreatic enzymes increase with the degree of diabetic disequilibrium, and mainly correlate with metabolic factors such as hyperglycaemia, dehydration and acidosis. Increased pancreatic enzyme activities in patients with DKA, even in combination with abdominal pain, should not be diagnosed as acute pancreatitis; this could be important, particularly for younger clinicians.",1999.0,0,0 147,10436712,[Comparative effects of policosanol and two HMG-CoA reductase inhibitors on type II hypercholesterolemia].,H Prat; O Román; E Pino,"Policosanol is a new cholesterol lowering agent derived from sugar cane. To compare the cholesterol lowering efficacy of policosanol with HMG CoA inhibitors. Patients with a LDL cholesterol over 160 mg/dl were studied. If, after 6 weeks of diet, cholesterol persisted elevated, they were doubly blind randomized to receive policosanol 10 mg/day (55 patients), lovastatin 20 mg/day (26 patients) or simvastatin 10 mg/day (25 patients). Serum cholesterol was measured again after 8 weeks of therapy. Initial demographic and laboratory data were similar among treatment groups. A 24% LDL cholesterol reduction was obtained with policosanol, compared with a 22% reduction with lovastatin and a 15% reduction with simvastatin. HDL cholesterol significantly increased in patients on policosanol and did not change in the other treatment groups. Adverse effects of policosanol were mild and unspecific. No changes in hepatic enzymes were observed. Policosanol is a safe and effective cholesterol reducing agent.",1999.0,0,0 148,10439497,"Treatment of hypertensive and hypercholesterolaemic patients in general practice. The effect of captopril, atenolol and pravastatin combined with life style intervention.",O P Foss; S Graff-Iversen; H Istad; E Søyland; L Tjeldflaat; B Graving,"To elucidate the effect on blood pressure and blood lipids of an angiotensin converting enzyme inhibitor (captopril), and a beta-receptor blocking agent (atenolol), given alone or in combination with a cholesterol reducing drug, the beta-hydroxy-methylglutaryl-coenzyme A reductase inhibitor pravastatin, in patients who were also encouraged to improve their lifestyle. A longitudinal study consisting of three phases. I: Lifestyle intervention alone. II: Continued lifestyle intervention combined with captopril or atenolol. III: Continued lifestyle intervention combined with the same drugs as in phase II and in addition pravastatin or placebo. Fifty-four general practice surgeries in Norway. Hypertensive patients, 210 females and 160 males, treated or untreated with antihypertensive drugs with a sitting diastolic blood pressure between 95 and 115 mmHg and a serum total cholesterol between 6.5 mmol/l (7.0 for those age 60-67 years) and 9.0 mmol/l. The antihypertensive effect of captopril and atenolol was not influenced by concurrent administration of pravastatin. The effect of pravastatin was not limited by concurrent medication with captopril or atenolol. Improvement in lifestyle seemed to reduce the need for supplementary treatment with diuretics. Pravastatin can be used in combination with captopril or atenolol in the treatment of hypertensive and hypercholesterolaemic patients.",1999.0,0,0 149,10441090,Meeting highlights. Highlights of the 48th scientific sessions of the American College of Cardiology.,J J Ferguson,,1999.0,0,0 150,10443573,Antiatherosclerotic activity of drugs in relation to nitric oxide function.,H Bult; A G Herman; K E Matthys,"Many studies have shown that loss of endothelium-derived nitric oxide is a major factor of ischemic episodes in patients with coronary artery disease and there is increasing evidence to suggest that nitric oxide might exert antiatherosclerotic actions. Based on these concepts, the results of animal studies on the effects of lipid lowering drugs, antioxidants, angiotensin converting enzyme inhibitors, Ca2+ channel blockers, estrogens and agents which modulate nitric oxide bioavailability are presented and compared to the results of patient studies and clinical trials. In spite of encouraging results obtained with antioxidants in animals, clinical trials could only show a clear positive effect of vitamin E treatment on the outcome of cardiovascular disease. Angiotensin converting enzyme inhibitors can ameliorate endothelial dysfunction in coronary heart disease, but their impact on disease progression remains unclear. There is evidence that estrogen replacement therapy in post-menopausal women may increase the bioavailability of nitric oxide. Finally, improved endothelial function and plaque stability clearly contribute to the clinical benefits of lipid lowering interventions, statins in particular. Taken together, these studies lend support to the concept that improving endothelial function and nitric oxide release might serve as valuable elements in the prevention or therapy of cardiovascular disease.",1999.0,0,0 151,10446437,Chronic antioxidant use and changes in endothelial dysfunction: a review of clinical investigations.,A Aminbakhsh; J Mancini,"There are tremendous clinical interest and speculation about the impact of reversing endothelial dysfunction. This paper reviews information from patient studies that have assessed the effect of chronic antioxidant use on endothelial dysfunction. A search of MEDLINE and Current Contents online, complemented by detailed analysis of references in the papers identified, was used to identify all studies pertaining to patients treated with oral antioxidants to modify endothelial dysfunction. Studies of single acute doses were excluded. Endothelium-mediated end points were vascular responses in conduit or resistance vessels, endothelial cell-monocyte interaction and measures of soluble adhesion molecules. Positive effects on conduit vessel dilation, endothelial cell-monocyte interactions and soluble adhesion molecules were common. Except for one study, negative effects were noted in resistance vessels. Further trials are required to clarify and define the impact of these findings on clinical outcome.",1999.0,0,0 152,10447220,Effect of lifibrol on the metabolism of low density lipoproteins and cholesterol.,G L Vega; K von Bergmann; S M Grundy; S Blumenschein; N B Carter; P Laeis; B Lindenthal; J von Bergmann; A Simatupang; D Lutjohann; B Adams-Huet,"Lifibrol is a powerful cholesterol-lowering drug of unknown mechanism of action. This investigation was carried out to determine whether the major action of lifibrol is to enhance clearance of low density lipoproteins (LDL) through the LDL-receptor pathway, and if so, whether the drug exerts its action by altering the excretion of bile acids (acidic steroids), the absorption of cholesterol, or the synthesis of cholesterol. In a first study, in two patients with complete absence of LDL receptors, lifibrol therapy had essentially no effect on plasma LDL concentrations; in two others who had a marked reduction in LDL-receptor activity, response to the drug was attenuated. These findings suggest that lifibrol requires an intact LDL-receptor pathway to exert its action. In a second study, in patients with primary moderate hypercholesterolemia, isotope kinetic studies showed that lifibrol enhanced the fractional catabolic rate of LDL-apolipoprotein B (apo B), but had no effect on transport rates of LDL; these observations likewise support the probability that lifibrol acts mainly to increase the activity of the LDL-receptor pathway. However, in a third study in hypercholesterolemic patients, lifibrol therapy failed to increase acidic steroid excretion, inhibit cholesterol absorption, or reduce net cholesterol balance. Furthermore, lifibrol treatment did not significantly reduce urinary excretion of mevalonic acid. In contrast, in a parallel study, simvastatin therapy, which is known to inhibit cholesterol synthesis, gave the expected decrease in net cholesterol balance and reduction in urinary excretion of mevalonic acid. Thus, lifibrol, like statins, appears to increase the activity of LDL receptors; but in contrast to findings with statins, it was not possible to detect a significant decreased synthesis of cholesterol, either from balance studies or from urinary excretion of mevalonic acid. This finding raises the possibility that lifibrol activates the LDL-receptor pathway through a different mechanisms which remains to be determined.",1999.0,0,0 153,10448609,Evaluation and management of lipid disorders.,S Rekhraj; J Hsia,"Plasma lipids play a key role in the development of atherosclerosis. Recent trial data support early identification of asymptomatic adults with high-risk lipid profiles for primary prevention of coronary heart disease. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors have been shown to reduce coronary events in both asymptomatic adults and those with known coronary heart disease. The optimal plasma low-density lipoprotein cholesterol for secondary coronary prevention remains controversial. The Second Report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II), published in 1993 by the National Cholesterol Education Program, recommends guidelines for evaluation and diagnosis of lipids. Subsequently, several clinical trials have identified populations benefiting from pharmacologic intervention and new approaches to the management of lipid disorders. Consequently, these guidelines should be applied with the interval evidence in mind.",1999.0,0,0 154,10448768,Cholesterol lowering in the elderly population. Coordinating Committee of the National Cholesterol Education Program.,S M Grundy; J I Cleeman; B M Rifkind; L H Kuller,"The incidence of coronary heart disease (CHD) peaks in the elderly population. In secondary and primary prevention trials, cholesterol-lowering therapy reduces risk for CHD in both older and younger participants. This benefit, therefore, can be extended to the elderly.",1999.0,0,0 155,10448784,Clinical outcomes in statin treatment trials: a meta-analysis.,S D Ross; I E Allen; J E Connelly; B M Korenblat; M E Smith; D Bishop; D Luo,"To determine the risk of cardiovascular events and death in patients receiving statin treatment for cholesterol regulation. Systematic review and meta-analysis of all randomized controlled trials that were published as of April 15, 1997. Primary or secondary prevention trials or regression trials were eligible. All-cause mortality, fatal myocardial infarction (MI) or stroke, nonfatal MI or stroke, angina, and withdrawal from the studies. Both random- and fixed-effects models were run for the outcomes of interests, and results are expressed as odds ratios (ORs). Sensitivity analyses tested the impact of the study type and duration, statin treatment type, and control arm event rates. Intent-to-treat denominators were used whenever they were available, and the number needed to treat was calculated when appropriate. Seventeen studies (21 303 patients) were included (2 secondary prevention studies, 5 mixed primary-secondary prevention population studies, and 10 regression trials). Treatment groups included lovastatin (t = 5), pravastatin (t = 10), and simvastatin (t = 3). For all-cause mortality, the OR was 0.76 (95% confidence interval [CI], 0.67-0.86) in favor of receiving statin treatment; for fatal MI, the OR was 0.61 (95% CI, 0.48-0.78); for nonfatal MI, the OR was 0.69 (0.54-0.88); for fatal stroke, the OR was 0.77 (95% CI, 0.57-1.04); for nonfatal stroke, the OR was 0.69 (95% CI, 0.54-0.88); and for angina, the OR was 0.70 (95% CI, 0.65-0.76). Patients who received statin treatment demonstrated a 20% to 30% reduction in death and major cardiovascular events compared with patients who received placebo. This advantage was generally present across study types and statin treatment types and for patients with less severe dyslipidemias. The benefit in clinical outcomes was noticeable as early as 1 year.",1999.0,0,0 156,10455083,Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of drug treatment.,D M Pickin; C J McCabe; L E Ramsay; N Payne; I U Haq; W W Yeo; P R Jackson,"To estimate the cost effectiveness of statin treatment in preventing coronary heart disease (CHD) and to examine the effect of the CHD risk level targeted and the cost of statins on the cost effectiveness of treatment. Cohort life table method using data from outcome trials. The cost per life year gained for lifelong statin treatment at annual CHD event risks of 4.5% (secondary prevention) and 3.0%, 2.0%, and 1.5% (all primary prevention), with the cost of statins varied from pound 100 to pound 800 per year. The costs per life year gained according to annual CHD event risk were: for 4.5%, pound 5100; 3.0%, pound 8200; 2.0%, pound 10 700; and 1.5%, pound 12 500. Reducing the cost of statins increases cost effectiveness, and narrows the difference in cost effectiveness across the range of CHD event risks. At current prices statin treatment for secondary prevention, and for primary prevention at a CHD event risk 3.0% per year, is as cost effective as many treatments in wide use. Primary prevention at lower CHD event risks (< 3.0% per year) is less cost effective and unlikely to be affordable at current prices and levels of health service funding. As the cost of statins falls, primary prevention at lower risk levels becomes more cost effective. However, the large volume of treatment needed will remain a major problem.",1999.0,0,0 157,10456002,Interaction between lovastatin and cyclosporine A after heart and kidney transplantation.,L Gullestad; K P Nordal; K J Berg; H Cheng; M S Schwartz; S Simonsen,,1999.0,0,0 158,10456618,Lipid-lowering therapy corrects endothelial cell dysfunction in a short time but does not affect hypercoagulable state even after long-term use in hyperlipidemic patients.,K Kario; T Matsuo; S Hoshide; H Kobayashi; T Sakata; O Mizuno; T Mitsuhashi; U Ikeda; T Miyata; K Shimada,"Lipid-lowering therapy reduces cardiac events to an extent that is disproportionate to the small degree of regression of coronary atherosclerosis observed among hyperlipidemic patients. We prospectively investigated the effects of lipid reduction using simvastatin on the endothelial dysfunction and hypercoagulability found in hyperlipidemic patients. We measured levels of coagulation factors [factor VII (FVII) coagulant activity (FVIIc), FVII antigen (FVIIAg), activated FVII (FVIIa), and fibrinogen], and markers of coagulation activation [prothrombin fragment 1 + 2 (F1 + 2)] and endothelial cell dysfunction [von Willebrand factor (vWF)] in 20 hyperlipidemic patients, 20 hypertensive patients, and 20 normotensive normolipidemic controls. The levels of FVIIa, FVIIc, FVIIAg, F1 + 2, and vWF were all higher in hyperlipidemic patients, but only FVIIa, F1 + 2, and vWF levels were higher in hypertensive patients than in controls. We measured the above parameters in 13 hyperlipidemic patients before and after 1, 3, 6, 12 and 24 months of simvastatin therapy and compared these values with those in 15 hypertensive patients at baseline and after 12 and 24 months. The median (25th-75th percentile) level of total cholesterol was decreased from 259 (255-278) to 206 (176-220) mg/dl after 1 month of simvastatin therapy and this reduction persisted for 2 years. The plasma level of vWF [136% (113-158%)] was not changed after 1 month of administration of simvastatin [132% (115-153%)], but was decreased after 3 months of treatment [114% (96-128%), P<0.01]. This decrease also persisted for 2 years during simvastatin therapy and both of these reductions were significant, compared with levels in hypertensive patients. In contrast, levels of fibrinogen, FVIIc, FVIIAg, FVIIa, and F1 + 2 did not change throughout the 2 years of simvastatin therapy. We conclude that lipid reduction using simvastatin corrects endothelial cell dysfunction but not hypercoagulability in hyperlipidemic patients. The improvement in endothelial cell function brought about by lipid-lowering therapy might contribute to the reduction in cardiac events within a relatively short time period in hyperlipidemic patients.",1999.0,0,0 159,10460940,Efficiency of 1-year treatment with fluvastatin in hyperlipidemic patients with nephrotic syndrome.,F K Matzkies; U Bahner; M Teschner; H Hohage; A Heidland; R M Schaefer,"The influence of fluvastatin, a liver-selective, competitive inhibitor of the 3-hydroxymethyl-glutaryl-coenzyme A reductase, on the lipoprotein metabolism was investigated in 9 patients with nephrotic syndrome. All patients had biopsy-proven renal disease as cause of their nephrotic syndrome and exhibited severe hyperlipidemia [baseline: serum cholesterol 358 +/- 46 mg/dl (9.3 mmol/l), low-density lipoprotein cholesterol 236 +/- 18 mg/dl (6.1 mmol/l), triglycerides 333 +/- 28 mg/dl (3.8 mmol/l), and lipoprotein Lp(a) 46 +/- 11 mg/dl]. After 1 year of 40 mg of fluvastatin, significant reductions of total cholesterol by 31% to 242 +/- 26 mg/dl (6.3 mmol/l) and low-density lipoprotein cholesterol by 29% to 162 +/- 12 mg/dl (4.2 mmol/l) were observed. Furthermore, triglyceride values were also lowered significantly by 19% to 268 +/- 21 mg/dl (3.1 mmol/l). Lipoprotein Lp(a) and high-density lipoprotein-cholesterol remained unchanged by fluvastatin. These improvements in lipid profile were maintained during the entire follow-up period of 1 year. There were no adverse events, and the slight increase in serum creatinine observed during the study was considered to be due to the primary renal disease. In conclusion, long- term administration of fluvastatin in patients with nephrotic syndrome appears to be an effective and safe treatment of the hyperlipidemia associated with this disorder.",1999.0,0,0 160,10463714,Users' guides to the medical literature: XIX. Applying clinical trial results. A. How to use an article measuring the effect of an intervention on surrogate end points. Evidence-Based Medicine Working Group.,H C Bucher; G H Guyatt; D J Cook; A Holbrook; F A McAlister,,2001.0,0,0 161,10463718,"Surrogate end points, health outcomes, and the drug-approval process for the treatment of risk factors for cardiovascular disease.",B M Psaty; N S Weiss; C D Furberg; T D Koepsell; D S Siscovick; F R Rosendaal; N L Smith; S R Heckbert; R C Kaplan; D Lin; T R Fleming; E H Wagner,,2001.0,0,0 162,10468086,Future cardiovascular end point studies: where will the research take us?,J C LaRosa,"Coronary artery disease is the most common cause of death in the world. Emerging concepts of atherosclerosis imply that atherosclerosis is a diffuse disease, and cannot be definitively treated with local, anatomic interventions, such as coronary artery bypass graft surgery or angioplasty. Cholesterol lowering, on the other hand, has been shown to dramatically lower the rate of both morbid and mortal coronary events. In trials with new statin drugs, coronary risk has been lowered by approximately 30%. Additional risk reduction will require other approaches, including (1) intervention for other risk factors, (2) more aggressive cholesterol lowering, or (3) increased attention to primary prevention. The last requires a combination of public health measures to change harmful diet and life-style patterns as well as case findings to identify and treat at-risk subjects. For all these approaches, measures that will increase compliance by both physicians and patients to regimens with proven benefits are required.",1999.0,0,0 163,10473485,British Hypertension Society guidelines for hypertension management 1999: summary.,L E Ramsay; B Williams; G D Johnston; G A MacGregor; L Poston; J F Potter; N R Poulter; G Russell,,1999.0,0,0 164,10482141,Hyperlipidaemia and cardiovascular disease.,N Khan; M Evans,,1999.0,0,0 165,10482143,,,,,0,0 166,10486692,Clinical trials and the cost of medical care.,C R Conti,,1999.0,0,0 167,10486694,Electron beam computed tomography: screening for coronary artery disease.,M J Budoff; B H Brundage,"The need to detect coronary atherosclerosis early in its course has been well recognized by clinicians and epidemiologists for decades. The ability to identify populations with a greater prevalence of coronary disease prior to manifestation of illness would greatly reduce cardiac morbidity and mortality. Electron beam computed tomography (EBCT) uniquely combines the characteristics of speed and excellent density resolution that have led to a rebirth of interest in detecting coronary calcium as a means of screening asymptomatic populations for coronary atherosclerosis. Electron beam computed tomography is noninvasive and widely applicable. It can both detect and quantitate the presence of coronary atherosclerosis. A positive test has diagnostic and prognostic significance, predicting future cardiac events and the extent of atherosclerosis, including the probability of obstructive coronary artery disease (CAD). Multiple studies demonstrate a 6- to 35-fold increased risk of developing a cardiac event with elevated calcium scores. A negative test is highly predictive for excluding obstructive CAD. The cost ranges from $300 to $400, similar to that of an exercise treadmill test. Moreover, scanning for coronary calcium does not require injection of contrast medium, requiring no patient preparation or exercise; therefore, a CT technician can perform the study without supervision. The entire procedure takes < 10 min to perform. These features make EBCT a potential screening test for occult CAD in symptomatic and asymptomatic persons.",1999.0,0,0 168,10487494,The effects of dyslipidemia on left ventricular systolic function in patients with stable angina pectoris.,T D Wang; C M Lee; C C Wu; T M Lee; W J Chen; M F Chen; C S Liau; F C Sung; Y T Lee,"Large-scale clinical trials have shown that long-term treatment with lipid-lowering therapy results in a significant reduction in the occurrence of heart failure among patients with coronary artery disease without previous evidence of congestive heart failure, suggesting dyslipidemia may have an adverse effect on left ventricular performance. To examine whether dyslipidemia has a detrimental effect on left ventricular systolic function and whether this effect is dependent on the corresponding severity of coronary atherosclerosis, 114 consecutive patients with stable angina and a positive exercise thallium-201 myocardial perfusion single-photon emission computed tomography were studied. All patients underwent measurement of serum lipid profiles, right-sided heart catheterization, left ventriculography, and selective coronary arteriography. Mean serum levels of total cholesterol and triglycerides were 4.5 and 1.4 mmol/l, respectively. In univariate analysis, a significant positive correlation between serum high-density lipoprotein (HDL) cholesterol and left ventricular ejection fraction (LVEF) (r = 0.49, P<0.0001) was found. Patients in the lower tertile of serum HDL cholesterol had a significantly lower mean LVEF than those in the upper tertile (55.9+/-15.2 vs. 72.8+/-6.8%, P<0.0001). Stepwise multiple linear regression analysis revealed that LVEF significantly correlated with HDL cholesterol (P<0.0001), the Gensini score (P = 0.008), and diabetes mellitus (P = 0.08) (r = 0.55, P<0.0001). In subgroup analysis of patients with angiographically normal coronary arteries, serum HDL cholesterol was still significantly associated with LVEF. The present study demonstrated an independent association between low HDL cholesterol and subclinical left ventricular systolic dysfunction in Chinese patients with stable angina whose serum levels of total cholesterol and triglycerides were relatively low. Moreover, this correlation remained significant even in patients with normal coronary angiograms, suggesting HDL cholesterol might influence left ventricular systolic performance through extra-atherosclerotic mechanisms.",1999.0,0,0 169,10487500,"Atorvastatin increases low-density lipoprotein size and enhances high-density lipoprotein cholesterol concentration in male, but not in female patients with familial hypercholesterolemia.",N Hoogerbrugge; H Jansen,"The effects of atorvastatin (Lipitor) were evaluated in 40 patients with familial hypercholesterolemia (FH). Following a 6 week drug-free baseline period 20 male and 20 female patients were treated with atorvastatin 40 mg once daily (QD) for the initial 6 weeks increasing to 80 mg QD during the following 6 weeks. Atorvastatin 40 and 80 mg resulted in a dose related reduction in LDL cholesterol of 44 and 50% (P<0.001), respectively. The reduction of triglycerides (TG) was 35% (P<0.001) with 40 and 80 mg atorvastatin. The lipoprotein lipase and the hepatic lipase activity decreased dose independently by 13% (P<0.05) and 18% (P<0.01), respectively. In males, a dose independent increase in high-density lipoprotein (HDL) cholesterol concentration was observed of 8%, (P<0.05). In females, the HDL cholesterol concentration did not change. Baseline LDL size in the females was significantly larger than in the males, being 268+/-6 A and 264+/-8 A (P<0.05), respectively. In males LDL size increased significantly from 264+/-8 A at baseline to269+/-6 A at 40 mg (P<0.05) and to 270+/-5 A (P<0.05) at 80 mg atorvastatin. In females LDL size did not change upon treatment with atorvastatin 40 and 80 mg QD. In conclusion, atorvastatin has the ability to decrease cholesterol and triglyceride concentrations as well as the activity of both lipoprotein and hepatic lipase activity. Additionally it has a favorable effect on LDL size and HDL cholesterol concentration in male, but not in female FH patients.",1999.0,0,0 170,10487795,Lipids and coronary restenosis:an elusive link.,P J de Feyter,,1999.0,0,0 171,10487800,Effects of lovastatin on progression of non-dilated and dilated coronary segments and on restenosis in patients after PTCA. The cholesterol lowering atherosclerosis PTCA trial (CLAPT).,A Kleemann; S Eckert; A von Eckardstein; W Lepper; U Schernikau; U Gleichmann; P Hanrath; E Fleck; A Neiss; S Kerber; G Assmann; G Breithardt; CLAPT Study,"The Cholesterol Lowering Atherosclerosis PTCA Trial (CLAPT) is a prospective, randomized trial with blinded angiographic end-points to assess the effect of 2-year's treatment with lovastatin initiated 4 weeks prior to PTCA, compared to usual care on non-dilated coronary segments and on dilated coronary lesions in male patients with total cholesterol between 200 and 300 mg. dl(-1)who underwent elective PTCA. Two hundred and twenty six patients were randomized 4 weeks prior to PTCA to special care (diet plus lovastatin n=112) or usual care (diet; n=114). One hundred and ninety-nine patients underwent PTCA at baseline and were finally included in the study. Quantitative coronary angiographic assessment was performed on blinded cinefilms at baseline (PTCA) and repeated after 4 and 24 months in 91% and 81% of the patients. The primary end-point was a change in the mean segment diameter of non-dilated segments. The mean lovastatin dose was 33 mg. day(-1). Total- and LDL-cholesterol decreased by 21% and 29% in the special care group and by 7% and 11% in the usual care patients. After 2 years, the mean segment diameter of non-dilated segments decreased by 0.03 mm in the usual care group and 0.004 mm in the special care group (P=0.27). The decrease in the mean segment diameter of dilated lesions was 0.17 mm (usual care) and 0.06 mm (special care) (P=0.04) after 4 months; 0.16 mm (usual care) and 0. 002 mm (special care) after 24 months, respectively (P=0.05). In both groups, the mean segment diameter of dilated lesions increased between 4 and 24 months after PTCA compared to a decrease in mean segment diameter of non-dilated segments (P<0.05). Restenosis (>50% diameter stenosis at follow-up) occurred in 28.4% of usual care and 22.2% of special care patients (P=0.17). Lovastatin reduced the progression of dilated lesions in men with elective PTCA. Independent of treatment allocation, the dilated lesions regressed and the non-dilated segments progressed during the study follow-up. Four weeks of pre-treatment with lovastatin did not influence the rate of restenosis. Lovastatin had no statistically significant effect on non-dilated segments.",1999.0,1,1 172,10488970,Opposite effects on serum cholesteryl ester transfer protein levels between long-term treatments with pravastatin and probucol in patients with primary hypercholesterolemia and xanthoma.,A Inazu; J Koizumi; K Kajinami; T Kiyohar; K Chichibu; H Mabuchi,"Long-term effects of pravastatin and probucol on serum cholesteryl ester transfer protein (CETP) and xanthoma/xanthelasma size were compared. Twenty-three patients with primary hypercholesterolemia and xanthoma/xanthelasma, including 11 patients with heterozygous familial hypercholesterolemia, were treated with pravastatin (20 mg/day) or probucol (1000 mg/day) for 24 months. Serum CETP levels were measured by sandwich ELISA. In 11 patients (six men and five women, 55 +/- 2 [SE] yr) treated with pravastatin, serum cholesterol levels decreased from 262 +/- 13 to 229 +/- 13 mg/dl during the 24-month treatment period (P = 0.05). Serum HDL cholesterol levels were not changed. Serum CETP levels decreased from 2.5 +/- 0.2 to 2.0 +/- 0.2 microg/ml (-21%, P = 0.002). By contrast, in 12 patients (four men and eight women, 57 +/- 4 year) treated with probucol, serum cholesterol levels did not significantly decrease from 236 +/- 11 to 207 +/- 13 mg/dl. Serum HDL cholesterol levels decreased from 44 +/- 2 to 30 +/- 2 mg/dl (P = 0.009). Serum CETP levels increased from 2.3 +/- 0.1 to 2.8 +/- 0.2 microg/ml (+23%, P = 0.02). Xanthelasma regression was found in two of four patients (50%) each treated with pravastatin and probucol, respectively. In contrast, Achilles' tendon xanthoma regressed in four of five patients (80%) treated with pravastatin, but only in two of five patients (40%) treated with probucol. Patients with xanthoma/xanthelasma regression after 2 years treatment had higher baseline levels of serum CETP than those without regression (2.7 +/- 0.2 microg/ml [n = 9] versus 2.1 +/- 0.2 microg/ml [n = 7], P = 0.05). Serial changes in serum CETP levels during treatment with pravastatin and probucol were discordant, but not related to the degree of xanthoma regression. However, higher level of serum HDL3 cholesterol was an independent factor in the smaller size of Achilles' tendon xanthoma at baseline. In addition, higher levels of serum HDL3 triglyceride on lipid-lowering therapy (6 months) appear to be a common predictor of regression of Achilles' tendon xanthoma in the treatment with either pravastatin or probucol.",1999.0,0,0 173,10488971,Atorvastatin and fibrinogen--a small subgroup shows extreme response.,H Sinzinger; M Rodrigues,,1999.0,0,0 174,10490827,"Bcl-2 differentially targets K-, N-, and H-Ras to mitochondria in IL-2 supplemented or deprived cells: implications in prevention of apoptosis.",A Rebollo; D Pérez-Sala; C Martínez-A,"IL-2 deprivation triggers apoptosis in the murine T cell line TS1alphabeta, a process that can be blocked by overexpression of Bcl-2. Here we show that Bcl-2 and Ras proteins interact in mitochondria from TS1alphabeta cells in the presence or absence of IL-2, as evidenced by co-immunoprecipitation. All three Ras proteins, K-, N- and H-Ras, interact with Bcl-2; however, their mitochondrial localization is differentially regulated in IL-2-supplemented or -deprived cells. K-Ras is found in mitochondria only in IL-2-supplemented cells, whereas H-Ras is observed in mitochondria only after IL-2 withdrawal. N-Ras is detected in mitochondria under both experimental conditions. Bcl-2 transfection partially restored K- and N-Ras association with mitochondria in IL-2-deprived cells and rendered H-Ras association independent of IL-2 withdrawal. Inhibitors of Ras posttranslational processing did not alter the IL-2-induced differential pattern of mitochondrial localization. The processed forms of K- and N-Ras associated with mitochondria, although unprocessed H-Ras was also detected in mitochondria from mevastatin-treated cells. These results evidence a distinct behavior among the three Ras proteins in TS1alphabeta cells, depending on IL-2 supply, and suggest homologue-specific roles for Ras proteins in IL-2-dependent events.",1999.0,0,0 175,10492062,The effect of short-term dipyrone administration on cyclosporin pharmacokinetics.,Y Caraco; E Zylber-Katz; M Fridlander; D Admon; M Levy,"A large number of drugs have been shown to affect the metabolism of cyclosporin A (CSA) and, since cyclosporin is characterized by a narrow therapeutic range, the consequences of such drug interactions may often be of clinical importance. To evaluate the effect of short-term administration of dipyrone on steady state CSA pharmacokinetics. Six kidney- and two heart-transplanted patients on chronic CSA therapy participated in this study, which consisted of two 4-day study periods separated by 3-week washout periods. The patients received, in addition to their usual drugs, dipyrone 500 mg or placebo t.i.d., as identical-looking tablets, and the order of administration was randomized. CSA concentrations were measured in whole blood by means of radio-immunoassay (CYCLO-Trac SP) daily during the study periods and periodically over 24 h on the fourth study day. CSA concentrations over time were reduced after dipyrone (ANOVA, P < 0.01), but statistical significance was noted only at 2, 4, 5 and 10 h after drug intake (P < 0.05). Peak CSA concentration was not altered by dipyrone, but the time required to reach maximal concentration was longer with dipyrone treatment than with the placebo (3.8 +/- 2.6 h vs 2.1 +/- 0.6 h, P < 0.05). No consistent changes were noted for CSA trough level, elimination half-life and area under the concentration-time curve from 0 h to 12 h. Separate analysis of the kidney transplanted patients yielded similar results. Short-term administration of dipyrone is associated with a mild decrease in CSA blood concentration, which is most prominent in the first few hours after drug intake. In practice, no dose adjustment of CSA seems to be indicated during a short course of dipyrone treatment.",1999.0,0,0 176,10493153,[The RICO rat (genetically hypercholesteremic): a good model for testing a food substance or a drug specific for a key enzyme of cholesterol metabolism].,C Lutton,"The genetically hypercholesterolemic RICO rat: a good model for testing a food substance or a drug specific for a key enzyme involved in cholesterol metabolism? The genetically hypercholesterolemic RICO rat, whose cholesterolemia is situated between 1.3 and 1.5 mg x mL(-1), possibly reaching 2 mg x mL(-1), after the addition of cholesterol to its food, possesses a different lipoprotein spectrum than man, because approximatively 70% of the plasma cholesterol is carried by HDL (28% of which are carried by the light HDL1 subfraction, rich in apolipoproteinE (apoE). The effects of certain substances in food (carbohydrates, cholesterol, allyldisulfide, etc.) or drugs (ethinylestradiol, streptozotocin, statins, inhibitors of ACAT, etc.) on the cholesterolemia of the rat were studied, in relation to certain important parameters of cholesterol metabolism (LDLr, VLDL liver secretion, activities of lipolytic enzymes: LPL, HL, etc.). The increase in a number of LDL receptors (LDLr) in the RICO rat, induced by ethinylestradiol, streptozotocin, etc., provokes an important decrease in the apoE-rich HDL concentration, filtered out by its receptors. This decrease is observed in man for LDL. Simvastatin, which stimulates LDLr in man and not in rat, lowers the level of LDL in man and has no effect on the cholesterolemia of the RICO rat. In rat and man, the concentration of plasma cholesterol is inversely proportional to the rate of cholesterol synthesis in the organism and to its plasma turnover rate. The concentration of cholesterol in the plasma carried by the HDL1 of the rat, is however, proportional to hepatic cholesterogenesis. This fraction is positively correlated to the activity of hepatic lipase (HL) and negatively to the activity of lipoprotein lipase (LPL), released by heparin. These data demonstrate the importance of the liver and lipolytic enzymes in the intraplasmatic hydrolysis of HDL3 (precursors of HDL1), murine particles that can be considered similar to human LDL.",1999.0,0,0 177,10493319,"Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects.",M H Davidson; M A Dillon; B Gordon; P Jones; J Samuels; S Weiss; J Isaacsohn; P Toth; S K Burke,"To compare colesevelam hydrochloride (Cholestagel), a nonabsorbed hydrogel with bile acid-sequestering properties, with placebo for its lipid-lowering efficacy, its effects on laboratory and clinical safety parameters, and the incidence of adverse events. Following diet and placebo lead-in periods, placebo or colesevelam was administered at 4 dosages (1.5, 2.25, 3.0, or 3.75 g/d) for 6 weeks with morning and evening meals to men and women with hypercholesterolemia (low-density lipoprotein cholesterol level >4.14 mmol/L [>160 mg/dL]). Patients returned to the clinic every 2 weeks throughout the treatment period for lipid parameter measurements and adverse event assessments. Samples were collected for serum chemistry profiles, hematologic studies, coagulation studies, and vitamin level assessment at baseline and after 6 weeks of treatment. Among the 149 patients randomized, 137 completed the study. Low-density lipoprotein cholesterol concentrations decreased in a dosage-dependent manner by 0.11 mmol/L (4.2 mg/dL) (1.8%) in the 1.5-g/d colesevelam treatment group and up to 1.01 mmol/L (39 mg/dL) (19.1%) in the 3.75-g/d colesevelam treatment group. Low-density lipoprotein cholesterol concentrations at the end of treatment were significantly reduced from baseline levels in the 3.0- and 3.75-g/d colesevelam treatment groups (P = .01 and P<.001, respectively). Total cholesterol levels demonstrated a similar response to colesevelam treatment, with an 8. 1% decrease from baseline in the 3.75-g/d treatment group (P<.001). High-density lipoprotein cholesterol levels rose significantly in the 3.0- and 3.75-g/d colesevelam treatment groups, by 11.2% (P=.006) and 8.1% (P=.02), respectively. Median triglyceride levels did not change from baseline, nor were there any significant differences between treatment groups. The incidence of adverse events was similar among all groups. Colesevelam therapy is effective for lowering low-density lipoprotein cholesterol concentrations in persons with moderate hypercholesterolemia. It lacks the constipating effect of other bile acid sequestrants, demonstrating the potential for increased compliance.",1999.0,0,0 178,10496299,Clinical pharmacokinetics of troglitazone.,C M Loi; M Young; E Randinitis; A Vassos; J R Koup,"Troglitazone is a new thiazolidinedione oral antidiabetic agent approved for use to improve glycaemic control in patients with type 2 diabetes. It is rapidly absorbed with an absolute bioavailability of between 40 and 50%. Food increases the absorption by 30 to 80%. The pharmacokinetics of troglitazone are linear over the clinical dosage range of 200 to 600 mg once daily. The mean elimination half-life ranges from 7.6 to 24 hours, which facilitates a once daily administration regimen. The pharmacokinetics of troglitazone are similar between patients with type 2 diabetes and healthy individuals. In humans, troglitazone undergoes metabolism by sulfation, glucuronidation and oxidation to form a sulfate conjugate (M1), glucuronide conjugate (M2) and quinone metabolite (M3), respectively. M1 and M3 are the major metabolites in plasma, and M2 is a minor metabolite. Age, gender, type 2 diabetes, renal impairment, smoking and race do not appear to influence the pharmacokinetics of troglitazone and its 2 major metabolites. In patients with hepatic impairment the plasma concentrations of troglitazone, M1 and M3 increase by 30%, 4-fold, and 2-fold, respectively. Cholestyramine decreases the absorption of troglitazone by 70%. Troglitazone may enhance the activities of cytochrome P450 (CYP) 3A and/or transporter(s) thereby reducing the plasma concentrations of terfenadine, cyclosporin, atorvastatin and fexofenadine. It also reduces the plasma concentrations of the oral contraceptive hormones ethinylestradiol, norethindrone and levonorgestrel. Troglitazone does not alter the pharmacokinetics of digoxin, glibenclamide (glyburide) or paracetamol (acetaminophen). There is no pharmacodynamic interaction between troglitazone and warfarin or alcohol (ethanol). Pharmacodynamic modelling showed that improvement in fasting glucose and triglyceride levels increased with dose from 200 to 600 mg. Knowledge of systemic troglitazone exposure within a dose group does not improve the prediction of glucose lowering response or adverse effects beyond those based on the administered dose.",1999.0,0,0 179,10498131,Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin.,G Dangas; D A Smith; J J Badimon; A H Unger; J H Shao; P Meraj; A M Cohen; D Levine; J T Fallon; J A Ambrose,"Thrombotic risk in hyperlipidemic women and its response to lipid therapy is unknown. We prospectively studied 28 men and 29 women with high low-density lipoprotein (LDL) cholesterol during 6 months of therapy with pravastatin. Women had significantly higher high-density lipoprotein (HDL) cholesterol (54.2 +/- 1.7 vs 39.5 +/- 2.2 mg/dl, p <0.01), lower prevalence of coronary artery disease (41% vs 67%, p = 0.04), and otherwise similar baseline characteristics compared with men. Both genders achieved a 33% reduction in LDL at 6 weeks (188 +/- 6 to 133 +/- 5 mg/dl) and maintained similar LDL levels throughout the study. Systemic hemostatic markers and thrombus formation under dynamic flow conditions were evaluated at baseline, and at 3 and 6 months of follow-up. Prothrombin fragment F1.2, a marker of thrombin generation, was higher in women versus men at baseline (2.4 +/- 0.2 vs 1.4 +/- 0.3 nmol/L, p = 0.02). The levels decreased in women to 2.0 +/- 0.3 nmol/L at 3 months and to 1.6 +/- 0.2 nmol/L at 6 months (p <0.045, analysis of variance), whereas it remained unchanged in men. Plasminogen activator inhibitor-I significantly decreased at 3 and 6 months of follow-up: by 12.6% and 18.7%, respectively, in women, and by 18.8% and 23.5%, respectively, in men. Similarly, tissue plasminogen activator decreased significantly by 7.4% in women and 11.8% in men at 6 months compared with baseline. Fibrinogen showed an increase in both genders at follow-up. Thrombus formation was similar at baseline between the 2 genders, and decreased at 3 and 6 months compared with baseline by 12.5% and 29.5% in women, and by 18.6% and 19.4% in men (p <0.04 at 6 months vs baseline in both men and women). Other markers, including C-reactive protein, fibrinopeptide A, D-dimer, and factor VIIa, did not differ between genders and did not change with therapy. Thus, despite higher HDL, and lower incidence of coronary disease, women with high LDL had a comparable thrombotic and/or fibrinolytic profile to men and even evidence of increased thrombin generation at baseline. Blood thrombogenicity was reduced with pravastatin in both genders; in addition, thrombin generation was gradually reduced in women to a level similar to that of men by 6 months of follow-up.",1999.0,0,0 180,10498134,Effect of simvastatin treatment on the electronegative low-density lipoprotein present in patients with heterozygous familial hypercholesterolemia.,J L Sánchez-Quesada; C Otal-Entraigas; M Franco; O Jorba; F González-Sastre; F Blanco-Vaca; J Ordóñez-Llanos,"Most described modifications of low-density lipoprotein (LDL) cholesterol share an increase in its negative electric charge; in fact, an electronegative form of LDL can be identified and isolated from plasma. Although the exact nature of the chemical modification of electronegative LDL is still controversial, its toxicity on endothelial cells has been demonstrated. Statins have protective effects against cardiovascular disease that are independent of their lipid-lowering action and which could be due, at least in part, to the prevention of LDL modification. We evaluated the effect of 6 months of simvastatin therapy (40 mg/day) on electronegative LDL proportion and LDL susceptibility to in vitro induced oxidation in 21 patients with heterozygous familial hypercholesterolemia (FH). Eleven normolipemic subjects were analyzed as a control group. Total cholesterol as well as LDL and very low density lipoprotein cholesterol, triglycerides, and apoprotein B decreased 30% after the first month of therapy, with no further decreases thereafter. LDL susceptibility to oxidation was similar in FH patients and controls and did not change throughout the treatment. Electronegative LDL proportion was 35.1 +/- 9.9% in FH patients and 9.1 +/- 2.4% in control subjects (p <0.0001) but, in contrast to total LDL cholesterol and the rest of lipid parameters, it decreased to 28.6 +/- 9.1% in the third month and to 21.2 +/- 7.7% in the sixth month of therapy. The decrease in these cytotoxic particles may be a relevant mechanism by which simvastatin protects against cardiovascular disease.",1999.0,0,0 181,10500066,Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac.,B Agarwal; C V Rao; S Bhendwal; W R Ramey; H Shirin; B S Reddy; P R Holt,"3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HRIs) were found incidentally to reduce new cases of colon cancer in 2 large clinical trials evaluating coronary events, although most patients in both treatment and control group were taking nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are associated with reduced colon cancer incidence, predominantly by increasing apoptosis. We showed previously that lovastatin induces apoptosis in colon cancer cells. In the present study we evaluated the potential of combining lovastatin with sulindac for colon cancer chemoprevention. Lovastatin, 10-30 micromol/L, augmented sulindac-induced apoptosis up to 5-fold in 3 colon cancer cell lines. This was prevented by mevalonate (100 micromol/L) or geranylgeranylpyrophosphate (10 micromol/L) but not farnesylpyrophosphate (100 micromol/L), suggesting inhibition of geranylgeranylation of target protein(s) as the predominant mechanism. In an azoxymethane rat model of chemical-induced carcinogenesis, the total number of colonic aberrant crypt foci per animal (control, 161 +/- 11) and the number of foci with 4+ crypts (control, 40 +/- 4.5) decreased to 142 +/- 14 (NS) and 43 +/- 2.9 (NS), respectively, with 50 ppm lovastatin alone; to 137 +/- 5.4 (P = 0.053) and 36 +/- 2.1 (NS) with 80 ppm sulindac alone; and to 116 +/- 8.1 (P = 0.004) and 28 +/- 3.4 (P = 0.02) when 50 ppm lovastatin and 80 ppm sulindac were combined. Addition of an HRI such as lovastatin may augment chemopreventive effects of NSAIDs or/and may allow lower, less toxic doses of these drugs to be used.",1999.0,0,0 182,10500601,Fluvastatin in the treatment of hypercholesterolemia in renal transplantation.,G Gómez; M L Alvarez; P Errasti; F J Lavilla; N García; B Ballester; I García; A Purroy,,1999.0,0,1 183,10500602,Effect of atorvastatin of the treatment of hypercholesterolemia after renal transplantation.,M L Alvarez; P Errasti; G Gómez; F J Lavilla; N García; B Ballester; I García; A Purroy,,1999.0,0,1 184,10500900,Preventive cardiology.,J A Foody,"Over the past year, significant new advances have been made in preventive cardiology. New trials of lipid lowering, estrogen therapy, and hypertension control have added to our understanding of the pathophysiology and prevention of coronary atherosclerosis. This review highlights these new trials and provides insight into their applications in the practice of cardiology.",1999.0,0,0 185,10501272,Plasma lipids and stroke.,P B Gorelick; T Mazzone,"High plasma levels of lipids are an important modifiable risk factor for coronary heart disease, but are not established as a risk factor for stroke. Pathophysiologic evidence that links lipids to major systemic artery disease, and the results of clinical trials of coronary heart disease prevention in relation to lipid-lowering suggest that lipids may play an important role in the causation of stroke. We discuss the controversy concerning plasma lipids as a risk factor for stroke. A clinical trial targeted at lowering levels of lipids with the aim of primary stroke prevention would be a timely and important contribution. Armed with this information, we could further clarify the plasma lipid-stroke controversy and move into the 21st century with a better understanding of stroke prevention.",1999.0,0,0 186,10501408,Compliance to multiple interventions in a high risk population.,M B Pettinger; M A Waclawiw; K B Davis; T Thomason; R Garg; B Griffin; D A Egan,"Assess compliance with study medications and examine reasons for noncompliance. Individuals with peripheral arterial disease present the clinician with a unique combination of symptoms and therapeutic needs; the treatment of this population has not been adequately studied. The Arterial Disease Multiple Intervention Trial was a randomized double-blind placebo-controlled trial that randomized 468 participants to a combination of antioxidants, niacin and warfarin or matching placebos. Men and women (mean age 65 yrs) with peripheral arterial disease and low-density lipoprotein (LDL) < 190 mg/dl were enrolled and followed for one year. Compliance to the study medications was measured by pill count for each medication. An overall measure of compliance was determined by combining pill counts from all study visits. Mean overall pill counts ranged from 88 to 94% in the eight treatment groups. No statistically significant differences were found in mean pill counts over time or between active and placebo groups. History of coronary artery disease and number of follow-up visits were associated with higher overall pill counts while low compliance during screening was associated with lower counts during follow-up. Participants with an overall mean pill count < 80% had more adverse events compared to those with a higher count. Side effects were reported as the reason for missing pills significantly more often in the active versus placebo niacin group. Individuals with peripheral arterial disease were able to comply with the complex drug regimen. The ability of this drug combination to reduce cardiovascular events and improve quality of life warrants study.",1999.0,0,0 187,10501818,Lowering effects of four different statins on serum triglyceride level.,A Branchi; A M Fiorenza; A Rovellini; A Torri; F Muzio; S Macor; D Sommariva,"The main effect of statins is the decrease of serum level of low-density lipoprotein (LDL) cholesterol, due to the inhibition of intracellular cholesterol biosynthesis which brings about an upregulation of LDL receptors. A minor effect is the decrease of serum triglycerides. The present study was undertaken to verify whether all statins are effective in reducing serum triglycerides and whether their effect on triglycerides is related to the LDL cholesterol lowering activity. Of 197 hypercholesterolaemic patients on stable low-fat low-cholesterol diet, 49 were put on atorvastatin 10 mg per day, 48 on fluvastatin 40 mg per day, 50 on pravastatin 20 mg per day and 50 on simvastatin 10 mg per day. After 2 months, mean percentage change in serum triglycerides and LDL cholesterol resulted to be significantly different among the four treatment groups, whereas the ratio between the percentage decrease in serum triglycerides and that of LDL cholesterol (Deltatriglyceride/DeltaLDL cholesterol ratio) was not significantly different. Only baseline serum triglycerides resulted to be significantly associated with Deltatriglycerides/DeltaLDL cholesterol ratio. All statins are then effective in decreasing triglyceride levels. The lack of a significant difference in Deltatriglycerides/DeltaLDL cholesterol ratio among the treatment groups suggests that the more effective the statin is in decreasing LDL cholesterol, the more it will also be in decreasing serum triglycerides.",1999.0,0,1 188,10501825,Cardiovascular drugs: discrepancies in demographics between pre- and post-registration use.,N F Wieringa; P A de Graeff; G T van der Werf; R Vos,"To study discrepancies in demographic characteristics between patients participating in pre-registration phase III trials of cardiovascular drugs, registered in the Netherlands, and patient populations in daily practice representing the actual users of the drugs after registration. Comparison of age and sex distribution in registration files of 15 cardiovascular drugs [angiotensin-converting enzyme (ACE)inhibitors/angiotensin II receptor antagonists, calcium channel blockers, beta-adrenergic blocking agents, vasodilators, HMG-CoA reductase inhibitors and thrombolytics] with patients selected from a general practitioner (GP) registration database, who had received prescriptions for drugs from the therapeutic classes for the registered indications (hypertension, hypercholesterolaemia or angina pectoris) or were diagnosed with myocardial infarction. Moderate discrepancy was defined as more than 10% difference between the populations, large discrepancy by more than 20% difference. Clinical trials were also analysed by region of trial performance with respect to patient selection criteria, differences in male/female ratios and ethnic origin of patients. Phase III clinical trials in registration files of drugs registered for hypertension, angina pectoris and myocardial infarction had a moderate to large under-representation of female patients. Patients aged more than 65 years, who accounted for more than 50% of drug use indicated for hypertension, angina pectoris and myocardial infarction, were under-represented in the clinical trials of drugs registered for all indications. Trials performed in North America included relatively fewer female patients compared with European trials, and showed different patterns in the ethnic origin between indications. Clinically relevant subgroups of cardiovascular patients are under-represented in pre-registration phase III trials. These findings concern major areas of cardiovascular diseases, i.e. hypertension, hypercholesterolaemia, angina pectoris and myocardial infarction. Widely used therapeutic classes of drugs are affected and regional differences in trial performance are present.",1999.0,0,0 189,10503169,Hormone replacement and simvastatin in the therapy of hypercholesterolemic postmenopausal women.,M Averbuch; D Ayalon; N Eckstein; I Dotan; I Shapira; Y Levo; A Pines,"To prospectively investigate the effect of cholesterol lowering diet, hormone replacement therapy and simvastatin on plasma lipid levels using a 3-month stepwise protocol. Participants were postmenopausal women under the age of 60 with hypercholesterolemia (plasma total cholesterol > 240 mg/dl). The study started with 3 months of Step-One diet (phase I) followed by 3 months of diet and hormone replacement therapy (0.625 mg conjugated estrogens daily combined with 5 mg medroxyprogesterone acetate at days 13-25 of each cycle) (phase II). In women whose total cholesterol remained above 240 mg/dl or LDL-cholesterol above 160 mg/dl by the end of phase II, simvastatin at 10 mg daily was added (phase III). Plasma cholesterol levels as well as safety measurements were closely monitored. Sixteen (21%) of 75 patients who entered the study had satisfactory cholesterol levels by the end of 6 months. Another 25 patients (33%) dropped out of the study for various reasons by that time. In the 34 patients who started simvastatin, plasma total cholesterol levels did not significantly change during phase I and II, however, LDL-cholesterol significantly decreased (204 +/- 31 to 187 +/- 26 mg/dl, p = 0.04) and HDL increased (53 +/- 12 to 62 +/- 16 mg/dl, p = 0.04). A dramatic decrease occurred in both total and LDL-cholesterol levels after one month of phase III (281 +/- 26 to 213 +/- 30 mg/dl 187 +/- 26 to 122 +/- 30 mg/dl respectively, p < 0.0001), with no further changes during the rest of the study period. No significant changes occurred in HDL-cholesterol and triglyceride plasma levels at this phase. Adverse effects were few and minor throughout the study. Some of the hypercholesterolemic postmenopausal women will benefit from hormone replacement therapy as a single cholesterol lowering treatment in addition to diet (21% in our series). Nevertheless, combination therapy of estrogens and low dose simvastatin proved to be extremely effective in lowering cholesterol levels with no significant side effects. Such therapeutic regimen may also have a synergistic anti-atherogenic effect.",1999.0,0,0 190,10503814,Cardiovascular pharmacology of hormone replacement therapy.,G M Rosano; G Panina,"The incidence of cardiovascular disease in women is negligible before natural or surgically-induced menopause, and increases after menopause. Epidemiological data suggest that estrogen replacement therapy reduces the occurrence of coronary artery, and possibly cerebrovascular, disease by 25 to 50% in treated women compared with non-users. These findings are supported by the evidence that estrogens have a beneficial effect on cholesterol metabolism and deposition, contributing to the inhibition of atherosclerotic plaque formation in arterial walls. Early reports suggested that up to 60% of the protective effect of estrogens on coronary artery disease was attributable to favourable changes in plasma lipids. Reanalysis of the data indicated that the lipid changes probably account for approximately 25% of the cardioprotective effect of estrogens and that other effects are, therefore, likely to be important. The influence of estrogens on carbohydrate metabolism, atheroma formation and cardiovascular haemodynamics may also play an integral role in the overall beneficial effect of the hormones. Animal and human studies have shown that the administration of estrogens leads to a restoration of endothelial function, an increase in cardiac output, an increase in arterial flow velocity, a decrease in vascular resistance, and a decrease in systolic and diastolic blood pressure. Recent studies on hormone replacement regimens have shown that estrogens may favourably affect fibrinolysis and reduce plasma fibrinogen to premenopausal levels. Despite these effects of estrogens the recent Heart and Estrogen/Progestin Replacement Study (HERS) failed to show a cardioprotective effect of hormone replacement therapy (HRT) in elderly women with coronary artery disease. However, the HERS study has several limitations and stands alone against the large body of evidence that suggest that HRT may reduce cardiovascular mortality and morbidity.",1999.0,0,0 191,10505300,Biopharmaceutical profile of cerivastatin: a novel HMG-CoA reductase inhibitor.,W Mück; K Ochmann; A Mazzu; J Lettieri,"The biopharmaceutical properties of cerivastatin were evaluated in a series of worldwide clinico-pharmacological studies. Young healthy males aged 18-45 years were randomized to receive 0.05-0.8 mg cerivastatin orally, given either as single or multiple once-daily doses under fed or fasting conditions in the morning, with evening meal or at bedtime. Following administration, cerivastatin was rapidly and almost completely absorbed into the gastrointestinal tract (> 98%), with maximum plasma concentrations (Cmax) reached at 2-3 h post dose. The plasma concentration/time profile of the tablet is similar to an aqueous oral solution (relative bioavailability is 100%). The dose-proportionality of cerivastatin (0.05-0.8 mg) in area under the curve and Cmax showed low intra- and interindividual variability. The effect of food (single-dose studies testing administration of cerivastatin with a high-fat meal and clinical investigations in patients) or time of administration (single- and multiple-dose once-daily/twice-daily studies) had no clinically relevant effects on the pharmacokinetics of cerivastatin. Marketed tablet strengths and drug formulations from different sources were found to be bioequivalent. Cerivastatin is a noncomplicated drug with respect to its biopharmaceutical profile and bioavailability.",1999.0,0,0 192,10505301,"Efficacy and safety of 300 micrograms and 400 micrograms cerivastatin once daily in patients with primary hypercholesterolaemia: a multicentre, randomized, double-blind, placebo-controlled study.",M Hanefeld; J P Deslypere; L Ose; P N Durrington; M Farnier; N Schmage,"This study examined the action of cerivastatin, a new statin, in subjects with primary hypercholesterolaemia. The effects of two oral doses of cerivastatin (400 micrograms/day or 300 micrograms/day) were compared with placebo in 349 patients using a multicentre, randomized, double-blind, placebo-controlled study design. Cerivastatin treatment lasted 8 weeks and produced significant reductions in low density lipoprotein-cholesterol (LDL-C) levels from baseline compared with placebo. The reduction in LDL-C was significantly greater with 400 micrograms than with 300 micrograms cerivastatin. When responder rates were examined, the higher (400 micrograms/day) cerivastatin dose was found to be more effective in producing larger (> 40%) reductions in LDL-C levels. Cerivastatin treatment was well tolerated. Only two withdrawals due to adverse events during active treatment occurred, neither of which was considered to be due to the study medication. In addition, no clinically relevant increases in the levels of creatine phosphokinase and hepatic transaminases (alanine transaminase and aspartate transaminase) compared with placebo were seen in this study. In conclusion, cerivastatin treatment produced a significant lowering of LDL-C levels, with the higher dose providing the greatest benefit.",1999.0,0,0 193,10506395,[Short- and long-term effects of intensified versus conventional antilipidemic therapy in patients with coronary heart disease. Results from the Lipid-Coronary Artery Disease (L-CAD) Study].,H R Arntz; W Wunderlich; L Schnitzer; R Stern; F Fischer; R Agrawal; T Linderer; H P Schultheiss,"In a prospective, randomized study of patients with acute manifestation of coronary heart disease and hypercholesterolemia (LDL cholesterol >/= 130 or =10 years of age may be effective when diet therapy alone has failed to obtain the recommended maximum LDL-C concentration of 130 mg/dL. The use of statins during childhood and adolescence is generally safe, but large, long-term studies should be performed before statins are routinely prescribed to children with elevated cholesterol or lipoprotein concentrations.",1999.0,0,0 230,10573494,,,,,0,0 231,10580441,Gauging the impact of statins using number needed to treat.,C R Kumana; B M Cheung; I J Lauder,,2001.0,0,0 232,10584091,Drug interactions and the statins.,R J Herman,"Drug interactions commonly occur in patients receiving treatment with multiple medications. Most interactions remain unrecognized because drugs, in general, have a wide margin of safety or because the extent of change in drug levels is small when compared with the variation normally seen in clinical therapy. All drug interactions have a pharmacokinetic or pharmacodynamic basis and are predictable given an understanding of the pharmacology of the drugs involved. Drugs most liable to pose problems are those having concentration-dependent toxicity within, or close to, the therapeutic range; those with steep dose-response curves; those having high first-pass metabolism or those with a single, inhibitable route of elimination. Knowing which drugs possess these intrinsic characteristics, together with a knowledge of hepatic P-450 metabolism and common enzyme-inducing and enzyme-inhibiting drugs, can greatly assist physicians in predicting interactions that may be clinically relevant. This article reviews the pharmacology of drug interactions that can occur with hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) to illustrate the scope of the problem and the ways in which physicians may manage this important therapeutic class of drugs.",1999.0,0,0 233,10584766,Olanzapine increases weight and serum triglyceride levels.,D N Osser; D M Najarian; R L Dufresne,"Previous studies have suggested that clozapine is associated with increases in both weight and serum triglyceride (but not cholesterol) levels. Because of the pharmacologic similarities between clozapine and olanzapine, we decided to evaluate if olanzapine use was associated with an increase in triglycerides. Twenty-five inpatients (21 men, 4 women) were treated with olanzapine, and their outcomes were tracked prospectively in a medication utilization evaluation study. After 12 weeks on a mean +/- SD dose of 13.8+/-4.4 mg/day, weight increased a mean of 12 lb (5.4 kg; from 190+/-37 lb [85.5+/-16.7 kg] to 202+/-30 lb [90.9+/-13.5 kg]), while fasting triglycerides increased a mean of 60 mg/dL (from 162+/-121 mg/dL to 222+/-135 mg/dL). Both increases were significant at p < .05. Fasting total cholesterol did not increase. The triglyceride increase was even larger when we excluded 8 patients who received various interventions to lower lipid levels (e.g., pravastatin, low-fat diet) during the olanzapine trial. There was a strong association between weight change and triglyceride change (p < .02); after controlling for weight, analysis of covariance showed no independent increase in triglycerides. These results suggest olanzapine has significant effects on weight and serum triglyceride levels. Clinical implications are discussed.",1999.0,0,0 234,10591387,Preventing coronary artery disease by lowering cholesterol levels: fifty years from bench to bedside.,D Steinberg; A M Gotto,"In the more than 50 years since the founding of the National Heart, Lung, and Blood Institute and the American Heart Association, medical science has moved from an era in which hypercholesterolemia, as it is now defined, was not believed to be abnormal to one in which controlling hypercholesterolemia is known to reduce not only coronary artery disease morbidity and mortality but also total mortality. While the efforts and successes of many researchers involved in this evolution are impressive, atherosclerosis is still a major cause of death and disability in many developed nations, mostly in the form of myocardial infarction and stroke, and is an increasing cause of morbidity and mortality in developing nations. Many questions about the detailed pathogenesis of the disease remain. Elucidating the roles of high-density lipoprotein, other lipoproteins, and homocysteine, as well as the roles of cytokines and growth factors, will permit better understanding and treatment of atherosclerosis. With continuing support for research and encouragement of physicians and patients to follow recommended preventive regimens, further progress can be made against this major cause of death.",2001.0,0,0 235,10591388,An evidence-based assessment of the NCEP Adult Treatment Panel II guidelines. National Cholesterol Education Program.,B J Ansell; K E Watson; A M Fogelman,"The Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) was issued without the benefit of multiple recently published large clinical trials. To analyze the panel's guidelines for treatment of high cholesterol levels in the context of currently available clinical trial results. MEDLINE was searched for all English-language clinical trial data from 1993 through February 1999 relating to the effects of cholesterol treatment on cardiovascular clinical outcomes. Studies that were selected for detailed review assessed the effects of cholesterol lowering on either coronary events, coronary mortality, stroke, and/or total mortality, preferably by randomized, double-blind, placebo-controlled design. Selection was by consensus of a general internist, a lipid clinic director, and a researcher in atherosclerotic plaque biology. A core of 37 of the 317 initially screened studies were selected and used as the primary means by which to assess the guidelines. By consensus of the group, only prespecified end points of trials were included, unless post hoc analysis addressed issues not studied elsewhere. Recent clinical trial data mostly support the Adult Treatment Panel II guidelines for cholesterol management. While existing trials have validated the target low-density lipoprotein cholesterol (LDL-C) goals in the report, studies are lacking that address mortality benefit from reduction below these levels. Few lipid-lowering trials have treated patients with low high-density lipoprotein cholesterol and/or elevated triglyceride levels with LDL-C levels at or below treatment goals. Lipid-lowering therapy generally should be more aggressively applied to patients with diabetes and/or at the time of coronary heart disease (CHD) diagnosis. The evidence for statin use in secondary CHD prevention in postmenopausal women outweighs current evidence for use of estrogen replacement in this setting. Further studies are needed to address the effects of lipid modification in primary prevention of CHD in populations other than middle-aged men and to study markers of lipid metabolism other than LDL-C.",2001.0,0,0 236,10592547,[When and how do we treat our hypercholesterolemic patients?].,S Bonet; I García Villena; P Tomás Santos; I Tapia Mayor; P Gussinyé Canabal; X Mundet Tuduri,"To compare patients with hypercholesterolaemia (HC) for factors relating to the decision to treat a patient with medication or not; and to assess the suitability of a previously established protocol of HC diagnosis and treatment. Retrospective, descriptive study. Primary care centre. 331 patients diagnosed with HC in the register of risk factors at our centre. 175 patients treated with medication (TM) and 156 not treated with medication. Mean age was 61.2 and 191 were women. 68.8% of the population under study had 2 or more factors of cardiovascular risk (FCVR). 56 patients were in secondary prevention (71.4% TM). 275 patients (83.08%) were in primary prevention. 135 of these received TM, which was indicated only in 45 (37.5%). Mean plasma concentrations (PC) of cholesterol (total and LDL) were greater in the patients treated. 99.3% of non-treated patients and 96.9% of treated patients received dietary counselling. This was maintained in 95% of non-treated patients. The reduction of cholesterol in the PC reached 8% in diet-treated patients by the end of the study. Initially 42.8% were treated with fibrates, 38.9% with statins and 18.3% with resins. By the end of the study 53.6% were treated with statins. The association of HC and other FCVR is common. In primary prevention, a high proportion of patients treated present cardiovascular risk which does not justify medical prescription. In secondary prevention we are closer to the current guidelines.",1999.0,0,0 237,10593310,Is cholesterol a risk factor for stroke?: Yes.,A M Demchuk; D C Hess; L M Brass; F M Yatsu,,1999.0,0,0 238,10593311,Is cholesterol a risk factor for stroke?: No.,W M Landau,,1999.0,0,0 239,10597756,,,,,0,0 240,10601131,Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia.,N Glorioso; C Troffa; F Filigheddu; F Dettori; A Soro; P P Parpaglia; S Collatina; M Pahor,"Certain hydroxymethylglutaryl coenzyme A reductase inhibitors, ie, statins, may cause vasodilation by restoring the endothelial dysfunction that frequently accompanies hypertension and hypercholesterolemia. Several studies have found that a blood pressure reduction is associated with the use of statins, but conclusive evidence from controlled trials is lacking. After an 8-week placebo and diet run-in period, 30 persons with moderate hypercholesterolemia and untreated hypertension (total cholesterol 6.29+/-0.52 mmol/L, systolic and diastolic blood pressure 149+/-6 and 97+/-2 mm Hg) were randomized in a double-blind manner to placebo or pravastatin (20 to 40 mg/d) in a crossover design. In 25 participants who completed the 32-week trial, pravastatin decreased total and LDL cholesterol (both -1.09 mmol/L, P=0.001), systolic and diastolic blood pressure (-8 and -5 mm Hg, both P=0.001), and pulse pressure (-3 mm Hg, P=0.011) and blunted the blood pressure increase caused by the cold pressor test (-4 mm Hg, P=0.005) compared with placebo. It also reduced the level of circulating endothelin-1 (P=0.001). The blood pressure results were virtually unchanged in stratified analyses according to gender and age and in intention-to-treat analyses that included the 5 patients who dropped out of the study. When the participants were taking either placebo or pravastatin, blood pressure was not significantly correlated with total or LDL cholesterol or with circulating endothelin-1. Pravastatin decreases systolic, diastolic, and pulse pressures in persons with moderate hypercholesterolemia and hypertension. This antihypertensive effect may contribute to the documented health benefits of certain statins.",1999.0,0,0 241,10608479,Implication of recent trials with b-hydroxy-b-methylglutaryl coenzyme A reductase inhibitors for hypertension management.,I U Haq; E J Wallis; P R Jackson; W W Yeo; L E Ramsay,"There is broad agreement that statin treatment should be targeted at absolute coronary heart disease (CHD) risk but no consensus on the level of risk to target. We have examined the implications of adopting three different treatment policies for the management of hypertensive patients in the UK using data from treated hypertensives aged 35-69 years included in the Health Survey for England (1993). We calculated the proportion of hypertensive patients with existing atherosclerotic cardiovascular disease requiring statin treatment for secondary prevention of CHD. For those without atherosclerotic cardiovascular disease (primary prevention), we estimated CHD risk from the Framingham equation and examined the proportion with CHD risk exceeding thresholds of 4.5, 3 and 1.5% per year. Twenty-one percent of treated hypertensives would require statin treatment for secondary prevention of CHD. When the CHD event threshold for statin treatment was set at > or =4.5% per year [equivalent to a number needed to treat (NNT) in 5 years of 13] a further 0.6% of hypertensive patients were identified for treatment; at a threshold of 3.0% per year (NNT = 20) 5.5% of patients were identified for primary prevention; and at a threshold of 1.5% per year (NNT = 40) 28.5% of patients were identified for primary prevention. Those needing secondary prevention are first priority for statins and 21% of hypertensive patients will require treatment Formulation of guidelines for primary prevention should take into account the NNT; the proportion of patients targeted for treatment; the cost-effectiveness and the total cost of treatment. Current British guidance will entail treating an additional 5.5% of hypertensive patients for primary prevention and therefore 27% of hypertensive patients.",1999.0,0,0 242,10610245,Anti-lipid trial endpoints.,D G Orloff,,1999.0,0,0 243,10610464,Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease.,D J Cohen; J P Carrozza; D S Baim,,2000.0,0,0 244,10610568,Cholesterol-lowering drugs may boost bones.,G Vogel,,1999.0,0,0 245,10612296,Is there a place for LDL-apheresis in non-homozygous patients?,B Stegmayr,,1999.0,0,0 246,10612322,Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials.,J C LaRosa; J He; S Vupputuri,"Lowering low-density lipoprotein cholesterol (LDL-C) is known to reduce risk of recurrent coronary heart disease in middle-aged men. However, this effect has been uncertain in elderly people and women. To estimate the risk reduction of coronary heart disease and total mortality associated with statin drug treatment, particularly in elderly individuals and women. Trials published in English-language journals were retrieved by searching MEDLINE (1966-December 1998), bibliographies, and authors' reference files. Studies in which participants were randomized to statin or control treatment for at least 4 years and clinical disease or death was the primary outcome were included in the meta-analysis (5 of 182 initially identified). Information on sample size, study drug duration, type and dosage of statin drug, participant characteristics at baseline, reduction in lipids during intervention, and outcomes was abstracted independently by 2 authors (J.H. and S.V.) using a standardized protocol. Disagreements were resolved by consensus. Data from the 5 trials, with 30 817 participants, were included in this meta-analysis. The mean duration of treatment was 5.4 years. Stati n drug treatment was associated with a20% reduction in total cholesterol, 28% reduction in LDL-C, 13% reduction in triglycerides, and 5% increase in high-density lipoprotein cholesterol. Overall, statin drug treatment reduced risk 31 % in major coronary events (95% confidence interval [CI], 26%-36%) and 21 % in all-cause mortality (95% CI, 14%-28%). The risk reduction in major coronary events was similar between women (29%; 95% Cl, 13 %-42 %) and men (31 %; 95% CI, 26%-35%), and between persons aged at least 65 years (32%; 95% CI, 23%-39%) and persons younger than 65 years (31 %; 95% CI, 24%-36%). Our meta-analysis indicates that reduction in LDL-C associated with statin drug treatment decreases the risk of coronary heart disease and all-cause mortality. The risk reduction was similar for men and women and for elderly and middle-aged persons.",2001.0,1,1 247,10613627,Lipid-lowering and skin vascular responses in patients with hypercholesterolaemia and peripheral arterial obstructive disease.,F Khan; S J Litchfield; P A Stonebridge; J J Belch,"Elevated blood cholesterol is a major risk factor for atherosclerosis. Recent studies show that lowering cholesterol reduces the risk of vascular disease, but the precise mechanisms for vascular improvement are not fully understood. Furthermore, it is not known whether the beneficial effects of cholesterol lowering extend to the skin microvasculature. In this unrandomized, open design study, we used iontophoresis and laser Doppler flowmetry to examine forearm skin perfusion in hypercholesterolaemic patients with PAOD before and after cholesterol-lowering therapy with fluvastatin. Endothelium-dependent and -independent vasodilatation were measured following skin iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively. Before cholesterol-lowering, vascular responses to ACh and SNP were reduced significantly in patients compared with responses in control subjects (p < 0.001 and p < 0.05, ANOVA, respectively). Fluvastatin therapy (40 mg/day) for 24 weeks significantly reduced total cholesterol (7.3+/-0.3 to 6.0+/-0.2 mmol/l, p < 0.001) and LDL cholesterol (5.4+/-0.5 to 4.2+/-0.4 mmol/l, p < 0.01). Vasodilatation to SNP was significantly improved at week 24 (p < 0.05). In patients with hypercholesterolaemia and PAOD, cholesterol-lowering with statin therapy significantly improved endothelium-independent vascular responses to SNP in skin microvessels. The application of the non-invasive techniques of iontophoresis and laser Doppler flowmetry may provide useful markers for the assessment of microvascular function in this group of patients.",1999.0,0,0 248,10613632,Statins and cerebrovascular disease: plaque attack to prevent brain attack.,E R Mohler; N Delanty; D J Rader; E C Raps,"Stroke is the third leading cause of death in the USA and in the developed world. The beneficial role of cholesterol reduction in decreasing stroke has been uncertain. However, recent data indicate that statin treatment in patients with a history of myocardial infarction not only reduces the risk of a second myocardial infarction, coronary heart disease, revascularization procedures and death, but also significantly reduces the risk of stroke. However, the mechanism(s) by which statins reduce stroke remain uncertain. Thus, the therapeutic armamentarium for the reduction of stroke in secondary prevention now includes cholesterol reduction with statins.",2001.0,0,0 249,10614803,Efficacy of vitamin E compared with either simvastatin or atorvastatin in preventing the progression of atherosclerosis in homozygous familial hypercholesterolemia.,F J Raal; G J Pilcher; M G Veller; M J Kotze; B I Joffe,"Over a 4-year period, antioxidant therapy (vitamin E) was compared with high-dose statin therapy in 15 patients with homozygous familial hypercholesterolemia. Carotid intima-media thickness, used as an in vivo assessment of atherosclerosis, progressed rapidly during the period of vitamin E therapy but regressed on statin therapy.",1999.0,0,0 250,10617243,A double-blind placebo controlled trial of simvastatin for the treatment of dyslipidaemia in renal allograft recipients.,F Lepre; R Rigby; C Hawley; D Saltissi; A Brown; Z Walsh,"With current techniques, renal failure patients are now able to regain near-normal health following renal transplantation. However, the development of premature cardiovascular disease is a major problem. Dyslipidaemia may be an important contributor to this. The use of lipid lowering agents in renal allograft recipients has been limited by potential interaction of these agents with the now widely used immunosuppressive agent, cyclosporine. This study was designed to investigate efficacy and safety of simvastatin in subjects taking either cyclosporine or azothioprine post renal transplantation. Fifty-one subjects (32 females, 19 males -- mean age 51 +/- 12.5 yr) who were at least 1 yr post transplant, had creatinine < or = 2.5 mmol/L and a total cholesterol > or = 6 mmol/L were enrolled in a prospective, double-blind, placebo-controlled study. After an initial 10-wk dietary period, the last 4 wk on placebo, subjects were randomised to receive either 5 mg simvastatin/d for 6 wk followed by 10 mg simvastatin/d for 6 wk, or matching placebo. After this 12-wk double-blind phase, there was an open-label phase when all subjects were treated with 10 mg simvastatin/d for a period of 36 wk. Compared to placebo, 5 mg simvastatin/d significantly decreased total cholesterol by 20% (p < 0.01), low-density lipoprotein cholesterol (LDL cholesterol) by 29% (p < 0.01), and Apolipoprotein B (ApoB) by 26% (p < 0.01). Increasing simvastatin to 10 mg/d did not lead to further significant changes. But high-density lipoprotein cholesterol (HDL cholesterol) increased by 9% (p < 0.01) and Apolipoprotein A1 (ApoA1) by 7% (p < 0.01) only on 10 mg simvastatin/d. During the open-label phase, subjects previously randomised to placebo achieved similar significant changes to their lipoprotein profile. The benefits achieved from simvastatin were maintained to the end of the study. There were three withdrawals from the study, all from the simvastatin/ cyclosporine group. Two subjects had musculoskeletal pain and 1 had abdominal pain. Minor adverse events were similar in both the simvastatin- and placebo-treated groups. Low-dose simvastatin is an effective and well-tolerated agent in the treatment of dyslipidaemia in renal allograft recipients.",2000.0,0,0 251,10618558,"The PRESTO (Prevention of restenosis with tranilast and its outcomes) protocol: a double-blind, placebo-controlled trial.",D Holmes; P Fitzgerald; S Goldberg; J m LaBlanche; A M Lincoff; M Savage; P W Serruys; J Willerson; J R Granett; R Chan; N H Shusterman; M Poland,"Tranilast is a unique drug in clinical development for the prevention of restenosis after percutaneous transluminal coronary revascularization (PTCR). Tranilast interferes with proliferation and migration of vascular medial smooth muscle cells induced by platelet-derived growth factor and transforming growth factor beta1. Collagen synthesis in vascular medial smooth muscle cells is inhibited by tranilast, which also inhibits the release or production of cyclooxygenase-2 and restores cytokine-induced nitric oxide production. These mechanisms may contribute to the reduction of angiographic restenosis after coronary intervention previously reported in clinical studies. The primary objective of this multicenter study of 11,500 patients is to compare the composite clinical event rate of death, myocardial infarction, or the need for ischemia-driven target vessel revascularization of tranilast (300 and 450 mg twice daily) for 1 or 3 months with that of placebo in patients undergoing PTCR with or without stenting for single or multiple vessels over a 9-month period. The lesions can be de novo or restenotic. All revascularization procedures and the use of glycoprotein IIb/IIIa agents are permitted. The inclusion criteria are meant to allow an ""all comer"" approach for generalization of results to the broadest possible PTCR population. A subset population (n = 2000) will undergo 9-month follow-up angiography, 1000 of which will also undergo intravascular ultrasound (n = 1000). This study is the first tranilast trial to be conducted in a Western population to confirm the improved angiographic findings reported in Japanese patients and to determine if the clinical sequelae of restenosis are also reduced. This multicenter study is the largest restenosis trial planned to date. It will test whether tranilast, a drug with multiple actions aimed at affecting proliferation and migration of vascular smooth muscle cells, can reduce clinical, angiographic, and intravascular ultrasound assessments of restenosis.",2000.0,0,0 252,10620739,The Canadian Study of Cardiac Transplantation. Atherosclerosis. Investigators of the CASCADE Study.,M Carrier; M Rivard; W Kostuk; D Latter; P Daly; R Davies; K Teo; V Gudas; J Sullivan; M White,"To describe risk factors associated with the development of transplantation coronary artery disease (TCAD). A retrospective study of the Canadian experience. Seven hundred and nineteen patients with follow-up of at least 12 months following transplantation and a minimum of one coronary angiogram were analyzed. Two hundred and fourteen patients (30%) developed angiographic evidence of TCAD during an average follow-up of 50+/-25 months. Actuarial freedom rate from TCAD averaged 60%, and survival averaged 85% five years following transplantation. Abnormal coronary angiograms increased from 11% to 40% between the first and the fifth year following transplantation. The Cox multivariate final model showed that recipients of donor hearts of 50 years and older (RR 4.35, 95% CI 2.32 to 8.15), patients with two or more episodes of acute rejection (RR 1.56, 95% CI 1.11 to 2.21) and patients with a diagnosis of ischemic cardiomyopathy before transplantation (RR 1.38, 95% CI 1.03 to 1.84) were at higher risk of TCAD. The same risk factors also had a significant effect on survival, although patients who were administered a hepatic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor during follow-up had a higher survival rate (95% versus 85%, P=0.01) five years following heart transplantation. Recipients of hearts from older donors, patients with an ischemic heart disease before transplantation and those with several episodes of acute rejection are at increased risk for TCAD. Patients who are administered an HMG-CoA reductase inhibitor during follow-up have a higher survival rate five years following transplantation.",2000.0,0,0 253,10622068,An assessment of the efficacy of atorvastatin in achieving LDL cholesterol target levels in patients with coronary heart disease: a general practice study.,H A Neil; G Fowler; H Patel; Z Eminton; S Maton,"Adherence to evidence-based guidelines for the secondary prevention of coronary heart disease (CHD) has been shown to be poor in a number of surveys. In this open-label, non-comparative 17-week trial, 399 patients with existing CHD and LDL cholesterol concentration > 3.4 mmol/l (130 mg/dl) were treated with atorvastatin 10 mg daily. After 5 weeks, the dose of atorvastatin was adjusted according to a patient's LDL cholesterol level. Of the 379 patients remaining in the study after five weeks of treatment, dose titration was not required for 355 patients (94%) who had reached the target LDL cholesterol of < or = 3.4 mmol/l. Of the 23 patients titrated to higher doses, 11 achieved the target LDL cholesterol after treatment for 17 weeks. Atorvastatin was well tolerated during the course of the study. Achieving LDL cholesterol targets without the need for dose titration simplifies clinical management and should encourage better adherence to evidence-based recommendations for secondary prevention of CHD.",2000.0,0,0 254,10624080,Pharmacomodulation of endothelial dysfunction: clinical relevance.,J J Dalal,,2000.0,0,0 255,10626120,Emerging new therapies for cutaneous T-cell lymphoma.,M Duvic; J C Cather,"Improved therapy for CTCL will depend on a better understanding of the pathogenesis of this disease at a molecular level. It is clear that the T cells in MF and CTCL do not undergo normal programmed cell death and have prolonged lifespans. Skin flora or other antigens may stimulate the initial proliferation, offering another approach to change the course of the disease. There has been tremendous interest in biological response modifiers, and the first targeted fusion toxin to activated T cells has been approved for CTCL. New retinoids with increased selectivity and decreased side effects are being tested for this disease. In summary, the treatment of CTCL should continue to improve and should be focused on strategies that preserve the immune function in these patients.",2000.0,0,0 256,10627270,Dosing of atorvastatin and increases in fibrinogen level.,H Sinzinger; M Rodrigues; C D Furberg,,2000.0,0,0 257,10627271,Effects of atorvastatin in patients with homozygous familial hypercholesterolemia.,A Postiglione; S Montefusco; P Pauciullo; M Mancini; T Piliego,,2000.0,0,0 258,10627888,Atorvastatin compared with simvastatin-based therapies in the management of severe familial hyperlipidaemias.,A S Wierzbicki; P J Lumb; Y Semra; G Chik; E R Christ; M A Crook,"We compared atorvastatin with simvastatin-based therapies in a prospective observational study of 201 patients with severe hyperlipidaemia. Atorvastatin 10 mg therapy was substituted for simvastatin 20 mg, 20 mg for 40 mg, 40 mg for simvastatin 40 mg plus resin, and 80 mg for simvastatin-fibrate-resin therapy. Lipid and safety profiles were assessed. Atorvastatin reduced total cholesterol by 31 +/- 11-40 +/- 14% vs. 25 +/- 12-31 +/- 11%; LDL by 38 +/- 16-45 +/- 18% vs. 31 +/- 18-39 +/- 18% and geometric mean triglycerides by 29.3-37.3% vs. 16.6-24.8%, but reduced HDL 11% +/- 47% at 80 mg compared with a 16% +/- 34% increase with simvastatin-based therapy. Target LDL < 3.5 mmol/l was achieved more often with atorvastatin (63% vs. 50%; p < 0.001). Atorvastatin increased geometric mean fibrinogen by 12-20% vs. a 0-6% fall with simvastatin (p < 0.001). Side effects were noted in 10-36% of patients, including one case of rhabdomyolysis, and 36% discontinued therapy. These data suggest that atorvastatin is more effective than current simvastatin-based therapies in achieving treatment targets in patients with familial hypercholesterolaemia but at the expense of a possible increase in side-effects. This issue needs further study in randomized controlled trials.",2000.0,0,0 259,10629395,,,,,0,0 260,10631627,Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion.,R A Boyd; R H Stern; B H Stewart; X Wu; E L Reyner; E A Zegarac; E J Randinitis; L Whitfield,"The effect of atovarstatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady-state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady-state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0-24) values, respectively. Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P-glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P-glycoprotein transport, the influence of atorvastatin and its metabolites on P-glycoprotein-mediated digoxin transport in monolayers of the human colon carcinoma (Caco-2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a K(m) of 110 microM. Atorvastatin (100 microM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P-glycoprotein transport. Thus, the increase in steady-state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.",2000.0,0,1 261,10632286,Clinical goals and performance measures for cholesterol management in secondary prevention of coronary heart disease.,T H Lee; J I Cleeman; S M Grundy; C Gillett; R C Pasternak; J Seidman; C Sennett,"Guidelines from the National Cholesterol Education Program (NCEP) recommend reduction of low-density lipoprotein cholesterol (LDL-C) to 100 mg/dL (2.59 mmol/L) or less in patients with established coronary heart disease (CHD). However, the National Committee for Quality Assurance (NCQA) is implementing a new performance measure as part of the Health Plan Employer and Data Information Set (HEDIS) that appears to endorse a different target. The new HEDIS measure will require managed care organizations seeking NCQA accreditation to measure and report the percentage of patients who have had major CHD events who achieve LDL-C levels less than 130 mg/dL (3.36 mmol/L) between 60 and 365 days after discharge. These different LDL-C thresholds emphasize the difference between a clinical goal for the management of individual patients (< or =100 mg/dL) and a performance measure used to evaluate the care of a population of patients (<130 mg/dL). This article discusses the rationale for each threshold and explains the use of 2 different thresholds for these 2 purposes. Both the NCQA and NCEP expect that the new HEDIS measure will encourage managed care organizations to develop systems that improve secondary prevention of CHD.",2001.0,0,0 262,10632823,Efficacy of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for prevention of stroke.,S Warshafsky; D Packard; S J Marks; N Sachdeva; D M Terashita; G Kaufman; K Sang; A J Deluca; S J Peterson; W H Frishman,"To determine if 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are effective in preventing fatal and nonfatal strokes in patients at increased risk of coronary artery disease. Meta-analysis of randomized controlled trials. Clinical trials were identified by a computerized search of MEDLINE (1983 to June 1996), by an assessment of the bibliographies of published studies, meta-analyses and reviews, and by contacting pharmaceutical companies that manufacture statins. Trials were included in the analysis if their patients were randomly allocated to a statin or placebo group, and reported data on stroke events. Thirteen of 28 clinical trials were selected for review. Data were extracted for details of study design, patient characteristics, interventions, duration of therapy, cholesterol measurements, and the number of fatal and nonfatal stroke events in each arm of therapy. Missing data on stroke events were obtained by contacting the investigators of the clinical trials. Among 19,921 randomized patients, the rate of total stroke in the placebo group was 2.38% (90% nonfatal and 10% fatal). In contrast, patients who received statins had a 1.67% stroke rate. Using an exact stratified analysis, the pooled odds ratio (OR) for total stroke was 0.70 (95% confidence interval [CI] 0.57, 0.86; p =.0005). The pooled OR for nonfatal stroke was 0.64 (95% CI 0.51, 0.79; p =.00001), and the pooled OR for fatal stroke was 1.25 (95% CI 0.71, 2.24; p =.4973). In separate analyses, reductions in total and nonfatal stroke risk were found to be significant only for trials of secondary coronary disease prevention. Regression analysis showed no statistical association between the magnitude of cholesterol reduction and the relative risk for any stroke outcome. The available evidence clearly shows that HMG-CoA reductase inhibitors reduce the morbidity associated with strokes in patients at increased risk of cardiac events. Data from 13 placebo-controlled trials suggest that on average one stroke is prevented for every 143 patients treated with statins over a 4-year period.",2000.0,0,0 263,10632825,HMG coenzyme A reductase inhibitors: good news and bad news.,M J Klag,,2000.0,0,0 264,10636252,The evolving role of statins in the management of atherosclerosis.,C J Vaughan; A M Gotto; C T Basson,"Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--""statins."" Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.",2001.0,0,0 265,10636263,Cholesterol reduction improves myocardial perfusion abnormalities in patients with coronary artery disease and average cholesterol levels.,J M Mostaza; M V Gomez; F Gallardo; M L Salazar; R Martín-Jadraque; L Plaza-Celemín; I Gonzalez-Maqueda; L Martín-Jadraque,"We sought to evaluate whether pravastatin treatment increases myocardial perfusion, as assessed by thallium-201 single-photon emission computed tomographic (SPECT) dipyridamole testing, in patients with coronary artery disease (CAD) and average cholesterol levels. Previous studies in hypercholesterolemic patients have demonstrated that cholesterol reduction restores peripheral and coronary endothelium-dependent vasodilation and increases myocardial perfusion. This was a randomized, placebo-controlled study with a cross-over design. Twenty patients with CAD were randomly assigned to receive 20 mg of pravastatin or placebo for 16 weeks and then were crossed over to the opposite medication for a further 16 weeks. Lipid and lipoprotein analysis and dipyridamole thallium-201 SPECT were performed at the end of each period. The SPECT images were visually analyzed in eight myocardial segments using a 4-point scoring system by two independent observers. A summed stress score and a summed rest score were obtained for each patient. Quantitative evaluation was performed by the Cedars-Sinai method. The magnitude of the defect was expressed as a percentage of global myocardial perfusion. Total and low density lipoprotein cholesterol levels during placebo were 214 +/- 29 mg/dl and 148 +/- 25 mg/dl, respectively. These levels with pravastatin were 170 +/- 23 mg/dl and 103 +/- 23 mg/dl, respectively. The summed stress score and summed rest score were lower with pravastatin than with placebo (7.2 +/- 2.3 vs. 5.9 +/- 2.3, p = 0.012 and 3.2 +/- 1.6 vs. 2.4 +/- 2.2, p = 0.043, respectively). Quantitative analysis showed a smaller perfusion defect with pravastatin (29.2%) as compared with placebo (33.8%) (p = 0.021) during dipyridamole stress. No differences were found at rest. Reducing cholesterol levels with pravastatin in patients with CAD improves myocardial perfusion during dipyridamole stress thallium-201 SPECT.",2000.0,0,0 266,10636265,Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin: the lipoprotein and coronary atherosclerosis study.,A J Marian; F Safavi; L Ferlic; J K Dunn; A M Gotto; C M Ballantyne,"Our objectives were to determine whether angiotensin-1 converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the severity of coronary artery disease (CAD) and its progression/regression in response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. Genetic factors are involved in susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which accounts for half of the variance of plasma and tissue levels of ACE, has been implicated in susceptibility to CAD and myocardial infarction (MI). Angiotensin-1 converting enzyme genotypes were determined by polymerase chain reaction (PCR). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. Ninety-one subjects had DD, 198 ID and 75 II genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of coronary lesions and total occlusions were not significantly different at baseline or follow-up among the genotypes. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In response to fluvastatin therapy, subjects with DD, compared with those with ID and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite progression was less (14%) and regression was more common (24%) in DD as compared with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023). Changes in the mean MLD and lesion-specific MLD also followed the same trend. Angiotensin-1 converting enzyme I/D polymorphism is associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of CAD.",2000.0,0,0 267,10637210,Current perspectives on statins.,D J Maron; S Fazio; M F Linton,"Statins (HMG-CoA reductase inhibitors) are used widely for the treatment of hypercholesterolemia. They inhibit HMG-CoA reductase competitively, reduce LDL levels more than other cholesterol-lowering drugs, and lower triglyceride levels in hypertriglyceridemic patients. Statins are well tolerated and have an excellent safety record. Clinical trials in patients with and without coronary heart disease and with and without high cholesterol have demonstrated consistently that statins reduce the relative risk of major coronary events by approximately 30% and produce a greater absolute benefit in patients with higher baseline risk. Proposed mechanisms include favorable effects on plasma lipoproteins, endothelial function, plaque architecture and stability, thrombosis, and inflammation. Mechanisms independent of LDL lowering may play an important role in the clinical benefits conferred by these drugs and may ultimately broaden their indication from lipid-lowering to antiatherogenic agents.",2000.0,1,1 268,10639300,Effects of simvastatin only or in combination with continuous combined hormone replacement therapy on serum lipid levels in hypercholesterolaemic post-menopausal women.,A S Fak; M Erenus; H Tezcan; O Caymaz; P Atagündüz; S Oktay; A Oktay,"To evaluate the effects of simvastatin only or combined with continuous hormone replacement therapy on the serum lipid profile in hypercholesterolaemic post-menopausal women. One hundred hypercholesterolaemic post-menopausal women were given either simvastatin 10 mg daily together with oestrogen 0.625 mg and medroxyprogesterone 2.5 mg daily (HRT+simvastatin group) (n:50) or simvastatin 10 mg daily (simvastatin only group) (n:50) in a prospective manner. Serum total, low density lipoprotein, and high density lipoprotein cholesterol and triglyceride levels were measured at baseline, at 3 and 6 months. The initial mean (+/-SD) cholesterol values were as follows for the HRT+simvastatin group and the simvastatin only group, respectively: total cholesterol 240. 0+/-28.0 and 248.9+/-28.2 mg x dl(-1); low density lipoprotein cholesterol 174.7+/-25.6 and 175.1+/-25.9 mg x dl(-1); high density lipoprotein cholesterol 37.2+/-5.0 and 39.9+/-7.3 mg x dl(-1). Compared with the baseline, total and low density lipoprotein cholesterol levels decreased; and high density lipoprotein cholesterol levels increased significantly at 3 and 6 months in both groups. However, the mean percent reduction in total cholesterol and low density lipoprotein cholesterol was significantly greater in the HRT+ simvastatin group compared with the simvastatin only group both at 3 months (12.3+/-7.0% vs 8.9+/-6.2%;P<0.01; and 19.0+/-10.6% vs 13.2+/-10.4%;P< 0.005, respectively) and at 6 months (14.6+/-7.7% vs 11.3+/-7.4%;P<0.05 and 23.3+/-9.7% vs 15.8+/-12.3%;P<0.005, respectively). The mean percent increase in serum high density lipoprotein cholesterol concentrations was also significantly greater in the HRT+simvastatin group compared with the simvastatin only group at both times (14.6+/-11.8% vs 9.8+/-11.8%;P<0.005, at 3 months, and 21.3+/-15.2% vs 11.1+/-12.5;P<0.005, at 6 months, respectively). Furthermore, significantly more patients in the HRT+simvastatin group than in the simvastatin only group attained their target treatment goals dictated by the National Cholesterol Education Program Adult Treatment Panel II Guidelines. Although the mean percent decrease in triglyceride levels was significantly greater in the HRT+simvastatin group at 3 months, the significance disappeared at 6 months. The combination of simvastatin and continuous combined hormone replacement therapy seems to be more effective than simvastatin only in the treatment of hypercholesterolaemia in post-menopausal women.",2000.0,0,0 269,10639539,,,,,0,0 270,10644862,"Pravastatin treatment of very low density, intermediate density and low density lipoproteins in hypercholesterolemia and combined hyperlipidemia secondary to the nephrotic syndrome.",R D Toto; S M Grundy; G L Vega,"In the current study pravastatin was used in nephrotic syndrome patients with hypercholesterolemia and combined hyperlipidemia to test whether the drug decreases production of LDL and reduces levels of VLDL and IDL. Thirteen patients (7 with high LDL alone and 6 with high VLDL, IDL and LDL) were randomized in a placebo-controlled study that had a crossover design. Patients were treated 8 weeks with pravastatin (40 mg/day) (or placebo) and switched to the corresponding placebo/drug for another 8 weeks. During each phase of the trial, patients had measurement of plasma levels of lipoprotein lipids, and turnover rates of autologous LDL apo B. Pravastatin increased LDL clearance by 16.7% and reduced total cholesterol content per LDL particle in patients with hypercholesterolemia. In combined hyperlipidemia, LDL clearance increased by 19% and there was no significant change in the production of LDL-apo B. Levels of VLDL+IDL apo B were not reduced significantly, while the total cholesterol content of these particles was reduced by 31.7%. Pravastatin effectively reduced LDL levels in both types of dyslipidemia by increasing LDL clearance. Treatment had no effect on production of LDL or on levels of VLDL+IDL-apo B. Thus, pravastatin increases LDL clearance. Statins do not seem to affect production rates of apo B-containing lipoproteins. Treatment of combined hyperlipidemia may require pravastatin and an added drug targeted to normalize levels of VLDL and IDL.",2000.0,0,0 271,10644914,Which dosage of simvastatin in renal transplant patients?,A Celik; A Unsal; I Mutaf; S Habif; E Ok; O Bayindir,,2000.0,0,1 272,10645752,Sex-related differences in response of plasma lipids to simvastatin: the Saitama Postmenopausal Lipid Intervention Study. S-POLIS Group.,K Nakajima,"The Saitama Postmenopausal Lipid Intervention Study was a multicenter, uncontrolled, collaborative study that investigated tolerability and sex-related differences in the response of serum lipids to simvastatin administered for 12 months in 122 postmenopausal women and 55 men with serum total cholesterol (TC) levels > or =220 mg/dL. With simvastatin treatment, TC and low-density lipoprotein cholesterol (LDL-C) levels decreased significantly at 1 month in both groups, and these decreased levels were maintained throughout treatment (P < 0.001). A significant decrease in triglyceride (TG) levels was also observed in both groups (P < 0.05). The mean percentage decreases in TC and LDL-C levels in women (20% and 28%, respectively) were significantly greater than those in men (15% and 20%, respectively) (P < 0.001). Mean percentage changes in TC and LDL-C levels in subgroups defined by stratification for baseline TC and LDL-C levels were also greater in women. There were no sex-related differences in the percentage changes in TG or high-density cholesterol levels, although the changes were influenced by baseline levels. Although the median dose of simvastatin (milligrams per kilogram of body weight) in women was significantly higher than in men (P < 0.001), the percentage changes in serum lipids were not correlated with the doses of simvastatin calibrated by body weight. Adverse reactions occurred in 8 men and 7 women, so there appeared to be no significant sex-related difference. Eleven patients had abnormal laboratory values. Simvastatin therapy for 12 months is well tolerated and effective for both women and men with hypercholesterolemia. Sex-related differences occurred in the response to simvastatin therapy of serum lipids, especially TC and LDL-C, with greater changes in lipid levels occurring in women.",2000.0,0,0 273,10656300,Vitamin E and heart disease: basic science to clinical intervention trials.,W A Pryor,"A review is presented of studies on the effects of vitamin E on heart disease, studies encompassing basic science, animal studies, epidemiological and observational studies, and four intervention trials. The in vitro, cellular, and animal studies, which are impressive both in quantity and quality, leave no doubt that vitamin E, the most important fat-soluble antioxidant, protects animals against a variety of types of oxidative stress. The hypothesis that links vitamin E to the prevention of cardiovascular disease (CVD) postulates that the oxidation of unsaturated lipids in the low-density lipoprotein (LDL) particle initiates a complex sequence of events that leads to the development of atherosclerotic plaque. This hypothesis is supported by numerous studies in vitro, in animals, and in humans. There is some evidence that the ex vivo oxidizability of a subject's LDL is predictive of future heart events. This background in basic science and observational studies, coupled with the safety of vitamin E, led to the initiation of clinical intervention trials. The three trials that have been reported in detail are, on balance, supportive of the proposal that supplemental vitamin E can reduce the risk for heart disease, and the fourth trial, which has just been reported, showed small, but not statistically significant, benefits. Subgroup analyses of cohorts from the older three trials, as well as evidence from smaller trials, indicate that vitamin E provides protection against a number of medical conditions, including some that are indicative of atherosclerosis (such as intermittent claudication). Vitamin E supplementation also produces an improvement in the immune system and protection against diseases other than cardiovascular disease (such as prostate cancer). Vitamin E at the supplemental levels being used in the current trials, 100 to 800 IU/d, is safe, and there is little likelihood that increased risk will be found for those taking supplements. About one half of American cardiologists take supplemental vitamin E, about the same number as take aspirin. In fact, one study suggests that aspirin plus vitamin E is more effective than aspirin alone. There are a substantial number of trials involving vitamin E that are in progress. However, it is possible, or even likely, that each condition for which vitamin E provides benefit will have a unique dose-effect curve. Furthermore, different antioxidants appear to act synergistically, so supplementation with vitamin E might be more effective if combined with other micronutrients. It will be extremely difficult to do trials that adequately probe the dose-effect curve for vitamin E for each condition that it might affect, or to do studies of all the possible combinations of other micronutrients that might act with vitamin E to improve its effectiveness. Therefore, the scientific community must recognize that there never will be a time when the science is ""complete."" At some point, the weight of the scientific evidence must be judged adequate; although some may regard it as early to that judgement now, clearly we are very close. In view of the very low risk of reasonable supplementation with vitamin E, and the difficulty in obtaining more than about 30 IU/day from a balanced diet, some supplementation appears prudent now.",2000.0,0,0 274,10657561,Mercury accumulation and accelerated progression of carotid atherosclerosis: a population-based prospective 4-year follow-up study in men in eastern Finland.,J T Salonen; K Seppänen; T A Lakka; R Salonen; G A Kaplan,"Basic research and our previous studies have suggested that mercury exposure enhances lipid peroxidation and the risk of myocardial infarction, but there are no studies concerning the association between mercury accumulation and atherosclerosis. We therefore investigated whether high hair mercury content is associated with accelerated progression of carotid atherosclerosis, determined by ultrasonographic assessment of common carotid intima-media thickness (IMT), in a prospective study among 1014 men aged 42-60 years. In a linear regression model adjusting for other atherosclerotic risk factors, high hair mercury content was one of the strongest predictors of the 4-year increase in the mean IMT (P2.81 microg/g (fifths) had an IMT increase of 0.105, 0.102, 0.113, 0.107 and 0.140 mm/4 years, respectively (P=0.041 for heterogeneity between groups). The IMT increase was 0.034 mm/4 years (31.9%) greater in the highest fifth than in the other fifths (P<0.05 for the difference). These findings suggest that mercury accumulation in the human body is associated with accelerated progression of carotid atherosclerosis.",2000.0,0,0 275,10657578,Hyperlipoproteinemia affects cytokine production in whole blood samples ex vivo. The influence of lipid-lowering therapy.,M F Mohrschladt; A W Weverling-Rijnsburger; F H de Man; D J Stoeken; A Sturk; A H Smelt; R G Westendorp,"Low-density lipoprotein (LDL)-receptor deficient mice, thus hypercholesterolemic, combine protection against infection with an ex vivo two- to threefold higher pro-inflammatory cytokine production in macrophages. A pro-inflammatory cytokine profile ex-vivo is also associated with survival of gram-negative sepsis in man. We hypothesized that high lipoprotein levels would be associated with a pro-inflammatory cytokine production and could explain the resistance to fatal infection. We treated 10 patients with familial hypercholesterolemia (FH) with HMG-CoA reductase inhibitors, and 13 patients with endogenous hypertriglyceridemia (HTG) with fibrates. Blood samples were stimulated ex vivo with lipopolysaccharide (LPS), to assess the cytokine production capacity. FH patients had significantly lower tumor necrosis factor-alpha (TNF-alpha) production, compared to normolipidemic controls (P=0. 001). Lipid lowering treatment in FH patients did not affect TNF-alpha production. HTG patients showed significantly higher TNF-alpha production at baseline than matched normolipidemic controls (P<0.001), while lowering of serum triglycerides in these patients resulted in a significant decrease in TNF-alpha production (P=0.019). The IL-10 production was not affected. These data refute our hypothesis that high LDL-cholesterol levels are associated with a pro-inflammatory cytokine production capacity. In contrast, the study suggests that very-low-density lipoprotein (VLDL) in hypertriglyceridemic patients augments TNF-alpha production.",2000.0,0,0 276,10662743,Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).,A M Gotto; E Whitney; E A Stein; D R Shapiro; M Clearfield; S Weis; J Y Jou; A Langendörfer; P A Beere; D J Watson; J R Downs; J S de Cani,"The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is the first primary-prevention study in a cohort with average total cholesterol (TC) and LDL cholesterol (LDL-C) and below-average HDL cholesterol (HDL-C). Treatment with lovastatin (20 to 40 mg/d) resulted in a 25% reduction in LDL-C and a 6% increase in HDL-C, as well as a 37% reduction in risk for first acute major coronary event (AMCE), defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. This article describes the relation between baseline and on-treatment lipid and apolipoprotein (apo) parameters and subsequent risk for AMCEs. With all available data from the entire 6605-patient cohort, a prespecified Cox backward stepwise regression model identified outcome predictors, and logistic regression models examined the relation between lipid variables and AMCE risk. Baseline LDL-C, HDL-C, and apoB were significant predictors of AMCE; only on-treatment apoB and the ratio of apoB to apoAI were predictive of subsequent risk; on-treatment LDL-C was not. When event rates were examined across tertiles of baseline lipids, a consistent benefit of treatment with lovastatin was observed. Persons with average TC and LDL-C levels and below-average HDL-C may obtain significant clinical benefit from primary-prevention lipid modification. On-treatment apoB, especially when combined with apoAI to form the apoB/AI ratio, may be a more accurate predictor than LDL-C of risk for first AMCE.",2000.0,0,1 277,10664901,Cardiac drug and psychotropic drug interactions: significance and recommendations.,J J Strain; G Caliendo; J D Alexis; R S Lowe; A Karim; M Loigman,"Understanding cardiac drug interactions with concurrent psychotropic prescriptions is essential for the practicing cardiologist and primary care physician, as well as for the psychiatrist. There has been an explosive use of new drugs in both psychiatry and cardiology without widespread knowledge of their potential interactions. The increasing tendency toward poly-pharmacy, the use of psychotropic medications by cardiologists and primary care physicians caring for cardiac patients, and the growth of the aging population present major challenges for the practitioner. Finally, there is a need to have models/paradigms for predicting potential drug interactions--e.g., the Cytochrome p450 schema. This paper describes a method to identify, understand, and codify the interactions between psychotropic and cardiac drugs, a systematic approach for updating this key database and specific cardiac-psychotropic drug interactions. Specifically, this paper 1) details the interactions, 2) addresses the level of their clinical significance, 3) describes the potential mechanism(s) of the interactions, and 4) offers recommendations to the clinician. Since the majority of the original clinical trials, either for cardiac medications or psychotropic drugs, do not include studies comparing these two drug domains contemporaneously, their interactions often become known only with their combined use in the clinical arena, using the patient as ""guinea pig,"" and through subsequent reporting.",2000.0,0,0 278,10665124,Statins and strokes--reducing the risk.,G Jackson,,2000.0,0,0 279,10668836,Sex bias and underutilization of lipid-lowering therapy in patients with coronary artery disease at academic medical centers in the United States and Canada. Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) Investigators.,M Miller; R Byington; D Hunninghake; B Pitt; C D Furberg,"The efficacy of lipid-lowering therapy (LLT) has been well established for patients with preexisting coronary artery disease (CAD). However, limited information is available assessing the extent to which these medications are prescribed in academic medical centers. The use of LLT for patients with CAD was prospectively evaluated in 825 men and women who were recruited from 16 academic medical centers in the United States and Canada to participate in the Prospective Evaluation of the Vascular Events of Norvasc Trial (PREVENT). The assessment of LLT use during the 3-year trial was evaluated in patients receiving amlodipine therapy and placebo; levels of low-density lipoprotein cholesterol (LDL-C) were used to assess the impact of LLT. Despite a baseline prevalence of LLT in 42% of men (38% in 1994), half of the patients had high levels of LDL-C (>3.36 mmol [>130 mg/dL]). During the subsequent 3 years, the prevalence of elevated LDL-C levels dropped in men (29%) but remained stagnant in women (48%). These changes were associated with increased LLT in men (55%) but not in women (35%) (P = .04). In 1994, the LDL-C target goal (<2.59 mmol/L [<100 mg/dL]) was attained in 17% of men and 6% of women (P = .006). At study completion in 1997, the LDL-C target goal was achieved in 31% of men and only 12% of women (P = .001). This study highlights the relatively low treatment rates of hyperlipidemia among patients with CAD overall and women in particular who were participating in a clinical trial at academic medical centers in the United States and Canada. Because LLT has been proven to reduce future cardiovascular events, these results suggest that more intensive efforts should be promoted in order to maximize CAD reduction.",2000.0,0,0 280,10668858,Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition.,G K Dresser; J D Spence; D G Bailey,"Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein. Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice. Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide. Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ('statins') and CYP3A4 inhibitors. Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil. Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors. Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor. Beneficial drug interactions can occur. Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant. Certain HIV protease inhibitors, e.g. saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir. The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index. In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age. Interactions may occur under single dose conditions or only at steady state. The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes. Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction.",2000.0,0,0 281,10673735,Does the Dundee Step Test predict outcome in treated hypertension? A sub-study protocol for the ASCOT trial. Anglo-Scandinavian Cardiac Outcome Trial.,P O Lim; P T Donnan; T M MacDonald,"Treated hypertensive subjects may remain five times more likely to die of cardiac and cerebrovascular diseases than normotensive subjects with equivalent resting blood pressure (BP) levels. Research evidence suggests that exercise BP is a better predictor of end-organ damage and mortality than resting BP, and data from our centre show that a significant proportion of treated hypertensives have uncontrolled BP during a 5-min Dundee Step Test. The prognostic usefulness of exercise BP has yet to be translated into clinical practice because of the lack of a suitable technique. The Dundee Step Test is being evaluated in the ASCOT (Anglo-Scandinavian Cardiac Outcome Trial) study, a 5-year follow-up multicentre, multinational trial comparing the effect of newer (amlodipine and perindopril) and older (bendroflumethiazide and atenolol) antihypertensive agents stratified according to cholesterol levels on cardiac outcome. If the value of the Dundee Step Test is proven, then it may be adopted into routine clinical practice for the assessment of exercise BP. This may result in the improved management of hypertension with a subsequent reduction in morbidity and mortality. The publication of this study protocol is meant to be a statement of on-going research which may stimulate interest among those with an interest in this area of research. Journal of Human Hypertension (2000) 14, 75-78.",2000.0,0,0 282,10674411,Antiplatelet drugs attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes.,M Kodama; Y Yamasaki; K Sakamoto; R Yoshioka; M Matsuhisa; Y Kajimoto; K Kosugi; N Ueda; M Hori,"The intima-media thickness of the carotid artery has been established as a surrogate of definite atherosclerosis in subjects with high risk of vascular events. This study was done to evaluate the effectiveness of long-term antiplatelet therapy in attenuating progression of the intima-media thickness of the carotid artery of subjects with type 2 diabetes. Subjects who had an intima-media thickness over the threshold of the normal subjects but showed no symptoms of vascular events were randomly divided into groups given antiplatelet drugs [ticlopidine (n = 34) or a small dose of aspirin (n = 40)] or no drugs (n = 74). For the follow-up period (3.0+/-0.06 years), the subjects not given antiplatelet drugs showed a significantly higher progression of intima-media thickness (0.067+/-0.009 mm/year) than those given ticlopidine (0.034+/-0.013 mm/year) or aspirin (0.033+/-0.010 mm/year). Stepwise multivariant regression analysis showed that long-term administration of ticlopidine or aspirin significantly reduced the progression of intima-media thickness of diabetic subjects by 0.041 mm/year or 0.032 mm/ year, respectively. These data indicated that despite differences of their pharmacological mechanisms, antiplatelet drugs could attenuate the progression of intima-media thickness of the carotid artery wall of asymptomatic type 2 diabetics who had early-stage carotid atherosclerosis.",2000.0,0,0 283,10676597,Amiodarone: what have we learned from clinical trials?,G V Naccarelli; D L Wolbrette; J T Dell'Orfano; H M Patel; J C Luck,"Amiodarone is an antiarrhythmic agent commonly used in the treatment of supraventricular and ventricular tachyarrhythmias. This paper reviews clinical trials in which amiodarone was used in one of the treatment arms. Key post-myocardial infarction trials include EMIAT and CAMIAT, both of which demonstrated that amiodarone reduced arrhythmic but not overall mortality. In patients with congestive heart failure (CHF), amiodarone was associated with a neutral survival in CHF/STAT and improvement in survival in GESICA. In patients with nonsustained ventricular tachycardia, the MADIT trial demonstrated that therapy with an implantable cardioverter-defibrillator (ICD) improved survival compared with the antiarrhythmic drug arm in such patients, most of whom were taking amiodarone. In sustained VT/VF patients, the CASCADE trial demonstrated that empiric amiodarone lowered arrhythmic recurrence rates compared with other drugs guided by serial Holter or electrophysiologic studies. Several trials including AVID, CIDS, and CASH have demonstrated the superiority of ICD therapy compared with empiric amiodarone in improving overall survival. Clinical implications of these trials are discussed.",2000.0,0,0 284,10676770,Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.,K R Baker; J L Moake,"Large and unusually large von Willebrand factor (vWf) multimers may be responsible for systemic platelet aggregation in thrombotic thrombocytopenic purpura (TTP). This possibility is supported by studies that show deficient vWf-cleaving metalloproteinase and increased platelet-vWf binding during TTP episodes. In acute idiopathic TTP, decreased vWf metalloproteinase is the result of autoantibodies against the enzyme. In familial and acquired hemolytic-uremic syndrome, vWf-cleaving metalloproteinase activity is normal. A deficiency or defect in factor H, which normally dampens the activation of C3 via the alternative complement pathway, has been seen in some patients with familial hemolytic-uremic syndrome. Ticlopidine therapy is an important risk factor for TTP.",2000.0,0,0 285,10680023,Methods used to interpret the 12-lead electrocardiogram: Pattern memorization versus the use of vector concepts.,J W Hurst,"This article extols the value of using Grant's approach to the interpretation of electrocardiograms (ECGs). The essay includes a discussion on how people learn and emphasizes the difference in memorizing information, thinking, and learning. Simply stated, the brains of most people are not designed to memorize countless numbers of ECG patterns. Accordingly, the essay supports the view that a method of interpretation must be used, and the reader is encouraged to use basic principles of electrocardiography, including vector concepts, to interpret each ECG.",2000.0,0,0 286,10680028,Lipid-altering efficacy and safety of simvastatin 80 mg/day: long-term experience in a large group of patients with hypercholesterolemia. World Wide Expanded Dose Simvastatin Study Group.,L Ose; M H Davidson; E A Stein; J J Kastelein; R S Scott; D B Hunninghake; S Campodonico; W Insull; I D Escobar; H G Schrott; M E Stepanavage; M Wu; A C Tate; M R Melino; M Mercuri; Y B Mitchel,"Elevated levels of low-density lipoprotein (LDL) cholesterol promote the development of atherosclerosis and coronary heart disease. Simvastatin 80 mg/day will be more effective than simvastatin 40 mg/day at reducing LDL cholesterol and will be well tolerated. Two similar, randomized, multicenter, controlled, double-blind, parallel-group, 48-week studies were performed to evaluate the long-term lipid-altering efficacy and safety of simvastatin 80 mg/day in patients with hypercholesterolemia. One study conducted in the US enrolled patients meeting the National Cholesterol Education Program (NCEP) LDL cholesterol criteria for pharmacologic treatment. In the other multinational study, patients with LDL cholesterol levels > or = 4.2 mmol/l were enrolled. At 20 centers in the US and 19 countries world-wide, 1,105 hypercholesterolemic patients, while on a lipid-lowering diet, were randomly assigned at a ratio of 2:3 to receive simvastatin 40 mg (n = 436) or 80 mg (n = 669) once daily for 24 weeks. Those patients completing an initial 24-week base study were enrolled in a 24-week blinded extension. Patients who had started on the 80 mg dose in the base study continued on the same dose in the extension, while those who had started on the 40 mg dose were rerandomized at a 1:1 ratio to simvastatin 40 or 80 mg in the extension. There was a significant advantage in the LDL cholesterol-lowering effect of the 80 mg dose compared with that of the 40 mg dose, which was maintained over the 48 weeks of treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol for the 40 and 80 mg groups were 41% (42, 39) and 47% (48, 46), respectively, for the 24-week base study, and 41% (43, 39) and 46% (47, 45), respectively, after 48 weeks of treatment (p < 0.001 between groups). Larger reductions in total cholesterol and triglycerides were also observed with the 80 mg dose compared with the 40 mg dose at Weeks 24 and 48. Both doses were well tolerated, with close to 95% of patients enrolled completing the entire 48 weeks of treatment. Myopathy (muscle symptoms plus creatine kinase increase > 10 fold upper limit of normal) and clinically significant hepatic transaminase increases (> 3 times the upper limit of normal) occurred infrequently with both doses. There was no significant difference between the groups in the number of patients with such increases, although there were more cases for both with the 80 mg dose. Compared with the 40 mg dose, simvastatin 80 mg produced greater reductions in LDL cholesterol, total cholesterol, and triglycerides. Both doses were well tolerated.",2000.0,0,0 287,10680048,Effects of statins on carotid disease and stroke.,J R Crouse,"The results of recent trials indicate that statin treatment reduces not only the risk of coronary heart disease, but also the risk of stroke, in patients with existing heart disease. The need for the treatment of such patients is now generally recognized. Mechanisms for risk reduction include the retardation of plaque progression, plaque stabilization, and reducing the risk of coronary events. Questions remain regarding the discrepancy between epidemiological data and statin trials data, the precise mechanism of action of statins, and their role in the prevention of recurrent stroke in individuals who have experienced a previous stroke or transient ischemic attack but are free of coronary disease.",2000.0,0,0 288,10680049,Low-density lipoprotein-independent effects of statins.,J Davignon; R Laaksonen,"Statins have pleiotropic properties that complement their cholesterol-lowering effects. These properties may partly account for their established benefit in the prevention of coronary artery disease beyond the reduction of LDL-cholesterol levels. The most widely recognized properties are reviewed here. They include: (i) nitric oxide-mediated improvement of endothelial dysfunction and upregulation of endothelin-1 expression; (ii) antioxidant effects; (iii) anti-inflammatory properties; (iv) inhibition of cell proliferation with anticarcinogenic actions in animals; (v) stabilization of atherosclerotic plaques; (vi) anticoagulant effects; and (vii) inhibition of graft rejection after heart and kidney transplantation. As advances are made in our knowledge, new properties are steadily being uncovered. Pleiotropic effects are currently being given consideration when instituting combination therapy for patients at high cardiovascular risk. Some pleiotropic effects are negative, and may account for occasional untoward drug interactions. For many of these new properties, the clinical relevance has not been established. The challenge for the future will be to design and carry out appropriate clinical trials to establish their relative importance in the prevention of coronary artery disease.",2000.0,0,0 289,10680050,"Fibrates, dyslipoproteinaemia and cardiovascular disease.",G F Watts; S B Dimmitt,"Recent epidemiological data have reaffirmed that elevated plasma triglyceride and low HDL-cholesterol levels are important risk factors for atherosclerotic vascular disease. The rationale for the clinical use of fibric acid derivatives, which are designed to correct this metabolic nexus, is now on firmer ground. The mechanism of action of fibrates on lipoprotein metabolism has recently been elucidated at the molecular level and involves the activation of peroxisome proliferator-activated receptor-alpha 1 in the liver, with the net effect of improving the plasma transport rates of several lipoproteins. Other potential anti-atherothrombotic effects include the inhibition of coagulation and enhancement of fibrinolysis, as well as the inhibition of inflammatory mediators involved in atherogenesis. These consequences probably underpin the favourable effects of fibrates seen in recent angiographic and clinical trials. Two important clinical trials on the effect of gemfibrozil (Veterans Administration-HDL-Cholesterol Intervention Trial) and bezafibrate (Bezafibrate Infarction Prevention Study) have recently been completed in subjects with elevated triglyceride, low HDL and normal or near-normal LDL-cholesterol levels. The results testify to the efficacy of these agents in decreasing the incidence of cardiovascular events, particularly in patients with multiple risk factors and plasma triglyceride levels of over 2.2 mmol/l. The findings of these trials are compared with the statin-based Air Force/Texas Coronary Atherosclerosis Prevention Study, with a recommendation that future studies in appropriately selected patients should examine the synergistic effect of the fibrate/statin combination. The absolute risk reduction in the incidence of coronary events in the Veterans Administration-HDL-Cholesterol Intervention Trial compares favourably with the statin trials. The therapeutic aspects of the efficacy and safety of fibrates are reviewed. Besides primary mixed hyperlipidaemias, particular indications for the clinical use of fibrates include type 2 diabetes, the metabolic syndrome and renal insufficiency. The St Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention Study has suggested that fibrates may decrease the incidence of coronary events in type 2 diabetes, but this hypothesis will be more extensively tested in the Diabetes Atherosclerosis Intervention Study, Fenofibrate in Event Lowering in Diabetes Study and Lipids in Diabetes Study projects. Although significant new knowledge has accrued over the past few years concerning the fundamental and clinical aspects of fibrates, the success of these agents in clinical practice depends on the availability of methods for assessing cardiovascular risk as well as on treatment guidelines, which as presently designed and recommended may be inaccurate and suboptimal.",2000.0,0,0 290,10682163,The management of hypercholesterolemia in patients with coronary artery disease: guidelines for primary care.,R A Vogel,"More than 10 million individuals in the United States currently have symptomatic coronary artery disease (CAD). Asymptomatic CAD is even more prevalent. CAD in the United States is responsible for approximately 1.5 million myocardial infarctions, 500,000 deaths, and a total economic burden in excess of $120 billion annually. Fortunately, CAD is preventable in many individuals. Our understanding of CAD has steadily progressed throughout the 20th century, and now several lines of evidence support the importance of cholesterol in both the genesis and management of coronary atherosclerosis. Following identification of the presence of cholesterol in atheromas, Anitschkov early this century demonstrated that atherosclerotic lesions can be induced in susceptible animals by high-saturated-fat and cholesterol diets. These lesions regressed when low-fat and cholesterol diets were resumed. In the 1970s and 1980s, findings from the landmark Framingham Heart, Seven Countries, and Multiple Risk Factor Intervention Trial studies firmly established that hypercholesterolemia was a major risk factor for cardiovascular morbidity and mortality. During the 1980s and 1990s, 21 of 22 angiographic trials demonstrated reduced progression of coronary and/or carotid artery disease using lifestyle, drug, and surgical means for reducing cholesterol. The later trials commonly employed hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), reflecting increasing clinical use of these drugs. In 1988, the Adult Treatment Panel of the National Cholesterol Education Program (NCEP) published guidelines on testing and treating hypercholesterolemic patients, which outlined a more aggressive approach to cholesterol lowering than was currently in practice. Since 1994, five large cardiovascular event trials and a large angiographic trial have shown that aggressive cholesterol lowering reduces both cardiac morbidity and mortality, largely substantiating the NCEP guidelines. Although important clinical questions remain regarding patient subsets and treatment goals, lifestyle changes and appropriate drug therapy have proved to be highly effective in preventing initial and recurrent cardiovascular events.",2000.0,0,0 291,10685126,Management of hypercholesterolemia.,D R Illingworth,"Benefit from the treatment of hyperlipidemia has now been conclusively documented, and this article has focused on the clinical trial data supporting diet and drug therapy in adult patients with different lipoprotein disorders and discussed therapeutic approaches with a focus on reducing plasma concentrations of LDL cholesterol. National guidelines for the use of hypolipidemic drugs are strongly supported by the clinical trials and have appropriately set lower target concentrations of LDL cholesterol for patients with established atherosclerosis or diabetic patients as compared with patients with more than two cardiovascular risk factors or, the lowest risk group, patients without evidence of atherosclerosis and fewer than two known cardiovascular risk factors. The goals of therapy in patients with established atherosclerosis are to prevent further progression and potentially induce regression, whereas in high-risk patients (e.g., those with heterozygous familial hypercholesterolemia) without evidence of atherosclerosis, the aims of therapy are to reduce LDL cholesterol to a concentration at which subclinical atherosclerosis and xanthomas regress and the patient does not develop premature cardiovascular disease. Evidence-based medicine strongly supports clinical benefit from the treatment of hypercholesterolemia in men and women with and without known coronary artery disease, and the main goal should be ensure that patients who could benefit from lipid-lowering therapy are effectively treated and followed to ensure long-term compliance, efficacy, and safety.",2000.0,0,0 292,10686445,Cholesterol reduction and stroke occurrence: an overview of randomized clinical trials.,R Di Mascio; R Marchioli; G Tognoni,"We performed a meta-analysis of randomized clinical trials of more than 6 months duration to describe how fatal and nonfatal strokes are related to cholesterol lowering and to the type of intervention. A total of 41 individual trials including approximately 80,000 subjects and followed for an average of about 4 years were included in the overview. There was a 16% (95% CI, 7-25%) reduction in risk of stroke among treated patients compared to control patients (test for heterogeneity, p = 0.76). When trials that used different interventions were separately examined, a significant reduction in stroke occurrence was observed only for those using statins as active treatment (risk reduction 23%; 95% CI 13-33%). A variance-weighted regression analysis of the logarithmic odds ratios for stroke incidence against the percentage of cholesterol reduction indicated that a reduction of fatal and nonfatal stroke can be obtained for a cholesterol reduction of 9% (95% CI 6.8-13.6%). The combined data of primary and secondary prevention trials indicate that a large reduction of blood cholesterol, achievable with statin drugs, can reduce the incidence of stroke.",2000.0,0,1 293,10686642,[Familial hypercholesterolemia].,G Turpin; E Bruckert,"Familial hypercholesterolemia is characterized by a high plasma LDL-cholesterol level. The low-density particles are the end-product of the triglyceride-rich particles, i.e. VLDL, synthetized by the liver. These triglyceride-rich particles are subsequently transformed into intermediate density lipoprotein by the lipoprotein lipase and LDL after further triglyceride hydrolysis by the hepatic lipase. The LDL particles are taken up in all cells by the mean of the LDL receptor. A large body of evidence (including experimental, clinical, epidemiological data as well as the results of large trial with lipid lowering drugs) has accumulated to establish that these particles are one of the major causative factor of atherosclerosis and its complications. Two different mechanisms may be at work in the familial hypercholesterolemia: a mutation in the LDL receptor or a single mutation in the apolipoprotein B100. Specific therapeutic intervention should be undertaken to decrease the risk to develop cardiovascular disease, mainly coronary heart disease. The therapeutic intervention includes both a diet low in saturated fatty acids and cholesterol and statins which are now the first line therapy. Fibrates are proposed to those who do not tolerate statins and LDL-apheresis is associated to statin in the rare homozygous familial hypercholesterolemia.",2000.0,0,0 294,10690964,HMG-CoA reductase inhibitors (statins): a promising approach to stroke prevention.,D C Hess; A M Demchuk; L M Brass; F M Yatsu,"Statins represent a promising class of agents to prevent stroke. In randomized trials of middle-aged patients with coronary artery disease, statins reduce the incidence of stroke. The reduction in stroke may not be solely related to cholesterol or low-density lipoprotein reduction but may involve nonsterol mechanisms effects on endothelial cells, macrophages, platelets, and smooth muscle cells. Statins also reduce the size of cerebral infarction in a murine stroke model, suggesting a neuroprotective effect. The best current evidence for stroke prevention is with pravastatin and simvastatin. Pravastatin reduces the risk of stroke in patients with coronary artery disease and average cholesterol levels; simvastatin reduces the risk of the combined endpoint of stroke and transient ischemic attack in hypercholesterolemic patients with coronary artery disease. Future studies of statins are needed in stroke populations, particularly the elderly.",2000.0,0,0 295,10692286,"Hypertension, proteinuria, and progression of autosomal dominant polycystic kidney disease: where do we go from here?",V E Torres,,2000.0,0,0 296,10692735,An assessment of the efficacy of atorvastatin in treating patients with dyslipidaemia to target LDL-cholesterol goals: the atorvastatin matrix study.,D McVey; H Patel; Z Eminton; S Maton,"A total of 531 patients from 57 hospital centres across the UK, who had previously been treated with lipid-lowering agents in combination or alone, in whom the degree of cholesterol reduction was insufficient to achieve European Atherosclerosis Society target levels, were treated with atorvastatin over a 12-week period. The dose of atorvastatin (10, 20 or 80 mg/day) was determined by assignment of risk based on entry level cholesterol levels and the presence of other established CHD risk factors. Atorvastatin was successful in achieving target LDL-cholesterol levels in 86% of mild risk patients, 88% of moderate risk patients and 52% of high risk patients. Compliance with atorvastatin was 96% and treatment was well tolerated. This study demonstrates that atorvastatin is effective in achieving target lipid levels in a large proportion of patients and that the dose required can be predicted by an assessment of the patient's risk profile.",2000.0,0,0 297,10692755,Comparison of therapy with simvastatin 80 mg and atorvastatin 80 mg in patients with familial hypercholesterolaemia.,A S Wierzbicki; P J Lumb; G Chik; M A Crook,"This study compared the efficacy of simvastatin 80 mg and atorvastatin 80 mg in the treatment of 26 patients with familial hypercholesterolaemia over 12 weeks using an open crossover trial format. Both, similarly, reduced LDL by 47 +/- 13% and 43 +/- 16% and median triglycerides by 22% and 27% respectively. However, atorvastatin reduced HDL by 2 +/- 24% compared with 8 +/- 30% increase with simvastatin (p = 0.05) affecting the LDL:HDL ratio achieved (4.478 +/- 1.56 vs 3.74 +/- 0.93, p = 0.001). Atorvastatin raised median fibrinogen by 15% compared with a non-significant 5% increase with simvastatin (p = 0.05). Simvastatin reduced lipoprotein (a) by a median 20% compared with baseline (p = 0.05) compared with 5% for atorvastatin. Side-effects, mostly gastrointestinal, were seen in four patients (16%) with atorvastatin compared with one case of myalgia with simvastatin (4%). We conclude both drugs are equally effective in LDL reduction but that simvastatin is superior in raising HDL and causes fewer side-effects. These results require confirmation in larger studies.",2000.0,0,0 298,10700443,"A variant of p22(phox), involved in generation of reactive oxygen species in the vessel wall, is associated with progression of coronary atherosclerosis.",C Cahilly; C M Ballantyne; D S Lim; A Gotto; A J Marian,"A series of pro-oxidant and antioxidant enzymes, such as the NADPH oxidase system, maintain the redox state in the vessel wall. A major component of NADPH oxidase is p22(phox), which is implicated in atherosclerosis. We prospectively studied the association of the histidine (H)(72)-->tyrosine (Y) mutation in p22(phox) with the severity and progression/regression of coronary artery disease (CAD), plasma lipid levels, clinical events, and response to treatment with fluvastatin in a well-characterized population. Genotypes were determined by polymerase chain reaction and restriction digestion with RsaI enzyme in 368 subjects in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Fasting plasma lipids and quantitative coronary angiograms were obtained at baseline and 2.5 years after randomization to fluvastatin or placebo. Subjects with CC genotype (n=157) were identified by the presence of 396-bp and 113-bp products on gel electrophoresis. Those with TT (n=39) were identified by the presence of 316-bp, 113-bp, and 80-bp products, and those with CT (n=172) by the presence of 396-bp, 316-bp, 113-bp, and 80-bp products. Baseline and final plasma levels of lipids and the baseline severity of CAD were not significantly different among the genotypes. In the placebo group, subjects with the mutation had a 3- to 5-fold greater loss in mean minimum lumen diameter (MLD) (TT: -0.15+/-0.15; CT: -0.17+/-0.26; and CC: -0.03+/-0.22 mm; P=0. 006) and lesion-specific MLD (TT: -0.15+/-0.06; CT: -0.18+/-0.03; and CC: -0.06+/-0.03 mm; P=0.038) than those without. Progression was also more (TT: 8/17 [47%]; CT: 35/73 [48%]; and CC: 17/62 [27%]) and regression less (TT: 0/17 [0%]; CT: 1/73 [1%]; and CC: 11/72 [18%]) common in those with the mutation (P=0.002). The C(242)T mutation in p22(phox), involved in maintaining the redox state in the vessel wall, is associated with progression of coronary atherosclerosis in the LCAS population.",2000.0,0,0 299,10702889,Effect of multiple cilostazol doses on single dose lovastatin pharmacokinetics in healthy volunteers.,S L Bramer; J Brisson; A E Corey; S Mallikaarjun,"To assess the effects of cilostazol on lovastatin pharmacokinetics. This was a single-centre, open-label, multiple dose, sequential treatment study. Participants received single oral doses of lovastatin 80 mg on days 1, 7 and 9, as well as oral cilostazol 100 mg twice daily on days 2 to 8, followed by a single oral 150 mg cilostazol dose on day 9. 15 healthy, nonsmoking male or female volunteers (aged 18 to 60 years) were enrolled, and 12 completed the study. Pharmacokinetic parameters were calculated using plasma concentrations of lovastatin and its beta-hydroxy metabolite and of cilostazol and its metabolites. Differences in the pharmacokinetics of each drug when given alone or in combination were assessed by analysis of variance. The maximum observed plasma concentration (Cmax) of lovastatin or its metabolite did not differ significantly when lovastatin was given alone and when it was given with 100 mg of cilostazol. The mean ratios of the area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUCt) for lovastatin coadministered with 100 mg of cilostazol to that with lovastatin given alone were 1.6 for lovastatin and 1.7 for its metabolite. With 150 mg of cilostazol, lovastatin Cmax did not change, whereas Cmax of the metabolite increased 2.2-fold. The mean AUCt ratios for lovastatin given with 150 mg cilostazol/lovastatin given alone were 1.6 and 2.0 for lovastatin and its metabolite, respectively. All increases in lovastatin and metabolite AUC were statistically significant, except for the 1.6-fold increase in lovastatin AUC with 150 mg of cilostazol. Maximum steady-state plasma drug concentration (Cssmax) and AUC during a dosage interval (AUC tau) for cilostazol 100 mg twice daily decreased 14 and 15%, respectively, upon lovastatin coadministration. Lovastatin and metabolite exposure is increased only by up to 2-fold when cilostazol is coadministered, which is considerably less than that observed for potent CYP3A inhibitors such as itraconazole and grapefruit juice. Absorption of cilostazol decreased approximately 15% when it was given with lovastatin. No dosage adjustments are necessary for cilostazol when coadministered with lovastatin, whereas lovastatin dose reductions may be needed when the 2 drugs are given together.",2000.0,0,1 300,10703153,Direct adsorption of lipoproteins (DALI) from whole blood: first long-term clinical experience with a new LDL-apheresis system for the treatment of familial hypercholesterolaemia.,M Jansen; S Banyai; S Schmaldienst; A Goldammer; M Rohac; W H Hörl; K Derfler,"The DALI (direct adsorption of lipoproteins) LDL-apheresis system is a novel device for the removal of lipoproteins from whole blood. We report the first long-term treatment experience (16.7 +/- 12.6 months; 57 +/- 43 treatments/patient) using different DALI adsorber sizes (DALI-500, DALI-750, DALI-1000) in seven patients with homozygous (n = 1) and severe heterozygous familial hypercholesterolaemia. For each treatment, 1.6 fold of the calculated blood volume was processed. Treatments were scheduled at weekly or two-weekly intervals. The smallest DALI-500 configuration was unable to achieve sufficient removal of LDL cholesterol, with the adsorber being exhausted already at desorption of 65% of the calculated blood volume. In contrast, both larger adsorber systems effectively removed lipoproteins until the end of treatment. Therefore, the DALI-750 device was used for long-term treatment. LDL cholesterol (mean pretreatment value: 179 +/- 44 mg/dl) was reduced by 73.4 +/- 7.7% and Lp(a) levels (mean pretreatment value: 43 +/- 33 mg/dl) by 69.5 +/- 8.3%. HDL cholesterol (mean pretreatment value: 47 +/- 15 mg/dl) was reduced by 16.3 +/- 8.0% during the treatment. In the long term, LDL cholesterol was reduced by 54.0 +/- 10.5%--from 259 +/- 101 mg/dl to 119 +/- 19 mg/dl. No serious side effects occurred during the treatment. Long-term evaluation of other laboratory parameters showed a reduction in haemoglobin due to treatment-associated blood loss despite frequent iron supplementation. Sufficient reductions in LDL cholesterol and Lp(a) were achieved using the DALI-750 system and the treatment was well tolerated. The easy use and short period of 153 +/- 22 minutes required for each treatment are the major advantages of the DALI system as compared to other available LDL-apheresis devices. Potential particle release from the adsorber into the circulation must be ruled out before the system can be introduced in clinical routine.",2000.0,0,0 301,10703816,Prenylation inhibitors in renal disease.,A Khwaja; J O'Connolly; B M Hendry,"Members of the superfamily of Ras GTPase signalling proteins (monomeric G proteins) require post-translational carboxy-terminal prenylation to function. Prenylation is the covalent attachment of a hydrophobic prenyl group (either farnesyl or geranylgeranyl), which localises the GTPase to cell membranes. Ras proteins exert substantial control on cell proliferation and gene-transcription events, and prenylation inhibitors are now included in clinical trials for cancer. Many renal diseases are highly proliferative and are driven by a range of profibrotic cytokines. We hypothesise that inhibition of prenylation could be of substantial therapeutic benefit in such diseases, providing greater selectivity against abnormal cytokine-driven proliferation and fibrogenesis than current treatments available to nephrologists.",2000.0,0,0 302,10704621,Inhibition of tissue-factor-mediated thrombin generation by simvastatin.,D Ferro; S Basili; C Alessandri; D Cara; F Violi,"A previous study has shown that simvastatin reduces in vivo clotting activation and monocyte tissue factor (TF) expression. This effect, however, was only in part attributable to the reduction of serum cholesterol, suggesting that more than one mechanism may be involved. Furthermore, it was not investigated if the inhibition of clotting activation was dependent upon the reduced expression of monocyte TF. In order to assess if simvastatin directly affects clotting activation, we developed an in vitro method in which clotting system is activated by monocytes stimulated with LPS. Monocytes were prepared from blood taken from healthy volunteers or patients with hypercholesterolemia and incubated with heparinized plasma plus either simvastatin (0.01-10 microM) or medium as control. Samples were then stimulated with LPS (4 microg/ml) and after 6 h the rate of thrombin generation, assessed by prothrombin fragment (F) 1+2, was measured. In separate experiments, we measured the expression of TF by monocytes which were incubated with simvastatin and then stimulated with LPS. The study showed that compared to control, LPS-stimulated monocytes induced abundant formation of F1+2, which was inhibited by simvastatin in a dose-dependent manner. Simvastatin also inhibited dose dependently the monocyte expression of TF. This study suggests that simvastatin inhibits the rate of thrombin generation by directly interfering with the monocyte expression of TF.",2000.0,0,0 303,10704623,Safety profile of atorvastatin-treated patients with low LDL-cholesterol levels.,R G Bakker-Arkema; J W Nawrocki; D M Black,"Data pooled from 21 atorvastatin clinical trials have been analyzed to establish the safety of reducing low density lipoprotein cholesterol (LDL-C) levels below currently recommended minimum targets in hypercholesterolemic patients. Safety data for atorvastatin-treated patients with at least one LDL-C value < or =80 mg/dl (2.1 mmol/l) (n = 319) during treatment (mean LDL-C level throughout treatment was 91 mg/dl [2.4 mmol/l]) were compared to those from all atorvastatin-treated patients (n = 2502) and patients treated with lovastatin, simvastatin or pravastatin (n = 742). The frequency of treatment-associated adverse events (AEs) in the atorvastatin LDL-C < or =80 mg/dl (2.1 mmol/l) subgroup (24%) was comparable to the frequencies observed for all atorvastatin-treated patients (20%) and for patients receiving the other statins (24%). Patient withdrawals due to treatment-associated AEs (constipation, dyspepsia and flatulence being the most common) were consistent and low across treatment groups. No treatment-associated deaths occurred in any group. Safety data for 21 atorvastatin-treated patients with LDL-C < or =50 mg/dl (1.3 mmol/l) were also analyzed and found to be similar to all atorvastatin-treated patients and patients treated with the other statins. While recognizing the short-term nature of the data (all patients who received atorvastatin were treated for < or =1 year and approximately 30% were treated for < or =6 months), this analysis suggests that reducing LDL-C levels below 80 (2.1 mmol/l) or 50 mg/dl (1.3 mmol/l) with atorvastatin does not alter its safety profile, as measured by frequency of AEs, which remains similar to those of other statins.",2000.0,0,1 304,10704632,Achievement of target plasma cholesterol levels in hypercholesterolaemic patients being treated in general practice.,P J Barter; R C O'Brien,"A total of 1028 hypercholesterolaemic men and women aged 18-75 participated in an open label, randomised, parallel group, 6-month treatment-to-target study conducted in 240 general practices throughout Australia. The study compared atorvastatin monotherapy with simvastatin monotherapy or, if necessary, with the combination of simvastatin and cholestyramine in terms of their abilities to achieve a plasma total cholesterol target of<5.0 mmol/l. The initial daily dose of each drug was 10 mg. If the target was not achieved, the dose was doubled at 6 week intervals to a maximum daily dose of 80 mg atorvastatin or 40 mg simvastatin, with the simvastatin supplemented if necessary with 4 g cholestyramine. The percentage of patients achieving the target at 10 and 20 mg doses of atorvastatin were comparable to 20 and 40 mg of simvastatin, respectively. Despite relatively high baseline levels of plasma total cholesterol (mean levels of 7.41 and 7.31 mmol/l in the atorvastatin and simvastatin groups, respectively) the majority of patients in each group achieved the plasma total cholesterol target of<5.0 mmol/l. Treatment with atorvastatin achieved the target in 83% of patients, while simvastatin (or simvastatin plus cholestyramine) achieved the target in 66% of the patients (P<0.005). The target was achieved with 10 mg atorvastatin in 38% of patients and with 10 mg simvastatin in 26% of cases (P<0.005). In patients whose baseline cholesterol levels were between 5.6 and 6.5 mmol/l, 95% of the atorvastatin group and 86% of the simvastatin group reached the target. Even with baseline cholesterol levels between 7.6 and 8.5 mmol/l, the target was reached in 78% of the atorvastatin group and 61% of the simvastatin group. It is thus realistic for general practitioners to expect the majority of their at risk patients to achieve target plasma cholesterol levels that have been shown in population studies to be associated with relatively low rates of coronary heart disease. These targets are achieved in significantly more patients and at lower mg doses with atorvastatin than simvastatin.",2000.0,0,1 305,10709162,Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers.,W J Pan; L E Gustavson; R Achari; M J Rieser; X Ye; C Gutterman; B A Wallin,"This study was conducted to evaluate the potential pharmacokinetic interaction between fenofibrate and pravastatin. A total of 23 healthy adult volunteers received single-dose 201 mg fenofibrate alone, 201 mg fenofibrate + 40 mg pravastatin, and 40 mg pravastatin alone in a three-period crossover experiment. Plasma samples were collected at predetermined times and were analyzed with validated methods for the quantitation of fenofibric acid, pravastatin, and 3 alpha-hydroxy-isopravastatin (3 alpha-iso-PV). Pharmacokinetic parameters of these three compounds were calculated using noncompartmental methods and compared by analyses of variance and bioavailability assessments. Concomitant administration of fenofibrate and pravastatin did not affect the pharmacokinetics of either fenofibric acid or pravastatin. However, the AUC0-infinity and Cmax of 3 alpha-iso-PV were increased by 26% and 29%, respectively. The moderate increase in the formation of this pravastatin metabolite should not raise any clinical concerns due to its much lower pharmacological potency compared to pravastatin and lack of toxicity.",2000.0,0,0 306,10709776,Effects of the antifungal agents on oxidative drug metabolism: clinical relevance.,K Venkatakrishnan; L L von Moltke; D J Greenblatt,"This article reviews the metabolic pharmacokinetic drug-drug interactions with the systemic antifungal agents: the azoles ketoconazole, miconazole, itraconazole and fluconazole, the allylamine terbinafine and the sulfonamide sulfamethoxazole. The majority of these interactions are metabolic and are caused by inhibition of cytochrome P450 (CYP)-mediated hepatic and/or small intestinal metabolism of coadministered drugs. Human liver microsomal studies in vitro, clinical case reports and controlled pharmacokinetic interaction studies in patients or healthy volunteers are reviewed. A brief overview of the CYP system and the contrasting effects of the antifungal agents on the different human drug-metabolising CYP isoforms is followed by discussion of the role of P-glycoprotein in presystemic extraction and the modulation of its function by the antifungal agents. Methods used for in vitro drug interaction studies and in vitro-in vivo scaling are then discussed, with specific emphasis on the azole antifungals. Ketoconazole and itraconazole are potent inhibitors of the major drug-metabolising CYP isoform in humans, CYP3A4. Coadministration of these drugs with CYP3A substrates such as cyclosporin, tacrolimus, alprazolam, triazolam, midazolam, nifedipine, felodipine, simvastatin, lovastatin, vincristine, terfenadine or astemizole can result in clinically significant drug interactions, some of which can be life-threatening. The interactions of ketoconazole with cyclosporin and tacrolimus have been applied for therapeutic purposes to allow a lower dosage and cost of the immunosuppressant and a reduced risk of fungal infections. The potency of fluconazole as a CYP3A4 inhibitor is much lower. Thus, clinical interactions of CYP3A substrates with this azole derivative are of lesser magnitude, and are generally observed only with fluconazole dosages of > or =200 mg/day. Fluconazole, miconazole and sulfamethoxazole are potent inhibitors of CYP2C9. Coadministration of phenytoin, warfarin, sulfamethoxazole and losartan with fluconazole results in clinically significant drug interactions. Fluconazole is a potent inhibitor of CYP2C19 in vitro, although the clinical significance of this has not been investigated. No clinically significant drug interactions have been predicted or documented between the azoles and drugs that are primarily metabolised by CYP1A2, 2D6 or 2E1. Terbinafine is a potent inhibitor of CYP2D6 and may cause clinically significant interactions with coadministered substrates of this isoform, such as nortriptyline, desipramine, perphenazine, metoprolol, encainide and propafenone. On the basis of the existing in vitro and in vivo data, drug interactions of terbinafine with substrates of other CYP isoforms are unlikely.",2000.0,0,0 307,10709902,The -323Ins10 polymorphism for factor VII is not associated with coronary atherosclerosis in symptomatic men. The REGRESS study group.,K J Lievers; L I Mennen; A P Rattink; A H Zwinderman; J W Jukema; E G Schouten; M P de Maat,"Elevated factor VII coagulant activity (FVII:C) has been associated with an increased risk of ischaemic heart disease, particularly for fatal events. Results of studies on the association between FVII:C and atherosclerosis are not consistent. FVII:C levels are influenced by several environmental factors and by genetic factors. One of the genetic factors is the -323Ins10 polymorphism in the promoter region of the factor VII gene, which is strongly related to FVII:C, and thus may be associated with ischaemic heart disease. We studied the association of this polymorphism with the severity and progression of atherosclerosis. In 511 male patients of the Regression Growth Evaluation Statin Study, the genotype for the -323Ins10 polymorphism was determined. The minimum obstruction diameter and the mean segment diameter were determined at baseline and after a 2-year follow-up period, and new lesion formation was assessed as well. Cardiovascular events were recorded. No relationship was observed between the -323Ins10 polymorphism and angiographic measures of disease progression, nor on the risk of new cardiovascular events. The results suggest that there is no association between the -323Ins10 polymorphism for factor VII and the severity or progression of coronary atherosclerosis in male patients with symptomatic coronary artery disease.",2000.0,0,0 308,10710119,Efficacy and tolerability of fluvastatin and bezafibrate in patients with hyperlipidemia and persistently high triglyceride levels.,L E Spieker; G Noll; M Hannak; T F Lüscher,"Hyperlipidemia is an important cardiovascular risk factor. Lipid-lowering therapy has been shown to decrease morbidity and mortality in these patients. Combination therapy with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and a fibric-acid derivative has been reported to be more efficacious to reduce low-density lipoprotein (LDL) cholesterol and triglycerides but may be associated with an increased risk of myositis. The aim of this study was to investigate the efficacy and tolerability of fluvastatin, an HMG-CoA reductase inhibitor, alone and in combination with bezafibrate, a fibric-acid derivative. In a randomized controlled trial with 454 hypercholesterolemic patients (mean cholesterol, 8.6 +/- 1.6 mM), fluvastatin (20 mg/day) significantly lowered total plasma cholesterol levels (-12.5%; p < 0.0001 vs. placebo), LDL cholesterol (-14%; p < 0.0001), and triglycerides (-4%; p = 0.05). A small increase in high-density lipoprotein (HDL) cholesterol levels (3%, NS) also was observed. Combination therapy with fluvastatin and bezafibrate (400 mg/day) in 71 patients with persistent hypertriglyceridemia during treatment with the statin resulted in a more pronounced reduction in triglyceride (-47%; p < 0.0001) and total cholesterol levels (-15%; p < 0.0001) than did fluvastatin alone. Furthermore, the additional bezafibrate significantly increased HDL cholesterol (+5%; p < 0.001). No significant increases in creatine phosphokinase levels or in frequency of myalgia were observed. In summary, fluvastatin decreases both cholesterol and triglyceride levels. In patients with persistent hypertriglyceridemia, combination therapy with fluvastatin and bezafibrate may be safely used to lower triglyceride and cholesterol levels more efficiently.",2000.0,0,0 309,10710121,Effects of fluvastatin treatment on red blood cell Na+ transport systems in hypercholesterolemic subjects.,A Saitta; M Castaldo; A Sardo; M N Saitta; M Cinquegrani; M Bonaiuto; P D'Arrigo; M Zema; F Squadrito,"This study was performed to ascertain the effects of short-term cholesterol-lowering therapy with fluvastatin on red blood cells Na+ transport systems. Forty familial hypercholesterolemic subjects (FH; 19 men and 21 women) without hypertension or cardiovascular disease were given a placebo for 4 weeks, and then randomized in two groups. Twenty (fluvastatin group) were given fluvastatin (40 mg/day), and the other 20 (placebo group) continued placebo administration. After the placebo period and after 4 and 12 weeks of placebo or fluvastatin treatment, we measured Na+/K+ pump activity, Na+/K+ cotransport (Na+/K+ Ct), Na+/Li+ countertransport (Na+/Li+ Cnt), passive Na+ permeability (Na+PP), and internal Na+ content (Na+i). The same parameters were measured in 23 control subjects (C) with normal cholesterolemic values, who were matched for sex and age. FH had higher Na+/Li+ Cnt values than C (193.2 +/- 59.4 vs. 139.8 +/- 48.7 microM cells/h; p < 0.01), an increase in Na(+)PP (0.034 +/- 0.012/h vs. 0.018 +/- 0.004/h; p < 0.001), and higher Na(+)i (7.5 +/- 1.5 vs. 6.2 +/- 0.9 mM cells; p < 0.001). In hypercholesterolemic subjects, Na(+)i values were correlated with cholesterol (total and LDL) and apo B levels, whereas an inverse correlation was found for HDL-c and apo AI levels. Reduced total and LDL cholesterol and apo B levels after fluvastatin treatment caused a decrease in both Na(+)/Li(+) Cnt (from 186.1 +/- 60.5 to 125.1 +/- 34.0 microM cells/h; p < 0.001) and Na(+) PP (from 0.035 +/- 0.013/h to 0.02 +/- 0.016/h; p < 0.01), and an increase in Na+/K+ pump activity (from 1,549.0 +/- 507.7 to 1,894.2 +/- 536.2 microM cells/h; p < 0.04), with a significant reduction in the internal Na+ content (from 7.5 +/- 1.6 to 5.8 +/- 2.4 mM cells; p < 0.001). Our findings show that hypercholesterolemia affects red blood cell Na+ transport systems, with an increase in Na+/Li+Cnt, Na+PP, and the internal Na+ content. Cholesterol-lowering treatment with fluvastatin influences Na+ transport systems and reduces the internal Na+ content. This might also be responsible for the greater vascular reactivity observed in hypercholesterolemic patients, and its amelioration after a reduction in cholesterol levels.",2000.0,0,0 310,10713909,Current concepts in secondary prevention after acute myocardial infarction.,R H Mehta; E Bossone; K A Eagle,"Acute myocardial infarction (MI) is the leading cause of death around the globe. Advances in the field of cardiology have identified several effective treatments that have lead to decrease in mortality from this cause over the past 3 decades. The purpose of this article is to review the existing literature in regards to secondary prevention after acute MI. A search of MEDLINE through August of 1999 was carried out to identify any available publications on secondary prevention after MI. Evidence on the use of both pharmacological and nonpharmacological interventions that was shown to be effective in improving morbidity and mortality was sought. Recommendations for the treatment of patients with acute MI are made based on existing evidence. Betablockers, aspirin and lipid-lowering agents for patients with low density lipoprotein-cholesterol > 130 mg% should be used for all patients following a MI. Angiotensin converting enzyme inhibitors are indicated for patients with congestive heart failure and/or reduced left ventricular ejection fraction and are likely protective in most patients. Calcium channel blockers (Verapamil and Diltiazem) are indicated as second-line therapy for patients who have contraindications or are intolerant to betablockers. The routine prophylactic use of antiarrhythmic drugs to suppress ventricular ectopic beats should be avoided. Recommendations regarding diet, smoking cessation and achievement of ideal body weight should be an integral part of patient management. Referral for outpatient rehabilitation should also be strongly encouraged. Finally, adequate control of blood pressure and diabetes cannot be overemphasized. Adherence to these goals in patients with acute MI will lead to better long-term outcomes and reduction in cardiac death, recurrent MI, stroke, and need for coronary revascularization.",2000.0,0,0 311,10715431,Early introduction of HMG-CoA reductase inhibitors could prevent the incidence of transplant coronary artery disease.,T Kato; T Tokoro; Y Namii; T Kobayashi; S Hayashi; I Yokoyama; S Morimoto; M Chan; N Giannetti; S A Hunt,,2000.0,0,0 312,10715475,Neoral dose monitoring with cyclosporine 2-hour postdose levels in heart transplant patients receiving anti-thymocyte globulin induction.,M Cantarovich; M Quantz; E Elstein; P Ergina; C Magnan; B de Varennes,,2000.0,0,0 313,10716454,Atheromas of the thoracic aorta: clinical and therapeutic update.,P A Tunick; I Kronzon,"Atherosclerotic lesions of the thoracic aorta have recently been recognized as an important cause of stroke and peripheral embolization, which may result in severe neurologic damage as well as multiorgan failure and death. Their prevalence is approximately 27% in patients with previous embolic events. Transesophageal echocardiography is the modality of choice for the diagnosis of these atheromas, although computed tomography, magnetic resonance imaging and intraoperative epiaortic ultrasound are complementary. Two clinical syndromes account for the embolic phenomena, atheroemboli and, more commonly, thromboemboli. In addition to such superimposed thrombi, plaque thickness (especially > or =4 mm) also correlates with embolic risk. This risk is high, with 12% of patients having a recurrent stroke within approximately one year, and up to 33% of patients having a stroke or peripheral embolus. In addition, aortic atheromas (as seen with intraoperative transesophageal echocardiography and intraoperative epiaortic ultrasound) are an important cause of stroke during heart surgery requiring cardiopulmonary bypass. Such strokes occur during approximately 12% of cardiac operations employing cardiopulmonary bypass when aortic arch atheromas are seen with transesophageal echocardiography (six times the general intraoperative stroke rate). Although anticoagulant strategies have been reported with encouraging results in nonrandomized studies, prospective, randomized data must be developed before an effective and safe treatment strategy can be determined. This review details the current state of knowledge in this area, including the clinical and pathologic evidence that thoracic aortic atherosclerosis is an important embolic source, data which guide current therapy and future directions for clinical investigation.",2000.0,0,0 314,10719651,Biological basis for statin therapy in stroke prevention.,R S Rosenson,"Hypercholesterolemia has not been considered an important risk factor for stroke; however, statin therapy reduces stroke in coronary heart disease patients. Statins may provide cerebrovascular protection through various mechanisms that include a reduction in the incidence of embolic stroke from cardiac, aortic and carotid sites, stabilization of vulnerable carotid atherosclerotic plaque, and improvement in cerebral blood flow.",2000.0,0,0 315,10720052,HMG-CoA reductase inhibitors increase BMD in type 2 diabetes mellitus patients.,Y S Chung; M D Lee; S K Lee; H M Kim; L A Fitzpatrick,"Recently, it was reported that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors increased bone mineral density (BMD) in mice. We studied the effect of HMG-CoA reductase inhibitors on BMD of type 2 diabetes mellitus by a retrospective review of medical records. Sixty-nine type 2 diabetic patients were included. The control group (n = 33) did not take HMG-CoA reductase inhibitors. The treatment group (n = 36) was administered either lovastatin, pravastatin, or simvastatin. BMD of the spine, femoral neck, femoral trochanter, and total hip were measured by dual-energy X-ray absorptiometry. There were no significant differences between control and treatment groups in age, sex, body mass index, glycemic control, and serum insulin levels. In the control group, BMD of the spine significantly decreased (from 1.116 +/- 0.165 to 1.081 +/- 0.178 g/cm2) after 14 months. In the treatment group, BMD of the femoral neck significantly increased (from 0.853 +/- 0.139 to 0.878 +/- 0.147 g/cm2) after 15 months. In male subjects treated with HMG-CoA reductase inhibitors, there was a significant increase in BMD of the femoral neck and femoral trochanter (from 0.899 +/- 0.139 to 0.934 +/- 0.139 and from 0.801 +/- 0.145 to 0.833 +/- 0.167 g/cm2, respectively), but in female subjects, only BMD of the femoral neck increased (from 0.819 +/- 0.132 to 0.834 +/- 0.143 g/cm2). Percentage increments of BMD of the femoral neck, femoral wards triangle, femoral trochanter, and total hip in the treatment group were significantly higher than in the control group (2.32% vs. -0.99, 1.77% vs. -1.25%, 1.40% vs. -1.21%, 0.88% vs. -1.03%, respectively). The proportion of subjects who had an increase in BMD of the spine and total hip more than two percentages was significantly larger in the treatment group than in the control group (30.6% vs. 15.2% and 30.6% vs. 9.1%, respectively). The increased increment in BMD of the treatment group was significantly greater than those in the control group after adjustment for age and body mass index (P < 0.05). These results suggest that HMG-CoA reductase inhibitors may increase BMD of the femur in male patients with type 2 diabetes mellitus.",2000.0,0,0 316,10728955,Treating isolated low high-density lipoprotein cholesterol: prescient or premature?,C R Harper; T A Jacobson,,2000.0,0,0 317,10732848,Effect of long-term cholesterol-lowering treatment with HMG-CoA reductase inhibitor (simvastatin) on myocardial perfusion evaluated by thallium-201 single photon emission computed tomography.,R Hosokawa; R Nohara; L Linxue; S Tamaki; T Hashimoto; M Tanaka; S Miki; S Sasayama,"Fifteen patients with either angina pectoris or old myocardial infarction, who had positive 201Tl single photon emission computed tomography (SPECT) imaging and coronary sclerosis of more than 50%, were treated with an HMG-CoA reductase inhibitor (simvastatin) for more than 1 year. They were compared with an untreated control group (n = 25). Total cholesterol decreased 22% and high-density lipoprotein (HDL) increased 9% with simvastatin; both changes were significantly different from those in controls. Long-term simvastatin induced improvement of myocardial perfusion on 201Tl SPECT images both during exercise and at rest, which was also significantly different from controls. In addition, the improvement of myocardial perfusion on 201Tl SPECT images was clearly related to the improvements in cholesterol values, especially nonHDL cholesterol. Thus, the greater the decrease in nonHDL cholesterol, the greater the improvement in myocardial perfusion at rest or during exercise with long-term treatment using an HMG-CoA reductase inhibitor. These findings indicate that the improvements in cholesterol values caused by HMG-CoA reductase inhibitor therapy are related to improvements of myocardial perfusion seen on 201Tl SPECT images.",2000.0,0,0 318,10732883,The Angiotensin-converting Enzyme Inhibition Post Revascularization Study (APRES).,L Kjøller-Hansen; R Steffensen; P Grande,"This study was performed to assess the effect of treatment with ramipril on the incidence of cardiac events after invasive revascularization in patients with asymptomatic moderate left ventricular dysfunction. In patients with angina pectoris and left ventricular dysfunction, both invasive revascularization and treatment with angiotensin-converting enzyme inhibitors reduce cardiac mortality and morbidity. Whether there is a benefit from combining the two treatment strategies has never been evaluated prospectively. After invasive revascularization, 159 patients with preoperative chronic stable angina pectoris, left ventricular ejection fraction between 0.30 and 0.50 and no clinical heart failure were randomly assigned to receive double-blind treatment with either ramipril or placebo and subsequently followed for a median of 33 months. Ramipril reduced the incidence of the triple-composite end point of cardiac death, acute myocardial infarction or clinical heart failure (risk reduction 58%; 95% confidence interval 7% to 80%, p = 0.031). The incidence of the quadruple-composite end point of cardiac death, acute myocardial infarction, clinical heart failure or recurrent angina pectoris was not altered with ramipril. These findings were consistent across subgroups with respect to left ventricular ejection fraction below or above 0.40, and whether coronary artery bypass grafting or percutaneous transluminal coronary angioplasty was performed. In patients with angina pectoris and asymptomatic moderate left ventricular dysfunction, long-term treatment with ramipril after invasive revascularization significantly reduced the incidence of the composite end point of cardiac death, acute myocardial infarction or clinical heart failure, indicating that the beneficial effects of angiotensin-converting enzyme inhibitor treatment may be extended to include treatment of this patient group.",2000.0,0,0 319,10732886,Optimal management of non-ST segment elevation myocardial infarction remains unclear.,F K Welty,,2000.0,0,0 320,10732887,Quality of life after coronary angioplasty or continued medical treatment for angina: three-year follow-up in the RITA-2 trial. Randomized Intervention Treatment of Angina.,S J Pocock; R A Henderson; T Clayton; G H Lyman; D A Chamberlain,"We sought to evaluate the impact of percutaneous transluminal coronary angioplasty (PTCA) and medical treatment on self-perceived quality of life among patients with angina. The second Randomized Intervention Treatment of Angina trial (RITA-2) implemented initial policies of PTCA or continued medical treatment in patients with angina, allowing assessment of long-term health consequences. A total of 1,018 patients were randomly assigned (504 to PTCA and 514 to medical treatment). The short form 36 (SF-36) self-administered quality-of-life questionnaire was completed at randomization and three months, one year and three years later. To date, 98% of patients reached one year and 67% reached three years. The PTCA group had significantly greater improvements in physical functioning, vitality and general health at both three months and one year, but not at three years. These quality-of-life scores were strongly related to breathlessness, angina grade and treadmill exercise time both at baseline and at one year. The treatment differences in quality of life are explained by the PTCA group's improvements in breathlessness, angina and exercise time. The attenuation of treatment difference at three years is partly attributed to 27% of medically treated patients receiving nonrandomized interventions in the interim. For both groups, there were also improvements in ratings of physical role functioning, emotional role functioning, social functioning, pain and mental health, but for these the superiority of PTCA over medical treatment was less pronounced. After one year, 33% and 22% of the PTCA and medical groups, respectively, rated their health much better. Coronary angioplasty substantially improves patient-perceived quality of life, especially physical functioning and vitality, as compared with continued medical treatment. These differences are attributed to alleviation of cardiac symptoms (specifically, breathlessness and angina), but must be balanced against the small procedure-related risks of PTCA.",2000.0,0,0 321,10736278,The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction : a substudy of the Scandinavian simvastatin survival study.,L U Gerdes; C Gerdes; K Kervinen; M Savolainen; I C Klausen; P S Hansen; Y A Kesäniemi; O Faergeman,"Carriers of the epsilon4 allele of the apolipoprotein E gene are at a higher risk of coronary heart disease than individuals with other genotypes. We examined whether the risk of death or a major coronary event in survivors of myocardial infarction depended on apolipoprotein E genotype and whether the benefits of treatment with simvastatin differed between genotypes. Cox proportional hazards models were used to analyze 5.5 years of follow-up data from 966 Danish and Finnish myocardial infarction survivors enrolled in the Scandinavian Simvastatin Survival Study. A total of 16% of the 166 epsilon4 carriers in the placebo group died compared with 9% of the 312 patients without the allele, which corresponds to a mortality risk ratio of 1.8 (95% confidence interval, 1.1 to 3.1). The risk ratio was unaffected by considerations of sex, age, concurrent angina, diabetes, smoking, and serum lipids in multivariate analyses. Simvastatin treatment reduced the mortality risk to 0.33 (95% confidence interval, 0.16 to 0.69) in epsilon4 carriers and to 0.66 (95% confidence interval, 0. 35 to 1.24) in other patients (P=0.23 for treatment by genotype interaction). Apolipoprotein E genotype did not predict the risk of a major coronary event. Baseline serum levels of lipoprotein(a) also predicted mortality risk and could be combined with epsilon4-carrier status to define 3 groups of patients with different prognoses and benefits from treatment. Myocardial infarction survivors with the epsilon4 allele have a nearly 2-fold increased risk of dying compared with other patients, and the excess mortality can be abolished by treatment with simvastatin.",2000.0,0,0 322,10740137,Statins: effective antiatherosclerotic therapy.,R S Blumenthal,"Statins are the most effective agents currently available for lowering plasma levels of low-density lipoprotein cholesterol (LDL-C) and are the mainstay of therapy for hyperlipidemia. The statins are highly liver-selective, inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a key enzyme in the synthesis of cholesterol. Several large, controlled clinical trials have confirmed significant reductions in rates of coronary heart disease morbidity and death with long-term statin therapy in patients with mild to severe hypercholesterolemia. This review article is based on a literature search of more than 60 relevant articles from peer-reviewed journals. Search engines included Medline and Embase. In surveying clinical and angiographic evidence, we found that statins appear to reduce the incidence of coronary events by slowing the progression of atherosclerosis and preventing atheromatous lesion formation. We found that the 6 statins currently marketed-atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin-differ in their inhibitory action on the HMG-CoA reductase enzyme. The use of more potent statins such as atorvastatin and simvastatin affords greater lowering of LDL-C and triglyceride levels, allowing more patients to achieve target goals. The question of how low LDL-C levels should be lowered will be answered by ongoing clinical trials.",2000.0,0,0 323,10740160,Benefits of lipid lowering on vascular reactivity in patients with coronary artery disease and average cholesterol levels: a mechanism for reducing clinical events?,J D Cohen; J H Drury; J Ostdiek; J Finn; B R Babu; G Flaker; K Belew; T Donohue; A Labovitz,"The favorable effects of lowering low-density lipoprotein (LDL)-cholesterol on reducing clinical events in patients with coronary disease have been well established. The mechanisms responsible for this benefit, however, have not been fully understood. This study examined the impact of lipid-lowering therapy on endothelium-dependent vasoreactivity in a subgroup of patients after myocardial infarction with average cholesterol levels who participated in the Cholesterol Recurrent Events (CARE) study to determine whether an effect on endothelial function is a viable mechanism for the observed reduction in clinical events. Participants were recruited from among volunteers in the CARE trial at 2 university-based outpatient cardiology clinics. Patients were randomly assigned to pravastatin or placebo. Plasma lipids were measured at baseline and semiannually thereafter. During the final 6 months of the trial, vasoreactivity was assessed by change in ultrasound-determined brachial artery diameter in response to blood pressure cuff-induced ischemia (endothelium-dependent) and to nitroglycerin, a direct vasodilator. Differences in response were examined between the 2 randomized groups. The relation between change in LDL-cholesterol from baseline to year 5 and the magnitude of endothelium-dependent vasodilation also was examined. There was significantly greater endothelium-dependent vasodilation observed in the pravastatin group compared with the placebo group (13% vs 8%, P =.0002), with no difference between the groups in their response to the endothelium-independent vasodilator nitroglycerin. The magnitude of the endothelium-dependent vasodilation was significantly correlated with the percent change in LDL-cholesterol from baseline to final visit (r = 0.49, P =.015). These findings indicate that the use of pravastatin in patients after myocardial infarction with average cholesterol levels is associated with greater endothelium-dependent vasodilation compared with those who received placebo. The magnitude of this vasodilatory response is correlated to the reduction in LDL-cholesterol. This improvement in endothelium-dependent vasoreactivity may be a likely mechanism, at least in part, for the reduction in recurrent clinical events observed and reported in the CARE study.",2000.0,0,0 324,10742707,Celiprolol augments the effect of physical exercise on insulin sensitivity and serum lipid levels in chronic heart failure.,M Pietilä; K Malminiemi; R Huupponen; J Rouru; K Pulkki; E Pere; L M Voipio-Pulkki,"Impaired insulin sensitivity has been linked with chronic heart failure (CHF). Exercise has a beneficial effect on insulin sensitivity in healthy subjects. It is used also as an adjunctive therapy in patients with CHF. We studied the effect of randomized treatment with celiprolol, a vasodilating beta(1)-adrenoceptor antagonist, 200 mg once daily (n=20) or placebo (n=11) on serum lipid levels and insulin sensitivity in patients with CHF. In addition, all subjects participated in a 6-month exercise training protocol. Thirteen subjects in the celiprolol and eight subjects in the control group were on additional beta(1)-adrenoceptor antagonist as part of their tailored CHF therapy. Insulin sensitivity was determined using the hyperinsulinemic euglycemic clamp test (diabetic subjects excluded, n=11 for the celiprolol group and n=8 for the placebo group). Insulin sensitivity index (ISI) increased by 33% (P<0.05) in the celiprolol group and by 17% (NS) in the control group. The mean increase in the whole group was 20% [from 68.2+/-11.5 to 81.7+/-10.7 ml/min/kg (mU/l), P<0.05]. No change was found in the total cholesterol level. HDL cholesterol levels increased by 12% (from 0.98+/-0.05 to 1.10+/-0.05 mmol/l, P<0. 005), and HDL/total cholesterol and HDL/LDL cholesterol ratios by 15% and 16%, respectively (P<0.005). The increase in serum fasting HDL cholesterol level was greater in the celiprolol-treated group (P<0.05). At baseline ISI correlated with maximal oxygen uptake (r=0. 65, P<0.0001) and body mass index (r=-0.55, P<0.001). The change in ISI correlated weakly with the improvement in muscle exercise capacity (r=0.53, P<0.05). Insulin sensitivity and serum lipid levels may be favorably affected by exercise training in subjects with mild-to-moderate CHF. Celiprolol, a vasodilating beta1- selective adrenoceptor antagonist, potentiates this effect.",2000.0,0,0 325,10743305,Where to draw the line using statins: lessons from 4S to AFCAPS/TexCAPS.,D L Sprecher,,2000.0,0,0 326,10743480,Double-blind study of the addition of high-protein soya milk v. cows' milk to the diet of patients with severe hypercholesterolaemia and resistance to or intolerance of statins.,C R Sirtori; F Pazzucconi; L Colombo; P Battistin; A Bondioli; K Descheemaeker,"Total substitution of soyabean protein for animal protein in the diet has been repeatedly shown to lower plasma cholesterol levels in hypercholesterolaemic individuals. A new, highly palatable, high-protein soya drink may allow replacement of a significant percentage of animal protein in the diet. The soya drink was given, within a crossover design v. a cows' milk preparation of similar composition and taste, to twenty-one severely hypercholesterolaemic patients (mean baseline plasma cholesterol 8.74 mmol/l) with a history of resistance to or intolerance of statin treatment. Each dietary supplement was given for 4 weeks, with a 4-week interval between treatments, Plasma lipid levels were monitored every 2 weeks during each dietary sequence. The concomitant dietary treatment, which had been followed for a long time by all patients, was carefully monitored throughout the study. The soya supplementation reduced plasma total cholesterol level by 6.5%, when given first, and by 7.4% when given after cows' milk. When given first, cows' milk resulted in a small, non-significant reduction of plasma cholesterol level (-3.9%), and when given after soya, it changed total plasma cholesterol to a minimal extent (-1.6%). Changes in total and LDL-cholesterol levels after 2 and 4 weeks of soya v. cows' milk treatment were, thus, respectively -6.1, -7.0 and -6.2, -7.8% (both P < 0.05). These first data from a double-blind study confirm a significant cholesterol-lowering effect of soyabean protein, even when only partly replacing animal protein in the diet, in individuals with extreme plasma cholesterol elevations.",2000.0,0,0 327,10743692,Effects of portal versus systemic venous drainage in kidney-pancreas recipients.,X Martin; P Petruzzo; M Dawahra; L C Feitosa Tajra; M Da Silva; L Pibiri; F Chapuis; J M Dubernard; N Lefrançois,"A randomized study of combined kidney-pancreas transplantation was performed on 30 insulin-dependent diabetic patients with end-stage renal disease to compare the consequences of pancreas transplantation with portal venous (PV) and systemic venous (SV) drainage. Fourteen patients (SV) group) received systemically drained and sixteen (PV group) portally drained pancreas allografts. Enteric drainage was performed in both groups. The routine follow-up included documentation of the clinical course and detailed endocrine studies. At 1 year after transplantation, the patient survival rate was 92% for the SV group and 96% for the PV group; the graft survival rate was 78% and 82%, respectively. Endocrine studies indicated no difference in fasting and stimulated glucose or in glycosylated hemoglobin between the two groups. In addition, no hyperinsulinemia and lipidic abnormalities were evidenced in either group Long-term studies are required to conclude whether PV and SV drainage in pancreas transplantation are equivalent in terms of patient and graft survival as well as metabolic consequences.",2000.0,0,0 328,10745972,"Diagnosis, management and prevention of the common dyslipidaemias in South Africa--clinical guideline, 2000. South African Medical Association and Lipid and Atherosclerosis Society of Southern Africa Working Group.",,"The optimum management of dyslipidaemia requires a comprehensive, diagnostic work-up. This, minimally, includes: Characterisation of any hyperlipidaemic disorder present. Identification of additional risk factors so as to assess overall (global) risk of future coronary heart disease (CHD). The global risk is best assessed by a calculation combining the risk factors in the individual. In severe monogenic dyslipidaemias and in patients with confirmed pre-existing CHD the risk is usually high; in most such cases the use of lipid-modifying drugs (LMDs) is indicated. Assessment of psychosocial, economic and educational factors relevant to management. Prevention and cost-effective management of even moderately dyslipidaemic patients require appropriate modification of lifestyle: avoidance of tobacco smoking, participation in regular exercise, and a health-promoting diet. Depending on individual circumstance, vigorous, personalised intervention and expert assistance from dieticians, biokineticists and other health care personnel may determine success. The correct choice of patient for drug treatment is a key therapeutic decision and is best done after full lifestyle modification. Recent evidence confirms that appropriately prescribed LMD therapy can lower morbidity and mortality from CHD as well as all-cause mortality. Patients with the following features are candidates for LMD therapy: have clinical CHD and a low-density lipoprotein cholesterol (LDLC) level > 3.0 mmol/l despite optimum non-pharmacological intervention, or suffer from familial hypercholesterolaemia (FH) or equivalent severe, monogenic disorder, or have a 10-year risk of an acute clinical coronary event of > 20% (or > 30% risk if extrapolated to the age of 60 years) owing to the presence of the hyperlipidaemia alone or in combination with contributory risk factors. The ideal target LDLC concentration is < or = 3 mmol/l, but a reduction of at least 45% should be regarded as a minimum target in severe cases who do not reach this goal. Successful therapy requires on-going attention to compliance, therapeutic response and side-effects, and may necessitate adjustment or reinforcement. Concurrent or contributory conditions, such as smoking, hypertension and diabetes mellitus, must also be treated along with the clinically manifest CHD. Severely hyperlipidaemic, complicated or unresponsive high-risk cases should be referred to an appropriate specialist or lipid clinic. Prevention of CHD in the community should be encouraged through public and professional education, the provision of community facilities for exercise and recreation, and legislation directed at reducing the use of tobacco products and ensuring the appropriate labelling of food products.",2000.0,0,0 329,10750701,Therapy and clinical trials.,I Jialal; N Abate,,2000.0,0,0 330,10760335,Effect of statin therapy on restenosis after coronary stent implantation.,D H Walter; V Schächinger; M Elsner; S Mach; W Auch-Schwelk; A M Zeiher,"The effect of statins on the development of restenosis and clinical outcome after coronary stent implantation was assessed in a retrospective analysis of 525 consecutive patients. Baseline clinical, angiographic, and procedural characteristics did not differ between 258 patients with and 267 patients without statin therapy. Statin therapy was associated with a significantly (p<0.04) improved survival free of myocardial infarction and a significant reduction in repeat target vessel revascularization procedures (27.9% vs. 36.7%, p<0.05) during 6-month follow-up. Minimal lumen diameter was significantly larger (1.98+/-0.88 vs. 1.78+/-0.88 mm, p = 0.01), late lumen loss was significantly less (0.64+/-0.8 vs. 0.8+/-0.8 mm, p = 0.032), and net gain significantly increased (1.2+/-0.88 vs. 0.98+/- 0.92 mm, p = 0. 009) in patients receiving statin therapy. Dichotomous angiographic restenosis (> or =50%) rates were significantly lower, with 25.4% in the statin group compared with 38% in the no-statin group (p<0.005). Multivariate analysis identified statin therapy (p = 0.005), minimal lumen diameter immediately after stenting (p = 0.02), and stent length (p = 0.02) as independent predictors for subsequent restenosis development. Thus, statin therapy is associated with reduced recurrence rates and improved clinical outcome after coronary stent implantation.",2000.0,0,0 331,10761170,Flow cytometric assessment of effects of fluvastatin on low-density lipoprotein receptor activity in stimulated T-lymphocytes from patients with heterozygous familial hypercholesterolemia.,B Raungaard; J U Brorholt-Petersen; H K Jensen; O Faergeman,"To test the effects of fluvastatin on low-density lipoprotein (LDL) receptor activity in patients with heterozygous familial hypercholesterolemia, the authors measured LDL receptor activity in stimulated T-lymphocytes prepared from 34 patients before and after treatment with 40 mg fluvastatin daily for 12 weeks. Maximally induced pretreatment LDL receptor activities did not correlate with pretreatment plasma cholesterol levels or with changes in plasma cholesterol levels during treatment, and there were no significant changes in LDL receptor activity during treatment. Barring methodological problems, two explanations are possible. Insofar that LDL receptor activity in lymphocytes reflects LDL receptor activity in the liver, the results suggest that the primary response to treatment with fluvastatin in heterozygous familial hypercholesterolemia (FH) patients is not enhanced LDL receptor activity. Alternatively, fluvastatin increases LDL receptor activity in hepatocytes but has little effect on receptor-dependent lipoprotein catabolism in extrahepatic tissues in vivo.",2000.0,0,0 332,10762175,Simvastatin and plasma very-long-chain fatty acids in X-linked adrenoleukodystrophy.,A Verrips; M A Willemsen; E Rubio-Gozalbo; J De Jong; J A Smeitink,,2000.0,0,0 333,10769417,Regression of calcified coronary artery plaque assessed by electron beam computed tomography.,P Raggi,"Lipid lowering therapies and aggressive life style modifications can induce regression of coronary artery disease as demonstrated by several angiographic studies. Such regression has also been associated with greatly reduced cardiovascular event rates. However, coronary angiography is invasive and expensive and other non-invasive diagnostic approaches would be preferable. Electron beam computed tomography imaging is used to detect coronary artery calcification, it is non-invasive and considerably less expensive than angiography. This tool provides an opportunity to serially monitor the effectiveness of medical therapy for coronary artery disease via the follow-up of a surrogate marker of disease such as vascular calcification. We review the current status of the literature on the use of electron beam computed tomography as a tool to follow progression of disease.",2000.0,0,0 334,10770975,Predictors and evolution of renal function during 9 years following heart transplantation.,B Lindelöw; C H Bergh; H Herlitz; F Waagstein,"Over a 9-yr period, heart transplantation was performed in 200 patients at Sahlgrenska University Hospital. Of these 200 patients, 151 were followed for 1 to 9 yr with regard to renal function, hemodynamics, cyclosporin A concentrations, and complications. Patients with a preoperative serum creatinine >130 micromol/L received inotropic drugs to test for reversibility of renal dysfunction. The end point was graft failure. The average preoperative GFR of 66 +/- 17 ml/min per 1.73 m(2) declined to 52 +/- 19, 44 +/- 16, and 37 +/- 17 at 1, 5, and 9 yr after heart transplantation, respectively. Altogether, the average GFR declined by 44%. There was no significant correlation between the preoperative GFR and postoperative renal function or survival. Recipient age was a predictor of renal function during the entire follow-up. Severe renal dysfunction (GFR <20 ml/min per 1.73 m(2)) developed in 20% of the patients, which was predicted by the recipient age at transplantation together with the GFR 1 yr after transplantation. A nomogram that shows the risk of developing severe renal dysfunction after heart transplantation is presented. Cyclosporin A concentrations and treatment with statins, calcium channel blockers, or angiotensin-converting enzyme inhibitors did not correlate with the evolution of renal function. Patients with a preoperative depressed renal function who improved on inotropic treatment seemed to have a poorer outcome compared with the other study patients.",2000.0,0,0 335,10772372,"Impact of pharmacy counseling on compliance and effectiveness of combination lipid-lowering therapy in patients undergoing coronary artery revascularization: a randomized, controlled trial.",M A Faulkner; E C Wadibia; B D Lucas; D E Hilleman,"This randomized, controlled trial evaluated the impact of personalized follow-up on compliance rates in high-risk patients receiving combination lipid-lowering therapy over 2 years. A random sample of 30 patients 7-30 days after cardiac surgery had baseline fasting low-density lipoprotein levels higher than 130 mg/dl. All patients received lovastatin 20 mg/day and colestipol 5 g twice/day. Weekly telephone contact was made with each patient for 12 weeks. Short- and long-term compliance was assessed by pill and packet counts and refill records. Compliance and lipid profile results were significantly better in the intervention group (p<0.05) up to 2 years after the start of therapy than in the control group for all parameters except high-density lipoprotein. However, this effect was not apparent during the first 12 weeks of therapy. Short-term telephone follow-up favorably affected compliance and lipid profile results up to 2 years after start of therapy.",2000.0,0,0 336,10774784,Use of statins and blood pressure control in treated hypertensive patients with hypercholesterolemia.,C Borghi; M G Prandin; F V Costa; S Bacchelli; D Degli Esposti; E Ambrosioni,"High serum cholesterol has been frequently reported in patients with arterial hypertension in whom it might influence the blood pressure control. The aim of this study was to compare the extent of blood pressure changes in 41 patients with hypertension and hypercholesterolemia, taking antihypertensive drugs and treated for 3 months with statins (HC-S; pravastatin or simvastatin) and compared with matched controls with high (HC-D; 44) or normal serum cholesterol (NC-D; 45) undergoing antihypertensive treatment combined with dietary treatment alone. After 3 months of follow-up, a greater reduction of systolic (SBP) and diastolic (DBP) blood pressure values was observed in HC-S patients (ASBP/DBP, -11.3 +/-3/-10.6 +/- 2%) when compared with both HC-D (deltaSBP/DBP, -6.6 +/- 2/-6.1 +/- 2%; p < 0.05) and NC-D (deltaSBP/DBP, -6.9 +/- 2/-6.8 +/- 1.5%; p < 0.05). In statin-treated patients, a slight linear relation has been found between the percentage changes in DBP and those in plasma total cholesterol (R = 0.37, p = 0.043), whereas no relation was found with SBP changes (R =0.11; p = 0.35). In conclusion, the results of this study demonstrate that the use of statins in combination with antihypertensive drugs can improve blood pressure control in patients with uncontrolled hypertension and high serum cholesterol levels. The additional blood pressure reduction observed in patients treated with statins is clinically relevant and only partially related to the lipid-lowering effect.",2000.0,0,0 337,10781516,3 year simvastatin treatment and lens nuclear back scattering.,W Qian; P G Söderberg; E Chen; K Magnius; B Philipson,"To determine if 3 year treatment of hypercholesterolaemia with simvastatin causes an increase of lens nuclear back scattering. 160 patients with hypercholesterolaemia in the Scandinavian Simvastatin Survival Study (4S) were followed for 3 years. Half (80) of the patients took simvastatin and half (80) received placebo. The lens was photographed with a Topcon SL-45 slit lamp camera at the beginning and at 1 year intervals. A common lens nuclear area was used for measuring lens nuclear back scattering. Nuclear back scattering increased with age and there was more pronounced scattering in women than in men. Lens nuclear back scattering did not differ significantly between the simvastatin and placebo groups, but the power was low (0.2). Lens nuclear back scattering increased during the study period independently of baseline back scattering, age, and sex for both groups. Although no significant difference was found between the simvastatin and placebo groups, the currently available data are insufficient for exclusion of the possibility that taking simvastatin during a 3 year period increases nuclear back scattering. However, a possible minor increase of nuclear back scattering is clinically irrelevant considering known beneficial effects of simvastatin on coronary heart disease.",2000.0,0,0 338,10781640,Effects of combination therapy with estrogen plus simvastatin on lipoprotein metabolism in postmenopausal women with type IIa hypercholesterolemia.,A Wakatsuki; Y Okatani; N Ikenoue,"We investigated the effects of estrogen and simvastatin, administered both alone and in combination, on the plasma lipid levels and lipoprotein-related enzymes in 45 postmenopausal women with type IIa hypercholesterolemia. They received 0.625 mg conjugated equine estrogen (n=15), 5 mg simvastatin (n=15), or the combination (n=15) daily for 3 months. We measured the concentrations of cholesterol and triglyceride in the plasma, and in the very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL)1 (1.0190.05). Lipid-lowering therapy in patients with familial hyperlipidaemia free of symptomatic cardiovascular disease reverses the progression of early, preintrusive atherosclerosis of the carotid artery. It is a beneficial sign indicating the possibility for atherosclerosis regression.",2000.0,0,0 353,10812143,Comparison of the effects of simvastatin and pravastatin on acute rejection episodes in renal transplant patients.,M Tuncer; G Süleymanlar; F F Ersoy; G Yakupoğlu,,2000.0,0,0 354,10813375,Beneficial effects of fluvastatin on myocardial blood flow at two time-points in hypercholesterolemic patients with coronary artery disease.,H W Eichstädt; C B Abletshauser; T Störk; G Weidinger,"Hypercholesterolemia is a major risk factor initiating and accelerating atherosclerosis and leading to severe stages of coronary artery disease (CAD) with a high risk of cardiovascular events. We investigated the impact of lipid lowering in patients with hypercholesterolemia and evident CAD on clinically relevant parameters like myocardial perfusion. Myocardial imaging was performed with thallium-201 single photon-emission computed tomography at rest and after maximal bicycle exercise in 22 patients after a 4-week lead-in period, and after 12 and 24 weeks of therapy with fluvastatin. Perfusion defects occurred in all patients, indicating stress-induced myocardial ischemia. After 12 weeks of therapy, the perfusion of the ischemic segments increased by 26% (277+/-99 to 349+/-96 cpm; p < 0.001), whereas the value of the normal segments was augmented only by 4% (478+/-44 to 497+/-28 cpm; p < 0.05). The results slightly improved further after 24 weeks. Moreover, a subgroup analysis elucidated a more pronounced effect in patients without lipid-lowering premedication. This nonpretreated group (n = 11) revealed an improvement of ischemic segments at stress by 42% at week 24. In contrast, pretreated patients had an increase of only 18% (between groups, p < 0.05), indicating a carryover effect of premedication. In conclusion, short-term therapy with fluvastatin acts beneficially on impaired vascular function in hypercholesterolemic patients with CAD.",2000.0,0,0 355,10817086,Efficacy and safety of cerivastatin for type 2 diabetes and hypercholesterolaemia. Hyperlipidaemia in Diabetes Mellitus investigators.,A Rubinstein; F J Maritz; S G Soule; A Markel; T Chajek-Shaul; M Maislos; S Tal; D Stolero,"The prevalence of coronary heart disease (CHD) is markedly increased in diabetic patients compared with non-diabetic individuals, and its prognosis is less good. Serum total and low-density lipoprotein (LDL) cholesterol concentrations have been shown to be powerful predictors of CHD morbidity and mortality in patients with type 2 diabetes. The available data suggest that the target cholesterol concentration in patients with diabetes should be similar to that in non-diabetic individuals with a previous myocardial infarction. This led us to investigate the efficacy, tolerability and safety of a new, highly potent statin, cerivastatin, in diabetic hyperlipidaemia. This was a multinational, multicentre, double-blind, randomized study in type 2 diabetic patients with hypercholesterolaemia (LDL cholesterol >3.35 mmol/l; triglycerides <4.56 mmol/l). Eligible patients were randomly assigned to groups to receive cerivastatin 0.1 mg or 0.3 mg or placebo in a ratio of 2:2:1 for 12 weeks. They were monitored in the clinic every 4 weeks. Of the 453 patients screened, 265 were allocated to the study groups. Fifty-one received placebo and 107 patients were assigned to each active treatment group (0.1 mg and 0.3 mg cerivastatin). At the close of the study, total cholesterol had decreased by 13.7% and 23.5%, LDL cholesterol decreased by 20.2% and 33.8%, and triglyceride concentrations decreased by 3.9% and 12.3% in the cerivastatin 0.1 mg and 0.3 mg groups, respectively. There was no significant difference between the groups in haemoglobin A1c, adverse events or increases in liver and muscle enzymes during the study period. Hypercholesterolaemic patients with type 2 diabetes had a significant reduction in LDL cholesterol and total cholesterol concentrations after cerivastatin treatment once daily. The dose of 0.3 mg cerivastatin is effective in diabetic hypercholesterolaemia, with co-reduction of triglyceride concentrations. The effect of cerivastatin on coronary morbidity and mortality is currently being investigated in clinical trials.",2000.0,0,0 356,10819700,Cost-effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor therapy in older patients with myocardial infarction.,D A Ganz; K M Kuntz; G A Jacobson; J Avorn,"3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy has proven efficacy in reducing the rate of coronary and cerebrovascular events in patients 75 years of age or younger with a history of myocardial infarction. However, in patients older than 75 years of age, the efficacy and potential cost-effectiveness of statins are unknown. To estimate the incremental cost-effectiveness of statin therapy compared with usual care in patients 75 to 84 years of age with previous myocardial infarction. Cost-effectiveness analysis. Published data from cohort studies. Patients 75 to 84 years of age with a history of myocardial infarction. Lifetime. Societal. Statin therapy. Life expectancy, quality-adjusted life expectancy, and incremental cost-effectiveness. The incremental cost-effectiveness of statin therapy compared with usual care in patients 75 to 84 years of age with previous myocardial infarction was $18800 per quality-adjusted life-year (QALY). On the basis of a probabilistic sensitivity analysis, there is a 75% chance that statin therapy costs less than $39800 per QALY compared with usual care. If the cost of statin therapy and efficacy of statin therapy at reducing myocardial infarction were set to their most favorable values, statin therapy cost $5400 per QALY; if cost and efficacy were set to their least favorable values, statin therapy cost $97800 per QALY. The cost-effectiveness ratios of statin therapy in older patients with previous myocardial infarction are reasonable under a wide variety of assumptions about drug efficacy, drug cost, and rates of cardiac and cerebrovascular events. Pending results of randomized, controlled trials of secondary prevention in patients in this age group, statin therapy seems to be as cost-effective as many routinely accepted medical interventions in this setting.",2000.0,0,1 357,10822898,Fluvastatin reduces soluble P-selectin and ICAM-1 levels in hypercholesterolemic patients: role of nitric oxide.,M Romano; A Mezzetti; C Marulli; G Ciabattoni; F Febo; S Di Ienno; S Roccaforte; S Vigneri; G Nubile; M Milani; G Davì,"Lipid-lowering therapy with 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase inhibitors reduces the incidence of atherosclerosis-related cardiovascular events. Adhesion molecules, regulating interactions between vascular and circulating cells, may play a central role in the pathogenesis of atherosclerosis and related complications. In the present report we examined the impact of the HMG-CoA reductase inhibitor fluvastatin on plasma levels of P-selectin and ICAM-1. Plasma levels of P-selectin and ICAM-1 were determined using an enzyme immunoassay in 26 patients with type IIa hypercholesterolemia randomized to treatment with either fluvastatin (80 mg/d) or placebo in a double blind fashion for 12 weeks. Fluvastatin administration reduced either P-selectin (118 +/- 63 vs 81 +/- 36 ng/mL [-31%], P = 0.0015) or ICAM-1 (264 +/- 75 vs 228 +/- 68 ng/mL [-13.7%], P = 0.0033) levels. Fluvastatin also lowered urinary 11-dehydro-TXB2 (1396 +/- 536 vs 1009 +/- 378 pg/mg creatinine [-27%], P = 0.0015) and von Willebrand Factor levels (1456 +/- 716 vs 1203 +/- 527 U/L [-17.4%], P = 0.0275), and a direct correlation was observed between P-selectin and 11-dehydro-TXB2 levels (r = 0.588, P = 0.0033). Patients treated with fluvastatin displayed an increase in nitric oxide (NO) generation, evaluated with measurements of serum NO2-/NO3-, (4.7 +/- 1 vs 8.9 +/- 3.1) mumol/L [98%], P = 0.0046). Moreover, an inverse correlation was observed between NO2-/NO3- and P-selectin (r = -0.420; P = 0.0343), 11-dehydro-TXB2 (r = -0.511; P = 0.0106), or LDL (r = -0.742; P = 0.0002) levels. These results may provide novel biochemical basis for the beneficial clinical effects of HMG-CoA reductase inhibitors in hypercholesterolemia.",2000.0,0,0 358,10823314,Photoscratch testing in systemic drug-induced photosensitivity.,V Conilleau; A Dompmartin; M Michel; L Verneuil; D Leroy,"Because of numerous false-negative results, photopatch testing is seldom relevant in systemic drug-induced photosensitivity. These false-negative photopatch test results can be attributed to the inability of the drug to penetrate into the epidermis. In order to enhance the penetration of the tested drug into the epidermis, some authors proposed to breach the cutaneous barrier. We performed a prospective study comparing photopatch and photoscratch testing. Fifteen patients presenting with a systemic drug-induced photosensitivity, proved by a favourable outcome after discontinuing the drug, were tested. For each drug, photopatch and photoscratch tests were performed. Two-thirds of the patients had negative photopatch and photoscratch tests with the suspected drugs. Photopatch and photoscratch tests were positive and relevant, respectively, in 3 and 4 patients. Photoscratch tests induced more false-positive results due to irritation confirmed on control subjects. Our study proves that photoscratch tests do not change the sensitivity of phototesting.",2000.0,0,0 359,10824361,A randomised comparison of simvastatin versus simvastatin and low cholesterol diet in the treatment of hypercholesterolaemia.,S Thuraisingham; K H Tan; K S Chong; S F Yap; K Pasamanikam,"There is little evidence to show that strict dietary modification alone confers any significant impact on cardiac events in primary and secondary prevention of coronary heart disease. Given the efficacy of the statins, the need for strict dietary modification in patients on statin therapy has been questioned. This study was performed to assess 1) the added benefit on serum lipid levels of a strict low-fat dietary regimen in patients with hypercholesterolaemia already treated with simvastatin; 2) the efficacy of simvastatin on the lipid profile of our sample Asian population; and 3) the tolerability and side-effect profile of simvastatin. This study was a prospective evaluation of 60 patients with hypercholesterolaemia treated with simvastatin who were subjected to either a normal diet or a dietitian guided low-fat diet. Assessment of the effects on serum lipid levels, side-effects, biochemical and haematological markers were performed. After 24 weeks of treatment, a strict dietitian guided low-fat diet conferred no additional benefit over and above what was achieved by simvastatin alone. Furthermore, a higher dose of simvastatin was needed in the dietitian guided diet group to achieve the target LDL-cholesterol level. Simvastatin resulted in a significant positive alteration of lipid profiles in all patients. The drug was well tolerated, with no significant change in either haematological or biochemical indices. Simvastatin is a highly effective cholesterol-lowering drug with a beneficial effect on the entire lipid spectrum in a cross-section of Asian patients, and is well tolerated. A dietitian guided dietary approach confers no additional advantage once statin therapy has been initiated.",2000.0,0,0 360,10824369,The role of tirofiban in acute coronary syndromes.,A Gomma; J Collinson; H Purcell; M Flather,"Platelet activation and aggregation play an important and essential role in the formation of intracoronary thrombus in acute coronary syndromes (ACS). ACS still carries unacceptably high rates of morbidity and mortality despite intensive antianginal therapy and the wide use of aspirin and heparin. Two glycoprotein IIb/IIIa receptor inhibitors are now licensed for concomitant use with heparin and aspirin in ACS. Glycoprotein IIb/IIIa receptor inhibitors block the final step for platelet aggregation and fibrinogen binding, thus preventing thrombus formation. Tirofiban is a potent, synthetic, non-peptide and specific glycoprotein IIb/IIIa receptor inhibitor. In three major international trials involving over 7200 patients (PRISM, PRISM-PLUS and RESTORE), tirofiban was shown to be well tolerated and to reduce the risk of ischaemic complications in patients with unstable angina, non-Q-wave myocardial infarction and high-risk patients undergoing revascularisation when used in combination with aspirin and heparin. These and ongoing studies are discussed.",2000.0,0,0 361,10826894,"Hyperlipidemia associated with HIV protease inhibitor use: pathophysiology, prevalence, risk factors and treatment.",S R Penzak; S K Chuck,"Despite potent antiretroviral activity, the HIV-1 protease inhibitors have recently been associated with abnormal serum lipoprotein concentrations. The purpose of this review is to describe serum lipid abnormalities related to protease inhibitor use. A MEDLINE search up to June 1, 1999, and abstracts from recent scientific meetings were primary data sources. Lipid disturbances in HIV-infected patients receiving protease inhibitors generally consist of elevated triglycerides and total cholesterol levels; HDL cholesterol is often reduced. The pathophysiological mechanism by which the protease inhibitors induce these lipid abnormalities has been hypothesized, but is unknown. Cases of pancreatitis and coronary heart disease have been described in hyperlipidemic patients receiving protease inhibitors. Treatment of protease inhibitor-related hyperlipidemia is unknown. Exchanging the offending protease inhibitor for nevirapine may be helpful in certain patients. Atorvastatin in combination with gemfibrozil has been used with limited success in a small number of individuals.",2000.0,1,1 362,10829251,HMG-CoA reductase inhibition: anti-inflammatory effects beyond lipid lowering?,W März; H Wieland,"Atherosclerosis has many features of a chronic inflammatory disease. Atherosclerotic lesions contain inflammatory cells like activated T-lymphocytes and macrophages. Systemic markers of inflammation such as white blood cells, C-reactive protein, serum amyloid A, interleukin 6 and soluble adhesion molecules are predictive of future cardiovascular events, even after adjustment for the contribution of established cardiovascular risk factors. Atherogenic lipoprotein particles, in particular modified low-density lipoproteins (LDL), elicit pro-inflammatory responses of cellular elements of the vessel wall, including endothelial dysfunction and activation of monocyte-derived macrophages. Treatment, with HMG-CoA reductase inhibitors has proven the most successful strategy to reduce the concentration of LDL in the circulatory system. These compounds lower LDL cholesterol by inhibiting the mevalonate pathway in the liver, which in turn depletes the regulatory pool of cholesterol and enhances the activity of LDL receptors. Five prospective clinical trials have convincingly demonstrated that HMG-CoA reductase inhibitors can effectively lower the incidence of cardiovascular events in primary and secondary prevention. Post hoc analyses of these trials suggest that the clinical benefit brought about by HMG-CoA reductase inhibitors may not entirely be due to their effect on the levels of circulating lipoproteins. In-vitro observations of anti-inflammatory actions of HMG-CoA reductase inhibitors on vascular cells have been suggested to explain effects beyond lipid-lowering. It is, however, not clear whether these findings are relevant to the in-vivo situation. Further investigation is now necessary in order to determine the relative significance of cholesterol lowering and of ancillary effects to the overall clinical benefit of statin treatment.",2000.0,0,0 363,10831029,Adverse effects of high-dose olanzapine in treatment-refractory schizophrenia.,B D Bronson; J P Lindenmayer,,2000.0,0,0 364,10843815,Is a mechanical or a metabolic approach superior in the treatment of coronary disease? Results of the atorvastatin versus revascularization (AVERT) trial.,D Waters,,2000.0,0,0 365,10846948,Development of thyroid follicular adenoma on simvastatin therapy.,E L McCord; S Goenka,"HMG-CoA reductase inhibitors (lovastatin, simvastatin, fluvastatin, pravastatin) constitute a potent class of cholesterol-lowering agents, which are increasingly being used these days for primary and secondary prevention of atherosclerotic heart disease. Despite having good overall safety and efficacy profiles, these medications can still cause significant adverse effects including transient elevation of hepatic transaminases, myopathy, and rhabdomyolysis. Preclinical studies have demonstrated a potential of neoplasia in rats. However in clinical trials HMG-CoA reductase inhibitors have not been found to be neoplastic in humans. The dosage used in humans is also significantly lower and therefore it is expected to have a good safety margin. But this may not be entirely true considering the mechanism of neoplastic transformation, which is thought to be different in humans as compared to other species. We report a patient, who developed follicular adenoma with prominent Hurthle cell changes after being on simvastatin for three months but not during one year of pravastatin therapy. In elderly female patients with hyperlipidemia requiring pharmacologic treatment, especially those with a prior history of multinodular goiter, one should consider using an agent which has not been shown to cause thyroid tumors even in animal models. Patients should continue to be followed with frequent periodic thyroid palpation in addition to the usual biochemical monitoring required while on these agents.",2000.0,0,0 366,10849014,The effect of cholesterol lowering on carotid and femoral artery wall stiffness and thickness in patients with familial hypercholesterolaemia.,T J Smilde; F W van den Berkmortel; H Wollersheim; H van Langen; J J Kastelein; A F Stalenhoef,"Early in the process of atherosclerosis, changes in vessel wall stiffness and thickness may occur. The present study evaluates the effect of cholesterol reduction on artery wall stiffness and intima media thickness in patients with familial hypercholesterolaemia (FH). Forty-five patients with familial hypercholesterolaemia (mean age 46+/-10 years) with untreated LDL cholesterol concentration > 9 mmol L(-1), were studied before and after one year of cholesterol lowering therapy with statins (simvastatin, atorvastatin 40-80 mg day(-1). The distensibility (DC in 10-3 kPa(-1) and compliance (CC in mm2. kPa(-1) of the common carotid artery (CCA) (right and left side) and common femoral artery (CFA) (right side) were determined by a wall track system (Pie Medical). The intima media thickness (IMT) (both right and left) of the CCA, bulb (BUL), internal carotid artery (ICA) and CFA were measured in mm by high-resolution ultrasound (Biosound). The mean concentration of total cholesterol (TC), LDL-cholesterol (LDL-C) and triglycerides (TG) were reduced significantly by 43%, 51% and 25%, respectively, whereas HDL-cholesterol (HDL-C) increased by 13% (P<0.001). In the CFA, the DC and CC increased significantly (DC from 7.9+/-3.0 to 9.1+/-3.7 in 10(-3) kPa(-1); CC 0.5+/-0.2-0.6+/-0.3 in mm2. kPa(-1), whereas the DC and CC did not change in the CCA. In contrast, the IMT of the CCA decreased significantly in both men and women whereas an IMT decrease was also seen in the BUL and ICA in premenopausal women. A LDL-cholesterol reduction of 44.8% and 45.4% was necessary to induce significant decreases in IMT and increases in DC and CC. One year of cholesterol lowering therapy in FH decreases the wall stiffness in the CFA and the arterial wall thickness in the CCA.",2000.0,0,0 367,10849941,Beneficial effects of atorvastatin in the treatment of hyperlipidemia after renal transplantation.,D Demetriou; A Shabpar; G Böhmig; S Schmaldienst; W H Hörl; B Watschinger,"Despite the availability of various lipid lowering drugs, the treatment of hyperlipidemia, one of the most important risk factors for morbidity and mortality after organ transplantation, remains a therapeutic challenge. We investigated the safety and efficacy of a new HMG-CoA reductase inhibitor, atorvastatin, in renal transplant patients whose serum lipids were insufficiently controlled by diet and treatment with other lipid lowering drugs. Twenty-four patients (14 males/10 females; mean age 51.2 +/- 2.3 years) were converted to low dose atorvastatin (10 mg/day) at a mean of 67.7 +/- 8.6 months after renal transplantation and prospectively followed for 3 months after initiation of the study drug. HDL, LDL, and total cholesterol, triglycerides, serum creatinine and CPK levels were evaluated pre (-3, -1, 0 months) and post conversion (+1, +3 months). In the eighteen patients who completed the study, low dose atorvastatin therapy led to a significant reduction in total cholesterol (304.6 +/- 13.2 vs. 247.6 +/- 12.0 mg/dl; p = 0.007) and LDL cholesterol (191.9 +/- 9.0 vs. 141.8 +/- 14.7 mg/dl; p < 0.0001) and a modest reduction in serum triglyceride levels at three months after conversion. We conclude that low dose atorvastatin (10 mg/day) can be successfully used and appears to be safe in the treatment of posttransplant hyperlipidemia. Its long-term effects on patient morbidity and mortality as well as graft survival should be investigated in larger and more prolonged prospective trials.",2000.0,0,0 368,10852435,Hyperlipidemia: diagnostic and therapeutic perspectives.,C M Ballantyne; S M Grundy; A Oberman; R A Kreisberg; R J Havel; P H Frost; S M Haffner,,2000.0,0,0 369,10852642,Diabetic dyslipidaemia: current treatment recommendations.,J D Best; D N O'Neal,"Insulin deficiency and hyperglycaemia in type 1 (insulin-dependent) diabetes mellitus produce lipid abnormalities, which can be corrected by appropriate insulin therapy. Diabetic nephropathy, which is the main risk factor for coronary heart disease (CHD) in type 1 diabetes, causes pro-atherosclerotic changes in lipid metabolism. Detection and treatment of elevated cholesterol levels is likely to be of benefit in these patients. Type 2 (noninsulin-dependent) diabetes mellitus is associated with abnormal lipid metabolism, even when glycaemic control is good and nephropathy absent. Elevated triglyceride levels, reduced high density lipoprotein (HDL) cholesterol and a preponderance of small, dense low density lipoprotein (LDL) particles are the key abnormalities that constitute diabetic dyslipidaemia. The prevalence of hypercholesterolaemia is the same as for the nondiabetic population, but the relative risk of CHD is greatly increased at every level of cholesterol. Based on effectiveness, tolerability and clinical trial results, treatment with HMG-CoA reductase inhibitors to lower LDL cholesterol is recommended as primary therapy. These agents are also moderately effective at reducing triglyceride and increasing HDL cholesterol levels. If hypertriglyceridaemia predominates, treatment with fibric acid derivatives is appropriate, although there is currently only limited clinical trial evidence that the risk of CHD will be reduced. In type 1 diabetes, but particularly in type 2 diabetes, lipid disorders are likely to contribute significantly to the increased risk of macrovascular complications. especially CHD. Management of the disordered lipid metabolism should be given a high priority in the clinical care of all patients with diabetes.",2000.0,0,1 370,10852644,Lipid-lowering treatment in coronary artery disease: how low should cholesterol go?,P H Jones,"The randomised clinical trial data, which supports preventing coronary heart disease (CHD) events by lowering low density lipoprotein cholesterol (LDL-C) levels, is substantial, consistent and highly significant. HMG-CoA reductase inhibitors (statins), which are the preferred medications for lowering LDL-C levels, are well tolerated, with greater efficacy than other lipid-altering medications. In 1993, the National Cholesterol Education Program (NCEP) guidelines recommended LDL-C target levels to be achieved with therapy in high-risk individuals. In particular, the LDL-C goal of therapy in patients with CHD was < or = 100 mg/dl (2.6 mmol/L), with no specific guidance as to the lower limit or whether additional clinical benefit could be expected. Because little clinical trial data existed at that time to offer support, and because some epidemiological data raised concern about the potential detriments associated with very low total cholesterol and LDL-C levels, the NCEP Adult Treatment Panel remained appropriately vague on the 'how low should you go' question. In the last few years, several additional clinical trials have provided sufficient efficacy and safety data to re-examine that question. Analyses of on-treatment LDL-C levels and subsequent CHD events from three landmark trials with HMG-CoA reductase inhibitors suggest that progressively lower LDL-C levels are associated with lower CHD events in a curvilinear fashion. The Post Coronary Artery Bypass Graft (Post-CABG) trial and Atorvastatin Versus Revascularisation Trial (AVERT) examined a more intensive versus less intensive drug regimen for LDL-C reduction, and concluded that the more aggressively treated patients had better angiographic and end-point outcomes. Most importantly, there did not appear to be any change in noncardiovascular end-points associated with lower LDL-C levels. In several ongoing clinical trials, patients with CHD have been randomised to receive HMG-CoA reductase inhibitors with targets for LDL-C levels of 100 mg/dl versus 75 mg/dl (1.94 mmol/L). These trials have sufficient patient numbers and power to definitely determine if reducing LDL-C levels to approximately 75 mg/dl can provide an acceptable benefit-to-risk-ratio.",2000.0,0,0 371,10852999,Thrombotic thrombocytopenic purpura associated with clopidogrel.,C L Bennett; J M Connors; J M Carwile; J L Moake; W R Bell; S R Tarantolo; L J McCarthy; R Sarode; A J Hatfield; M D Feldman; C J Davidson; H M Tsai,"The antiplatelet drug clopidogrel is a new thienopyridine derivative whose mechanism of action and chemical structure are similar to those of ticlopidine. The estimated incidence of ticlopidine-associated thrombotic thrombocytopenic purpura is 1 per 1600 to 5000 patients treated, whereas no clopidogrel-associated cases were observed among 20,000 closely monitored patients treated in phase 3 clinical trials and cohort studies. Because of the association between ticlopidine use and thrombotic thrombocytopenic purpura and other adverse effects, clopidogrel has largely replaced ticlopidine in clinical practice. More than 3 million patients have received clopidogrel. We report the clinical and laboratory findings in 11 patients in whom thrombotic thrombocytopenic purpura developed during or soon after treatment with clopidogrel. The 11 patients were identified by active surveillance by the medical directors of blood banks (3 patients), hematologists (6), and the manufacturer of clopidogrel (2). Ten of the 11 patients received clopidogrel for 14 days or less before the onset of thrombotic thrombocytopenic purpura. Although 10 of the 11 patients had a response to plasma exchange, 2 required 20 or more exchanges before clinical improvement occurred, and 2 had relapses while not receiving clopidogrel. One patient died despite undergoing plasma exchange soon after diagnosis. Thrombotic thrombocytopenic purpura can occur after the initiation of clopidogrel therapy, often within the first two weeks of treatment. Physicians should be aware of the possibility of this syndrome when initiating clopidogrel treatment.",2000.0,0,0 372,10853881,Influence of renal function on the pharmacokinetics of cerivastatin in normocholesterolemic adults.,A L Mazzu; J T Lettieri; E Kelly; R Vargas; T Marbury; M C Liu; P Sundaresan,"The influence of impaired renal function on the pharmacokinetics of single and multiple doses of cerivastatin was evaluated in this nonrandomized, non-blinded, 7-day, multiple-dose study. Thirty-five adults between the ages of 21 years and 75 years with normal renal function (CL(CR) >90 ml/min/1.73 m2, n = 9), or patients with either mild (CL(CR) 61 ml/min/1.73 m2 to < or =90 ml/min/1.73 m2, n = 9), moderate (CL(CR) 30 ml/min/1.73 m2 to < or =60 ml/ min/1.73 m2, n = 8), or severe (CL(CR) <30 ml/min/ 1.73 m2, but not on dialysis, n = 9) renal impairment were given cerivastatin 0.3 mg daily each evening for 7 days. The steady-state pharmacokinetics of cerivastatin, including the area under the concentration-time curve (AUC)0-24, peak plasma concentration (Cmax), time to reach Cmax (tmax) and elimination half-life (t1/2), were determined on day 1 and day 7. The logarithm of the pharmacokinetic variables was analyzed using analysis of variance (ANOVA). Safety assessments included physical examination, fundoscopy, vital signs, electrocardiogram (ECG), adverse events, and laboratory safety indices. The day-1 AUC in patients with mild renal impairment was similar to that of patients with normal function (19.6 microg/h/l vs 19.2 microg/h/l, respectively). However, the AUC for cerivastatin patients with moderate or severe renal impairment was 40-60% higher (30.8 microg/h/l and 29.0 microg/h/l, respectively). Cmax values for patients with normal, mild, moderate, and severe renal impairment were 3.3, 3.4, 4.6, and 5.2 microg/l, respectively. This modest increase in plasma cerivastatin levels is nearly equivalent to a 0.4-mg daily dose, which has been recently approved in the United States. The mean t1/2 of cerivastatin was less than 4.5 h in all patients, indicating that renal dysfunction did not promote cerivastatin accumulation. This observation was confirmed by the finding that the cerivastatin plasma levels on day 1 and day 7 were similar in all patient groups. Furthermore, the mean AUC and Cmax values for both demethylated and hydroxylated cerivastatin were similar in the patients with the most severe renal dysfunction to the corresponding values in healthy subjects. Cerivastatin was well tolerated in all patients irrespective of renal function. Adverse events were observed in 37% of the subjects; nearly all were mild and generally of short duration, and most resolved without intervention. Incidence of adverse events was similar across all three renal groups and the control group. There were no clinically significant laboratory changes other than those consistent with renal disease. This study demonstrates that dosage adjustment of the daily 0.3-mg cerivastatin dose in patients with significant renal impairment is likely unnecessary.",2000.0,0,0 373,10856525,Differences in the effects of HMG-CoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture.,J R Sindermann; L Fan; K A Weigel; D Troyer; J G Müller; A Schmidt; K L March; G Breithardt,"We investigated the influence of lovastatin, simvastatin and pravastatin on proliferation and viability of vascular smooth muscle cells (SMC) in vitro and studied the effects of lovastatin on a mouse SMC line transgenic for a temperature-sensitive mutant of SV40 large T antigen (TAg), known to inhibit the function of p53 and pRb family members. We found that lovastatin and simvastatin inhibited cell proliferation by provoking G0/G1 phase arrest with concomitant depression of the proliferation antigen Ki-67/MIB-1. Lovastatin at high concentrations of 20 micromol/l caused cell death in the presence of serum but not under serum starved conditions, which was verified on the basis of increased DNA strand breaks, decreased DNA content and morphological alterations seen by electron microscopy. Cell death was also found for simvastatin, whereas pravastatin did not exhibit antiproliferative or cytotoxic effects. Mouse SMC transgenic for TAg did not show any impaired sensitivity to the antiproliferative and cell death inducing effect of lovastatin, but both effects could be antagonized by the supplementation of mevalonate. The data indicate that antiproliferative and cytotoxic effects of lovastatin are caused by the using up of products of mevalonate metabolism and do not require the presence of p53 or pRb.",2000.0,0,0 374,10856535,Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia.,F J Raal; A S Pappu; D R Illingworth; G J Pilcher; A D Marais; J C Firth; M J Kotze; T M Heinonen; D M Black,"Patients with homozygous familial hypercholesterolaemia (HoFH) have markedly elevated low density lipoprotein (LDL) cholesterol levels that are refractory to standard doses of lipid-lowering drug therapy. In the present study we evaluated the effect of atorvastatin on steady state concentrations of plasma lipids and mevalonic acid (MVA), as well as on 24-h urinary excretion of MVA in patients with well characterized HoFH. Thirty-five HoFH patients (18 males; 17 females) received 40 mg and then 80 mg atorvastatin/day. The dose of atorvastatin was increased further to 120 mg/day in 20 subjects and to 160 mg/day in 13 subjects who had not achieved LDL cholesterol goal, or in whom the dose of atorvastatin had not exceeded 2.5 mg/kg body wt per day. LDL cholesterol levels were reduced by 17% at the 40 mg/day and by 28% at the 80 mg/day dosage (P<0.01). Reduction in LDL cholesterol in the five receptor negative patients was similar to that achieved in the 30 patients with residual LDL receptor activity. Plasma MVA and 24-h urinary excretion of MVA, as markers of in vivo cholesterol synthesis, were elevated at baseline and decreased markedly with treatment. Urinary MVA excretion decreased by 57% at the 40 mg/day dose and by 63% at the 80 mg/day dosage (P<0. 01). There was a correlation between reduction in LDL cholesterol and reduction in urinary MVA excretion; those patients with the highest basal levels of MVA excretion and thus the highest rates of cholesterol synthesis having the greatest reduction in LDL cholesterol (r=0.38; P=0.02). Increasing the dose of atorvastatin to 120 and 160 mg/day did not result in any further reduction in LDL cholesterol or urinary MVA excretion suggesting a plateau effect with no further inhibition of cholesterol synthesis at doses of atorvastatin greater than 80 mg/day.",2000.0,0,0 375,10856536,Efficacy and safety of a combination of fluvastatin and bezafibrate in patients with mixed hyperlipidaemia (FACT study).,P Pauciullo; C Borgnino; R Paoletti; M Mariani; M Mancini,"Preliminary data suggest that fluvastatin may be safely combined with fibrates. The Fluvastatin Alone and in Combination Treatment Study examined the effects on plasma lipids and safety of a combination of fluvastatin and bezafibrate in patients with coronary artery disease and mixed hyperlipidaemia. A total of 333 patients were randomly allocated in this multicentre double-blind trial to receive 40 mg fluvastatin alone (n=80), 400 mg bezafibrate (n=86), 20 mg fluvastatin+400 mg bezafibrate (n=85) or 40 mg fluvastatin+400 mg bezafibrate (n=82) for 24 weeks. Low-density lipoprotein (LDL)-cholesterol decreased >20% in all fluvastatin-containing regimens, with significantly greater decreases compared with bezafibrate alone (P<0.001). Bezafibrate alone and fluvastatin+bezafibrate combinations resulted in greater increases in high-density lipoprotein (HDL)-cholesterol and decreases in triglycerides compared with fluvastatin alone (P<0.001). Fluvastatin (40 mg)+bezafibrate was the most effective for all lipid parameters with a decrease from baseline at endpoint in LDL-cholesterol of 24%, a decrease in triglycerides of 38% and an increase in HDL-cholesterol of 22%. All treatments were well tolerated with no increase in adverse events for combination therapy versus monotherapy, or between combination regimens. No clinically relevant liver (aspartate aminotransferase [ASAT] or alanine aminotransferase [ALAT]) greater than three times the upper limit of normal) or muscular (creatine phosphokinase (CPK) greater than four times the upper limit of normal) laboratory abnormalities were reported. This large study shows 40 mg fluvastatin in combination with 400 mg bezafibrate to be highly effective and superior to either drug given as monotherapy in mixed hyperlipidaemia, and to be safe and well tolerated.",2000.0,0,0 376,10857949,Prevalence of renal artery stenosis in subjects with type 2 diabetes and coexistent hypertension.,J Valabhji; S Robinson; C Poulter; A C Robinson; C Kong; C Henzen; W M Gedroyc; M D Feher; R S Elkeles,"To assess the prevalence of renal artery stenosis (RAS) in subjects with type 2 diabetes and coexistent hypertension by using magnetic resonance angiography (MRA) of the renal arteries, to assess clinical and biochemical predictors of RAS, and to assess the hemodynamic significance of RAS, by using the captopril test (a measure of the response of plasma renin activity to a single oral dose of captopril). A total of 117 subjects with type 2 diabetes and coexistent hypertension between 40 and 70 years of age and with creatinine concentrations < 150 micromol/l were recruited from two inner-city general diabetes clinics. All subjects underwent MRA of the renal arteries. In a subgroup of 85 subjects, data concerning possible clinical and biochemical predictors of RAS were collected, and the captopril test was performed. For comparison of a continuous variable between subjects with a positive MRA and those with a negative MRA, the Mann-Whitney test was used. For comparison of a discrete variable between subjects with a positive MRA and those with a negative MRA, Fisher's exact test was used. The prevalence of RAS detected by using MRA in 117 hypertensive type 2 diabetic subjects was 17%; 19 subjects had unilateral RAS, and only 1 subject had bilateral RAS. A femoral bruit was significantly more common in subjects with a positive MRA versus subjects with a negative MRA (21 vs. 0%; Fisher's exact test P < 0.005); however, other clinical features of atherosclerotic disease were not statistically associated. Greater duration of hypertension and treatment with statins were features of subjects with RAS (P < 0.05). The captopril test was negative in all subjects, although the antihypertensive response to oral captopril was significantly greater in subjects with RAS detected by MRA. RAS is common in hypertensive type 2 diabetic subjects. The presence of a femoral bruit is a useful predictive clinical marker. The captopril test is not useful in predicting the hemodynamic significance of RAS in this patient group.",2000.0,0,0 377,10857969,Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity.,E Bonora; G Targher; M Alberiche; R C Bonadonna; F Saggiani; M B Zenere; T Monauni; M Muggeo,"To evaluate whether the homeostasis model assessment (HOMA) is a reliable surrogate measure of in vivo insulin sensitivity in humans. In the present study, we compared insulin sensitivity as assessed by a 4-h euglycemic (approximately 5 mmol/l) hyperinsulinemic (approximately 300 pmol/l) clamp with HOMA in 115 subjects with various degrees of glucose tolerance and insulin sensitivity. We found a strong correlation between clamp-measured total glucose disposal and HOMA-estimated insulin sensitivity (r = -0.820, P<0.0001), with no substantial differences between men (r = -0.800) and women (r = -0.796), younger (aged <50 years, r = -0.832) and older (r = -0.800) subjects, nonobese (BMI <27 kg/m2, r = -0.800) and obese (r = -0.765) subjects, nondiabetic (r = -0.754) and diabetic (r = -0.695) subjects, and normotensive ( r = -0.786) and hypertensive (r = -0.762) subjects. Also, we found good agreement between the two methods in the categorization of subjects according to insulin sensitivity (weighted k = 0.63). We conclude that the HOMA can be reliably used in large-scale or epidemiological studies in which only a fasting blood sample is available to assess insulin sensitivity",2000.0,0,0 378,10860137,"Treatment options for rheumatoid arthritis: celecoxib, leflunomide, etanercept, and infliximab.",B T Luong; B S Chong; D M Lowder,"To review new pharmacologic agents approved for use in the management of rheumatoid arthritis (RA). A MEDLINE search (1966-January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data. All controlled and uncontrolled trials were reviewed. Agents were reviewed with regard to mechanism of action, efficacy, drug interactions, pharmacokinetics, dosing, precautions/contraindications, adverse effects, and cost. Traditional pharmacologic treatments for RA have been limited by toxicity, loss of efficacy, or both. Increasing discoveries into the mechanisms of inflammation in RA have led to the development of new agents in hopes of addressing these limitations. With the development of celecoxib, a selective cyclooxygenase-2 inhibitor, the potential exists to minimize the gastrotoxicity associated with nonsteroidal antiinflammatory drugs. Leflunomide has been shown to be equal to or less efficacious than methotrexate, and may be beneficial as a second-line disease-modifying antirheumatic drug (DMARD). The biologic response modifiers, etanercept and infliximab, are alternatives that have shown benefit alone or in combination with methotrexate. However, they should be reserved for patients who fail to respond to DMARD therapy. Further studies should be conducted to evaluate the long-term safety and efficacy of these agents as well as their role in combination therapy. Celecoxib, leflunomide, etanercept, and infliximab are the newest agents approved for RA. Clinical trials have shown that these agents are beneficial in the treatment of RA; however, long-term safety and efficacy data are lacking.",2000.0,0,0 379,10862572,Role of transoesophageal echocardiography in infective endocarditis.,F A Flachskampf; W G Daniel,,2000.0,0,0 380,10862587,Oxygen uptake versus exercise intensity: a new concept in assessing cardiovascular exercise function in patients with congenital heart disease.,T Reybrouck; L Mertens; S Brusselle; M Weymans; B Eyskens; J Defoor; M Gewillig,"To assess the relation between exercise intensity and oxygen uptake during graded exercise in paediatric patients who underwent surgical repair of congenital heart disease, and to compare it with conventional measures of aerobic exercise function. Cross sectional study. Exercise testing was performed on a treadmill and gas exchange was measured on a breath by breath basis. 29 patients who underwent an atrial switch operation for transposition of the great arteries (TGA) (mean (SD) age at testing 10.3 (2.5) years) and 30 patients who underwent total repair of tetralogy of Fallot (TF) (age 12.1 (3.3) years) performed graded exercise testing. Exercise responses were compared with data obtained in 24 normal controls (age 11.4 (2.6) years). The slope of oxygen uptake versus exercise intensity averaged 1.50 (0. 64) ml O(2)/min(2)/kg in the patients with TGA and 1.68 (0.75) ml O(2)/min(2)/kg after TF repair, both lower (p < 0.005) than in normal controls (2.42 (0.68) ml O(2)/min(2)/kg). The lower slope of oxygen uptake was correlated with a subnormal value for ventilatory anaerobic threshold, which averaged 78.0 (13.3)% of normal in TGA and 85.1 (10.6)% in TF. This was associated with a steeper slope (p = 0.001) of carbon dioxide output versus oxygen uptake above the ventilatory anaerobic threshold in TGA (1.26 (0.20)) and TF (1.20 (0. 18)) compared with the normal controls (1.05 (0.13)), and also a steeper slope of ventilation versus carbon dioxide in TGA (47.0 (15. 4)) and TF (41.5 (13.7)) than in the controls (30.3 (8.5)). Calculation of the steepness of the slope of oxygen uptake versus exercise intensity is a valid measurement of oxygen flow to the exercising tissues, which may be limited in congenital heart disease.",2000.0,0,0 381,10863943,Therapy of X-linked adrenoleukodystrophy: prognosis based upon age and MRI abnormality and plans for placebo-controlled trials.,H W Moser; L Bezman; S E Lu; G V Raymond,Evaluation of the therapy of X-linked adrenoleukodystrophy (X-ALD) is hampered by its rarity and by the striking and unpredictable variation in phenotypic expression. We present two approaches that may facilitate therapy evaluation. (1) We have analysed data on 377 X-ALD patients who have been followed at the Kennedy Krieger Institute for a mean period of 38 months and have subdivided them into 18 subgroups on the basis of age and the degree of abnormality in brain magnetic resonance imaging (MRI) as assessed by the Loes score (Am. J. Neuroradrol 1994; 15: 1761). We find that grouping on the basis of age and MRI score provides information that is of significant prognostic value. (2) We present plans for the development of a placebo-controlled multicentre international study that will have sufficient biostatistical power to provide objective evaluation of new therapeutic interventions.,2001.0,0,0 382,10865931,Choosing drug therapy for patients with hyperlipidemia.,R S Safeer; C L Lacivita,"Almost 13 million American adults require drug therapy to meet the low-density lipoprotein goals set by the National Cholesterol Education Program. Attempts to achieve these goals through diet and exercise are often unsuccessful. Major studies in recent years have demonstrated that statins decrease low-density lipoprotein levels, coronary events and overall mortality. Statins are the most commonly prescribed lipid-lowering agents because they are effective, well tolerated and easy to administer. Niacin has beneficial effects on all of the main lipid components, and new extended-release tablets have fewer adverse effects. Fibrates remain the most effective agents in lowering triglyceride levels and should be limited to this use. Bile acid sequestrants are seldom prescribed because of their adverse gastrointestinal effects and cumbersome administration.",2000.0,0,0 383,10867084,Rates of progression of coronary calcium by electron beam tomography.,M J Budoff; K L Lane; H Bakhsheshi; S Mao; B O Grassmann; B C Friedman; B H Brundage,"In this study, we sought to determine the rate of progression of atherosclerosis using coronary calcium scores derived from electron beam tomography (EBT). We studied a variety of disease states (hypertension, high cholesterol, tobacco use, diabetes mellitus) followed for 1 to 6.5 years. We evaluated 299 asymptomatic persons (227 men and 72 women) who underwent 2 consecutive EBT scans at least 12 months apart. The average change in the calcium score (Agatston method) for the entire group was 33.2 +/- 9.2%/year. The treated group (receiving statins) demonstrated an average increase in calcium scores of 15 +/- 8%/year compared with 39 +/- 12%/year for untreated patients (p <0.001). Among the 60 patients on statin monotherapy, 37% had a decrease in the calcium score from baseline to follow-up scan. The relative increase in calcium scores did not vary significantly by gender or risk factors, with the exception of statin-treated hypercholesterolemic subjects. Scores of zero on the initial scan portend a low likelihood of significant calcific deposits on repeat scanning. Only 2 of 81 participants (2%) with scores of zero at baseline had scores >10 on repeat study. In this study, statin therapy induced a 61% reduction in the rate of coronary calcium progression. This study demonstrates that EBT may be a useful tool in assessing efficacy of different interventions to retard progression of atherosclerosis, noninvasively, over relatively short time periods.",2000.0,0,0 384,10867087,"Use of resources, quality of life, and clinical outcomes in patients with and without new Q waves after thrombolytic therapy for acute myocardial infarction (from the GUSTO-I trial).",A Barbagelata; R M Califf; E B Sgarbossa; S G Goodman; D Knight; D B Mark; C B Granger; D A Agranatti; B Mautner; E M Ohman; L D Suárez; P W Armstrong; K Gates; G S Wagner,"Previous reports indicate that patients who do not develop Q waves after thrombolytic therapy are a different population with a better long-term survival than those who do develop Q waves. However, the use of resources, quality of life, and health status of this population have not been fully evaluated. Using data from the Economics and Quality of Life subset of the Global Utilization of Streptokinase and tPA for Occluded Arteries study, we examined 30-day and 1-year mortality, use of resources, and quality-of-life measures among 1,830 of 3,000 patients with acute myocardial infarction and ST-segment elevation treated with thrombolytic therapy. At hospital discharge, 555 patients (30.2%) had not developed Q waves. These patients had lower mortality than patients with Q waves at 30 days (1.6% vs 4.5%, p <0.01) and at 1 year (4.7% vs 6.8%, p <0.04). Recurrent chest pain and dyspnea were similar at 30 days and 1 year. Patients without Q waves had significantly more angiography and trends toward higher readmission, revascularization, and use of calcium antagonists at 30 days. Angiography, revascularization, readmission, and quality of life were equivalent from 30 days to 1 year, with no sign of late instability. Logistic regression analysis showed an association between in-hospital revascularization and better survival and quality of life at 1 year. Conversely, there was no association between in-hospital use of calcium antagonists and outcome to explain the lower mortality in non-Q-wave patients. The absence of Q waves after thrombolytic therapy is a marker of success, implying better prognosis and equivalent quality of life, use of resources, and health status than for patients with Q-wave acute myocardial infarction and no sign of long-term unstable clinical course.",2000.0,0,0 385,10867089,Detection of coronary restenosis by exercise electrocardiography thallium-201 perfusion imaging and coronary angiography in asymptomatic patients after percutaneous transluminal coronary angioplasty.,F Beygui; C Le Feuvre; C Maunoury; G Helft; T Antonietti; J P Metzger; A Vacheron,"Noninvasive detection of restenosis in patients remaining asymptomatic after percutaneous transluminal coronary angioplasty (PTCA) remains a major clinical problem. The value of exercise electrocardiography (ECG) and exercise-redistribution thallium-201 single-photon emission computed tomography (SPECT) in detecting restenosis in such patients remains uncertain. Discordances between these tests and coronary angiography is a common situation. We studied 179 consecutive patients remaining asymptomatic after successful PTCA (208 vessels), who underwent 6 +/- 2 months of exercise ECG, SPECT, and coronary angiography. We sought to assess the diagnostic value of the noninvasive tests compared with coronary angiography, and identify the determinants of discordances between the tests. Restenosis (diameter stenosis >50%) was detected in 39% of patients and in 37% of vessels. The overall sensitivity, specificity, and accuracy for exercise ECG and SPECT in detecting restenosis in individual vessels were, respectively, 53% versus 63% (p = 0.06), 59% versus 77% (p = 0.0001), and 57% versus 72% (p = 0. 0001). On multivariate analysis, positive exercise ECG was associated with higher heart rate response (p = 0.02), incomplete revascularization (p = 0.004), and angiographic restenosis (p = 0. 03), whereas positive SPECT was associated with incomplete revascularization (p = 0.02), infarct-related artery PTCA (p = 0.01), and angiographic restenosis (p = 0.0001). Accuracies of the 2 tests were not significantly different in patients with incomplete revascularization or PTCA of an infarct-related vessel. Overall, SPECT is more accurate than exercise ECG in detecting asymptomatic restenosis. Nevertheless, incomplete revascularization and PTCA of an infarct-related artery could cause reversible perfusion defects regardless of restenosis, reducing the diagnostic value of SPECT in such patients.",2000.0,0,0 386,10867091,Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy.,S N Blair; D M Capuzzi; S O Gottlieb; T Nguyen; J M Morgan; N B Cater,"This study compares the effect of plant stanol ester spread with a placebo spread on cholesterol in patients taking statin therapy, but who still had elevated low-density lipoprotein (LDL) cholesterol. This was a randomized, double-blind, placebo-controlled clinical trial, with 67 women and 100 men with LDL cholesterol >/=130 mg/dl and triglycerides 10 times upper limit of normal occurred in 0%, 1% and 0.9% of patients receiving placebo, cerivastatin 0.4 mg or cerivastatin 0.8 mg, respectively. Cerivastatin 0.8 mg is an effective and safe treatment for patients with primary hypercholesterolaemia who need aggressive LDL-C lowering in order to achieve NCEP-recommended levels.",2001.0,0,0 399,10901509,Cell adhesion molecules in relation to simvastatin and hormone replacement therapy in coronary artery disease.,E Sbarouni; C Kroupis; Z S Kyriakides; K Koniavitou; D T Kremastinos,"To assess the effect of simvastatin, hormone replacement therapy and their combination on soluble cell adhesion molecules and plasma lipids, in hypercholesterolaemic post-menopausal women with coronary artery disease. We studied 16 post-menopausal women with coronary artery disease and hypercholesterolaemia (total cholesterol >200mg x dl(-1) and LDL cholesterol >130 mg x dl(-1)). We compared simvastatin (20 mg daily) with hormone replacement therapy (0.625 mg conjugated oestrogen and 2.5 mg medroxyprogesterone acetate daily) and their combination, in a randomized, crossover, placebo controlled study. Each treatment period was 8 weeks long with a 4 week washout interval between treatments. Circulating cell adhesion molecules and plasma lipids were evaluated at the end of each treatment period. All three active treatments--simvastatin, hormone replacement therapy and the combination therapy--significantly reduced total and LDL cholesterol, compared to placebo (P<0.001). Only hormone replacement therapy, alone and in combination with simvastatin, significantly decreased lipoprotein(a) when compared to placebo (P<0.05), whereas simvastatin had no significant effect. Likewise, hormone replacement therapy and the combination therapy significantly reduced the intercellular adhesion molecule (ICAM-1) plasma levels (P=0.03 and P=0.02, respectively), while simvastatin, which was superior to hormone replacement therapy in lowering total and LDL cholesterol, did not modify ICAM-1 levels; the combination therapy was not more effective than hormone replacement therapy alone in ICAM-1 reduction. Neither the effect, on any treatment when compared to placebo, of VCAM-1 nor E-selectin levels differed significantly. Hormone replacement therapy may limit the inflammatory response to injury by modulating the expression of cell adhesion molecules from the endothelial cells, possibly in association with lipoprotein (a) reduction.",2000.0,0,0 400,10904919,Therapeutic targets for type 2 diabetes post-UKPDS.,J S Yudkin,,2001.0,0,0 401,10907971,Pharmacoeconomic assessment of HMG-CoA reductase inhibitor therapy: an analysis based on the CURVES study.,D E Hilleman; S M Heineman; P A Foral,"We conducted a post hoc pharmacoeconomic analysis of a multicenter, open-label, randomized, parallel-group, 8-week efficacy-safety comparison of five HMG-CoA reductase inhibitors-atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. The 534 patients requiring cholesterol-lowering therapy took the drugs for 8 weeks with 15 different regimens. Low-density lipoprotein (LDL) was measured after 6 weeks of diet (baseline) and after 8 weeks of treatment with a study drug. At dosages of 10, 20, and 40 mg/day, atorvastatin was associated with significantly greater reductions in LDL than equivalent dosages of the other agents. Cost-effectiveness calculated as the annual acquisition cost/percentage LDL reduction was greatest with atorvastatin 10 mg ($17.96), fluvastatin 40 mg ($19.83), atorvastatin 20 mg ($22.85), and atorvastatin 40 mg ($24.96). All other dosages were above $25.00/year/percentage LDL reduction. Atorvastatin was the most cost-effective HMG-CoA reductase inhibitor. Fluvastatin 40 mg/day also had a favorable cost:effectiveness ratio but lowered LDL only by 23%.",2001.0,0,0 402,10908244,Treatment of cardiac diseases: evidence based or experience based medicine?,W Kübler,,2000.0,0,0 403,10910028,Influence of atorvastatin versus simvastatin on fibrinogen and other hemorheological parameters in patients with severe hypercholesterolemia treated with regular low-density lipoprotein immunoadsorption apheresis.,C Otto; H C Geiss; M G Donner; K G Parhofer; P Schwandt,"Low-density lipoprotein (LDL) apheresis is a treatment option in patients with coronary artery disease and elevated LDL cholesterol concentrations if maximal drug therapy fails to achieve adequate LDL cholesterol reduction. This therapy is more effective when combined with strong lipid-lowering drugs, such as atorvastatin. However, conflicting data have been published concerning the effect of atorvastatin on fibrinogen concentration. Therefore, we investigated the effect of atorvastatin compared to simvastatin on fibrinogen concentration and other hemorheological parameters in patients treated by weekly LDL apheresis. Hemorheological parameters were, studied twice in 9 patients (4 female, 5 male, 54.0+/-8.9 years) with coronary artery disease treated by weekly LDL immunoadsorption, once during concomitant simvastatin therapy (40 mg daily) and once during atorvastatin therapy (40 mg daily). Fibrinogen concentration, plasma and blood viscosity at different shear rates, parameters of red cell aggregation at stasis and shear rate 3/s, and erythrocyte filterability were determined 7 days after the last LDL apheresis after each drug had been given for a minimum for 8 weeks. Fibrinogen concentration did not show any statistically significant difference during therapy with atorvastatin (3.09+/-0.36 g/L) compared to simvastatin (3.13+/-0.77 g/L). Plasma and blood viscosity as well as erythrocyte filterability were also unchanged. The increase in red cell aggregation at stasis during atorvastatin treatment (5.82+/-1.00 U versus 4.89+/-0.48 U during simvastatin; p < 0.05) was inversely correlated with a lower high-density liprotein (HDL) cholesterol concentration (1.17+/-0.21 mmol/L versus 1.31+/-0.30 mmol/L during simvastatin; p < 0.05). LDL cholesterol showed a strong trend to lower concentrations during atorvastatin (4.14+/-0.61 mmol/L versus 4.56+/-0.66 mmol/L during simvastatin; p = 0.07), despite a reduced plasma volume treated (3,547+/-1,239 ml during atorvastatin versus 3,888+/-1,206 mL during simvastatin; p < 0.05). In conclusion, fibrinogen concentration and other hemorheological parameters were unchanged during atorvastatin compared to simvastatin therapy with the exception of a higher red cell aggregation at stasis. Therefore, with respect to hemorheology, we conclude that atorvastatin should not be withheld from hypercholesterolemic patients regularly treated with LDL immunoadsorption.",2001.0,0,0 404,10910373,Chronic rejection of renal transplants: new clinical insights.,M A Vazquez,"Chronic rejection is the most important cause for returning to dialysis after failure of a renal transplant. The term chronic allograft nephropathy refers to the progressive decline of renal function seen in some renal transplant recipients in association with alloantigen-dependent and alloantigen-independent factors. This review examines the role of factors related to allorecognition, injury, nephron dosing, and donor and recipient characteristics in the development of chronic allograft nephropathy. The clinical associations to chronic allograft nephropathy are presented in the context of pathogenetic mechanisms of renal damage and disease progression. As there is no therapy available at this time for established chronic allograft nephropathy, possible areas of intervention for the prevention of chronic rejection are discussed.",2000.0,0,0 405,10912308,Are women discriminated against for lipid lowering therapy? Results from a prospective cohort of women with coronary artery disease.,G Lloyd; A Cooper; E McGing; H Chia; G Jackson,"The objective of the study was to compare the lipid management of men and women with documented coronary artery disease in 587 patients (433 men and 154 women) undergoing coronary angiography between 1991 and 1995. A fasting total cholesterol (TC) was measured in all patients on the morning of angiography. A postal/telephone follow-up was carried out one year after angiography in a subpopulation of 278 patients (194 men and 84 women) who were not taking lipid-lowering therapy (LLT) or whose TC was > 5.2 mmol/l at the time of angiography. At baseline, mean TC was 5.89 mmol/l (SE 0.06) in the men and 6.47 mmol/l (SE 0.09) in the women (p = < 0.0001). Action or recommendation to institute LLT was taken in 141 (32.7%) men and 62 (40.3%) women (p = 0.09). In the follow-up population, comparing men with women, 74 (38.3%) vs 39 (46.4%) were taking LLT (p = 0.21); 56 (28.9%) vs 26 (31.0%) had not undergone repeat TC testing (p = 0.73); when performed, repeat TC was 5.75 (0.09) mmol/l vs 5.64 (0.16) mmol/l (p = 0.53); mean decrease in TC between baseline and follow-up was 0.86 (0.10) mmol/l vs 1.01 (0.21) mmol/l (p = 0.51). There was no significant gender difference in lipid management either at the time of coronary angiography or subsequent follow-up, although the level of lipid-lowering drug use remained inadequate in both sexes.",2000.0,0,0 406,10912491,Risk factors for the development of gallstone recurrence following medical dissolution. The British-Italian Gallstone Study Group.,M L Petroni; R P Jazrawi; P Pazzi; M Zuin; A Lanzini; M Fracchia; D Facchinetti; V Alvisi; R Ferraris; J M Bland; K W Heaton; M Podda; T C Northfield,"To assess risk factors for gallstone recurrence following non-surgical treatment. A prospective follow-up of a multicentre cohort of post-dissolution gallstone patients. Six gastroenterology units in the UK and Italy. One hundred and sixty-three patients with confirmed gallstone dissolution following non-surgical therapy (bile acids or lithotripsy plus bile acids), followed up by ultrasound scan and clinical assessment at 6-monthly intervals for up to 6 years (median, 25 months; range, 6-70 months). Subject-related variables (sex, age, height, weight, body mass index), gallstone-related variables (number, diameter, presence of symptoms, months to complete stone clearance), treatment modalities (bile acid therapy, extracorporeal shock wave lithotripsy) and follow-up related variables (weight change, use of non-steroidal anti-inflammatory agents, statins, pregnancies and/or use of oestrogens) were assessed by univariate and multivariate analysis as putative risk factors for gallstone recurrence. Forty-five gallstone recurrences were observed during the follow-up period. Multiple primary gallstones and length of time to achieve gallstone dissolution were the only variables associated with a significant increase in the recurrence rate. Appearance of biliary sludge during follow-up was also significantly related to development of gallstone recurrence. Use of statins or non-steroidal anti-inflammatory agents did not confer protection against recurrence. Patients with primary single stones are the best candidates for non-surgical treatment of gallstones, because of a low risk of gallstone recurrence. The positive association of recurrence with biliary sludge formation and time to dissolution of primary stones may provide indirect confirmation for the role of impaired gallbladder motility in the pathogenesis of this condition.",2001.0,0,0 407,10913488,Comparison of effects of simvastatin versus atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I levels.,J J Kastelein; J L Isaacsohn; L Ose; D B Hunninghake; J Frohlich; M H Davidson; R Habib; C A Dujovne; J R Crouse; M Liu; M R Melino; L O'Grady; M Mercuri; Y B Mitchel,,2000.0,1,1 408,10913499,,,,,0,0 409,10914753,Diabetes mellitus and coronary heart disease--from prevention to intervention: Part I.,H M Farouque; R C O'Brien; I T Meredith,,2001.0,0,0 410,10918670,Hyperlipidemia.,J N Yu; J A Cunningham; S R Thouin; T Gurvich; D Liu,"Coronary heart disease (CHD) is prevalent and often related to an unhealthy diet and hyperlipidemia. The diagnosis of hyperlipidemia should be carefully made, using more than one measurement in the manner described. An assessment of risks allows one to decide whom to treat. Patients with CHD should be treated aggressively but it is less clear how aggressive to be with patients without CHD. Diet and exercise recommendations are appropriate for almost all patients. For those for whom the benefit is greater than the potential risks, statins are first-line drug therapy and they appear to have beneficial effects aside from their lipid-lowering properties.",2000.0,0,0 411,10919369,Inhibitory effects of fluvastatin and its metabolites on hydrogen peroxide-induced oxidative destruction of hemin and low-density lipoprotein.,K Suzumura; K Tanaka; M Yasuhara; H Narita,"Some 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are used as hypolipidemic drugs, have been reported to have the potential to reduce the oxidizability of plasma low-density lipoprotein (LDL) when they are administered in vivo. Their in vivo mechanism is believed to be closely related to their hypolipidemic action based on the HMG-CoA reductase inhibitory activity. We hypothesized that some type of HMG-CoA reductase inhibitor has additional mechanism inhibiting LDL oxidation in vivo due not to its hypolipidemic action but to its direct antioxidative effect based on its unique chemical structure. We directly compared in vitro the antioxidative effects of well-known HMG-CoA reductase inhibitors (fluvastatin, pravastatin, simvastatin, cerivastatin and atorvastatin) on the hydrogen peroxide-induced oxidative destruction of hemin and LDL. Fluvastatin but not the others showed the inhibitory effect on this system. Its effect was dose-dependent and almost as strong as the natural antioxidants, alpha-tocopherol and ascorbic acid. Further, M2, which is a hydroxylated metabolite of fluvastatin, showed stronger antioxidative activity than did fluvastatin. We suggest that among these HMG-CoA reductase inhibitors, fluvastatin especially has an ability to retard the LDL oxidation which is based on not only its hypolipidemic action but also its direct antioxidative effect.",2001.0,0,0 412,10922421,Pravastatin therapy and the risk of stroke.,H D White; R J Simes; N E Anderson; G J Hankey; J D Watson; D Hunt; D M Colquhoun; P Glasziou; S MacMahon; A C Kirby; M J West; A M Tonkin,"Several epidemiologic studies have concluded that there is no relation between total cholesterol levels and the risk of stroke. In some studies that classified strokes according to cause, there was an association between increasing cholesterol levels and the risk of ischemic stroke and a possible association between low cholesterol levels and the risk of hemorrhagic stroke. Recent reviews of trials of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors have suggested that these agents may reduce the risk of stroke. In a double-blind trial (the Long-Term Intervention with Pravastatin in Ischaemic Disease study), we compared the effects of pravastatin on mortality due to coronary heart disease (the primary end point) with the effects of placebo among 9014 patients with a history of myocardial infarction or unstable angina and a total cholesterol level of 155 to 271 mg per deciliter (4.0 to 7.0 mmol per liter). Our goal in the present study was to assess effects on stroke from any cause and nonhemorrhagic stroke, which were secondary end points. There were 419 strokes among 373 patients over a follow-up period of six years. A total of 309 strokes were classified as ischemic, 31 as hemorrhagic, and 79 as of unknown type. Among the patients given placebo, the risk of stroke was 4.5 percent, as compared with 3.7 percent among those given pravastatin (relative reduction in risk, 19 percent; 95 percent confidence interval, 0 to 34 percent; P=0.05). Non-hemorrhagic stroke occurred in 4.4 percent of the patients given placebo, as compared with 3.4 percent of those given pravastatin (reduction in risk, 23 percent; 95 percent confidence interval, 5 to 38 percent; P=0.02). Pravastatin had no effect on hemorrhagic stroke (incidence, 0.2 percent in the placebo group vs. 0.4 percent in the pravastatin group; P=0.28). Pravastatin has a moderate effect in reducing the risk of stroke from any cause and the risk of nonhemorrhagic stroke in patients with previous myocardial infarction or unstable angina.",2000.0,0,0 413,10922429,Follow-up study of patients randomized in the Scandinavian simvastatin survival study (4S) of cholesterol lowering.,T R Pedersen; L Wilhelmsen; O Faergeman; T E Strandberg; G Thorgeirsson; L Troedsson; J Kristianson; K Berg; T J Cook; T Haghfelt; J Kjekshus; T Miettinen; A G Olsson; K Pyörälä; H Wedel,"The Scandinavian Simvastatin Survival Study (4S) and other randomized clinical trials have demonstrated that cholesterol-lowering treatment with statins improves prognosis in patients with coronary atherosclerosis compared with placebo. The effect of therapy with statins beyond the typical 5 to 6 years' duration of the trials, in particular regarding the risk of cancer, has not been investigated. This study examines the long-term effects of simvastatin for up to 8 years on cause-specific mortality in patients with coronary heart disease (CHD). We performed an observational, government registry-based study of mortality in the groups originally randomized to simvastatin or placebo in the 4S over an additional 2-year follow-up period, so that the median total follow-up period was 7.4 years (range 6.9 to 8.3 in surviving patients). Randomization took place at outpatient clinics at 94 clinical centers in Denmark, Finland, Iceland, Norway, and Sweden from 1988 to 1989. Of 4,444 patients with CHD, 2,223 and 2,221 were randomized to treatment with placebo or simvastatin therapy, respectively. Patients received treatment with simvastatin, starting at 20 mg/day, with titration to 40 mg/day at 12 or 24 weeks if total cholesterol was >5.2 mmol/L (200 mg/dl), or placebo. After the double-blind period, most patients in both treatment groups received simvastatin as open-label prescription. Of the 1,967 patients originally treated with placebo and surviving the double-blind period, 97 (4.9%) died during the following 2 years. In the group randomized to simvastatin the corresponding number was 74 of the 2, 039 survivors (3.6%). Adding these deaths to those occurring during the original trial, the total was 353 (15.9%) and 256 (11.5%) deaths in the groups originally randomized to placebo and simvastatin, respectively. The relative risk was 0.70 (95% confidence interval 0. 60 to 0.82, p = 0.00002). The total number of cancer deaths was 68 (3.1%) in the placebo group and 52 (2.3%) in the simvastatin group (relative risk 0.73, 95% confidence interval 0.51 to 0.05, p = 0. 087), and the numbers of noncardiovascular and other deaths were similar in both groups. We therefore conclude that treatment with simvastatin for up to 8 years in patients with CHD is safe and yields continued survival benefit.",2000.0,0,0 414,10924289,The VA HDL intervention trial: clinical implications.,H B Rubins; D Collins; S J Robins,,2000.0,0,0 415,10924713,Intestinal absorption of triglyceride and cholesterol. Dietary and pharmacological inhibition to reduce cardiovascular risk.,E Ros,"Triglycerides and cholesterol are important biological lipids, and their excessive intake in the diet is relevant to the development of two prevalent cardiovascular risk factors, obesity and hypercholesterolemia. Because most lipids are essentially water-insoluble molecules, their transport within and absorption from the aqueous medium of intestinal contents is rather complex. This takes place in a series of orderly and interrelated steps, including emulsification, hydrolysis by specific esterases, micellar transport, mucosal absorption, re-synthesis of parent molecules in enterocytes, and assembly with apolipoproteins and other molecules to form chylomicrons, the secretory product of intestinal cells. Many of these processes, however, are not well characterized at the molecular level. While in health the intestinal absorption of triglycerides is very efficient, the same does not apply to cholesterol absorption. Besides being generally inefficient, cholesterol absorption is highly variable, with a between-subject variability that depends in part on genetic factors and an intra-individual variability, which may be modulated by physiological and dietary conditions. All of the sequential steps in intestinal lipid absorption can be interfered with by dietary components or drugs and thus are potential therapeutic targets for inducing a controlled malabsorption of triglyceride, useful in the treatment of obesity, or for rendering cholesterol absorption even more inefficient in an attempt to lower blood cholesterol levels. Nevertheless, intestinally derived cholesterol available to the liver exerts complex feedback regulation on whole-body cholesterol homeostasis that limits the efficacy of cholesterol absorption inhibitors to lower blood cholesterol. This review focuses first on present knowledge of the physiology of intestinal fat absorption, necessary to understand the ways to manipulate it in order to obtain the desired effects on dietary triglyceride and cholesterol disposition. The second part discusses old, present and future ways, both dietary and pharmacological. of interfering with cholesterol and triglyceride absorption to reduce blood cholesterol and energy acquisition, respectively.",2001.0,0,0 416,10924726,,,,,0,0 417,10924737,Intima-media thickness after pravastatin stabilizes also in patients with moderate to no reduction in LDL-cholesterol levels: the carotid atherosclerosis Italian ultrasound study.,D Baldassarre; F Veglia; C Gobbi; G Gallus; A Ventura; G Crepaldi; M Fisicaro; S Rimondi; G Ricci; M Mancini; M G Bong; S Collatina; C R Sirtori,"The Carotid Atherosclerosis Italian Ultrasound study (CAIUS), a multicenter, double-blind clinical trial, performed in 305 asymptomatic, moderately hypercholesterolemic patients, clearly demonstrated beneficial effects of pravastatin on the carotid intima-media thickness (IMT) progression. The database of the CAIUS study was examined in order to investigate the presence of a relationship, if any, between the activity of pravastatin on IMT progression rate and its hypocholesterolemic effect. Quantitative B-mode ultrasound imaging was used to quantify the individual mean maximum IMT progression rate in 3 years. In the overall group of patients (placebo and pravastatin) covariance analysis showed that while the variable 'treatment' (0 = placebo, 1 = pravastatin) was significantly related to the reduction of IMT progression (F= 6.6, P = 0.01), the IMT progression did not correlate with the extent of LDL-C lowering (F= 0.00, P = 0.98). To further investigate this issue. the pravastatin treated group was stratified into quartiles of LDL-C reduction. In contrast to what was observed in the placebo group, in which a positive mean IMT progression rate was observed, independent of the extent of LDL-C reduction, no IMT progressionwas observed in any subgroup treated with pravastatin. No significant difference was found among quartiles and no trend could be identified. In conclusion, the effect of pravastatin treatment on carotid IMT progression rate is beneficial; however the CAIUS study demonstrated that lowering LDL-C by itself, does not explain the variability of beneficial changes in IMT.",2001.0,0,1 418,10925336,Current perspectives on the management of hypertriglyceridemia.,M Miller,"Observational studies have demonstrated that triglycerides are an independent risk factor for coronary heart disease. Atherothrombosis may be mediated by uptake and incorporation of triglyceride-rich lipoproteins by macrophages and through an association with small, dense LDL and HDL particles. There are considerable data that lowering LDL cholesterol reduces cardiovascular events. However, the importance of triglyceride lowering remains elusive. A summary of major arteriographic and clinical end point trials is reviewed. Studies evaluating various strategies, including dietary and hygienic measures as well as pharmacologic therapies, are discussed. Dietary reduction of saturated fat, coupled with aerobic activity, reduces triglyceride levels approximately 20% to 24%. Omega-3 fatty acids may also reduce triglyceride levels appreciably. Effective pharmacologic therapies that lower triglyceride levels include nicotinic acid (20% to 40%), fibrates (20% to 55%), and statins (10% to 30%). Nevertheless, an independent benefit of triglyceride lowering on coronary event rate has not been demonstrated. There are little data that triglyceride reduction improves cardiovascular event rate. In contrast, lowering LDL cholesterol and, more recently, raising HDL cholesterol are proven therapies in coronary heart disease prevention. As such, these modalities remain the top priority in the management of dyslipidemia with triglyceride reduction as an adjunctive consideration.",2000.0,0,0 419,10925339,"Effect of atorvastatin on blood lipid levels in the first 2 weeks of treatment: a randomized, placebo-controlled study.",H G Schrott; H Knapp; M Davila; L Shurzinske; D Black,"The rate and degree of LDL cholesterol reduction, in the first 2 weeks of therapy, may relate to the early benefit of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy. In patients with similar baseline LDL cholesterol levels as in the Cholesterol and Recurrent Events (CARE) trial, we report the results of a 2-week placebo-controlled, double-blind investigation of 10 mg/day atorvastatin. The 22 participants were non-Hispanic whites younger than age 72 (average age 47 years) who were modestly overweight and had normal blood pressure. There were no significant baseline lipid and lipoprotein differences. By day 5, there were significant (P <.01) reductions in total cholesterol and LDL levels. The total cholesterol level fell by 25% (226 mg/dL to 169 mg/dL) and LDL cholesterol fell 35% by day 14 (P <.001). Triglyceride levels declined by 24% (from 137 mg/dL to 104 mg/dL) by day 14, but this was not statistically significant. There was no significant difference in HDL cholesterol. The total/HDL level dropped from 4.54 (day 0) to 3.32 (day 14), and the LDL/HDL level dropped from 2.92 to 1.88; both results were highly significant (P <. 001). The rapid lipid reduction observed with atorvastatin may benefit the vascular endothelium.",2000.0,0,0 420,10927723,Long-term safety of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors: the role of metabolism-monograph for physicians.,M Bottorff; P Hansten,,2000.0,0,1 421,10927735,3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study.,L Blais; A Desgagné; J LeLorier,"During the past 15 years there has been an exponential increase in the number of prescriptions for lipid-lowering drugs. Uncertainties remain about the long-term impact of these medications on cancer, which is particularly bothersome given that the duration of these treatments may extend for several decades. To explore the association between 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and cancer incidence. Using the administrative health databases of the Régie de l'Assurance-Maladie du Québec we performed a nested case-control study. We selected a cohort of 6721 beneficiaries of the health care plan of Quebec who were free of cancer for at least 1 year at cohort entry, 65 years and older, and treated with lipid-modifying agents. Cohort members were selected between 1988 and 1994 and were followed up for a median period of 2.7 years. From the cohort, 542 cases of first malignant neoplasm were identified, and 5420 controls were randomly selected. Users of HMG-CoA reductase inhibitors were compared with users of bile acid-binding resins as to their risk of cancer. Specific cancer sites were also considered. Users of HMG-CoA reductase inhibitors were found to be 28% less likely than users of bile acid-binding resins to be diagnosed as having any cancer (rate ratio, 0.72; 95% confidence interval, 0.57-0.92). All specific cancer sites under study were found to be not or inversely associated with the use of HMG-CoA reductase inhibitors. The results of our study provide some degree of reassurance about the safety of HMG-CoA reductase inhibitors.",2000.0,0,0 422,10929930,"Current, new and future treatments in dyslipidaemia and atherosclerosis.",P H Chong; B S Bachenheimer,"The new therapeutic options available to clinicians treating dyslipidaemia in the last decade have enabled effective treatment for many patients. The development of the HMG-CoA reductase inhibitors (statins) have been a major advance in that they possess multiple pharmacological effects (pleiotropic effects) resulting in potent reductions of low density lipoproteins (LDL) and prevention of the atherosclerotic process. More recently, the newer fibric acid derivatives have also reduced LDL to levels comparable to those achieved with statins, have reduced triglycerides, and gemfibrozil has been shown to increase high density lipoprotein (HDL) levels. Nicotinic acid has been made tolerable with sustained-release formulations, and is still considered an excellent choice in elevating HDL cholesterol and is potentially effective in reducing lipoprotein(a) [Lp(a)] levels, an emerging risk factor for coronary heart disease (CHD). Furthermore, recent studies have reported positive lipid-lowering effects from estrogen and/or progestogen in postmenopausal women but there are still conflicting reports on the use of these agents in dyslipidaemia and in females at risk for CHD. In addition to lowering lipid levels, these antihyperlipidaemic agents may have directly or indirectly targeted thrombogenic, fibrinolytic and atherosclerotic processes which may have been unaccounted for in their overall success in clinical trials. Although LDL cholesterol is still the major target for therapy, it is likely that over the next several years other lipid/lipoprotein and nonlipid parameters will become more generally accepted targets for specific therapeutic interventions. Some important emerging lipid/lipoprotein parameters that have been associated with CHD include elevated triglyceride, oxidised LDL cholesterol and Lp(a) levels, and low HDL levels. The nonlipid parameters include elevated homocysteine and fibrinogen, and decreased endothelial-derived nitric oxide production. Among the new investigational agents are inhibitors of squalene synthetase, acylCoA: cholesterol acyltransferase, cholesteryl ester transfer protein, monocyte-macrophages and LDL cholesterol oxidation. Future applications may include thyromimetic therapy, cholesterol vaccination, somatic gene therapy, and recombinant proteins, in particular, apolipoproteins A-I and E. Non-LDL-related targets such as peroxisome proliferator-activating receptors, matrix metalloproteinases and scavenger receptor class B type I may also have clinical significance in the treatment of atherosclerosis in the near future. Before lipid-lowering therapy, dietary and lifestyle modification is and should be the first therapeutic intervention in the management of dyslipidaemia. Although current recommendations from the US and Europe are slightly different, adherence to these recommendations is essential to lower the risk of atherosclerotic vascular disease, more specifically CHD. New guidelines that are expected in the near future will encompass global opinions from the expert scientific community addressing the issue of target LDL goal (aggressive versus moderate lowering) and the application of therapy for newer emerging CHD risk factors.",2001.0,0,0 423,10932925,[Treatment of hypertriglyceridemia. Current aspects].,M Malaguarnera; I Giugno; P Ruello; E Vinci; M P Panebianco; M Motta,"The hypertriglyceridemia attends the physiopathology of the atherosclerosis by various mechanisms: association of low levels of high density lipoprotein-cholesterol (HDL-c), modification of quality of low density lipoprotein-cholesterol (LDL-c), influence on hemostatic processes, association with other hazard's factors (obesity, hypertension, etc.). The hypertriglyceridemia distinguishes in primary and secondary. In primary forms the origin is essentially genetic, while the secondary ones are metabolic consequence of various pathologies (renal, thyroid, diabetes mellitus etc.). The hypertriglyceridemia's treatment is founded on a correct feeding and/or on eventual use of drugs. Apart from the secondary forms, in which is obligatory to treat at first the basal disease, the pharmacological therapy of the hypertriglyceridemia is suggested only in resistant cases to alone dietetic therapy and overall in presence of other factors of atherothrombotic hazard. The most utilized drugs are: omega-3 fatty acids, the nicotinic acid and its derivatives, the fibrates and the statins. The stronghold of alpha-glucosidases inhibitors is the acarbose. It reduces the biosynthesis of very low density lipoproteins (VLDL) by the reduction of substrata with an improvement of glucidic metabolism. Atorvastatin and cerivastatin develop a greater action to reduce serum levels of triglycerides as to the foregoing ones because of the better selectivity of receptor binding, the greater halflife and inhibition of the apolipoprotein's B100 synthesis.",2000.0,0,0 424,10933291,Onychomycosis: improved cure rates with itraconazole and terbinafine.,T K Harrell; W W Necomb; W H Replogle; D S King; S L Noble,"Onychomycosis is a disease that is important to our patients. Based on the current literature, recent developments of newer antifungal agents have improved cure rates of onychomycosis in the past few years (Table 3). No significant differences in safety and tolerability between itraconazole and terbinafine exist. Terbinafine does appear to have a preferable drug interaction profile. Daily therapy with either agent at standard doses has been shown to be effective when compared with placebo. When studies have directly compared daily administration of terbinafine and itraconazole, both medications have shown similar efficacy. Daily terbinafine therapy, however, appears to be more effective than pulse therapy with itraconazole. In addition, one small study showed a trend in favor of continuous rather than intermittent terbinafine therapy and similar efficacy of intermittent itraconazole and intermittent terbinafine therapy. Furthermore, terbinafine is more cost-effective than itraconazole. Finally, as quality-of-life data suggest, onychomycosis is important to our patients and affects both physical and psychosocial components of our patients' lives.",2001.0,0,0 425,10933343,Management of coronary artery disease: therapeutic options in patients with diabetes.,T Hammoud; J F Tanguay; M G Bourassa,"The aim of this review is to discuss the particularities of coronary artery disease (CAD), the effect of intensive medical management and the outcome of percutaneous and surgical revascularization in patients with diabetes mellitus (DM). CAD represents the leading cause of death in patients with DM. Numerous clinical, biological and angiographic risk factors have been shown to be associated with CAD in diabetic patients. Metabolic abnormalities in patients with DM including insulin resistance, hyperglycemia and dyslipidemia are briefly discussed. Then the potential roles of medical management and of percutaneous and surgical coronary revascularization are more extensively reviewed. More vigorous control of hyperglycemia, hyperlipidemia, hypertension and other risk factors may be of crucial importance for risk reduction. Despite remarkable progress in recent years, the choice of a coronary revascularization strategy remains a challenge in these patients. Diabetic patients with CAD are predisposed to higher cardiovascular events after balloon angioplasty. Whether stenting and new antiplatelet drugs improve the results of percutaneous revascularization in this population needs further evaluation. The superiority of the surgical approach is also not definitely established. Therefore, many aspects of coronary revascularization are still unclear in these patients. The results of ongoing randomized trials comparing multiple coronary stents to bypass surgery will likely provide some answers to our questions and additional randomized trials evaluating intensive diabetic control with or without coronary revascularization are needed to determine the best therapeutic approach in these patients.",2000.0,0,0 426,10933350,Atorvastatin but not L-arginine improves endothelial function in type I diabetes mellitus: a double-blind study.,M J Mullen; D Wright; A E Donald; S Thorne; H Thomson; J E Deanfield,"We sought to determine the effects of oral L-arginine and the hexamethylglutaryl coenzyme A reductase inhibitor atorvastatin on endothelial function in young patients with type I diabetes mellitus (DM). Endothelial dysfunction, a key early event in atherosclerosis, occurs in young patients with type I DM, and its reversal may benefit the progression of vascular disease. Cholesterol reduction in L-arginine improve endothelial function in nondiabetic subjects, but their effect in patients with type I DM is unknown. In a double-blind, 2x2 factorial study, we investigated the effect of L-arginine (7 g twice daily) and atorvastatin (40 mg/day) on conduit artery vascular function in 84 normocholesterolemic young adults (mean+/-SD: age 34 years [range 18 to 46], low density lipoprotein [LDL] cholesterol 2.96+/-0.89 mmol/liter) with type I DM. Brachial artery dilation to flow (flow-mediated dilation [FMD]) and to the direct smooth muscle dilator glyceryl trinitrate (GTN) were assessed noninvasively using high resolution ultrasound at baseline and after six weeks of treatment. Atorvastatin resulted in a 48+/-10% decrease in serum LDL cholesterol levels, whereas L-arginine levels increased by 247+/-141% after L-arginine therapy. By analysis of covariance, treatment with atorvastatin resulted in a significant increase in FMD (p = 0.018. L-Arginine therapy had no significant effect on endothelial function, and there was no significant change in dilation to GTN after either intervention. In young patients with type I DM, improvement in endothelial dysfunction can be demonstrated after just six weeks of treatment with atorvastatin. In contrast to studies of hypercholesterolemia, however, L-arginine had no benefit. Treatment with atorvastatin at an early stage may have an impact on the progression of atherosclerosis in these high risk patients.",2000.0,0,0 427,10933353,Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia.,D Ferro; S Parrotto; S Basili; C Alessandri; F Violi,"The purpose of this study was to assess if simvastatin has an anti-inflammatory activity in patients with hypercholesterolemia. Simvastatin, an inhibitor of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase, reduced cardiovascular events in patients with myocardial infarction and hypercholesterolemia. Sixteen patients with polygenic hypercholesterolemia were randomly allocated to diet (n = 8) or diet plus 20 mg/day simvastatin (n = 8) for eight weeks. Before and at the end of treatment period, lipid profile and monocyte expression of tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1beta) were measured. At baseline no difference in lipid profile and monocyte expression of TNF and IL-1beta were observed between the two groups. In patients allocated to diet alone, no change in lipid profile and monocyte expression of TNF and IL-1beta was seen. In patients with diet plus simvastatin, significant decreases of total cholesterol (-27%, p<0.02), low density lipoprotein-cholesterol (-33%, p<0.02), and monocyte expression of TNF (-49%, p<0.02) and IL-1beta (-35%, p<0.02) were observed. At the end of treatment period, patients treated with simvastatin had lower cholesterol and monocyte TNF and IL-1beta than did patients assigned to diet alone. This study suggests that simvastatin possesses anti-inflammatory activity via the inhibition of pro-inflammatory cytokines TNF and IL-1beta expressed by monocytes.",2000.0,0,0 428,10933514,The relationship between cholesterol and stroke: implications for antihyperlipidaemic therapy in older patients.,C Sarti; M Kaarisalo; J Tuomilehto,"Various studies on the relationship between serum cholesterol level and the risk of stroke have been published recently. Subsequent reviews have extrapolated information on stroke from the clinical trials originally aimed at lowering cholesterol for the primary and secondary prevention of myocardial infarction (MI) in middle-aged patients. We have reviewed the epidemiological knowledge on the relationship between serum cholesterol levels and stroke, and also focused on possible reduction of the risk of stroke with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor treatment. Possible benefits from such therapy are particularly relevant for the elderly population which is at particularly high risk for stroke. The effects of serum cholesterol levels on the risk for haemorrhagic and ischaemic stroke have been evaluated. Indirect epidemiological evidence indicates that serum levels of total cholesterol and its subfractions are determinants of stroke, but their associations are relatively weak. When exploring the possible association of serum cholesterol levels with the increased risk of stroke with aging, we concluded that, as in younger adults, elevated total cholesterol and decreased high density lipoprotein-cholesterol levels predispose to ischaemic stroke in the elderly. The mechanism through which serum cholesterol levels increase stroke risk is based on its actions on the artery walls. Indirect evidence suggests that the reduction in the stroke risk with HMG-CoA reductase inhibitors is larger than would be expected with reduction of elevated serum cholesterol level alone. Therefore, antioxidant and endothelium-stabilising properties of HMG-CoA reductase inhibitors may contribute in reducing the risk of stroke in recipients. Lowering high serum cholesterol with HMG-CoA reductase inhibitors has been beneficial in the primary and secondary prevention of MI. No trials have specifically tested the effect of cholesterol lowering with HMG-CoA reductase inhibitors on stroke occurrence. High serum cholesterol levels are a risk factor for ischaemic stroke, although the risk imparted is lower than that for MI. Although the relative risk of stroke associated with elevated serum cholesterol levels is only moderate, its population attributable risk is high given the increase in the elderly population worldwide. The effect of cholesterol reduction with HMG-CoA reductase inhibitors on prevention of ischaemic stroke should be evaluated in prospective, randomised, placebo-controlled trials in the elderly. The tolerability of lipid-lowering drugs in the elderly and the cost effectiveness of primary prevention of stroke using lipid-lowering drugs also needs to be assessed in the elderly.",2001.0,0,0 429,10934672,Irbesartan does not affect the pharmacokinetics of simvastatin in healthy subjects.,M R Marino; N N Vachharajani; O W Hadjilambris,"This open-label, single-dose, crossover study was conducted to assess the effect of irbesartan on the pharmacokinetics of total simvastatin acid in 14 healthy subjects. Subjects were randomized to receive one simvastatin 40 mg tablet or one simvastatin 40 mg tablet + one irbesartan 300 mg tablet. Subjects were crossed over to the other treatment after a 7- to 10-day washout period. Serum samples were collected at specified times before and over a 24-hour period after dosing. Safety was assessed by monitoring vital signs, laboratory tests, and adverse events. Irbesartan did not exhibit a clinically significant effect on the peak serum concentration and area under the concentration versus time curve to infinity (AUC0-infinity) of total simvastatin acid. The mean AUC0-infinity of total simvastatin acid was 74.55 ng x h/mL when simvastatin was given alone and 67.55 ng x h/mL when simvastatin and irbesartan were given concomitantly. The time to peak serum concentration for both treatments was 3 hours. No serious adverse events occurred during the study, and both agents were well tolerated. In summary, irbesartan had no significant effect on the single-dose pharmacokinetics of total simvastatin acid.",2001.0,0,0 430,10936933,[Comparison of patterns of drug therapy in Hungary and in developed Western countries for acute coronary syndromes].,M Keltai,"Analysis of the data of international multicentric clinical pharmacology trials disclosed that the Hungarian (and Eastern European) patients are more sick, than their western counterparts. The drug prescription habits in Hungary are close to that of international standards. The Hungarian doctors order more nitrates, anticoagulants and ACE inhibitors, but less cholesterol-lowering medication than in other countries. The door-to-needle time in Hungarian patients scheduled for thrombolysis was shorter than the mean. The high price of certain thrombolytic medications prevents Hungarian hospital's doctors to use optimal thrombolytic therapy. The high price of statins in Hungary relative to that of other medications for secondary prevention and to the average per capita income is one of the possible causes that this class of medication is used less frequently in Hungary than in Western Europe. This fact may prevent the decrease of cardiovascular morbidity and mortality on the long-term.",2000.0,0,0 431,10939028,"Effects of policosanol and pravastatin on lipid profile, platelet aggregation and endothelemia in older hypercholesterolemic patients.",G Castaño; R Más; M L Arruzazabala; M Noa; J Illnait; J C Fernández; V Molina; A Menéndez,"This randomized, double-blind study was undertaken to compare the effects of policosanol and pravastatin administered at 10 mg/day on lipid profile, platelet aggregation and endothelemia in older patients with type II hypercholesterolemia and high coronary risk. After 6 weeks on a lipid-lowering diet, patients with low-density lipoprotein (LDL) cholesterol levels > 3.4 mmol/l were randomized to receive, under double-blind conditions, policosanol or pravastatin 10 mg tablets that were taken with the evening meal for 8 weeks. Policosanol significantly (p < 0.00001) lowered LDL-cholesterol (19.3%), total cholesterol (13.9%) and the ratios of LDL-cholesterol/high-density lipoprotein (HDL)-cholesterol (28.3%) and total cholesterol/HDL-cholesterol (24.4%). Pravastatin significantly (p < 0.00001) lowered LDL-cholesterol (15.6%), total cholesterol (11.8%) and the ratios (p < 0.0001) of LDL-cholesterol/HDL-cholesterol (18.9%) and total cholesterol/HDL-cholesterol (15.7%). Policosanol, but not pravastatin, significantly increased (p < 0.001) levels of HDL-cholesterol (18.4%) and reduced (p < 0.01) triglycerides (14.1%). Policosanol was more effective (p < 0.05) than pravastatin in inhibiting platelet aggregation induced by all agonists and it significantly reduced (p < 0.0001) platelet aggregation induced by arachidonic acid at 1.5 and 3 mmol/l by 42.2% and 69.5%, respectively, platelet aggregation induced by collagen 0.5 microgram/ml (p < 0.05) (16.6%) and that induced by adenosine diphosphate 1 mumol/l (p < 0.01) (20.3%). Pravastatin significantly reduced (p < 0.001) (27%) only platelet aggregation induced by arachidonic acid 3 mmol/l. Both drugs significantly decreased (p < 0.00001) endothelemia levels but final values were significantly lower (p < 0.001) in the policosanol than in the pravastatin group. Both treatments were safe and well tolerated. Pravastatin significantly (p < 0.01) increased serum levels of alanine amine transferase but individual values remained within normal. Two patients on pravastatin discontinued the study because of adverse experiences (myocardial infarction and jaundice, respectively). In conclusion, the effects of policosanol (10 mg/day) on lipid profile, platelet aggregation and endothelemia in older patients with type II hypercholesterolemia and high coronary risk are more favorable than those induced by the same doses of pravastatin.",2001.0,0,0 432,10939029,Comparative study of the efficacy and tolerability of policosanol and lovastatin in patients with hypercholesterolemia and noninsulin dependent diabetes mellitus.,N Crespo; J Illnait; R Más; L Fernández; J Fernández; G Castaño,"This randomized, double-blind study was undertaken to compare the efficacy and tolerability of policosanol (10 mg/day) and lovastatin (20 mg/day) in patients with hypercholesterolemia and noninsulin dependent diabetes mellitus. After 6 weeks on a lipid lowering diet, 53 patients were randomized to receive either policosanol or lovastatin tablets that were taken o.i.d. for 12 weeks under double-blind conditions. Both groups were similar at randomization. Policosanol significantly (p < 0.001) lowered low-density lipoprotein (LDL)-cholesterol (20.4%), total cholesterol (14.2%) and the ratio of LDL-cholesterol to high-density lipoprotein (HDL)-cholesterol (23.7%). Lovastatin significantly (p < 0.01) lowered LDL-cholesterol (16.8%), total cholesterol (14.0%) and the ratio (p < 0.05) of LDL-cholesterol to HDL-cholesterol (14.9%). Triglyceride levels did not significantly change after therapy. Policosanol, but not lovastatin, significantly increased (p < 0.01) levels of HDL-cholesterol (7.5%). Comparison between groups showed that changes in HDL-cholesterol induced by policosanol were significantly greater (p < 0.01) than those induced by lovastatin. Both treatments were safe and well tolerated. Lovastatin moderately but significantly (p < 0.05) increased levels of aspartate aminotransferase, creatine phosphokinase and alkaline phosphatase. Adverse reactions were more frequent in the lovastatin group (p < 0.01) than in the policosanol group. In conclusion, policosanol administered at 10 mg/day produces more advantageous changes in HDL-cholesterol and has a better safety and tolerability profile than lovastatin 20 mg/day.",2001.0,0,0 433,10939556,Cost-effectiveness of sevelamer versus calcium carbonate plus atorvastatin to reduce LDL in patients with chronic renal insufficiency with dyslipidemia and hyperphosphatemia.,D F Brophy; J F Wallace; D T Kennedy; T W Gehr; D A Holdford,We conducted a cost-effectiveness analysis to compare costs and clinical outcomes of sevelamer versus calcium carbonate plus atorvastatin for treatment of dyslipidemia in patients with chronic renal insufficiency. The model was from the third-party payer perspective. Efficacy and adverse event rates for each regimen were obtained from published clinical trials. Drug costs were based on average wholesale prices; monitoring costs were based on Medicare reimbursement rates. Our model suggests that the combination of calcium carbonate plus atorvastatin is substantially more cost-effective than sevelamer in reducing low-density lipoprotein (LDL) in these patients. One-way sensitivity analyses were performed to assess if 25% and 50% price reductions in sevelamer affected overall cost-effectiveness results. A 50% sevelamer price reduction was less expensive than combination therapy but remained less cost-effective. A two-way sensitivity analysis on the probability that a patient achieves the goal of a 35% LDL reduction resulted in calcium carbonate plus atorvastatin remaining more cost-effective. Further cost-effectiveness studies are necessary to corroborate our data.,2001.0,0,0 434,10942738,Cost-effectiveness of treating hyperlipidemia in the presence of diabetes : who should be treated?,S A Grover; L Coupal; H Zowall; M Dorais,"The objective of this study was to estimate the long-term costs and benefits of treating hyperlipidemia among diabetic patients with and without known cardiovascular disease after validating the Cardiovascular Life Expectancy Model. The model estimates were compared with the Scandinavian Simvastatin Survival Study (4S) and used to estimate the long-term costs and benefits of treatment with simvastatin. Simulations were performed for men and women, 40 to 70 years of age, having pretreatment LDL cholesterol values of 5.46, 4.34, and 3.85 mmol/L (211, 168, and 149 mg/dL). We forecasted the long-term risk of cardiovascular events, the need for medical and surgical interventions, and the associated costs in 1996 US dollars. The model validated well against the observed results of the of the 4S diabetic patients. In this validation, the model estimates fell within the 95% confidence interval of the observed results for 7 of the 8 available end points (coronary deaths, total deaths, and so forth). Treatment with simvastatin for patients with cardiovascular disease is cost-effective for men and women, with or without diabetes. Among diabetic individuals without cardiovascular disease, the benefits of primary prevention were also substantial and the cost-effectiveness ratios attractive across a wide range of assumptions ( approximately $4000 to $40 000 per year of life saved). These conclusions were robust even among diabetics with lower baseline LDL values and smaller LDL reductions as observed in the Cholesterol and Recruitment Events (CARE) trial. Among adults with hyperlipidemia, the presence of diabetes identifies men and women among whom lipid therapy is likely to be effective and cost-effective even in the absence of other risk factors or known cardiovascular disease.",2000.0,0,0 435,10945714,Lipid-lowering drug therapy: more knowledge leads to more problems for composers of guidelines.,P N Durrington; D R Illingworth,,2001.0,0,0 436,10945715,Cost-effectiveness of statins.,J P Reckless,"The efficacy of lipid-lowering with statins has become clear. Indirect estimations, and direct measurements from long-term randomized trials have also demonstrated cost-effectiveness, both in secondary and primary prevention of coronary heart disease. Targeting care efficiently to high-risk groups by calculating absolute risk is essential. However, it is clear that what would normally be very cost-effective interventions will put substantial strain on health care resources because of the common nature of coronary disease and risk factors.",2001.0,0,0 437,10945716,Debate: at what level of coronary heart disease risk should a statin be prescribed?,P R Jackson; L E Ramsay,"3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are effective treatments for the primary and secondary prevention of coronary heart disease, but an outstanding issue is determining who should have such treatment. The benefit from treatment with statins appears to be proportional to the underlying risk of coronary heart disease and independent of the factors increasing risk. Most benefit will therefore be achieved by treating people at increased risk of coronary heart disease. Statins reduce coronary morbidity even when the risk of coronary heart disease is relatively low (6% over 10 years), but reduction in all-cause mortality, the true measure of safety has been shown only when the risk of a major coronary heart disease event is 15% over 10 years or greater. At this level of risk patients appear willing to take treatment to gain the benefit expected from statin treatment, and the cost effectiveness of statin treatment is within the range accepted for other treatments. The major impediments to the systematic introduction of statin treatment at this level of risk are the very high overall cost and the large workload in countries like Britain, where the population risk of coronary heart disease is high. For this reason, recent British guidelines correctly advise statin treatment for secondary prevention and primary prevention when the 10 year coronary heart disease risk is 30% or greater as the first priority, moving to a lower coronary heart disease threshold for primary prevention only when resources permit.",2001.0,0,0 438,10945717,At what level of coronary heart disease risk should a statin be prescribed?,A Gaw; C J Packard,"Statin therapy has been conclusively shown to offer patients clinical benefit, virtually irrespective of their baseline risk status. However, the absolute risk reductions observed in different clinical trials, which have recruited patients across a spectrum of lipid levels and vascular disease states, show that baseline global risk determines the absolute benefit gained and in turn will specify the number of patients needed to be treated in order to realize this benefit. Global risk assessment is therefore central to the clinically meaningful use of statin therapy, and a strong case is now argued in the literature for a high-risk primary prevention strategy that goes hand in hand with standard secondary prevention. The routine use of Framingham-based risk assessment tools is advocated because these are the most widely evaluated and have been repeatedly shown to predict the risk of coronary heart disease accurately in western populations. The risk threshold in primary prevention that should determine pharmacological intervention is the subject of controversy. The currently used annual risk figure of 3% would clearly capture all very high-risk individuals but would also deny treatment to many individuals who will subsequently die from their first coronary event. Although a 1.5% annual risk threshold is economically untenable in the present UK health system, a level of 2% is, we believe, both achievable and affordable.",2001.0,0,0 439,10945718,Management of dyslipidemia after coronary artery bypass grafting.,P Alaupovic,"The results of serial angiographic studies and intervention trials in patients after coronary artery bypass artery grafting have provided ample evidence that abnormalities of the plasma lipoprotein system are one of the most significant risk factors for a rapid atherosclerotic attrition of saphenous vein grafts. In addition to confirming the well recognized role and contribution of cholesterol-rich LDL or lipoprotein B particles to the progression of atherosclerotic lesions, intervention trials have also provided strong evidence for the atherogenic capacity of some intact and partly delipidized triglyceride-rich very low density lipoprotein and intermediate density lipoprotein (lipoprotein B complex) particles, and the protective effect of some (high density lipoprotein 3) but not all high density lipoprotein particles. Most importantly, those studies have emphasized the need for an early, aggressive treatment of dyslipoproteinemias with pharmacological agents as the most efficient therapeutic approach to delaying, if not preventing, the detrimental effect of atherosclerosis on saphenous vein grafts.",2001.0,0,0 440,10945727,Bimonthly update. Hyperlipidaemia and cardiovascular disease.,N J Stone,,2001.0,0,0 441,10945729,Bimonthly update. Therapy and clinical trials.,P D Mistry; R S Elkeles,,2001.0,0,0 442,10946033,Effects of simvastatin (40 and 80 mg/day) in patients with mixed hyperlipidemia.,E Stein; D Plotkin; H Bays; M Davidson; C Dujovne; S Korenman; M Stepanavage; M Mercuri,"Mixed hyperlipidemia is characterized by both elevated total cholesterol and triglycerides. It is estimated to account for 10% to 20% of patients with dyslipidemia. This study assessed the lipid-altering efficacy and tolerability of simvastatin 40 and 80 mg/day as monotherapy. One hundred thirty patients (62 women [48%], 24 [16%] with type 2 diabetes mellitus, mean age 53 years) with mixed hyperlipidemia (baseline low-density lipoprotein [LDL] cholesterol 156 mg/dl [mean], and triglycerides 391 mg/dl [median) were randomized in a multicenter, double-masked, placebo-controlled, 3-period, 22-week, balanced crossover study, and received placebo, and simvastatin 40 and 80 mg/day each for 6 weeks. Compared with placebo, simvastatin produced significant (p <0.01) and dose-dependent changes in all lipid and lipoprotein parameters (LDL cholesterol 2.1%, -28.9%, and -35.5%; triglycerides -3.5%, -27.8%, and -33.0%; high-density lipoprotein cholesterol 3.3%, 13.1%, and 15. 7%; apolipoprotein B 3.8%, -23.1%, and -30.6%; and apolipoprotein A-I 4.0%, 8.2%, and 10.5% with placebo, and simvastatin 40 and 80 mg/day, respectively). The changes were consistent in patients with diabetes mellitus. One patient taking simvastatin 80 mg/day had an asymptomatic and reversible increase in hepatic transaminases 3 times above the upper limit of normal. Simvastatin 40 and 80 mg/day is effective in patients with mixed hyperlipidemia across the entire lipid and lipoprotein profile. The reductions in LDL cholesterol and triglycerides are large, significant, and dose dependent. The increase in high-density lipoprotein cholesterol was greater than that observed in patients with hypercholesterolemia, and appears dose dependent.",2000.0,0,0 443,10946527,Efficacy and safety of cerivastatin and pravastatin in the treatment of primary hypercholesterolemia.,E Saunders; K Ferdinand; L G Yellen; M J Tonkon; S Krug-Gourley; M Poland,"In this randomized, double-blind, parallel group study, the efficacy and safety of cerivastatin (0.3 mg) and pravastatin (20 mg) were compared in 402 patients with primary hypercholesterolemia with and without documented coronary heart disease or peripheral vascular disease. After 8 weeks of treatment, cerivastatin provided significantly greater reductions than pravastatin in low-density lipoprotein (LDL)-cholesterol (31.1% vs. 26.0%; p < 0.0001) and total cholesterol (21.1% vs. 17.8%; p < 0.0001). A greater proportion of patients treated with cerivastatin than pravastatin achieved > 30% and > 40% reductions from baseline in LDL-cholesterol. Both agents also increased high density lipoprotein-cholesterol and reduced triglycerides. Overall, 65.1% of patients treated with cerivastatin and 63.3% of patients with pravastatin achieved LDL-cholesterol goals defined by the National Cholesterol Education Program. Both drugs were well tolerated, with most adverse events being mild. These results demonstrate that cerivastatin (0.3 mg) is a highly effective 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, which enables a large proportion of patients to achieve clinically meaningful reductions in LDL-cholesterol.",2000.0,0,0 444,10947198,"Proceedings of the 4th International Workshop of the Adrenoleukodystrophy International Research Group (ALD-IRG), University of York, 3 September 1998.",S Alger; A Green; W Köhler; P Sokolowski; H Moser,,2001.0,0,0 445,10947889,Cardiovascular risk factors and testing of relatives amongst patients with familial hyperlipidaemia one decade after a clinical trial.,S Tonstad; I Hjermann,"We examined the cardiovascular disease risk factor status of men and women with familial hyperlipidaemia (FH) 10-11 years after a clinical trial and asked whether first-degree relatives had undergone lipid testing. Subjects started lipid-lowering drugs in 1987-88. Of 60 subjects, 12 had died, one emigrated and 35 men and 12 women took part in a follow-up clinical examination in 1998. Total cholesterol level was reduced by 41% and high-density lipoprotein (HDL) cholesterol level increased by 13% compared with baseline (diet alone). Low-density lipoprotein (LDL) cholesterol level was lower at the end of the trial than at follow-up (3.6 +/- 1.5 vs. 4.6 +/- 2.2 mmol L-1; P = 0.01) and was higher in the group taking a low dose of a statin alone compared with other drug groups. Thus, two-thirds of the subjects required adjustment of lipid-lowering drugs to reach target lipid levels. One-fifth consumed at least two food groups rich in saturated fat regularly. Body mass index (BMI) increased from 25.6 +/- 2.9 to 26.8 +/- 3.3 kg m-2 (P < 0.001). Five subjects compared with one at baseline had type II diabetes or glucose intolerance; 12 compared with four at baseline had a blood pressure of >/= 160 mmHg systolic or >/= 95 mmHg diastolic. Plasma total homocysteine was higher in subjects with coronary artery disease than in subjects without disease (11.7 +/- 3.9 vs. 9.0 +/- 2.3 micromol L-1; P = 0.01). Barriers to testing for lipids amongst children or siblings included family feuds, fear of increased insurance and psychiatric disease. The majority of subjects were undertreated. Increases in BMI, blood pressure and glucose levels and the diet posed challenges to risk reduction. Plasma homocysteine levels should be considered in this group. Testing of all first-degree relatives may not be achievable because of psychological barriers.",2000.0,0,0 446,10952477,Effect of fluconazole on plasma fluvastatin and pravastatin concentrations.,T Kantola; J T Backman; M Niemi; K T Kivistö; P J Neuvonen,"To study the effects of fluconazole on the pharmacokinetics of fluvastatin and pravastatin, two inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Two separate randomised, double-blind, two-phase, crossover studies with identical study design were carried out. In each study, 12 healthy volunteers were given a 4-day pretreatment with oral fluconazole (400 mg on day 1 and 200 mg on days 2-4) or placebo, according to a randomisation schedule. On day 4, a single oral dose of 40 mg fluvastatin (study I) or 40 mg pravastatin (study II) was administered orally. Plasma concentrations of fluvastatin, pravastatin and fluconazole were measured over 24 h. In study 1, fluconazole increased the mean area under the plasma fluvastatin concentration-time curve (AUC0-infinity) by 84% (P < 0.01), the mean elimination half-life (t1/2) of fluvastatin by 80% (P < 0.01) and its mean peak plasma concentration (Cmax) by 44% (P < 0.05). In study II, fluconazole had no significant effect on the pharmacokinetics of pravastatin. Fluconazole has a significant interaction with fluvastatin. The mechanism of the increased plasma concentrations and prolonged elimination of fluvastatin is probably inhibition of the CYP2C9-mediated metabolism of fluvastatin by fluconazole. Care should be taken if fluconazole or other potent inhibitors of CYP2C9 are prescribed to patients using fluvastatin. However, pravastatin is not susceptible to interactions with fluconazole or other potent CYP2C9 inhibitors.",2001.0,0,0 447,10952837,"Clinical outcomes, risk stratification and practice patterns of unstable angina and myocardial infarction without ST elevation: Prospective Registry of Acute Ischaemic Syndromes in the UK (PRAIS-UK)",J Collinson; M D Flather; K A Fox; I Findlay; E Rodrigues; P Dooley; P Ludman; J Adgey; T J Bowker; R Mattu,"To determine characteristics, outcomes, prognostic indicators and management of patients with acute coronary syndromes without ST elevation. A prospective registry was carried out with follow-up for 6 months after index hospital admission. A history of acute cardiac chest pain was required plus ECG changes consistent with myocardial ischaemia and/or prior evidence of coronary heart disease. Patients with ST elevation or those receiving thrombolytic therapy were excluded. A total of 1046 patients were enrolled from 56 U.K. hospitals. The mean age was 66+/-12 years and 39% were female. The rate of death or non-fatal myocardial infarction at 6 months was 12.2% and of death, new myocardial infarction, refractory angina or re-admission for unstable angina at 6 months was 30%. In a multivariate analysis, patients >70 years had a threefold risk of death or new myocardial infarction compared with those <60 years (P<0.01) and those with ST depression or bundle branch block on the ECG had a five-fold greater risk than those with normal ECG (P<0.001). Aspirin was given to 87% and heparin to 72% of patients in hospital. At 6 months 56% received no lipid-lowering therapy at all. The 6-month rate of coronary angiography was 27% and any revascularization 15%. In this cohort there was a one in eight chance of death or myocardial infarction, and a one in three chance of death, new myocardial infarction, refractory angina or re-admission for unstable angina, over 6 months. Age and baseline ECG were useful markers of risk. Aspirin, heparin and statins were not given to about one-sixth, one-third and one-half respectively. Rates of angiography and revascularization appear low. A review of treatment strategies of unstable angina and myocardial infarction without ST elevation is warranted in the U.K. to ensure that patients are receiving optimum treatments to reduce mortality and morbidity.",2001.0,0,0 448,10952945,Cardiovascular benefit of cholesterol-lowering therapy: does improved endothelial vasodilator function matter?,R O Cannon,,2000.0,0,0 449,10952951,Effect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease.,J A Vita; A C Yeung; M Winniford; J M Hodgson; C B Treasure; J L Klein; S Werns; M Kern; D Plotkin; W J Shih; Y Mitchel; P Ganz,"Improved endothelial function may contribute to the beneficial effects of cholesterol-lowering therapy. In this randomized, double-blind study, we compared the effect of 6 months of simvastatin (40 mg/d) treatment with that of placebo on coronary endothelial vasomotor function in 60 patients with coronary artery disease. Simvastatin lowered LDL-cholesterol by 40+/-12% from 130+/-28 mg/dL (P<0.001). Peak intracoronary acetylcholine infusion produced epicardial coronary constriction at baseline in both the simvastatin (-17+/-13%) and placebo (-24+/-16%) groups. After treatment, acetylcholine produced less constriction in both groups (-12+/-19% and -15+/-14%, respectively, P=0.97). The increase in coronary blood flow during infusion of the peak dose of substance P was blunted at baseline in both the simvastatin (42+/-50%) and placebo (55+/-71%) groups, reflecting impaired endothelium-dependent dilation of coronary microvessels. After treatment, the flow increase was 82+/-81% in the simvastatin group and 63+/-53% in the placebo group (P=0.16). Six months of cholesterol-lowering therapy has no significant effect on coronary endothelial vasomotor function in the study population of patients with coronary artery disease and mildly elevated cholesterol levels. These findings suggest that the effects of cholesterol lowering on endothelial function are more complex than previously thought.",2000.0,0,0 450,10953258,Are statins anti-inflammatory? Issues in the design and conduct of the pravastatin inflammation C-reactive protein evaluation.,P M Ridker,,2001.0,0,0 451,10953872,[Unaltered homocysteine levels during simvastatin therapy].,H Sinzinger; F Chehne; P Schmid; H Kritz,"Homocysteinemia is regarded as a risk factor for vascular disease. Several risk factors and diseases, but also various drugs, amongst them some lipid lowering medications, have been shown to increase plasma homocysteine concentrations. We therefore assessed the influence of simvastatin on plasma homocysteine levels in 57 patients suffering from severe familial heterozygous hypercholesterolemia. After 1, 3 and 6 months of simvastatin therapy plasma homocysteine levels did not show any change compared to the levels before therapy. Males had typically higher homocysteine levels than females and concentrations in smokers were in most subgroups significantly higher than in non-smokers. No difference in patients taking either 20 or 40 mg simvastatin was apparent and no correlation to the lipid lowering action was found. These findings indicate that in contrast to a number of other lipid lowering agents, simvastatin does not affect plasma homocysteine levels.",2000.0,0,0 452,10954339,"Non lipid, dose-dependent effects of pravastatin treatment on hemostatic system and inflammatory response.",V Di Garbo; M Bono; D Di Raimondo; R De Simone; G Raneli; G Avellone,"The aim of the present study was to evaluate the effects of pravastatin treatment on lipid, inflammation, and coagulation parameters in patients suffering from myocardial infarction with or without carotid atherosclerotic lesions (groups 1 and 2, respectively). In the first phase of the study, a cross-sectional comparison of lipid, inflammation, and coagulation parameters was performed between the patients and the control group (group 3). Highly significant differences in these parameters were observed, especially in group 1. In the second phase of the study, we assessed the effects of a persistent reduction in cholesterol synthesis induced by increasing doses of pravastatin (20 mg daily for 8 weeks and 40 mg daily for a further 8 weeks). In addition to the well-established lipid-lowering effect, significant changes in inflammation and coagulation parameters were observed. In particular, pravastatin at a dosage of 20 mg/ day significantly reduced only fibrinogen levels, while at a dosage of 40 mg/day significantly reduced factor VII, fibrinogen, prothrombin fragments 1 and 2, thrombin-antithrombin complexes, tissue plasminogen activator antigen (tPA:Ag) before venous occlusion (b.o.), inhibitor of plasminogen activator activity (PAI) b.o., PAI activity after occlusion (a.o.), the human autoantibodies against oxidized low-density lipoprotein (LDL), and the c fraction of the third component system levels, and significantly increased tPA:Ag a.o. levels. Our results show that in patients suffering from myocardial infarction the risk of thrombotic complications can be decreased with pravastatin, especially by larger doses. However, the relationship must be further investigated because the observed reductions in the hemostatic system and inflammatory response seemed to be dose dependent, while the effects of pravastatin treatment were not significantly correlated with total and LDL cholesterol changes.",2001.0,0,0 453,10954957,Low density lipoprotein cholesterol lowering: are the treatment guidelines still appropriate?,J P Deslypere,"The availability of treatment guidelines has revolutionised our approach to detection, evaluation and treatment of dyslipidaemias in adults. Such guidelines focus on lowering low-density lipoprotein-cholesterol (LDL-C), the primary risk factor for coronary heart disease, and provide physicians with specific goals to be attained by dietary and, if necessary, pharmacological therapy. However, the guidelines were published in 1993, which means that the pivotal findings from large intervention trials with statins were not included. This has led to calls for the guidelines to be amended to take into account the findings of these studies and other evolving issues such as the pathogenesis of the acute coronary event and the contribution of low HDL-C and other lipid parameters. More importantly, the mostly epidemiological basis of the guidelines has instilled the concept that the lower the LDL-C level after lipid-lowering intervention the better the result in terms of prevention of coronary events. Available data now refute this assumption. Indeed, maximal therapeutic benefit is already obtained with a decrease in LDL-C level of 20-30%, irrespective of baseline levels or LDL-C levels on treatment and, until now, there have been no data to suggest that decreases in LDL-C of > 30% give any additional benefit to patients in terms of improving their long-term outcome. The concept of absolute LDL-C treatment goals therefore needs to be revisited. A more appropriate goal of lipid-lowering therapy with statins is to ensure LDL-C levels are reduced by 20-30%, with statin dosages as used in the intervention trials. Furthermore, there are insufficient data to advise that LDL-C levels should be lowered to 2.6 mmol/l. This issue will be resolved only when the results of the appropriate intervention trials are published.",2000.0,0,1 454,10955373,"Effects of NK-104, a new hydroxymethylglutaryl-coenzyme reductase inhibitor, on low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia. Hokuriku NK-104 Study Group.",K Kajinami; J Koizumi; K Ueda; S Miyamoto; T Takegoshi; H Mabuchi,"The clinical efficacy of NK-104, a novel and totally synthetic hydroxymethylglutaryl-coenzyme A reductase inhibitor, was assessed in 30 patients (men/women = 15/15, mean age 51 years) with heterozygous familial hypercholesterolemia. After a placebo phase of >4 weeks, NK-104 was given at an initial dose of 2 mg/day for 8 weeks, which was increased to 4 mg/day for a further 8 weeks. As a result of 2 mg/day of NK-104 treatment, mean +/- SD of total and low-density lipoprotein cholesterol levels decreased significantly (p<0.0001) from baseline, namely from 8.80+/-1.38 to 6.11+/-1.09 mmol/L (-31%) and from 6.81+/-1.52 to 4.09+/-1.03 mmol/L (-40%), respectively. They decreased further (p<0.0001) as a result of 4-mg/day administration, to 5.52+/-0.81 mmol/L (-37%) and 3.55+/-0.85 mmol/L (-48%), respectively. Changes in high-density lipoprotein cholesterol levels failed to reach statistical significance. Serum triglyceride levels decreased significantly (p<0.0001) from baseline as a result of 4 mg/day of NK-104, from 1.99+/-1.72 to 1.35+/-0.90 mmol/L (-23%). Serum apolipoprotein B, CII, CIII, and E levels significantly decreased: mean changes from baseline at the end of the study were -41% (p<0.0001), -27% (p<0.0001), -19% (p = 0.002), and -37% (p<0.0001), respectively. On the other hand, apolipoprotein AI and All levels significantly increased as a result of the treatment: + 10% (p = 0.002) and +6% (p = 0.008), respectively. There were no adverse events observed in either clinical or laboratory findings that could be attributed to the treatment. These results suggest that the potency of NK-104 appears to be dose-dependent, and that NK-104 is safe and well tolerated in the treatment of patients with heterozygous familial hypercholesterolemia, and thus also provides a new therapeutic choice for subjects requiring lipid-modifying therapy.",2000.0,0,0 455,10959773,New advances in pharmacogenomics.,B Destenaves; F Thomas,"In the years to come, pharmacogenomics will make an impact on the development of new drugs. Numerous publications have shown that gene polymorphism can influence drug toxicity and/or efficacy. In order to improve current applications of pharmacogenomics, some technical limitations regarding marker generation, genotyping and biostatistical analysis are being overcome.",2001.0,0,0 456,10961170,Lipoprotein (a) and stroke.,H J Milionis; A F Winder; D P Mikhailidis,"Strokes are one of the most common causes of mortality and long term severe disability. There is evidence that lipoprotein (a) (Lp(a)) is a predictor of many forms of vascular disease, including premature coronary artery disease. Several studies have also evaluated the association between Lp(a) and ischaemic (thrombotic) stroke. Several cross sectional (and a few prospective) studies provide contradictory findings regarding Lp(a) as a predictor of ischaemic stroke. Several factors might contribute to the existing confusion--for example, small sample sizes, different ethnic groups, the influence of oestrogens in women participating in the studies, plasma storage before Lp(a) determination, statistical errors, and selection bias. This review focuses on the Lp(a) related mechanisms that might contribute to the pathogenesis of ischaemic stroke. The association between Lp(a) and other cardiovascular risk factors is discussed. Therapeutic interventions that can lower the circulating concentrations of Lp(a) and thus possibly reduce the risk of stroke are also considered.",2000.0,0,0 457,10963717,Oxidative stress as a signaling mechanism of the vascular response to injury: the redox hypothesis of restenosis.,L C Azevedo; M A Pedro; L C Souza; H P de Souza; M Janiszewski; P L da Luz; F R Laurindo,"The prominent role of redox processes in tissue injury and in vascular cell signaling suggest their involvement in the repair reaction to vessel injury, which is a key determinant of restenosis post-angioplasty. Experimental studies showed a protective effect of superoxide dismutase or antioxidants on vasospasm, neointimal thickening or remodeling after balloon injury. It was also shown that oxidized thiols induce chelatable metal-dependent amplification of the vascular repair reaction. Ongoing or completed clinical trials show a promising effect of the antioxidant probucol against restenosis. However, few studies addressed the molecular physiological mechanisms underlying the redox hypothesis of restenosis. We recently showed evidence for marked oxidative stress early after balloon injury, with superoxide production mediated primarily by non-endothelial NAD(P)H oxidase-type flavoenzyme(s). This effect was closely related to the degree of injury. There is evidence supporting a role for such early redox processes in apoptotic cell loss and NF-kappa B activation. We present new data on the time course of oxidative stress after balloon injury of intact rabbit iliac arteries. Our data show that despite substantial neointimal growth and lumen narrowing, superoxide production and glutathione levels are unaltered at day 14 and 28 after balloon injury. At day 7 after injury, the peak neointimal proliferation in this model, there was significant decrease of vascular superoxide dismutase activity, without clear evidence of spontaneous superoxide production. Thus, oxidative stress after injury is likely to be an early transient event, which parallels the inflammatory and proliferative phases of the vascular response. We propose that such early redox processes act as dose-dependent signal transducers of gene programs that affect the final repair.",2000.0,0,0 458,10964582,Each administration of cyclosporin A enhances skin microvascular reactivity in renal transplant recipients.,A Asberg; K J Berg; A Hartmann,"Both impaired and enhanced microvascular function have been described in humans on cyclosporin A (CsA) therapy. In the present study we investigated the acute microvascular effects of a single CsA administration in renal transplant recipients on maintenance CsA therapy. Fourteen renal transplant recipients, median age 48 years (range 24-63 years), transplanted 4-12 weeks earlier, were included in this placebo-controlled, double-blinded, crossover study. All recipients had stable renal function; median serum creatinine was 116 micromol/L (range 80-184 micromol/L). Immunosuppressive therapy consisted of CsA, prednisolone, and either azathioprine or mycophenolate. Microvascular function was assessed by laser Doppler flowmetry in combination with acetylcholine (endothelium dependent) stimulation and the postocclusive reactive hyperemia test. Measurements were performed before (control) and 2.5 h following administration of CsA (Neoral) or matching placebo and repeated with reversed medication after at least 6 days. Vasodilative responses to acetylcholine stimulation were significantly higher following CsA ingestion compared with placebo. The mean change in AUC(1.5) (area under the flux versus time curve) from control to 2.5 h was 100 +/-145 for CsA and -292 +/- 140 AU x min for placebo (P = 0.047, n = 10). The postocclusive hyperemic response AUC(rh) was also significantly higher following CsA intake (39 +/- 4 AU x min) compared to placebo (30 +/- 4 AU x min) (P = 0.006, n = 12). This study shows that each dose of CsA induces a transient increase in skin microvascular reactivity in renal transplant recipients. We speculate that this might be due to the potentiation of one or several endothelial-dependent compensatory vasodilative mechanisms in the microvascular bed.",2001.0,0,0 459,10971313,Intravenous diltiazem and CYP3A-mediated metabolism.,A L Masica; N E Azie; D C Brater; S D Hall; D R Jones,"To study whether intravenous diltiazem, a calcium channel blocker commonly prescribed for hypertension and stable angina, is an inhibitor of the CYP3A enzymes by using oral lovastatin, an HMG Co-A reductase inhibitor, as a substrate. Ten healthy volunteers were studied in a randomized two-way crossover design. The two arms were 1) administration of a 20 mg dosage of lovastatin orally and 2) administration of a 20 mg dosage of lovastatin orally 1 h after an intravenous loading dosage and constant infusion of diltiazem. Blood samples were collected up to 25 h in order to quantify lovastatin and diltiazem concentrations in the separated serum. Lovastatin and diltiazem concentrations were quantified by GC-MS and h.p.l.c., respectively. Intravenous diltiazem did not significantly affect the oral AUC, Cmax, t(1/2), or tmax of lovastatin. These data suggest that the interaction of lovastatin with diltiazem does not occur systemically and is primarily a first-pass effect. Thus, drug interactions with diltiazem may become evident when a patient is moved from intravenous to oral dosing.",2001.0,0,0 460,10972631,Benefits of early lipid-lowering intervention in high-risk patients: the lipid intervention strategies for coronary patients study.,T R Pedersen; K E Jahnsen; S Vatn; A G Semb; F Kontny; A Zalmai; T Nerdrum,"There is controversy about whether lipid-lowering pharmacotherapy should be initiated immediately after an acute coronary event or only after diet and lifestyle changes have proved inadequate. This study, known as the Lipid Intervention Strategies for Coronary Patients Study, compared the efficacy of immediate versus deferred simvastatin treatment in conjunction with dietary advice about reducing lipid levels in hypercholesterolemic patients with acute coronary syndromes. This randomized, open-label, parallel-group study included 151 hypercholesterolemic (low-density lipoprotein cholesterol [LDL-C] >3.0 mmol/L) men and women aged 35 to 75 years. Within 4 days of diagnosis of acute myocardial infarction (MI) or unstable angina pectoris, all patients received dietary advice from a specially trained nurse. Subsequently, patients were randomized to 2 treatment groups: 1 group received immediate treatment with simvastatin 40 mg/d; patients in the other group received simvastatin 40 mg/d after 3 months only if their LDL-C remained >3.0 mmol/L. The immediate-simvastatin group (n = 73) and the deferred-simvastatin group (n = 78) were balanced with respect to baseline characteristics. Of the 151 patients, 25% were women, 25% had concomitant hypertension, and 75% had a diagnosis of MI on enrollment. At 3 months, 90% of the patients receiving dietary advice plus immediate simvastatin treatment had achieved the recommended European target LDL-C level of <3.0 mmol/L, compared with 7% of those treated with diet alone. By 6 months, when 92% of the study participants were receiving simvastatin 40 mg/d, the proportion of patients achieving target LDL-C levels was 92% in the group that received immediate simvastatin therapy and 81% in the group that received deferred simvastatin therapy. The reductions in LDL-C (42%-48%) were considered to be clinically comparable between the 2 groups at 12 months. On the basis of these results, we concluded that few patients with hypercholesterolemia and acute coronary syndromes reach the recommended European target LDL-C level of <3.0 mmol/L with dietary advice alone. However, early treatment with simvastatin 40 mg/d combined with dietary advice and follow-up at a dedicated outpatient clinic specializing in coronary heart disease resulted in 9 out of 10 patients reaching a recommended target LDL-C level of <3.0 mmol/L. Initiation of simvastatin therapy while a patient is hospitalized may increase the likelihood of the patient's lipid levels being managed according to current recommendations after he or she is discharged.",2001.0,0,0 461,10974215,"Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability.",K K Koh,"Clinical trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statin therapy demonstrate an improvement in cardiovascular end points and coronary stenosis. However, an improvement in cardiovascular end points and coronary stenosis is incompletely explained by the baseline or treated LDL cholesterol level. The beneficial effects of statins on clinical events may involve nonlipid mechanisms that modify endothelial function, smooth muscle cells, and monocyte-macrophage: vasomotor function, inflammatory responses, and plaque stability. Augmented bioactivity of NO by statin therapy either indirectly by its effect on lipoprotein levels and protection of LDL from oxidation, or directly by effects on NO synthesis and release, might account for enhancement of endothelium-dependent vasodilation. Recent experimental and animal studies have demonstrated that statins dose-dependently decrease smooth muscle cells migration and proliferation, independently of their ability to reduce plasma cholesterol. Moreover, statins are able to reduce the in vitro cholesterol accumulation in macrophages and expression of matrix metalloproteinase, resulting in plaque stability. These effects of statins were completely prevented by the addition of mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites, probably through prenylated proteins, in regulating these cellular events. Statins have been shown to prevent the activation of monocytes into macrophages, inhibit the production of pro-inflammatory cytokines, C-reactive protein, and cellular adhesion molecules. Statins decrease the adhesion of monocyte to endothelial cells. Accordingly, statins exert their cardiovascular benefits through a direct antiatherogenic properties in the arterial wall, beyond their effects on plasma lipids.",2001.0,0,0 462,10975586,"Systemic, pulmonary, and renal hemodynamic effects of endothelin ET(A/B)-receptor blockade in patients with maintained left ventricular function.",M Fleisch; G Sütsch; X W Yan; R R Wenzel; C Binggeli; M G Bianchetti; B Meier; W Kiowski; T F Lüscher,"Endothelin-1 (ET-1) regulates vascular tone in congestive heart failure and modulates renal function. Its role in patients with normal left ventricular (LV) function and its renal effects are unclear. Cardiac and renal hemodynamics were studied in 24 patients with normal LV function and coronary arteries after single-dose, double-blind, randomized administration of TAK-044 (25, 50, or 100 mg, i.v.), an ET(A/B)-receptor antagonist, or placebo. Hemodynamics were monitored using Swan-Ganz and arterial catheters, and ET levels were measured. Renal function was assessed by clearance techniques. In the absence of a dose-response relation, TAK-044 patients were analyzed as a single group. Most hemodynamic effects occurred during the first 4 h. TAK-044 reduced mean arterial (-9.3 mm Hg, p < 0.001), pulmonary (-1.8 mm Hg, p = 0.01), and pulmonary capillary wedge pressure (-1.6 mm Hg, p < 0.001) between 30 min and 4 h. Mean reduction in systemic vascular resistance was 279 dyne/s/cm2 (p < 0.001), whereas heart rate increased 6.1 beats/min (p < 0.001) and cardiac index by 0.37 L/m2 (p = 0.01). Stroke volume index, right atrial pressure, and pulmonary vascular resistance did not change. TAK-044 increased renal plasma flow in proportion to the increase in cardiac output (+119 ml/min, 4 h after TAK-044; p < 0.05) and ET-1 levels (2.5-fold; p < 0.05). No serious side effects were noted. In patients with normal cardiac function, ET-receptor blockade causes vasodilation and reduces systemic but not pulmonary vascular resistance and increases cardiac index and renal plasma flow.",2001.0,0,0 463,10976657,Clinical pharmacokinetics of cerivastatin.,W Mück,"Cerivastatin sodium, a novel statin, is a synthetic, enantiomerically pure, pyridine derivative that effectively reduces serum cholesterol levels at microgram doses. Cerivastatin is readily and completely absorbed from the gastrointestinal tract, with plasma concentrations reaching a peak 2 to 3 hours postadministration followed by a monoexponential decay with an elimination half-life (t1/2beta) of 2 to 3 hours. Cerivastatin pharmacokinetics are linear: maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) are proportional to the dose over the range of 0.05 to 0.8 mg. No accumulation is observed on repeated administration. Cerivastatin interindividual variability is described by coefficients of variation of approximately 30 to 40% for its primary pharmacokinetic parameters AUC, Cmax and t1/2beta. The mean absolute oral bioavailability of cerivastatin is 60% because of presystemic first-pass effects. Its pharmacokinetics are not influenced by concomitant administration of food nor by the time of day at which the dose is given. Age, gender, ethnicity and concurrent disease also have no clinically significant effects. Cerivastatin is highly bound to plasma proteins (>99%). The volume of distribution at steady state of about 0.3 L/kg indicates that the drug penetrates only moderately into tissue; conversely, preclinical studies have shown a high affinity for liver tissue, the target site of action. Cerivastatin is exclusively cleared via metabolism. No unchanged drug is excreted. Cerivastatin is subject to 2 main oxidative biotransformation reactions: demethylation of the benzylic methyl ether moiety leading to the metabolite M-1 [catalysed by cytochrome P450 (CYP) 2C8 and CYP3A4] and stereoselective hydroxylation of one methyl group of the 6-isopropyl substituent leading to the metabolite M-23 (catalysed by CYP2C8). The product of the combined biotransformation reactions is a secondary minor metabolite, M-24, not detectable in plasma. All 3 metabolites are active inhibitors of hydroxymethylglutaryl-coenzyme A reductase with a similar potency to the parent drug. Approximately 70% of the administered dose is excreted as metabolites in the faeces, and 30% in the urine. Metabolism by 2 distinct CYP isoforms renders cerivastatin relatively resistant to interactions arising from inhibition of CYP. If one of the pathways is blocked, cerivastatin can be effectively metabolised by the alternative route. In addition, on the basis of in vitro investigations, there is no evidence for either cerivastatin or its metabolites having any inducing or inhibitory activity on CYP. The apparent lack of any clinically relevant interactions with a variety of drugs commonly used by patients in the target population supports this favourable drug-drug interaction profile.",2001.0,0,0 464,10979113,Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: A randomized trial. Arterial Disease Multiple Intervention Trial.,M B Elam; D B Hunninghake; K B Davis; R Garg; C Johnson; D Egan; J B Kostis; D S Sheps; E A Brinton,"Although niacin increases low levels of high-density lipoprotein cholesterol (HDL-C), which frequently accompany diabetes, current guidelines do not recommend use of niacin in patients with diabetes because of concerns about adverse effects on glycemic control; however, this is based on limited clinical data. To determine the efficacy and safety of lipid-modifying dosages of niacin in patients with diabetes. Prospective, randomized placebo-controlled clinical trial conducted in 6 clinical centers from August 1993 to December 1995. A total of 468 participants, including 125 with diabetes, who had diagnosed peripheral arterial disease. After an active run-in period, participants were randomly assigned to receive niacin (crystalline nicotinic acid), 3000 mg/d or maximum tolerated dosage (n = 64 with diabetes; n = 173 without diabetes), or placebo (n = 61 with diabetes; n = 170 without diabetes) for up to 60 weeks (12-week active run-in and 48-week double-blind). Plasma lipoprotein, glucose, hemoglobin A(1c) (HbA(1c)), alanine aminotransferase, and uric acid levels; hypoglycemic drug use; compliance; and adverse events, in patients with diabetes vs without who were receiving niacin vs placebo. Niacin use significantly increased HDL-C by 29% and 29% and decreased triglycerides by 23% and 28% and low-density lipoprotein cholesterol (LDL-C) by 8% and 9%, respectively, in participants with and without diabetes (P<.001 for niacin vs placebo for all). Corresponding changes in participants receiving placebo were increases of 0% and 2% in HDL-C and increases of 7% and 0% in triglycerides, and increases of 1% and 1% in LDL-C. Glucose levels were modestly increased by niacin (8.7 and 6.3 mg/dL [0.4 and 0.3 mmol/L]; P =.04 and P<.001) in participants with and without diabetes, respectively. Levels of HbA(1c) were unchanged from baseline to follow-up in participants with diabetes treated with niacin. In participants with diabetes treated with placebo, HbA(1c) decreased by 0.3% (P =.04 for difference). There were no significant differences in niacin discontinuation, niacin dosage, or hypoglycemic therapy in participants with diabetes assigned to niacin vs placebo. Our study suggests that lipid-modifying dosages of niacin can be safely used in patients with diabetes and that niacin therapy may be considered as an alternative to statin drugs or fibrates for patients with diabetes in whom these agents are not tolerated or fail to sufficiently correct hypertriglyceridemia or low HDL-C levels. JAMA. 2000;284:1263-1270",2000.0,0,0 465,10979886,Update in women's health.,R Verdery,,2000.0,0,0 466,10980214,"Rationale, design, and baseline characteristics of a trial of prevention of cardiovascular and renal disease with fosinopril and pravastatin in nonhypertensive, nonhypercholesterolemic subjects with microalbuminuria (the Prevention of REnal and Vascular ENdstage Disease Intervention Trial [PREVEND IT]).",G F Diercks; W M Janssen; A J van Boven; A A Bak; P E de Jong; H J Crijns; W H van Gilst,"This study describes the rationale, design, and baseline characteristics of a trial to determine whether treatment with fosinopril 20 mg/day and/or pravastatin 40 mg/ day will prevent cardiovascular and renal disease in nonhypertensive (RR <160/100 mm Hg and not using antihypertensive medication) and nonhypercholesterolemic (total cholesterol <8.0 or <5.0 mmol/L in case of previous myocardial infarction and not using lipid lowering medication) men and women with persistent microalbuminuria (urinary albumin excretion >10 mg/L once in an early morning spot urine and 15 to 300 mg/24-hour at least once in two 24-hour urine collections). The Prevention of REnal and Vascular ENdstage Disease Intervention Trial is a single-center, double-blind, randomized, placebo-controlled trial with a 2 x 2 factorial design. The 864 randomized subjects will be monitored for a minimum of 4 years and a maximum of 5 years. The primary efficacy parameter is defined as the combined incidence of all-cause mortality or hospital admission for documented (1) nonfatal myocardial infarction, (2) myocardial ischemia, (3) heart failure, (4) peripheral vascular disease, (5) cerebrovascular accident and/or (6) end-stage renal disease.",2001.0,0,0 467,10980845,Fibrates and high-dose statins to prevent coronary heart disease events.,P H Jones,,2001.0,0,0 468,10980910,Global risk assessment for lipid therapy to prevent coronary heart disease.,C M Nass; S D Wiviott; J K Allen; W S Post; a R Blumenthal,"Randomized clinical trials have established that lipid- lowering pharmacologic therapy can substantially reduce morbidity and mortality in patients with known coronary artery disease (CAD). Researchers are now working to define the role of lipid-lowering agents in the primary prevention of CAD to extend their benefit to patients at increased risk for future coronary events. The risk assessment models presently used for secondary prevention are not sufficient to identify high-risk, asymptomatic patients. Building on the accumulated data about the physiologic mechanisms and metabolic factors that contribute to CAD, novel serum markers and diagnostic tests are being critically studied to gauge their utility for the assessment of high-risk patients and occult vascular disease. New risk prediction models that combine traditional risk factors for CAD with the prudent use of new screening methods will allow clinicians to target proven risk reduction therapies at high-risk patients before they experience a cardiac event.",2000.0,0,0 469,10980911,Implications of the atorvastatin versus revascularization treatment (AVERT) study for the clinician.,D Eisenberg,"The underlying disorder in the vast majority of cases of cardiovascular disease is atherosclerosis, for which low-density lipoprotein cholesterol is recognized as a major risk factor. Data from epidemiologic studies have suggested that lower cholesterol levels are associated with a lower overall risk of morbidity and mortality due to coronary heart disease. Numerous clinical trials with lipid-lowering agents support these epidemiologic data. Of these, studies with the HMG-CoA (3-hydroxy 3-methylglutaryl coenzyme A) reductase inhibitors, or statins, have shown the greatest lipid-lowering effects. Data from recent trials such as the Atorvastatin Versus Revascularization Treatment contribute to a growing body of evidence that suggests that aggressive reduction of cholesterol can yield additional clinical benefits above and beyond that observed with less robust treatment regimens. Aggressive cholesterol-lowering strategies have the potential therefore to have a significant impact on levels of atherosclerotic disease throughout the westernized world. Such effects argue in favor of renaming the entire class of drugs as anti- atherosclerotic rather than lipid-lowering agents.",2000.0,0,0 470,10980912,Primary prevention of coronary heart disease: implications of the Air Force/Texas coronary atherosclerosis prevention study (AFCAPS/TexCAPS).,A S Brown,"Over the past 15 years several studies have examined the benefits of treating patients with dyslipidemia in order to prevent a first cardiac event and to prevent the onset of clinical symptoms of coronary atherosclerosis. Some of the pitfalls of these studies have been that they have been performed predominantly in men, and also in patients with extremely high cholesterol levels. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) provides substantial additional information regarding the benefits of primary prevention in the general population. The study included large numbers of women as well as subjects with a wide variety of ethnic backgrounds, and showed substantial benefit across this population. Patients with average cholesterol levels, but below-average high-density lipoproteins, had substantial reduction in risk of a first cardiac event with aggressive treatment of their dyslipidemia, using lovastatin. The majority of the patients in the AFCAPS/TexCAPS study would not warrant therapy, based on the current National Cholesterol Education Program Adult Treatment Panel guidelines. The data suggest that new strategies are warranted to better identify those patients who are at high risk and those who will receive benefit from aggressive lipid-lowering therapy.",2000.0,0,0 471,10983019,Clinical outcome of patients with familial hypercholesterolemia and coronary artery disease undergoing partial ileal bypass surgery.,J S Issa; A Garrido; S D Giannini; N Forti; J Diament; H W Pinotti,"Familial hypercholesterolemia is characterized by high serum levels of total cholesterol and LDL-cholesterol. It may be homozygous or heterozygous. In homozygous patients, LDL-cholesterol levels range from 500 to 1000 mg/dL and coronary artery disease is precocious, usually manifesting itself between the 2nd and 3rd decades of life. The diagnosis is often made by the presence of xanthoma tuberosum and tendinous xanthomas that appear between the 1st and 2nd decades of life. The use of high doses of statins or even unusual procedures (apheresis, partial ileal bypass surgery, liver transplantation, gene therapy), or both, is necessary for increasing survival and improving quality of life, because a reduction in cholesterol levels is essential for stabilizing the coronary artery disease and reducing xanthomas. We report our experience with 3 patients with xanthomatous familial hypercholesterolemia and coronary artery disease, who underwent partial ileal bypass surgery. Their follow-up over the years (approximately 8 years) showed a mean 30% reduction in total cholesterol, with a significant reduction in the xanthomas and stabilization of the coronary artery disease.",2000.0,0,0 472,10983656,Efficacy and tolerability of pravastatin for the treatment of HIV-1 protease inhibitor-associated hyperlipidaemia: a pilot study.,F Baldini; S Di Giambenedetto; A Cingolani; R Murri; A Ammassari; A De Luca,,2001.0,0,1 473,10984551,Identifying patients at risk for coronary heart disease: implications from trials of lipid-lowering drug therapy.,C G Isles; J R Paterson,"Abnormal lipid levels contribute significantly to the risk of coronary heart disease (CHD), which is increased further in the presence of other risk factors. The association between elevated low-density lipoprotein (LDL) cholesterol and CHD risk is well established, and large primary and secondary prevention studies of HMG-CoA reductase inhibitors (statins) have shown conclusively that lowering LDL cholesterol levels reduces CHD events and total mortality. Regardless of the intervention used (diet, surgery, drugs), reduction of plasma cholesterol has consistently produced a reduction in cardiovascular risk. Absolute benefit is greatest in those who are at highest risk initially, and trial results suggest that the lower the LDL cholesterol level achieved, at least down to LDL of 3.0 mmol/l, then the lower is the CHD event risk. Epidemiological data also point to the negative impact of other lipids on CHD risk. Low levels of high-density lipoprotein (HDL) and high levels of triglycerides (particularly in conjunction with an LDL/HDL ratio >5) are particularly strong risk factors for CHD. Thus, although prevention trials to date have primarily assessed the impact of LDL lowering on CHD events, the initial assessment of CHD risk should consider a more detailed atherogenic profile including HDL and triglyceride levels. A general approach to preventing cardiovascular disease should include strategies to reduce the overall CHD risk by lifestyle modification and management of modifiable risk factors such as smoking, hypertension and diabetes. Based on data from recent prevention studies, and because they are the most potent lipid-lowering agents available for lowering LDL cholesterol, statins have appropriately become the drug of choice for most patients with hyperlipidaemia who require drug therapy.",2001.0,0,0 474,10985515,Clinical trials and clinical practice--bridging the gaps in type 2 diabetes. An evidence-based approach to risk factor modification in type 2 diabetes.,J R Greenfield; D J Chisholm,,2001.0,0,0 475,10987582,Medical therapy versus coronary angioplasty in stable coronary artery disease: a critical review of the literature.,R S Blumenthal; G Cohn; S P Schulman,"The recent publication of the Atorvastatin Versus Revascularization Treatment (AVERT) trial has renewed debate on the optimal management strategy for relatively stable patients with coronary artery disease. Currently, coronary angiography and percutaneous coronary intervention are often performed in stable patients with good exercise tolerance who have not been treated with proven medications such as aspirin, statins and beta-adrenergic blocking agents in conjunction with comprehensive lifestyle modification. We review the results of prior trials comparing medical therapy with angioplasty and assess their strengths and limitations and then make conclusions about the aggregate data. Next, we describe the ongoing Clinical Outcome Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, which will be the largest of the studies comparing optimal medical therapy and percutaneous revascularization. This study will employ intensive medical management in all patients with coronary disease, and the incremental benefit of state of the art revascularization techniques in terms of clinical event reduction, quality of life issues and cost-effectiveness will be addressed. For now, aggressive medical therapy and revascularization should be viewed as complementary rather than opposing strategies. All patients with coronary heart disease should receive proven medical and lifestyle prescriptions to favorably alter the atherosclerotic process. Percutaneous revascularization without comprehensive risk factor modification is a suboptimal therapeutic strategy.",2000.0,0,1 476,10987598,Prevention of recurrent life-threatening arrhythmias: will lipid-lowering therapy make a difference?,S H Hohnloser,,2000.0,0,0 477,10987719,,,,,0,0 478,10988008,A need to redefine the consensus on the use of statins in coronary heart disease prevention.,J C Fruchart,,2001.0,0,0 479,10988016,Application of the National Cholesterol Education Program and joint European treatment criteria and clinical benefit in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).,A M Gotto; E Whitney; E A Stein; D R Shapiro; M Clearfield; S Weis; J Y Jou; A Langendörfer; P A Beere; D J Watson; J R Downs; J S de Cani,"The Air Force/Texas Coronary Atherosclerosis Prevention Study reported that diet with lovastatin, 20-40 mg daily, reduced the risk for a first coronary event by 37%. Because only 17% of this cohort would have qualified for drug therapy according to current U.S. guidelines, we assessed clinical benefit by risk categories. The main outcome measures were event rates of first acute major coronary events stratified by National Cholesterol Education Program and European criteria and target goal. Both those who would and would not be eligible for drug therapy, according to National Cholesterol Education Program guidelines, benefited from intervention. As expected, drug-eligible participants (event rate: lovastatin 1%/year, placebo 1.87%/year [relative risk 0.53, 95% confidence interval: 0.33, 0.84]) were at greater absolute risk for acute major coronary events than non-eligible participants (lovastatin 0.62%/year, placebo 0.93%/year [relative risk 0.67, 95% confidence interval: 0.51, 0.88]). Similar results were found using European guidelines for coronary risk management. Treatment to a target goal suggested a non-significant trend to greater benefit. The consistent relative benefit across risk categories suggests that it may be possible to improve identification of at-risk persons who would benefit from primary prevention, and to recommend appropriate goals of such treatment.",2001.0,0,1 480,10988199,Cholesterol lowering with pravastatin improves resistance artery endothelial function: report of six subjects with normal coronary arteriograms.,J L Houghton; T A Pearson; R G Reed; M T Torosoff; N L Henches; P A Kuhner; E F Philbin,"Improvement in coronary artery endothelial function has been demonstrated after cholesterol lowering in hypercholesterolemic patients with significant atherosclerosis. However, to our knowledge, no previous study has shown improvement in resistance artery function in subjects with normal coronary arteries after cholesterol lowering. The purpose of our study was to investigate the effect of cholesterol lowering with pravastatin on coronary resistance artery endothelial function in the setting of angiographically normal coronary arteries. Invasive testing of coronary endothelial and vasomotor function was performed at baseline and after 6 months of pravastatin treatment in six patients with normal coronary arteriograms. After 6 months of pravastatin treatment, low-density lipoprotein cholesterol level dropped from 157+/-11 to 117+/-8 mg/dL (p = 0.02) and percent increase in coronary blood flow after acetylcholine improved from 97+/-13% to 160+/-16% (p = 0.01). There was a trend (p = 0.17) toward enhanced epicardial dilation in response to acetylcholine after pravastatin treatment when compared with the baseline study. Our study demonstrates significant improvement in coronary resistance artery endothelial function after 6 months of cholesterol lowering with pravastatin in six subjects presenting with chest pain who were found to have normal coronary arteriograms. A trend toward improved epicardial vasomotion was also observed.",2000.0,0,0 481,10992997,[Cost effectiveness of pravastatin in secondary coronary prevention in patients with myocardial infarct or unstable angina in Germany. An analysis on the basis of the LIPID trial].,T D Szucs; K Berger; W März; J R Schäfer,"Secondary coronary prevention with lipid lowering drugs has become a major issue in health policy formulation due to the large upfront investment in drug therapy. The recently completed LIPID trial with pravastatin in secondary prevention immediately raise the question whether pravastatin might be cost-effective in Germany. We conducted a cost-effectiveness analysis from the perspective of third party payers. The following costs were included in the analysis: daily treatment costs of pravastatin, non-fatal myocardial infarction, coronary bypass operations and stroke. Life years gained were obtained by applying the declining exponential approximation of life expectancy. All calculations were standardized to 1,000 treated patients. The net costs of treating 1,000 patients (i.e. drug costs minus the costs of sequelae and interventions) are DM 8.4 Mio. In addition, a total of 405 life years may be saved through treatment. The corresponding cost-effectiveness of pravastatin treatment is DM 20,674,-(DM 17,314,-, discounted by 3% p.a.).",2000.0,0,0 482,10995396,Need for large scale randomised evidence about lowering LDL cholesterol in people with diabetes mellitus: MRC/BHF heart protection study and other major trials.,J Armitage; R Collins,,2000.0,0,0 483,10995974,Serum lipids and hemostasis in kidney allograft recipients treated with fluvastatin (Lescol) for 3 months.,J S Malyszko; J Malyszko; M Mysliwiec,,2000.0,0,0 484,10996333,Cardiovascular risk changes after lipid lowering medications: are they predictable?,C R Sirtori; L Calabresi; R Marchioli; H B Rubins,"Changes in cardiovascular risk after lipid lowering medications are generally expressed as relative risk reduction (RRR). Comparison of the eight major studies published in this last decade indicates that the RRRs ranged from a minimum (19%) for the LRC Study with cholestyramine, to maximal values of 34-37% for studies such as the HHS, 4S and AFCAPS/TexCAPS. These RRRs were barely related to the drugs' effects on major lipid parameters, e.g. LDL cholesterol. Instead, by using the absolute risk reduction (ARRs), easily calculated by subtracting the percentage end points for the drug treated from these values of the placebo group in all studies, a wide range of values was found, also adding to the series a non pharmacological study such as the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial. Calculated ARRs were directly correlated to the baseline cardiovascular (CV) risk in all studies, thus allowing an easy prediction of a drug's effect in the selected population. Drugs with different mechanisms (statins, fibrates and resins) all fitted into this correlation nomogram. These findings clearly indicate that the CV effects of lipid changes, such as LDL cholesterol and triglyceride reduction or HDL rises, are in the same direction, and can be well predicted. The similar, almost identical behavior of drugs affecting LDL cholesterolemia to a different degree or not at all, indicates that novel approaches should be sought to improve risk reduction and that individual therapy should be ideally pursued, rather than a 'one drug' approach.",2001.0,0,0 485,10996358,Inhibitors of HMG-CoA reductase sensitize human smooth muscle cells to Fas-ligand and cytokine-induced cell death.,A C Knapp; J Huang; G Starling; P A Kiener,"Hydroxymethylglutaryl CoA (HMG CoA) reductase inhibitors, or statins, have been shown to reduce atherosclerotic cardiovascular morbidity and mortality. Atherosclerotic plaque lesions can be chronically inflamed and vulnerable to rupture or stable and less rupture-prone. Human smooth muscle cells (SMC) are critically important in maintaining the stability of atherosclerotic plaques. This stability may be greatly influenced by pro-inflammatory mediators such as IFN-gamma, TNF-alpha, and Il-1beta and Fas ligand (FasL) that are present in human atheroma. The purpose of the present study was to examine the effect of the statins on apoptosis of SMC. We have found that SMC are normally resistant to Fas or cytokine-induced apoptosis, but can be sensitized to these agents with pharmacological concentrations of some statins. Simvastatin and lovastatin strongly sensitized the cells to apoptotic agents while atorvastatin was less effective. In contrast to the lipophilic statins, the hydrophilic statin pravastatin did not induce this sensitization of SMC to apoptosis. Treatment of SMC with either mevalonate, the product of the HMG-CoA reductase, or geranylgeranylpyrophosphate, a down stream intermediate, prevented lipophilic statin-induced sensitization to apoptosis. These results suggest that prenylation of one or more proteins is critically involved in regulating the sensitivity of SMC to apoptotic stimuli. Our data support the emerging evidence that through this pathway the various statins may have effects which are beyond a simple lowering of the levels of circulating cholesterol.",2001.0,0,0 486,10998478,"Efficacy and safety of atorvastatin in hyperlipidemic, type 2 diabetic patients. A 34-week, multicenter, open-label study.",C A Aguilar-Salinas; F J Gómez-Pérez; C Posadas-Romero; C Vázquez-Chávez; E Meaney; A Gulías-Herrero; L E Guillén; A Alvarado Vega; E Mendoza Pérez; L Eduardo Romero-Nava; R Angélica Gómez-Díaz; S Salinas-Orozco; R Moguel; G Novoa,"Hyperlipidemia is common in type 2 diabetic patients and is an independent risk factor for cardiovascular disease. The aim of this trial was to evaluate the efficacy and safety of once-daily atorvastatin 10-80 mg for the treatment of hyperlipidemia in type 2 diabetics with plasma low-density lipoprotein cholesterol (LDL-C) levels exceeding 3.4 mmol/l (130 mg/dl). One hundred and two patients met the study criteria and received 10 mg/day atorvastatin. Patients who reached the target LDL-C level of 6.4 mmol/l) obtained the greatest cholesterol reduction (mean +/- SEM, 7.13 +/- 0.14 mmol/l vs. 5.76+/-0.31 mmol/l, P<0.05). A cholesterol-lowering effect of GH therapy was evident in patients who had elevated pre-GH total cholesterol levels even if they were already receiving and continuing lipid lowering medication (mean +/- SEM, 5.62+/-0.22 vs. 5.03+/-0.285, P<0.05). A modest increment in high density lipoprotein (HDL)-cholesterol was evident at 18 months but there was no significant change in triglycerides at any time point. Fasting plasma glucose increased significantly at 6 months but remained within the reference range. Glycated haemoglobin increased significantly at 6 months and was maintained throughout the study; one patient developed frank diabetes mellitus while receiving treatment. There was a weak but significant correlation between the increment in glycated haemoglobin and pretreatment BMI (r = + 0.215, P<0.05). The effect of GH on lowering total and low density lipoprotein-cholesterol is more prominent in patients with higher pretreatment cholesterol levels and is evident even in patients receiving other lipid-lowering medication. A modest increment in mean fasting glucose (within the reference range) and mean glycated haemoglobin persisted throughout the study. One patient developed diabetes mellitus. A GH replacement regimen using low dose and careful titration to avoid elevated IGF-I levels and adverse effects is associated with sustained beneficial effects on circulating lipids.",2001.0,0,0 503,11015169,"""The lower the better"" in hypercholesterolemia therapy: a reliable clinical guideline?.",T A Jacobson,"Since the publication of the second set of guidelines by the National Cholesterol Education Program, a solid body of data from landmark clinical studies has demonstrated that reduction in low-density lipoprotein (LDL) cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (""statin"") therapy sharply diminishes the risk for coronary artery disease. These trials include the Scandinavian Simvastatin Survival Study, the West of Scotland Coronary Prevention Study, the Air Force/Texas Coronary Atherosclerosis Prevention Study, the Cholesterol and Recurrent Events investigation, and the Long-Term Intervention with Pravastatin in Ischaemic Disease trial. Coronary event rates and, in some cases, all-cause mortality decreased significantly after about 5 years of statin therapy in patients at risk for and those who had coronary artery disease at baseline. In contrast, recent subgroup analyses of these pivotal studies have in the aggregate challenged the premise that lower LDL cholesterol levels necessarily lead to further declines in risk for coronary artery disease, particularly among the patients most likely to be seen by the clinician: those with moderately elevated or normal cholesterol profiles. Indeed, when LDL cholesterol levels are in this range, further lowering with statin therapy elicits diminishing returns in terms of coronary event rates. These findings are readily accommodated by the curvilinear, or log-linear, model between serum cholesterol level and risk for coronary artery disease, which is predicated on data from large epidemiologic studies. In light of the current climate involving competing health care costs, the pursuit of progressively diminishing returns in terms of reductions in coronary artery disease risk through more aggressive lowering of LDL cholesterol levels appears to be unwarranted. Until data are published from ongoing randomized, clinical trials that can more effectively resolve the clinical utility of aggressive lipid-lowering strategies to improve coronary event rates, a prudent, evidence-based strategy seems warranted.",2000.0,0,0 504,11016019,Comparison of the efficacy and tolerability of simvastatin and atorvastatin in the treatment of hypercholesterolemia.,C S Recto; S Acosta; A Dobs,"Simvastatin and atorvastatin are effective statins for treating hypercholesterolemia. The study was undertaken to compare the efficacy and tolerability of simvastatin 20 and 40 mg/day and atorvastatin 10 and 20 mg/day. In this multinational, open-label, crossover study, 258 patients with primary hypercholesterolemia were randomized after 4 weeks of diet plus placebo to once-daily administration of a starting dose sequence of simvastatin (20 mg) or atorvastatin (10 mg), or a higher dose sequence of simvastatin (40 mg) or atorvastatin (20 mg) for 6 weeks. Patients were then switched after a 1-week washout to the corresponding starting or higher dose of the alternate drug for a second 6-week period. The primary endpoint was the mean percent change from baseline to Week 6 in low-density lipoprotein (LDL) cholesterol; percent changes from baseline in total cholesterol, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B were also compared. Safety was assessed through adverse experiences and laboratory measurements. Both statins produced statistically significant improvements in all measured plasma lipids and lipoproteins. The main treatment comparison showed no statistically significant difference in changes in LDL cholesterol and triglycerides, whereby the overall effects were comparable when doses of 20 mg and 40 mg of simvastatin were compared with atorvastatin 10 mg and 20 mg. The mean percent reductions for LDL cholesterol from baseline to Week 6 ranged from 35-42% for the entire study cohort. An LDL cholesterol level < or = 130 mg/dl (3.4 mmol/l) was achieved in approximately 70% of patients treated with both drugs in this study. Simvastatin and atorvastatin were well tolerated at the doses studied. In patients with hypercholesterolemia, the most commonly used doses of simvastatin and atorvastatin produced similar changes in LDL cholesterol and achieved an LDL cholesterol level < or = 130 mg/dl (3.4 mmol/l) in a similar number of patients. Both statins were well tolerated.",2001.0,1,1 505,11018193,Pravastatin reduces restenosis two years after percutaneous transluminal coronary angioplasty (REGRESS trial).,H J Mulder; E T Bal; J W Jukema; A H Zwinderman; M J Schalij; A J van Boven; A V Bruschke,"The Regression Growth Evaluation Statin Study (REGRESS) is a placebo-controlled multicenter study designed to assess the effect of 2-year treatment with pravastatin on the progression and regression of angiographically documented coronary artery disease. One of the secondary end points was the occurrence of 2-year restenosis in the percutaneous transluminal coronary angioplasty (PTCA) block. We randomly assigned eligible patients to receive pravastatin 40 mg once daily or placebo. The end point was the percent diameter stenosis of the target lesion at 24 months, as assessed by (semi)quantitative coronary angiography. Two hundred twenty-one patients underwent scheduled PTCA, which was considered successful in 201 patients. One hundred seventy-eight patients underwent angiographic restudy (89%). The patients in the pravastatin group (n = 109) and placebo group (n = 112) were similar at baseline. Percent diameter stenosis before angioplasty was 78 +/- 14% (mean +/- SD) in the pravastatin group and 80 +/- 14% in the placebo group (p = 0.46). At follow-up, the percent diameter stenosis was 32 +/- 23% in the pravastatin group and 45 +/- 29% in the placebo group (p < 0.001). Clinical restenosis was significantly lower in the pravastatin group (7%) compared with the placebo group (29%) (p < 0.001). Risk reduction for all events was 58%. We conclude that treatment with pravastatin reduces 2-year clinical and angiographic restenosis.",2001.0,0,0 506,11018196,Efficacy and safety of an extended-release formulation of fluvastatin for once-daily treatment of primary hypercholesterolemia.,C M Ballantyne; J McKenney; B S Trippe,"An extended-release (ER) formulation of fluvastatin 80 mg has been developed for once-daily treatment of primary hypercholesterolemia in patients who require fluvastatin dosages of > 40 mg/day. The study aimed to determine the efficacy and safety of the new formulation and to assess the dose response over the range of 40 to 160 mg/day. After a 4-week placebo/dietary run-in period, 123 patients with primary hypercholesterolemia (Fredrickson type IIa/IIb) were randomized to receive fluvastatin 40, 80, or 160 mg/day for 6 weeks. The 40 mg/day dosage was administered as the marketed immediate-release (IR) capsule and the 80 mg/day dosage as 1 80-mg ER tablet. Patients receiving 160 mg/day were administered 80 mg/day (1 ER tablet) for the first 2 weeks, followed by 160 mg/day (2 ER tablets) for the remainder of the study. All doses were administered once daily at bedtime. The results showed a linear dose-response relation. Doubling the fluvastatin dosage resulted in a 6% greater mean percent reduction in low-density lipoprotein cholesterol (40 mg IR -29%; 80 mg ER -35%; 160 mg ER -41%). In the 160-mg ER group, 62% of patients achieved > or = 40% reductions in low-density lipoprotein cholesterol compared with 32% and 10% of patients in the 80-mg ER and 40-mg IR groups, respectively. Dose ordering of the response was also observed for the other lipid parameters. Fluvastatin ER was well tolerated. Thus, the new ER formulation of fluvastatin was effective and well tolerated in the once-daily treatment of primary hypercholesterolemia.",2001.0,0,1 507,11018199,Effect of simvastatin on restenosis after percutaneous transluminal angioplasty of femoropopliteal arterial obstruction.,T Hagenaars; E J Gussenhoven; M R van Sambeek; J W Jukema; S E Kranendonk; N Bom,"This retrospective observational intravascular ultrasound study evaluated whether simvastatin therapy limits lumen area reduction 1-year after percutaneous transluminal angioplasty (PTA) by reducing reactive plaque growth, reducing reactive vasoconstriction, or both. This study showed that plaque growth is a general response 1 year after PTA regardless of the use of simvastatin; simvastatin has the potential to induce positive vascular remodeling, thereby reducing the occurrence of restenosis.",2001.0,0,0 508,11023927,Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT).,K K Teo; J R Burton; C E Buller; S Plante; D Catellier; W Tymchak; V Dzavik; D Taylor; S Yokoyama; T J Montague,"This long-term, multicenter, randomized, double-blind, placebo-controlled, 2 x 2 factorial, angiographic trial evaluated the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis in normocholesterolemic patients. There were a total of 460 patients: 230 received simvastatin and 230, a simvastatin placebo, and 229 received enalapril and 231, an enalapril placebo (some subjects received both drugs and some received a double placebo). Mean baseline measurements were as follows: cholesterol level, 5.20 mmol/L; triglyceride level, 1.82 mmol/L; HDL, 0.99 mmol/L; and LDL, 3.36 mmol/L. Average follow-up was 47.8 months. Changes in quantitative coronary angiographic measures between simvastatin and placebo, respectively, were as follows: mean diameters, -0.07 versus -0.14 mm (P:=0.004); minimum diameters, -0.09 versus -0.16 mm (P:=0. 0001); and percent diameter stenosis, 1.67% versus 3.83% (P:=0.0003). These benefits were not observed in patients on enalapril when compared with placebo. No additional benefits were seen in the group receiving both drugs. Simvastatin patients had less need for percutaneous transluminal coronary angioplasty (8 versus 21 events; P:=0.020), and fewer enalapril patients experienced the combined end point of death/myocardial infarction/stroke (16 versus 30; P:=0.043) than their respective placebo patients. This trial extends the observation of the beneficial angiographic effects of lipid-lowering therapy to normocholesterolemic patients. The implications of the neutral angiographic effects of angiotensin-converting enzyme inhibition are uncertain, but they deserve further investigation in light of the positive clinical benefits suggested here and seen elsewhere.",2001.0,1,1 509,11028504,The aggressive low density lipoprotein lowering controversy.,J S Forrester; C N Bairey-Merz; S Kaul,"Recent clinical trials have provided unequivocal evidence of major cardiovascular benefits from low density lipoprotein (LDL) lowering with statins. However, the three critical unresolved questions about aggressive LDL lowering are the shape of the curve relating cardiac events to LDL, the best surrogate measurement for assessing therapeutic efficacy and the best target for LDL therapy. The relation between cardiac events and LDL is curvilinear, both epidemiologically and during therapy. The benefit of lipid lowering diminishes progressively and becomes difficult to detect at lower LDL levels without a very large sample size. Assessment of the benefits of lipid lowering is further confounded by differences in the level of pretreatment LDL and by the non-LDL lowering effects of statins. Both epidemiologic studies and large randomized clinical trials have produced conflicting results concerning the best LDL target. Failure to reduce the event rate in patients with pretreatment LDL <125 mg (Cholesterol And Recurrent Events [CARE] trial) alerts us to the risk of extrapolating epidemiologic data to clinical practice, yet subset analysis of some clinical trials suggests the greatest benefit appears in those patients with the lowest on-treatment LDL levels (Scandinavian Simvastatin Survival Study [4S]). This controversy should be resolved in the next few years by several important on-going trials. In the face of seemingly contradictory data from current clinical trials, we can only speculate that very aggressive LDL lowering to <80 mg/dl could be accompanied by a modest therapeutic benefit beyond the current recommendations of the National Cholesterol Education Program. If any benefit is observed, it will have to be balanced against a small potential for increased adverse events.",2001.0,0,1 510,11029845,HMG-CoA reductase inhibitors: assessing differences in drug interactions and safety profiles.,S L Beaird,"To review the cytochrome P450 system and associated metabolic differences between the HMG-CoA reductase inhibitors. A MEDLINE search (1993-99) was conducted for English-language articles using key search terms including adverse drug reactions, cytochrome P450, drug metabolism, drug interactions, hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, myopathy, and rhabdomyolysis. Review articles, clinical trials, and case reports concerning HMG-CoA reductase inhibitor metabolism, drug interactions, and adverse drug reactions were evaluated. By the author. No software or assistants were used to extract information from the chosen studies. The cytochrome P450 enzymes, which can be divided into families, subfamilies, and isoenzymes, act as a major catalyst for drug oxidation in the liver. CYP3A4 is a major enzyme, accounting for about 60% of drug metabolic capacity in the liver and 70% of such function in the intestine. Lovastatin, simvastatin, and atorvastatin are substrates of CYP3A4, whereas fluvastatin is metabolized by CYP2C9. Pravastatin is not extensively metabolized by either of these isoenzymes; rather, it is transported into hepatocytes by a sodium-independent, carrier-mediated uptake system that normally transports bile acids. Compared with other statins, pravastatin thus has a reduced potential for drug interactions with other substrates, inhibitors, or inducers of the CYP3A4 and CYP2C9 systems. Pharmacists must understand the functions of these enzymes to identify potential drug interactions, especially in high-risk patient populations, and to make appropriate therapeutic recommendations that prevent or minimize adverse clinical outcomes.",2001.0,1,1 511,11030197,Treatment of hyperlipidemia.,Y Nakashima,"In the treatment of hyperlipidemia, when to begin and end therapy is important. In recent years, potent anti-hyperlipidemia drugs have been widely used, and the results of many intervention trials have shown that combinations of diet, exercise and drug therapies are effective for the primary and secondary prevention of coronary heart disease. The present paper summarizes these trials; introduces the therapy guidelines for adult hyperlipidemia established by Japan Atherosclerosis Society in 1997; and discusses the drugs for hyperlipidemia.",2001.0,0,0 512,11030791,Is there a connection between the concentration of cholesterol circulating in plasma and the rate of neuritic plaque formation in Alzheimer disease?,R W Haley; J M Dietschy,,2001.0,0,0 513,11030795,Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors.,B Wolozin; W Kellman; P Ruosseau; G G Celesia; G Siegel,"Increasing evidence suggests that cholesterol plays a role in the pathophysiology of Alzheimer disease (AD). For instance, an elevated serum cholesterol level has been shown to be a risk factor for AD. To determine whether patients taking 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which are a group of medicines that inhibit the synthesis of cholesterol, have a lower prevalence of probable AD. The experiment uses a cross-sectional analysis comparing the prevalence of probable AD in 3 groups of patients from hospital records: the entire population, patients receiving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (hereafter referred to as the statins), and patients receiving medications used to treat hypertension or cardiovascular disease. The subjects studied were those included in the computer databases of 3 different hospitals for the years October 1, 1996, through August 31, 1998. Diagnosis of probable AD. We find that the prevalence of probable AD in the cohort taking statins during the study interval is 60% to 73% (P < .001) lower than the total patient population or compared with patients taking other medications typically used in the treatment of hypertension or cardiovascular disease. There is a lower prevalence of diagnosed probable AD in patients taking 2 different 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors-lovastatin and pravastatin. While one cannot infer causative mechanisms based on these data, this study reveals an interesting association in the data, which warrants further study. Arch Neurol. 2000;57:1439-1443",2001.0,0,0 514,11031077,,,,,0,0 515,11031398,Use of simvastatin treatment in patients with combined hyperlipidemia in clinical practice. For the Simvastatin Combined Hyperlipidemia Registry Group.,R M Vicari; G J Wan; A M Aura; C M Alexander; L E Markson; S M Teutsch,"To describe and understand current care of simvastatin-treated patients with combined hyperlipidemia in routine clinical practice. A 6-month prospective observational study. Demographics, simvastatin dosage, cardiac risk factors, and lipid profile were collected from August 1997 to December 1998 at 20 sites (230 patients) across the United States. Overall mean percentage of reduction in total cholesterol levels was 27% (P<.001), low-density lipoprotein cholesterol (LDL-C) was 35% (P<.001), and triglyceride values was 28% (P<.001). Among those patients with low baseline high-density lipoprotein cholesterol (HDL-C) values (<0.91 mmol/L [<35 mg/dL]) (N = 49), there was a 17% increase in HDL-C (P< or =.001); 35% of these patients achieved National Cholesterol Education Program HDL-C goal (ie, < or =0.91 mmol/L [> or =35 mg/dL]). Coronary heart disease (CHD) patients were given significantly higher initial doses (mean, 15.1 mg) compared with non-CHD patients (mean, 11.5 mg) (P< or =.001). Overall, 74% of patients achieved LDL-C goal (52% on starting dose, 22% after 1 titration). Among those patients who were not at goal and had a follow-up lipid profile result available, only 1 patient (2%) was at the maximum dose (80 mg); 69% were receiving 20 mg or less. Approximately 63% of patients with CHD, 80% of patients with 2 or more risk factors, and 91% of patients with fewer than 2 risk factors achieved LDL-C goal. Multiple factors contribute to LDL-C goal achievement in a usual care setting. A significant opportunity exists to increase the number of patients who achieve LDL-C goal by appropriate dose titration and/or give patients a higher initial dose of simvastatin.",2001.0,0,0 516,11034934,"VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial.",F M Sacks; P Alaupovic; L A Moye; T G Cole; B Sussex; M J Stampfer; M A Pfeffer; E Braunwald,"Plasma triglyceride concentration has been an inconsistent independent risk factor for coronary heart disease, perhaps because of the metabolic heterogeneity among VLDL particles, the main carriers of triglycerides in plasma. We conducted a prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin in 4159 patients with myocardial infarction and average LDL concentrations at baseline (115 to 174 mg/dL, mean 139 mg/dL). Baseline concentrations of VLDL-apolipoprotein (apo) B (the VLDL particle concentration), VLDL lipids, and apoCIII and apoE in VLDL+LDL and in HDL were compared in patients who had either a myocardial infarction or coronary death (cases, n=418) with those in patients who did not have a cardiovascular event (control subjects, n=370) in 5 years of follow-up. VLDL-cholesterol, VLDL-triglyceride, VLDL-apoB, apoCIII and apoE in VLDL+LDL and apoE in HDL were all interrelated, and each was a univariate predictor of subsequent coronary events. The significant independent predictors were VLDL-apoB (relative risk [RR] 3.2 for highest to lowest quintiles, P:=0.04), apoCIII in VLDL+LDL (RR 2.3, P:=0.04), and apoE in HDL (RR 1.8, P:=0.02). Plasma triglycerides, a univariate predictor of coronary events (RR 1.6, P:=0.03), was not related to coronary events (RR 1.3, P:=0.6) when apoCIII in VLDL+LDL was included in the model, whereas apoCIII remained significant. Adjustment for LDL- and HDL-cholesterol did not affect these results. The plasma concentrations of VLDL particles and apoCIII in VLDL and LDL are more specific measures of coronary heart disease risk than plasma triglycerides perhaps because their known metabolic properties link them more closely to atherosclerosis.",2001.0,0,0 517,11034935,Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project.,F M Sacks; A M Tonkin; J Shepherd; E Braunwald; S Cobbe; C M Hawkins; A Keech; C Packard; J Simes; R Byington; C D Furberg,"Previous trials have had insufficient numbers of coronary events to address definitively the effect of lipid-modifying therapy on coronary heart disease in subgroups of patients with varying baseline characteristics. The data from 3 large randomized trials with pravastatin 40 mg were pooled and analyzed with the use of a prospectively defined protocol. Included were 19 768 patients, 102 559 person-years of follow-up, 2194 primary end points (coronary death or nonfatal myocardial infarction), and 3717 expanded end points (primary end point, CABG, or PTCA). Pravastatin significantly reduced relative risk in younger (<65 years) and older (>/=65 years) patients, men and women, smokers and nonsmokers, and patients with or without diabetes or hypertension. The relative effect was smaller, but absolute risk reduction was similar in patients with hypertension compared with those without hypertension. Relative risk reduction was significant in predefined categories of baseline lipid concentrations. Tests for interaction were not significant between relative risk reduction and baseline total cholesterol (5% to 95% range 177 to 297 mg/dL, 4.6 to 7.7 mmol/L), HDL cholesterol (27 to 58 mg/dL, 0.7 to 1.5 mmol/L), and triglyceride (74 to 302 mg/dL, 0.8 to 3.4 mmol/L) concentrations, analyzed as continuous variables. However, for LDL cholesterol, the probability values for interaction were 0.068 for the prespecified primary end point and 0.019 for the expanded end point. Relative risk reduction was similar throughout most of the baseline LDL cholesterol range (125 to 212 mg/dL, 3.2 to 5.5 mmol/L) with the possible exception of the lowest quintile of CARE/LIPID (<125 mg/dL) (relative risk reduction 5%, 95% CI 19% to -12%). Pravastatin treatment is effective in reducing coronary heart disease events in patients with high or low risk factor status and across a wide range of pretreatment lipid concentrations.",2001.0,0,0 518,11036120,Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group.,C J Packard; D S O'Reilly; M J Caslake; A D McMahon; I Ford; J Cooney; C H Macphee; K E Suckling; M Krishna; F E Wilkinson; A Rumley; G D Lowe,"Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events. A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-associated phospholipase A2, C-reactive protein, and fibrinogen levels, and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by dividing the range of values according to quintiles. Levels of C-reactive protein, the white-cell count, and fibrinogen levels were strong predictors of the risk of coronary events; the risk in the highest quintile of the study cohort for each variable was approximately twice that in the lowest quintile. However, the association of these variables with risk was markedly attenuated when age, systolic blood pressure, and lipoprotein levels were included in multivariate models. Levels of lipoprotein-associated phospholipase A2 (platelet-activating factor acetylhydrolase), the expression of which is regulated by mediators of inflammation, had a strong, positive association with risk that was not confounded by other factors. It was associated with almost a doubling of the risk in the highest quintile as compared with the lowest quintile. Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of lipoprotein-associated phospholipase A2 appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk.",2000.0,0,0 519,11039939,Statins: underused by those who would benefit.,S B Hulley; D Grady; W S Browner,,2001.0,0,0 520,11039962,Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials.,M Pignone; C Phillips; C Mulrow,"To summarise the effect of primary prevention with lipid lowering drugs on coronary heart disease events, coronary heart disease mortality, and all cause mortality. Meta-analysis. Systematic search of the Medline database from January 1994 to June 1999 for English language studies examining drug treatment for lipid disorders (use of the MeSH terms ""hyperlipidemia"" and ""anticholesteremic agents,"" keyword searches for individual drug names, and a search strategy for identifying randomised trials to capture relevant articles); identification of older studies through systematic reviews and hand search of bibliographies. All randomised trials of at least one year's duration that examined drug treatment for patients with no known coronary heart disease, cerebrovascular disease, or peripheral vascular disease and that measured clinical end points, including all cause mortality, coronary heart disease mortality, and non-fatal myocardial infarctions. Review of the articles and extracted relevant data by two authors separately, with disagreements resolved by consensus. Four studies met eligibility criteria. Drug treatment reduced the odds of a coronary heart disease event by 30% (summary odds ratio 0.70, 95% confidence interval 0.62 to 0.79) but not the odds of all cause mortality (0.94, 0.81 to 1.09). When statin drugs were considered alone, no substantial differences in results were found. Treatment with lipid lowering drugs lasting five to seven years reduces coronary heart disease events but not all cause mortality in people with no known cardiovascular disease.",2001.0,0,0 521,11041122,Are the WOSCOPS clinical and economic findings generalizable to other populations? A case study for Belgium. The WOSCOPS Economic Analysis Group. West of Scotland Coronary Prevention Study.,J J Caro; K F Huybrechts; G De Backer; D De Bacquer; M C Closon,"As the West of Scotland Coronary Prevention Study (WOSCOPS) was conducted in Scotland, a country well-known for its high cardiovascular risk, the generalizability of its findings on pravastatin's clinical and economic effects has been questioned. This study examines the legitimacy of this concern, using Belgium as a case study. Local information on the prevalence and clustering of risk factors in individual patients was used in a risk equation to estimate the reference risk in Belgium. In contrast to prevailing beliefs, this risk was shown to coincide with the trial population's risk. As the relative risk reduction documented in a trial should apply across populations, the health benefits observed in WOSCOPS can clearly be extrapolated. This information in combination with local costs was then used to assess the economic efficiency of primary prevention with pravastatin in Belgium by means of a previously developed model. In parallel with the original estimates for the United Kingdom, the cost-effectiveness ratios remain well within the range of what is considered strong to moderate evidence for adoption and appropriate utilization, over a wide range of input values. This study demonstrates that the clinical and economic findings from WOSCOPS can indeed be generalized to other populations.",2001.0,0,1 522,11044760,Efficacy and cost of HMG-CoA reductase inhibitors in the treatment of patients with primary hyperlipidemia.,S Perreault; C Levinton; J Le Lorier,"Screening for hyperlipidemia is a substantial cost burden, as is its treatment. The choice of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and the dose level may have significant implications for both efficient and cost effective therapy. To compare the efficiency and cost of statins. A meta-analysis was conducted of randomized, controlled trials of monotherapy with fixed doses of statins published in the literature until June 1998. Two authors independently extracted data from 49 trials comprising 14,130 patients. The percentage reduction (95% confidence intervals) of low density lipoprotein (LDL) cholesterol levels was calculated using a random-effects model. Cost efficiency was defined as the percentage decline of LDL cholesterol per dollar of drug cost. The population evaluated had a mean baseline LDL cholesterol concentration of 5.31 mmol/L, a mean age of 53.5 years and a mean 59% proportion of males. In reducing LDL cholesterol concentrations to less than 25% of the baseline concentration, a significantly higher cost efficiency was achieved with simvastatin 2.5 mg (-53.3%/dollar). By targeting a reduction between 25% and 29%, significantly higher cost efficiencies were found with simvastatin 5 mg (-28.9%/dollar), cerivastatin 0.2 mg (-23.8%/dollar) and fluvastatin 40 mg (-23.3%/dollar). For reductions in LDL cholesterol concentrations of 30% to 34%, statistically higher cost efficiencies were achieved with simvastatin 20 mg (-15.0%/dollar) and pravastatin 40 mg (-14. 4%/dollar). Finally, atorvastatin 10 mg yielded a value of -22. 9%/dollar for a 36% reduction in LDL cholesterol concentration. At current prices of the various doses of statins, the cost efficiency of standard and more aggressive therapies varies substantially. In the context of health care budgets, targeting at-risk patients and using statins judiciously should facilitate the efforts of clinicians and patients to reduce lipid profiles optimally and decrease the cost burden.",2001.0,0,0 523,11044791,Usefulness of HMG-CoA reductase inhibitor in Japanese hyperlipidemic women within seven years of menopause.,H Ohta; A Masuda; T Fuyuki; I Sugimoto; Y Suda; K Makita; K Takamatsu; F Horiguchi; S Nozawa,"To assess the therapeutic value of treatment with an HMG-CoA reductase inhibitor in women with hypoestrogenic hyperlipidemia caused by menopause. Fifty-six women with total cholesterol (TC) levels of 220 mg/dl or more who were within 7 years of menopause were randomly assigned to receive an HMG-CoA reductase inhibitor (pravastatin 10 mg/day; treated group, 26 patients) or no medical treatment (nontreated group, 30 patients) in this 6-month nonblinded prospective trial. In the treated group, the mean (SD) TC levels decreased significantly from 254.5+/-22.3 mg/dl at baseline to 204.7+/-22.2 mg/dl (19.6%), and the mean low-density lipoprotein cholesterol (LDL-C) level decreased significantly from 146.7+/-30.5 to 104.3+/-22.5 mg/dl (28.9%); the mean arteriosclerotic index decreased significantly from 2.98 to 2.08 (30.2%). There were no significant changes in either triglyceride levels or high-density lipoprotein cholesterol (HDL-C) levels. In the nontreated group, there were no significant changes in the TC, HDL-C, LDL-C, or triglyceride levels; there was also no change in the arteriosclerotic index. After 6 months, the TC level, LDL-C level, and arteriosclerotic index were significantly lower in the treated group compared with the nontreated group (p<0.01). The results indicate that the HMG-CoA reductase inhibitor lowered TC and LDL-C levels and was useful in the treatment of hypoestrogenic hyperlipidemia for periods of at least 6 months.",2001.0,0,0 524,11050781,"Statins and the prevention of coronary heart disease: striking a balance that is desirable, affordable, and achievable.",L D Ritchie,,2001.0,0,0 525,11050782,The primary prevention of coronary heart disease with statins: practice headache or public health?,P H Evans,,2001.0,0,0 526,11053704,Evidence that triglycerides are an independent coronary heart disease risk factor.,P Cullen,"In the past, the relation between hypertriglyceridemia and coronary heart disease (CHD) has been uncertain. However, a recent multivariate analysis of 8-year follow-up data from the large-scale Prospective Cardiovascular Münster study found hypertriglyceridemia to be an independent risk factor for major coronary events after controlling for low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. Hypertriglyceridemia combined with elevated LDL cholesterol and high LDL:HDL cholesterol ratio (>5) increased the CHD event risk by approximately sixfold. Similarly, a large meta-analysis of 17 prospective trials reported hypertriglyceridemia to be an independent risk factor for cardiovascular disease. In this study, an 88 mg/dl (1.0 mmol/L) increase in plasma triglyceride levels significantly increased the relative risk of cardiovascular disease by approximately 30% in men and 75% in women; the corresponding rates were somewhat lower (14% and 37%) but still statistically significant after adjustment for HDL cholesterol level. These data and observations from patients in the Helsinki Heart Study and the Stockholm Ischemic Heart study, that the greatest coronary benefit during lipid-lowering drug therapy occurred among hypertriglyceridemic patients, argue strongly for an independent role for hypertriglyceridemia in CHD risk. In the recent Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial, the use of gemfibrozil to raise HDL cholesterol levels and lower levels of triglycerides without lowering LDL cholesterol levels reduced coronary events in men with established CHD, whereas preliminary results from the Bezafibrate Infarction Prevention Trial indicate a reduction in coronary end points in patients with elevated baseline triglyceride levels. To achieve the greatest possible reduction in CHD risk, antihyperlipidemic treatment strategies should also be aimed at reducing elevated triglycerides.",2001.0,0,0 527,11054511,The influence of treatment of hypercholesterolemic patients with simvastatin on plasma chemotactic activity and adherence of neutrophils.,E Deskur-Smielecka; A Wykretowicz; A Banaszak; A Szczepanik; J Furmaniuk; H Wysocki,"there is some evidence to indicate that statins may affect the function of immune and inflammatory cells. This study investigates the influence of short term treatment with simvastatin on plasma chemotactic activity and adherence of polymorphonuclear neutrophils in hypercholesterolemic patients. 20 hypercholesterolemic patients (250-400 mg/dl) were given simvastatin (20 mg daily for 12 weeks). Peripheral blood samples were taken before and after 4 and 12 weeks of the therapy. The percentage of neutrophils adhering to plastic surface coated with albumin was significantly higher when cells were incubated with plasma obtained after 12 weeks of treatment with simvastatin in comparison with plasma collected before the therapy (unstimulated neutrophils: 5.945+/-0.475% vs. 8.155+/-0.96%, P=0.0477, stimulated neutrophils: 39.09+/-4.540% vs. 29.18+/-3.702%, P=0.032). There was a significant negative correlation between adherence of stimulated neutrophils and total cholesterol levels ((r)=-0.2796, 95% CI -0. 4999 to -0.02526, r(2)=0.07817, P=0.032). Migration of neutrophils towards plasma obtained after 12 weeks of treatment with simvastatin was significantly higher than towards plasma collected before the therapy (7.038+/-1.127 vs. 4.505+/-0 618 P=0.0475). treatment of hypercholesterolemic patients with simvastatin increases the chemotactic activity of plasma and augments the adherence of human neutrophils.",2001.0,0,0 528,11054628,Effective and safe modification of multiple atherosclerotic risk factors in patients with peripheral arterial disease.,R Garg; M B Elam; J R Crouse; K B Davis; J W Kennedy; D Egan; J A Herd; D B Hunninghake; W C Johnson; J B Kostis; D S Sheps; W B Applegate,"Patients with peripheral arterial disease (PAD) are at an increased risk of cardiovascular mortality and morbidity and thus are an excellent group in whom to evaluate the feasibility and the effect of an aggressive multifactorial intervention on atherosclerotic vascular disease risk factors. The Arterial Disease Multiple Intervention Trial (ADMIT) was designed to determine the efficacy, safety, and compliance of an multifactorial therapy on selected atherosclerotic disease risk factors in patients with PAD. By a 2 x 2 x 2 factorial design, eligible participants (N = 468) were randomly assigned to low-dose warfarin, antioxidant vitamins, and niacin or its corresponding placebo, and followed up for 1 year. All participants were encouraged to use aspirin. Pravastatin was added to the drug regimen for those who needed to reduce LDL cholesterol to recommended levels. Niacin increased HDL cholesterol levels by 30%, with the majority of effect achieved at a dosage of 500 mg twice daily. Warfarin had an anticoagulant effect. The antioxidant vitamins resulted in a significant increase in vitamin E, C, and beta-carotene plasma levels. Overall, compliance was high and few adverse effects were reported. ADMIT demonstrates that it is both feasible and safe to modify multiple atherosclerotic disease risk factors effectively with intensive combination therapy in patients with PAD.",2001.0,0,0 529,11056097,Peripheral arterial disease in randomized trial of estrogen with progestin in women with coronary heart disease: the Heart and Estrogen/Progestin Replacement Study.,J Hsia; J A Simon; F Lin; W B Applegate; M T Vogt; D Hunninghake; M Carr,"Postmenopausal estrogen use has been associated with reduced carotid atherosclerosis in observational studies, but this relationship has not been confirmed in a clinical trial. The impact of estrogen on atherosclerotic disease in other peripheral arteries is unknown. Postmenopausal women with coronary heart disease (CHD) and an intact uterus (n=2763) were randomly assigned to conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) daily or to placebo in a secondary CHD prevention trial. This analysis focuses on incident peripheral arterial procedures and deaths in the 2 treatment groups; peripheral vascular disease was a predefined secondary outcome. During a mean of 4.1 years of follow-up, 311 peripheral arterial events were reported in 213 women, an annual incidence of 2.9%. The number of women who had peripheral arterial events was 99 among those assigned to active estrogen/progestin and 114 among those assigned to placebo, a nonsignificant difference (relative hazard 0. 87, 95% CI 0.66 to 1.14). In the placebo group, hypertension and diabetes mellitus were independently associated with higher rates of peripheral arterial events, and plasma HDL cholesterol and body mass index were associated with lower rates of peripheral arterial events. In the estrogen/progestin group, current smoking and diabetes were independent predictors of peripheral arterial events. Incident peripheral arterial disease was not a significant predictor of coronary, cardiovascular, or total mortality. Treatment with oral conjugated estrogen plus medroxyprogesterone acetate was not associated with a significant reduction in incident peripheral arterial events in postmenopausal women with preexisting CHD.",2001.0,0,0 530,11058714,Statins and cardiovascular diseases: the multiple effects of lipid-lowering therapy by statins.,U Rauch; J I Osende; J H Chesebro; V Fuster; D A Vorchheimer; K Harris; P Harris; D A Sandler; J T Fallon; S Jayaraman; J J Badimon,"Cholesterol lowering involving different therapies improves the clinical outcome of patients. To define the underlying pathomechanism, we studied whether treatment with statins was associated with changes in blood thrombogenicity, endothelial dysfunction and soluble adhesion molecule levels. Fifty hypercholesterolemic patients were treated with pravastatin (40 mg/day, n=24) or simvastatin (20 mg/day, n=26). Lipid profile and blood thrombogenicity were assessed in all patients before and after 3 months of cholesterol reducing therapy. Blood thrombogenicity was assessed as thrombus formation, perfusing non-anticoagulated blood directly from the patients' vein through the Badimon perfusion chamber (shear rate 1690/s). Endothelial-dependent vasomotor response was tested by laser-Doppler flowmeter. Soluble adhesion molecule level were measured by ELISA. Total and LDL cholesterol were reduced in the two treatment groups by statin therapy. Statin therapy was associated with a significant reduction in blood thrombogenicity and endothelium-dependent vasoresponse. No differences were observed between simvastatin or pravastatin treatment. Lipid lowering by statins had no effect on plasma levels of fibrinogen, sL-selectin, sP-selectin and sICAM-1 antigen. Cholesterol lowering by both statins reduced the increased blood reactivity and endothelial dysfunction present under hypercholesterolemia. The multiple effects of lipid lowering therapy by statins may explain the benefits observed in recent epidemiological trials.",2001.0,0,0 531,11060668,Cerivastatin: the low-dose HMG-COA reductase inhibitor.,M J Tikkanen,,2001.0,0,0 532,11060717,Pharmacology and clinical experience with repaglinide.,M Massi-Benedetti; P Damsbo,"Repaglinide (NovoNorm((R))) is a novel oral antidiabetic agent, the first of a new class of insulin secretagogues known as the prandial glucose regulators to be approved for use in patients with Type 2 diabetes. Prandial glucose regulation is aimed at restoring the first-phase insulin response that follows consumption of a meal, which is missing in patients with Type 2 diabetes. After repaglinide administration, the resulting insulin profile reflects that of healthy individuals more closely, providing tighter glycaemic control and reducing the risk of hypoglycaemic events. Repaglinide is quickly absorbed and rapidly eliminated through biliary excretion, making it suitable for use in patients with renal impairment. It appears in the bloodstream within 15 to 30 min of dosing, stimulating short-term insulin release from the pancreatic beta-cells by binding to a unique site on the beta-cell membrane. Rapid elimination ensures that postprandial insulin levels quickly return to preprandial levels as the high prandial glucose level subsides. Repaglinide is given on a 'one meal, one tablet; no meal, no tablet' basis. It is particularly effective in patients who have not previously been treated with an oral antidiabetic agent, significantly reducing glycosylated haemoglobin (HbA(1c)) levels by 1.6%. It also offers increased mealtime flexibility and safety, compared with other oral antidiabetic agents. As a result of the short plasma half-life and lack of accumulation of repaglinide with repeated dosing, the risk of between-meal and nocturnal hypoglycaemia is substantially reduced compared with other oral antidiabetic agents. Repaglinide acts synergistically with metformin, consistently improving glycaemic control in patients who were insufficiently controlled by metformin alone. Results from recent studies have shown similar synergistic effects with neutral protamine Hagedorn (NPH)-insulin or troglitazone.",2001.0,0,0 533,11060827,NK-104: a novel synthetic HMG-CoA reductase inhibitor.,K Kajinami; H Mabuchi; Y Saito,"An elevated level of low-density lipoprotein (LDL)-cholesterol has been recognised as the most important risk factor for coronary artery disease (CAD). Development of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) ('statins'), a rate-limiting key enzyme of cholesterol synthesis pathway, has revolutionised the cholesterol-lowering therapy. In the last decade, effective primary and secondary preventive measures have been established in several statin trials to prevent future events of CAD by lowering LDL-cholesterol levels. These results supported the 'lower is better' hypothesis in the relationship between LDL-cholesterol levels and CAD. NK-104 (pitavastatin, previously named as itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) has recently been developed as a new chemically synthesised and powerful statin. On the basis of reported data, the potency of NK-104 is dose-dependent and appears to be equivalent to that of atorvastatin. This new statin is safe and well-tolerated in the treatment of patients with hypercholesterolaemia. The cytochrome P450 system only slightly modifies NK-104, which suggests the clinical advantage of this agent, because the prevalence of clinically significant interactions with a number of other commonly used drugs can be considered to be extremely low. NK-104 can provide a new and potentially superior therapeutic agent when compared with currently available other statins. Randomised controlled clinical trials to assess the long-term effects of this new statin on CAD would be required.",2001.0,0,0 534,11060828,"Colesevelam hydrochloride: a non-absorbed, polymeric cholesterol-lowering agent.",M H Davidson; M R Dicklin; K C Maki; R M Kleinpell,"Colesevelam hydrochloride (formerly known as Cholestagel((R)) and re-named WelCholtrade mark, GelTex Pharmaceuticals, Inc. and Sankyo Parke-Davis) is a new, polymeric, high potency, water-absorbing hydrogel. It has been shown to be a safe and effective cholesterol-lowering agent with a non-systemic mechanism of action, good tolerability and minimal side effects. To date, the lipid-lowering activity of colesevelam has been evaluated in approximately 1400 subjects. Colesevelam reduces low density lipoprotein (LDL)-cholesterol levels, in a dose-dependent manner, by as much as 20% (median) in patients with hypercholesterolaemia. Dosing regimen evaluations indicate that colesevelam is effective at both once per day and twice daily dosing and that concurrent administration of colesevelam with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), specifically lovastatin, does not alter the absorption of the statin. Combination therapy with HMG-CoA reductase inhibitors, including lovastatin, simvastatin and atorvastatin, produces an additional reduction (8 - 16%) in LDL-cholesterol levels above that seen with the statin alone. The overall incidence of adverse effects with colesevelam alone and in combination with statins is comparable with that seen with placebo. Colesevelam lacks the constipating effect seen with typical bile acid sequestrants, a trait that would be expected to improve compliance with lipid-lowering therapy. Colesevelam, recently approved by the US FDA, represents a valuable non-absorbed alternative in the armamentarium against hypercholesterolaemia, both for monotherapy and combination therapy, as an adjunct to diet and exercise.",2001.0,1,1 535,11061279,HMG-CoA reductase inhibitors (statins): a promising approach to stroke prevention.,M Di Napoli,,2001.0,0,0 536,11061362,Pharmacogenetics: a molecular sophistication or a new clinical tool for cardiologists?,C Dirckx; M B Donati; L Iacoviello,"The study of genetic risk factors for multifactorial diseases is attracting increasing interest. In particular interest has been focused on the interaction between genetic polymorphisms and environmental factors in determining the risk of disease. Among environmental factors therapeutic approaches should be considered. Therapeutic responses to a given drug, failure of drug efficacy, interindividual variability in side effects and toxicity of drugs could be at least partially accounted for by genetic polymorphisms. This paper summarizes the presently available applications of genetic concepts to some drugs commonly used in patients with cardiovascular disease. Statins and probucol fail to lower cholesterol levels in carriers of specific polymorphisms. The progression of cardiovascular disease is decreased by pravastatin only when certain polymorphisms are present. Induction problems and bleeding complications of warfarin occur in subgroups of populations carrying specific genetic variants of key enzymes in the drug metabolism. A new interpretation of the results of a thrombosis prevention trial will be given in the light of a genetic approach to pharmacology; indeed, prevention and treatment of thrombotic disease could be better focused on the basis of this knowledge. Future clinical trials and cost-effectiveness evaluation of drugs should be conducted taking these gene-drug interactions into account.",2001.0,0,0 537,11065222,Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women.,S Marchesi; G Lupattelli; D Siepi; G Schillaci; G Vaudo; A R Roscini; H Sinzinger; E Mannarino,"Endothelial dysfunction represents the earliest stage of atherosclerosis and is usually present in hypercholesterolemia. Treatment with statins has been shown to normalize endothelial function in middle-aged men with hypercholesterolemia. We evaluated the effect over time of atorvastatin on the endothelial reactivity in postmenopausal hypercholesterolemic women (mean age, 58 +/- 6 years), receiving atorvastatin, 10 mg daily (n = 20) or American Heart Association step 1 diet (n = 10) for 8 weeks. Lipid profile and brachial artery flow-mediated vasodilation (FMV) were determined at baseline and after 1, 2, 4, and 8 weeks. FMV increased progressively in subjects treated with atorvastatin, and the difference was significant (p < 0.05 vs. baseline) after the second week (baseline 3.8 +/- 3%; first week, 4.8 +/- 3%; second week, 9.2 +/- 3%; fourth week, 11.0 +/- 3%; eighth week, 11.7 +/- 3%). No significant changes were observed in subjects receiving diet (baseline, 3.1 +/- 4%; first week, 2.4 +/- 2%; second week, 2.9 +/- 2%; fourth week, 3.1 +/- 2%; eighth week, 3.3 +/- 2%; p = NS). In the atorvastatin group, low-density lipoprotein (LDL) cholesterol showed a significant decrease since the first week (baseline, 228 +/- 37 mg/dl; first week, 171 +/- 32; second week, 147 +/- 27; fourth week, 139 +/- 29; eighth week, 135 +/- 27; all p < 0.05). In the control group, LDL cholesterol showed a smaller but significant (p < 0.05) reduction after the second week (baseline, 226 +/- 17 mg/dl; first week, 225 +/- 16; second week, 220 +/- 17; fourth week, 203 +/- 27; eighth week, 198 +/- 27). In conclusion, hypercholesterolemic women treated with atorvastatin show a significant improvement in endothelial reactivity after as early as 2 weeks of therapy. The extent to which these beneficial effects are attributable to cholesterol reduction or to a direct effect of the drug remains to be established.",2001.0,0,0 538,11067569,Is hypercholesterolemia a risk factor and should it be treated in the elderly?,K M Hall; R V Luepker,"The 1993 National Cholesterol Education Program guidelines recommend cholesterol screening for elderly patients with and without known coronary heart disease. This review summarizes clinical trial evidence from the medical literature that addresses cholesterol treatment in the elderly. References were obtained from a MEDLINE search, bibliographies, metaanalyses, and review articles. Randomized, controlled clinical trials, including all lipid intervention trials with elderly participants or subgroup analyses of the elderly designed to measure major cardiovascular disease endpoints, were selected. A MEDLINE search of all clinical trials using key search terms yielded 1360 references. Journal titles and abstracts were reviewed for all references by one of us (K.M.H.). A full journal review was undertaken for 41 references to clinical trials. Five clinical trials fulfilled all criteria and represented unique data. A MEDLINE search (from 1966 to January 2000) and bibliography reviews yielded five important clinical trials with analyses of elderly participants. Data are presented in text form and a summary table. Clinical trial evidence supports treating hyperlipidemia in elderly persons for secondary prevention of coronary heart disease. Evidence from four secondary prevention trials demonstrated that major coronary heart disease risk decreased by 25% to 30% in elderly subjects treated for 5 years. Unanswered questions include cholesterol treatment for primary prevention in the elderly, gender effect, and benefit of treatment in persons older than 70.",2000.0,0,0 539,11068074,Update in internal medicine.,F López-Jiménez; M Brito; Y W Aude; P Scheinberg; M Kaplan; D A Dixon; N Schneiderman; J F Trejo; L H López-Salazar; E J Ramírez-Barba; R Kalil; C Ortiz; J Goyos; A Buenaño; S Kottiech; G A Lamas,"More than 500,000 new medical articles are published every year and available time to keep updated is scarcer every day. Nowadays, the task of selecting useful, consistent, and relevant information for clinicians is a priority in many major medical journals. This review has the aim of gathering the results of the most important findings in clinical medicine in the last few years. It is focused on results from randomized clinical trials and well-designed observational research. Findings were included preferentially if they showed solid results, and we avoided as much as possible including only preliminary data, or results that included only non-clinical outcomes. Some of the most relevant findings reported here include the significant benefit of statins in patients with coronary artery disease even with mean cholesterol level. It also provides a substantial review of the most significant trials assessing the effectiveness of IIb/IIIa receptor blockers. In gastroenterology many advances have been made in the H. pylori eradication, and the finding that the cure of H. pylori infection may be followed by gastroesophageal reflux disease. Some new antivirals have shown encouraging results in patients with chronic hepatitis. In the infectious disease arena, the late breaking trials in anti-retroviral disease are discussed, as well as the new trends regarding antibiotic resistance. This review approaches also the role of leukotriene modifiers in the treatment of asthma and discusses the benefit of using methylprednisolone in patients with adult respiratory distress syndrome, among many other advances in internal medicine.",2001.0,0,0 540,11070567,Transient ischaemic attacks: evaluation and management.,M J Hennessy; T C Britton,"Transient ischaemic attacks (TIAs) are temporary focal cerebral or retinal deficits that resolve within 24 hours. Attention should be given to the tempo and localisation of the clinical syndrome, as multiple and hemispheric TIAs are associated with the greatest incidence of early stroke. Evaluation of TIAs depends on the clinical symptoms, physical examination and investigations. Attention should be given to clinical evidence of generalised atherosclerotic disease, as death due to the complications of ischaemic heart disease is the commonest outcome in patients with TIA. Early attention should focus on risk factor modification, with emphasis on the treatment of hypertension and smoking cessation. Antiplatelet therapy should be instituted. Aspirin is the first-line treatment but, if not tolerated, clopidogrel is effective in preventing vascular complications. Anticoagulants are generally reserved for patients with atrial fibrillation and are associated with a significant reduction of stroke risk. The use of statins is becoming more widespread, with emerging evidence of their efficacy in reducing stroke risk. The risk of stroke is greatest in the weeks following TIA and patients should be referred for carotid duplex ultrasonography. Carotid endarterectomy for symptomatic internal carotid artery high grade stenosis virtually abolishes stroke risk in that vascular territory over subsequent years. TIAs should be regarded as an emergency requiring early diagnosis and prompt referral.",2001.0,0,0 541,11070569,The role of statins in acute coronary syndromes: managing the unmet need.,G Jackson,"Coronary heart disease is the major cause of death in the industrialised world. As the prevalence increases with advancing age, coronary heart disease will be a growing problem as the average age of the population increases. The cost of treatment following an acute coronary syndrome is considerable and there is a substantial risk of further episodes. However, there is much evidence that the disease is a dynamic and reversible process and further episodes are preventable. Numerous trials have shown the efficacy of statins in coronary heart disease. The most recent studies have shown efficacy in secondary prevention when statin therapy was started early (hours/days) after an acute episode. Although guidelines recommend that statin therapy should be initiated following an acute coronary syndrome, prescription rates seem to be static at around 40%. A number of measures need to be taken to improve the situation. Firstly, each hospital and coronary care unit should implement a clearly defined protocol delineating patient management following hospital admission. Provision of comprehensive discharge information should be a key feature of this communication. Secondly, regular audit of prescribing habits is essential to assess the situation. Finally, patient adherence to their regimen should be improved by collaborative involvement of doctor and patient in planning and implementing the treatment regimen.",2001.0,0,0 542,11073755,Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group.,M P Dubé; D Sprecher; W K Henry; J A Aberg; F J Torriani; H N Hodis; J Schouten; J Levin; G Myers; R Zackin; T Nevin; J S Currier; Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group,"Dyslipidemia is a prevalent condition that affects patients infected with human immunodeficiency virus (HIV) who are receiving antiretroviral therapy. These preliminary recommendations summarize the current understanding in this area and propose guidelines for management. Existing guidelines for the management of dyslipidemia in the general population formed the general basis for our recommendations. Data on the prevalence and treatment of dyslipidemia of HIV-infected patients, implications of treatment-related dyslipidemia in other chronically ill populations, and pharmacokinetic profiles for the available hypolipidemic agents in non-HIV populations were considered. Although the implications of dyslipidemia in this population are not fully known, the frequency, type, and magnitude of lipid alterations in HIV-infected people are expected to result in increased cardiovascular morbidity. We propose that these patients undergo evaluation and treatment on the basis of existing guidelines for dyslipidemia, with the caveat that avoidance of interactions with antiretroviral agents is paramount.",2001.0,0,0 543,11074745,Long-term assessment of psychological well-being in a randomized placebo-controlled trial of cholesterol reduction with pravastatin. The LIPID Study Investigators.,R A Stewart; K J Sharples; F M North; D B Menkes; J Baker; J Simes,"There is controversial evidence that a low serum cholesterol level is associated with an increased risk of depression, suicide, and violence. The aim of this study was to identify or exclude any small or infrequent adverse effect of long-term reduction of serum cholesterol with pravastatin sodium on psychological well-being. The study population consisted of 1130 respondents from a representative sample of 1222 patients with stable coronary artery disease participating in the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study. Subjects were randomized in a double-blind manner to treatment with pravastatin sodium, 40 mg/d (n = 559), or placebo (n = 571) for at least 4 years. Psychological well-being was assessed with a standard self-administered questionnaire at baseline and after 6 months, 1 year, 2 years, and 4 years. The questionnaire assessed anxiety and depression, anger, impulsiveness, alcohol consumption, and adverse life events. Serum cholesterol levels decreased by an average of 1.3 mmol/L (50 mg/dL) with pravastatin therapy and did not change with placebo. During follow-up there was no significant difference by treatment group in measures of anxiety and depression, anger expression, or impulsiveness (95% confidence interval excluded differences of >0.2 SD) and no difference in the proportion of subjects with excessive alcohol consumption or adverse life events (odds ratio, 1.0; 95% confidence interval, 0.8-1.2). There was no evidence of a treatment effect for persons whose baseline serum cholesterol level was in the lowest 10% (<4.6 mmol/L [178 mg/dL]) or whose scores for anxiety and depression, anger, or impulsiveness were in the highest 10% at baseline. There was no association between change in the serum cholesterol level and measures of anxiety and depression, anger, or impulsiveness during follow-up. Long-term reduction of serum cholesterol with pravastatin has no adverse effect on psychological well-being.",2001.0,0,0 544,11075313,"Simvastatin does not affect CYP3A activity, quantified by the erythromycin breath test and oral midazolam pharmacokinetics, in healthy male subjects.",T Prueksaritanont; J M Vega; J D Rogers; K Gagliano; H E Greenberg; L Gillen; M J Brucker; D McLoughlin; P H Wong; S A Waldman,"Potential for inhibition of CYP3A activity by simvastatin, an HMG-CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 microCi [14C N-methyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent 14C exhaled during the first hour (for EBT) and the pharmacokinetic parameters of midazolam (AUC, Cmax, t1/2) were not affected following multiple once-daily oral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.18 for EBT and 0.99 to 1.23 for midazolam AUC. In addition, the total urinary recoveries of midazolam and its 1'-hydroxy metabolites (free plus conjugate) obtained from both treatments were not statistically different (p > 0.200). These data demonstrate that multiple dosing of simvastatin, at the highest recommended clinical dose, does not significantly alter the in vivo hepatic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes.",2001.0,0,0 545,11075741,"Randomized comparison of the efficacy and safety of cerivastatin and pravastatin in 1,030 hypercholesterolemic patients. The Cerivastatin Study Group.",C A Dujovne; R Knopp; P Kwiterovich; D Hunninghake; T A McBride; M Poland,"To determine the relative efficacy and safety of cerivastatin and pravastatin in patients with type II hypercholesterolemia. In this prospective, double-blind, parallel-group study, hypercholesterolemic patients were randomized to treatment with cerivastatin, 0.3 mg (n=250) or 0.4 mg (n=258), or pravastatin, 20 mg (n=266) or 40 mg (n=256), for 8 weeks. Cerivastatin, 0.3 mg, was significantly more effective than pravastatin, 20 mg, in reducing low-density lipoprotein (LDL) cholesterol from baseline (-29.6% vs -26.8%; P=.008). Cerivastatin, 0.4 mg, was significantly more effective than pravastatin, 40 mg, in reducing LDL cholesterol (-34.2% vs -30.3%; P<.001). A larger proportion of cerivastatin-treated patients had greater than 40% reductions in LDL cholesterol than those receiving pravastatin (11.1% vs 6.0%). The percentage of patients who achieved the National Cholesterol Education Program (NCEP) target was 71.3% with cerivastatin, 0.3 mg, compared with 67.5% with pravastatin, 20 mg, and 74.0% with cerivastatin, 0.4 mg, compared with 71.1% with pravastatin, 40 mg (no significant difference). Cerivastatin, 0.3 mg, reduced total cholesterol to a greater extent than did pravastatin, 20 mg (P<.03). Both agents reduced triglycerides and increased high-density lipoprotein cholesterol to a similar degree (no significant differences). Cerivastatin and pravastatin were well tolerated. Cerivastatin, 0.3 mg and 0.4 mg, showed greater efficacy than pravastatin, 20 mg and 40 mg, respectively, in lowering LDL cholesterol. Cerivastatin is safe and effective for patients with hypercholesterolemia who require aggressive LDL cholesterol lowering to achieve NCEP-recommended targets.",2001.0,0,0 546,11077897,"Age, sex and practice variations in the use of statins in general practice in England and Wales.",A Majeed; K Moser; R Maxwell,"Statins are highly effective in reducing the risk of sudden cardiac death and other acute coronary events in patients with pre-existing ischaemic heart disease or with raised blood cholesterol levels. However, relatively little is known about how statins are used in primary care. The objectives of this study were to investigate age, sex and inter-practice variations in the prescribing of statins. This was an observational study of statin prescribing rates in 288 general practices in England and Wales that contributed data to the General Practice Research Database in 1996. In 1996, 0.7 per cent of men and 0.5 per cent of women received a prescription for a statin. In the subgroup of patients with a general practitioner (GP) diagnosis of ischaemic heart disease, 13.3 per cent of men and 8.2 per cent of women received a prescription for a statin in 1996. Below the age of 65 years, men with ischaemic heart disease were more likely to be prescribed a statin than were women. Patients aged 75 years and over with ischaemic heart disease were unlikely to be prescribed a statin irrespective of their sex. The percentage of patients prescribed statins in individual practices varied from 0.1 to 2.3 per cent in men and from 0 to 2.3 per cent in women. The recorded prevalence of ischaemic heart disease explained only 12 per cent of this variation in men and 7 per cent in women. There are large age, sex and inter-practice variations in the use of statins in primary care, which are poorly explained by measures of health need. Developing and implementing clinical guidelines to accompany the introduction of new drugs for the management of common chronic disorders should be seen as a priority for GPs, primary care groups and the National Institute of Clinical Excellence.",2001.0,0,0 547,11078228,G-33A mutation in the promoter region of thrombomodulin gene and its association with coronary artery disease and plasma soluble thrombomodulin levels.,Y H Li; J H Chen; H L Wu; G Y Shi; H C Huang; T H Chao; W C Tsai; L M Tsai; H R Guo; W S Wu; Z C Chen,"Thrombomodulin is an endothelial glycoprotein that decreases thrombin activity and activates protein C. A recent study has shown that G-33A promoter mutation of the thrombomodulin gene occurs particularly in Asians. In this study, we analyzed the distribution of G-33A mutation in the promoter region of the thrombomodulin gene in the Chinese population and determined whether the mutation might be a risk for coronary artery disease (CAD). In addition, the influence of this mutation on plasma soluble thrombomodulin levels in patients with CAD was also examined. We studied 320 consecutive patients (mean age 63 years; 73% men) with CAD and 200 age- and sex-matched control subjects. Screening for thrombomodulin G-33A promoter mutation was conducted using polymerase chain reaction, single-strand conformation polymorphism, and direct deoxyribonucleic acid sequencing. The frequency of the G-33A mutation (GA+AA genotypes) was significantly higher in the CAD group (23.8% vs 15.5%, odds ratio [OR] 1.70, p = 0.031). Multiple logistic regression analysis showed that the mutation was an independent risk factor (OR 1.81, p = 0.016) for CAD, as was hypertension (OR 1.44, p = 0.040), diabetes mellitus (OR 2.50, p <0.001), and smoking (OR 2.15, p <0.001). In CAD patients with GG genotype, the soluble thrombomodulin level increased with the extent of CAD (36 +/- 15 vs 47 +/- 18 vs 55 +/- 36 ng/ml in 1-, 2-, or 3-vessel CAD, p <0.001). However, in CAD patients with G-33A mutation, there was no difference between the levels of soluble thrombomodulin (39 +/- 17 vs 37 +/- 15 vs 42 +/- 18 ng/ml, p = NS) in 1-, 2-, or 3-vessel CAD. Our observations suggest that there is a significant association of the G-33A mutation in thrombomodulin gene with CAD, and this mutation may influence the soluble thrombomodulin levels in patients with CAD.",2001.0,0,0 548,11078229,Benefit of coronary reperfusion before intervention on outcomes after primary angioplasty for acute myocardial infarction.,B R Brodie; T D Stuckey; C Hansen; D Muncy,"Primary percutaneous transluminal coronary angioplasty has become the preferred reperfusion strategy for acute myocardial infarction in most institutions with interventional facilities and experienced operators. The benefit of establishing coronary reperfusion, with or without pharmacologic therapy, before primary angioplasty has not been established. Consecutive patients (n = 1,490) with acute myocardial infarction treated with aspirin and heparin followed by primary percutaneous transluminal coronary angioplasty were followed for 13 years. Follow-up angiography was obtained in 737 patients at 7.7 months. Thrombolysis In Myocardial Infarction (TIMI) 2 to 3 flow in the infarct artery at initial angiography was present in 18.3% of patients, and TIMI 0 to 1 flow in 81.7% of patients. Baseline variables were similar between the 2 groups, except patients with initial TIMI 2 to 3 flow had significantly less cardiogenic shock (1.7% vs 9.4%, p <0.0001) and a lower incidence of depressed ejection fraction <40% (12.6% vs 19.9%, p = 0.007). Procedural success was better in patients with initial TIMI 2 to 3 flow (97.4% vs 93.8%, p = 0.02), and catheterization laboratory events were less frequent. Patients with initial TIMI 2 to 3 flow had lower peak creatine kinase values (1,328 vs 2,790 IU/L, p <0.0001), higher acute ejection fraction (54.3% vs 51.6%, p = 0.05), higher late ejection fraction (59.2% vs 54.9%, p = 0.004), and lower 30-day mortality (4.8% vs 8.9%, p = 0.02). These data indicate that when reperfusion occurs before primary angioplasty, outcomes are strikingly better with less cardiogenic shock, improved procedural outcomes, smaller infarct size, better preservation of left ventricular function, and reduced mortality. This should encourage new strategies to establish reperfusion before ""primary"" angioplasty with ""catheterization laboratory friendly"" platelet inhibitors and/or low-dose thrombolytic drugs.",2001.0,0,0 549,11078237,Effect of combined fluvastatin-fenofibrate therapy compared with fenofibrate monotherapy in severe primary hypercholesterolemia. French Fluvastatin Study Group.,M Farnier; S Dejager,"This double-blind study was designed to assess the efficacy and safety of fluvastatin-fenofibrate combination therapy compared with fenofibrate monotherapy in severe primary hypercholesterolemia (low-density lipoprotein [LDL] cholesterol > or =190 mg/dl [4.9 mmol/L], triglycerides < or =350mg/dl [3.9 mmol/l]). After a 10-week placebo and dietary baseline period, 102 patients were randomized to receive micronized fenofibrate 200 mg, fluvastatin 20 mg plus micronized fenofibrate 200 mg, or fluvastatin 40 mg plus micronized fenofibrate 200 mg. At week 16, fenofibrate 200 mg alone lowered LDL cholesterol from baseline by 21% compared with 32% for fluvastatin 20 mg plus fenofibrate 200 mg and 41% for fluvastatin 40 mg plus fenofibrate 200 mg (p <0.001). Triglycerides decreased by 29% with fenofibrate 200 mg alone, 39% with fluvastatin 20 mg plus fenofibrate 200 mg, and 40% with fluvastatin 40 mg plus fenofibrate 200 mg (p <0.05). Safety was assessed by recording adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for the 3 treatment groups. One patient withdrew due to an increase in transaminase levels. No significant increase in creatine phosphokinase levels was observed with combination therapy. In conclusion, the addition of fluvastatin to micronized fenofibrate results in substantial improvement in atherogenic plasma lipids and is well tolerated.",2001.0,0,0 550,11078282,Raising low levels of high-density lipoprotein cholesterol is an important target of therapy.,W E Boden; T A Pearson,"Recent clinical trials in patients with coronary heart disease indicate, for the very first time, that increasing low levels of high-density lipoprotein (HDL) cholesterol significantly reduces the cumulative occurrence of cardiovascular and cerebrovascular events in patients whose only lipid abnormality was low HDL with normal levels of low-density lipoprotein (LDL) cholesterol and triglycerides. These data provide a compelling scientific basis for a more targeted and segmental approach to managing patients with dyslipidemia, where decreasing elevated levels of LDL cholesterol and increasing low levels of HDL cholesterol should comprise dual targets of pharmacotherapy.",2001.0,0,0 551,11078305,Effect of atorvastatin on hemorheologic-hemostatic parameters and serum fibrinogen levels in hyperlipidemic patients.,C A Dujovne; W S Harris; R Altman; R W Overhiser; D M Black,"Plasma fibrinogen and hemorheologic-hemostatic factors contribute to dyslipidemia-induced morbidity. Some of these parameters can be favorably affected when abnormal serum lipoprotein levels are corrected. Thus, we investigated whether treatment with atorvastatin would result in changes in plasma viscosity and other hemorheologic and hemostatic parameters. Twenty-two hyperlipidemic men at a university lipid clinic were treated single-blinded with atorvastatin 80 mg/day for 12 weeks to determine hemostatic-hemorheologic parameters including blood viscosity, fibrinogen levels, whole blood platelet aggregation, tissue plasminogen activator antigen, hematocrit, plasminogen activator inhibitor activity, factor VII activity, red blood cell (RBC) deformity and lipid ratio, sedimentation rate, and fasting serum lipoprotein levels. Atorvastatin treatment provided significant lowering of serum lipoprotein levels: low-density lipoprotein -53% (p = 0.0001), very low density lipoprotein -43% (p = 0.0001), and triglycerides -35% (p < 0.0001). These effects were accompanied by changes in plasma viscosity -10% (p = 0.0007), arachidonic acid-induced whole blood platelet aggregation -11% (p = 0.006), factor VII -8% (p = 0.001), RBC lipid composition +5% (p = 0.0003), and RBC sedimentation -33% (p = 0.0002). Plasma fibrinogen levels were not affected. Thus, atorvastatin 80 mg/day produced marked reductions in serum low-density lipoprotein cholesterol (-53%), very low density lipoprotein cholesterol (-43%), and triglycerides levels (-35%), and significant changes in plasma viscosity as well as other hemorheologic-hemostatic parameters, but no changes in plasma fibrinogen levels.",2001.0,0,0 552,11079660,Apolipoprotein E genotypes and response of plasma lipids and progression-regression of coronary atherosclerosis to lipid-lowering drug therapy.,C M Ballantyne; J A Herd; E A Stein; L L Ferlic; J K Dunn; A M Gotto; A J Marian,"We sought to examine the association of apolipoprotein (apo) E genotypes with baseline plasma lipid levels and severity of coronary artery disease (CAD), as well as the response to treatment with fluvastatin in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Apo E genotypes have been associated with plasma lipid levels and CAD. However, the influence of apo E genotypes on the response of plasma lipids and CAD progression or regression to statin treatment in patients with mildly to moderately elevated cholesterol remains unknown. Apo E genotypes were determined by polymerase chain reaction and restriction mapping. Plasma lipids were measured at baseline and 12 weeks after therapy with fluvastatin or placebo in 320 subjects. In 287 subjects, quantitative coronary angiography was performed at baseline and after 2.5 years of treatment. Subjects with the 3/3 genotype had greater reductions in total cholesterol (20.4% vs. 15.4%, p = 0.01) and low density lipoprotein (LDL) cholesterol (28.8% vs. 22.7%, p = 0.03) than did the subjects with the 3/4 or 4/4 genotype. In contrast, subjects with the 2/3 genotype (n = 10) had a greater increase in high density lipoprotein cholesterol (19.1%) than did the subjects with the 3/3 genotype (4.3%, p = 0.002) and those with the 3/4 or 4/4 genotype (7.0%, p = 0.02). Subjects with the 3/4 or 4/4 genotype had an increased frequency of previous angioplasty, but other measures of baseline CAD severity and baseline lipids did not differ significantly among the genotypes, nor did CAD progression or clinical events. Although subjects with the epsilon4 allele had less reduction in LDL cholesterol with fluvastatin, they had similar benefit in terms of CAD progression.",2001.0,0,0 553,11086336,Status report of lipid-lowering trials in diabetes.,D J Betteridge; H Colhoun; J Armitage,"The prevention and treatment of coronary heart disease is a major challenge in the overall management of the patient with type 2 diabetes. Diabetic dyslipidaemia is an important risk factor and is open to therapeutic intervention. However, as yet there are no primary or secondary coronary heart disease prevention trials of lipid-lowering therapy reported in diabetic populations. In this review, on-going clinical trials of lipid-lowering therapy in specific diabetic populations will be described.",2001.0,0,1 554,11088079,"An overview of acute stroke therapy: past, present, and future.",M Fisher; W Schaebitz,,2001.0,0,0 555,11089820,Statins and the risk of dementia.,H Jick; G L Zornberg; S S Jick; S Seshadri; D A Drachman,"Dementia affects an estimated 10% of the population older than 65 years. Because vascular and lipid-related mechanisms are thought to have a role in the pathogenesis of Alzheimer's disease and vascular dementia, we did an epidemiological study of the potential effect of HMGCoA (3 hydroxy-3methylglutaryl-coenzyme A) reductase inhibitors (statins) and other lipid-lowering agents on dementia. We used a nested case-control design with information derived from 368 practices which contribute to the UK-based General Practice Research Database. The base study population included three groups of patients age 50 years and older: all individuals who had received lipid-lowering agents (LLAs); all individuals with a clinical diagnosis of untreated hyperlipidaemia; and a randomly selected group of other individuals. From this base population, all cases with a computer-recorded clinical diagnosis of dementia were identified. Each case was matched with up to four controls derived from the base population on age, sex, practice, and index date of case. The study encompassed 284 cases with dementia and 1080 controls. Among controls 13% had untreated hyperlipidaemia, 11% were prescribed statins, 7% other LLAs, and 69% had no hyperlipidaemia or LLA exposure. The relative risk estimates of dementia adjusted for age, sex, history of coronary-artery disease, hypertension, coronary-bypass surgery and cerebral ischaemia, smoking and body mass index for individuals with untreated hyperlipidaemia (odds ratio 0.72 [95% CI 0.45-1.14]), or treated with nonstatin LLAs (0.96 [0.47-1.97], was close to 1.0 and not significant compared with people who had no diagnosis of hyperlipidaemia or exposure to other lipid-lowering drugs. The adjusted relative risk for those prescribed statins was 0.29 (0.13-0.63; p=0.002). Individuals of 50 years and older who were prescribed statins had a substantially lowered risk of developing dementia, independent of the presence or absence of untreated hyperlipidaemia, or exposure to nonstatin LLAs. The available data do not distinguish between Alzheimer's disease and other forms of dementia.",2001.0,0,0 556,11090787,Effect of lovastatin on cardiovascular resource utilization and costs in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). AFCAPS/TexCAPS Research Group.,A M Gotto; S J Boccuzzi; J R Cook; C M Alexander; J B Roehm; G S Meyer; M Clearfield; S Weis; E Whitney,"This cost-consequences analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study compares the costs of lovastatin treatment with the costs of cardiovascular hospitalizations and procedures. The cost of lovastatin treatment was defined as the average retail price and the cost of drug safety monitoring and adverse experiences. Costs were determined by actual rates of hospitalizations and procedures. Within a trial, lovastatin treatment cost approximately $4,654/patient. Lovastatin treatment significantly reduced the cumulative rate of cardiovascular hospitalizations and procedures (p = 0.002). Over the duration of the study, the cumulative number of cardiovascular hospitalizations and related therapeutic procedures was significantly reduced by 29%. The time to first cardiovascular-related hospitalization or procedure was significantly extended by lovastatin (p = 0.002). Lovastatin reduced the frequency of cardiovascular hospitalization (28%), and cardiovascular therapeutic (32%) and diagnostic procedures (23%). Among therapeutic procedures, treatment reduced coronary artery bypass graft surgery by 19% and percutaneous transluminal coronary angioplasty by 37%. Total cardiovascular-related hospital days were reduced by 26% (p = 0.025). The between-group offset in direct medical costs was $524, which resulted in a 11% cost offset of lovastatin therapy over the mean study duration of 5.2 years. Lovastatin provides meaningful reductions in cardiovascular-related resource utilization and reductions in direct cardiovascular-related costs associated with the onset of coronary disease.",2001.0,0,1 557,11090801,Lipid treatment goals achieved in patients treated with statin drugs in Norwegian general practice.,A Svilaas; K Risberg; M Thoresen; L Ose,"Statin drug treatment has still not achieved complete acceptance, and titration to recommended target goals is still not used by physicians in Norway.",2001.0,0,0 558,11092112,Unstable angina--a definitive role for statins in secondary prevention.,D Colquhoun,"Unstable angina is a life-threatening disease. The overall incidence is estimated to be between 0.1 and 0.2% and, of those admitted to hospital, up to 5% die within the first six weeks. With such a high prevalence and poor prognosis, there is still a clear need for improved secondary preventive treatment. Several landmark statin trials (CARE, LIPID and 4-S) have now shown the benefits of lowering cholesterol, starting months after an acute coronary event, and several smaller studies (such as L-CAD, PTT and RECIFE) have demonstrated the clinical benefits of very early statin treatment. Recent research suggests the underlying cause of the disease, atherosclerosis, is a dynamic and potentially reversible process. Statins may tip this balance in favour of resolution by cholesterol lowering and through pleiotropic effects independent of lipid lowering. Pravastatin, when given very early in the clinical course, has already been shown to improve both plaque stability and endothelial function, as well as clinical outcome, suggesting it as the drug of choice in early secondary prevention.",2001.0,0,0 559,11092643,"Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease.",B D Horne; J B Muhlestein; J F Carlquist; T L Bair; T E Madsen; N I Hart; J L Anderson,"The joint predictive value of lipid and C-reactive protein (CRP) levels, as well as a possible interaction between statin therapy and CRP, were evaluated for survival after angiographic diagnosis of coronary artery disease (CAD). Hyperlipidemia increases risk of CAD and myocardial infarction. For first myocardial infarction, the combination of lipid and CRP levels may be prognostically more powerful. Although lipid levels are often measured at angiography to guide therapy, their prognostic value is unclear. Blood samples were collected from a prospective cohort of 985 patients diagnosed angiographically with severe CAD (stenosis > or =70%) and tested for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and CRP levels. Key risk factors, including initiation of statin therapy, were recorded, and subjects were followed for an average of 3.0 years (range: 1.8 to 4.3 years) to assess survival. Mortality was confirmed for 109 subjects (11%). In multiple variable Cox regression, levels of TC, LDL, HDL and the TC:HDL ratio did not predict survival, but statin therapy was protective (adjusted hazard ratio [HR] = 0.49, p = 0.04). C-reactive protein levels, age, left ventricular ejection fraction and diabetes were also independently predictive. Statins primarily benefited subjects with elevated CRP by eliminating the increased mortality across increasing CRP tertiles (statins: HR = 0.97 per tertile, p-trend = 0.94; no statins: HR = 1.8 per tertile, p-trend < 0.0001). Lipid levels drawn at angiography were not predictive of survival in this population, but initiation of statin therapy was associated with improved survival regardless of the lipid levels. The benefit of statin therapy occurred primarily in patients with elevated CRP.",2001.0,0,0 560,11092646,Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management.,D Zanger; B K Yang; J Ardans; M A Waclawiw; G Csako; L M Wahl; R O Cannon,"The goal of our study was to determine whether hormone therapy alters markers of inflammation in postmenopausal women with chronic stable coronary artery disease (CAD) on appropriate medical management. Hormone therapy reduces some markers of inflammation associated with atherosclerosis risk (cell adhesion molecules) but increases levels of another marker of inflammation--C-reactive protein-in healthy postmenopausal women. Ten women (average age 66 years; range 59 to 76 years) with CAD on medical management (including aspirin [9], statin lipid-lowering therapy [7], angiotensin-converting enzyme inhibitors [3]) were randomly assigned to conjugated equine estrogens 0.625 mg (combined with medroxyprogesterone acetate 2.5 mg daily in five women with uterus intact) or placebo(s) daily for one month with crossover to the alternate therapy after one month off of hormone treatment in a double-blind study. At the end of each treatment phase, the following markers of inflammation were measured in serum: interleukin-6, C-reactive protein, E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and matrix metalloproteinase-9. Hormone therapy significantly lowered serum levels of cell adhesion molecules E-selectin (46.9+/-18.3 vs. 56.3+/-20.6 ng/mL, p = 0.006), intercellular adhesion molecule-1 (282+/-74 vs. 304+/-78 ng/mL, p = 0.013) and vascular cell adhesion molecule-1 (605+/-218 vs. 657+/-214 ng/mL, p = 0.01) but increased levels of matrix metalloproteinase-9 (648+/-349 vs. 501+/-285 ng/mL, p = 0.02). Interleukin-6 (4.33+/-4.78 vs. 3.04+/-1.47 pg/mL, p = 0.283) and C-reactive protein (0.88+/-1.13 vs. 0.61+/-0.50 mg/dL, p = 0.358) were not significantly elevated on hormone therapy compared with placebo values. Hormone therapy has divergent effects on serum markers of inflammation in women with CAD. Reduction in levels of cell adhesion molecules may reduce attachment of white blood cells to the vessel wall, but increases in matrix metalloproteinase-9 within the vessel wall could digest and weaken fibrous caps of vulnerable plaques, thus provoking thrombosis.",2001.0,0,0 561,11095163,"Hypertension drug trials: past, present, and future.",P S Sever; N R Poulter,,2001.0,0,0 562,11104736,Simvastatin improves disturbed endothelial barrier function.,G P van Nieuw Amerongen; M A Vermeer; P Nègre-Aminou; J Lankelma; J J Emeis; V W van Hinsbergh,"Recent clinical trials have established that inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) reduce the risk of acute coronary events. These effects of statins cannot be fully explained by their lipid-lowering potential. Improved endothelial function may contribute to the positive effects of statin treatment. In the present study, we report that simvastatin reduces endothelial barrier dysfunction, which is associated with the development of atherosclerosis. Treatment of human umbilical vein endothelial cells for 24 hours with 5 micromol/L simvastatin reduced the thrombin-induced endothelial barrier dysfunction in vitro by 55+/-3%, as assessed by the passage of peroxidase through human umbilical vein endothelial cell monolayers. Similar effects were found on the thrombin-induced passage of (125)I-LDL through human aortic endothelial cell monolayers. This reduction in barrier dysfunction by simvastatin was both dose and time dependent and was accompanied by a reduction in the thrombin-induced formation of stress fibers and focal adhesions and membrane association of RhoA. Simvastatin treatment had no effect on intracellular cAMP levels. In Watanabe heritable hyperlipidemic rabbits, treatment for 1 month with 15 mg/kg simvastatin reduced vascular leakage in both the thoracic and abdominal part of the aorta, as evidenced by the Evans blue dye exclusion test. The decreased permeability was not accompanied by a reduction of oil red O-stainable atherosclerotic lesions. These data show that simvastatin, in a relatively high concentration, improves disturbed endothelial barrier function both in vitro and in vivo. The data also support the beneficial effects of simvastatin in acute coronary events by mechanisms other than its lipid-lowering effect.",2001.0,0,0 563,11108325,The effect of high-protein diets on coronary blood flow.,R M Fleming,"Recent research has demonstrated that successful simultaneous treatment of multiple risk factors including cholesterol, triglycerides, homocysteine, lipoprotein (a) [Lp(a)], fibrinogen, antioxidants, endothelial dysfunction, inflammation, infection, and dietary factors can lead to the regression of coronary artery disease and the recovery of viable myocardium. However, preliminary work revealed that a number of individuals enrolled in the original study went on popular high-protein diets in an effort to lose weight. Despite increasing numbers of individuals following high-protein diets, little or no information is currently available regarding the effect of these diets on coronary artery disease and coronary blood flow. Twenty-six people were studied for 1 year by using myocardial perfusion imaging (MPI), echocardiography (ECHO), and serial blood work to evaluate the extent of changes in regional coronary blood flow, regional wall motion abnormalities, and several independent variables known to be important in the development and progression of coronary artery disease. Treatment was based on homocysteine, Lp (a), C-reactive protein (C-RP), triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and fibrinogen levels. Each variable was independently treated as previously reported. MPI and ECHO were performed at the beginning and end of the study for each individual. The 16 people (treatment group/TG) studied modified their dietary intake as instructed. Ten additional individuals elected a different dietary regimen consisting of a ""high-protein"" (high protein group/HPG) diet, which they believed would ""improve"" their overall health. Patients in the TG demonstrated a reduction in each of the independent variables studied with regression in both the extent and severity of coronary artery disease (CAD) as quantitatively measured by MPI. Recovery of viable myocardium was seen in 43.75% of myocardial segments in these patients, documented with both MPI and ECHO evaluations. Individuals in the HPG showed worsening of their independent variables. Most notably, fibrinogen, Lp (a), and C-RP increased by an average of 14%, 106%, and 61% respectively. Progression of the extent and severity of CAD was documented in each of the vascular territories with an overall cumulative progression of 39.7%. The differences between progression and extension of disease in the HPG and the regression of disease in the TG were statistically (p<0.001) significant. Patients following recommended treatment for each of the independent variables were able to regress both the extent and severity of their coronary artery disease (CAD), as well as improve their myocardial wall motion (function) while following the prescribed medical and dietary guidelines. However, individuals receiving the same medical treatment but following a high-protein diet showed a worsening of independent risk factors, in addition to progression of CAD. These results would suggest that high-protein diets may precipitate progression of CAI) through increases in lipid deposition and inflammatory and coagulation pathways.",2001.0,0,0 564,11108410,Re-thinking metabolic strategies for older people with type 2 diabetes mellitus: implications of the UK Prospective Diabetes Study and other recent studies.,A J Sinclair; G S Meneilly,,2001.0,0,0 565,11110349,Treating hyperlipidemia in African Americans.,L M Prisant; C Thurmond; V J Robinson,"The purpose of this paper is to provide information concerning the treatment of hyperlipidemia in African Americans. There is a similar prevalence of hypercholesterolemia in Blacks and Whites, but Blacks have been neglected in most pharmacological studies of hyperlipidemia. Intimal atherosclerotic involvement of the aorta and coronary artery occurs in young Black and White males. Epidemiological studies suggest there is a higher mortality rate due to coronary disease in Blacks vs Whites in the United States. Thirty-four percent of Blacks require a fasting lipid profile and 9% of Black adults aged 20 years or older would require lipid-lowering therapy. However, fewer Blacks (26%) than Whites (47%) are aware of their hypercholesterolemia. Studies with lovastatin and pravastatin show efficacy in the treatment of hypercholesterolemia. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is designed to determine all-cause mortality for subjects receiving pravastatin vs a control group receiving ""usual care."" Randomized, blinded, prospective trials are needed to assess the impact of hyperlipidemia as a risk factor, and the impact of its reduction in African Americans.",2001.0,0,0 566,11110741,Prevention of ischaemic stroke.,G Gubitz; P Sandercock,,2001.0,0,0 567,11111097,Cholesterol and atherosclerosis.,P Libby; M Aikawa; U Schönbeck,,2001.0,0,0 568,11111822,Outcome of patients on long term low-density lipoprotein apheresis with membrane differential filtration: a case study in three patients 14 years on treatment.,H von Baeyer; M Schartl; A Bimmermann,"Membrane differential filtration (MDF) (1,2) is a variety of cascade filtration. Three patients with primary hyperlipoproteinemia and coronary heart disease (2 patients with foregoing myocardial infarction) were treated with MDF for a period of 14 years. The mean treatment interval was 21 days. The basic level of low-density lipoprotein (LDL) cholesterol was about 450 mg/dl, and the level on LDL apheresis with comedication of statins was 180 to 200 mg/dl before treatment. Atherosclerosis progressed slowly during this period, and myocardial infarctions were avoided. However, in all 3 patients angiologic interventions became necessary. MDF is a well tolerated method that can be conducted without allergic hazards. The clinical results compare with those of other apheretic techniques.",2001.0,0,0 569,11113401,Beneficial effects of pravastatin (+/-colestyramine/niacin) initiated immediately after a coronary event (the randomized Lipid-Coronary Artery Disease [L-CAD] Study).,H R Arntz; R Agrawal; W Wunderlich; L Schnitzer; R Stern; F Fischer; H P Schultheiss,"Secondary prevention of coronary heart disease by antilipidemic therapy beginning at > or =3 months after an acute coronary syndrome is well documented. The impact, however, of immediate initiation of antilipidemic therapy on coronary stenoses and clinical outcome in patients with acute coronary syndrome is unknown. In our study, patients were randomized, on average, 6 days after an acute myocardial infarction and/or percutaneous transluminal coronary angioplasty secondary to unstable angina, to pravastatin (combined, when necessary, with cholestyramine and/or nicotinic acid) to achieve low-density lipoprotein cholesterol levels of < or =130 mg/dl (group A, n = 70). In controls (group B, n = 56), antilipidemic therapy was determined by family physicians. Quantitative coronary angiography was performed at inclusion, and at 6- and 24-month follow-up. The combined clinical end points were total mortality, cardiovascular death, nonfatal myocardial infarction, need for coronary intervention, stroke, and new onset of peripheral vascular disease. Minimal lumen diameter in group A increased by 0.05 +/- 0.20 mm after 6 months and 0.13 +/- 0.29 mm after 24 months, whereas it decreased by 0.08 +/- 0.20 mm and 0.18 +/- 0.27 mm, respectively, in group B (p = 0.004 at 6 months and p <0.001 at 24 months). After 2 years, 29 patients of 56 patients in group B, but only 16 of 70 patients in group A, experienced a clinical end point (p = 0.005; odds ratio 0.28, confidence intervals 0.13 to 0.6). We conclude that pravastatin-based therapy initiated immediately after an acute coronary syndrome is well tolerated and safe, lessens coronary atherosclerosis, and has a pronounced clinical benefit.",2001.0,1,1 570,11114960,Additive effects of Simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients.,G Tonolo; M G Melis; M Formato; M F Angius; A Carboni; P Brizzi; M Ciccarese; G M Cherchi; M Maioli,"Experimental evidence indicates that statins might have direct vascular effects independently from low-density lipoprotein (LDL) cholesterol reduction and we reported that the reduction in urinary albumin excretion rate during Simvastatin treatment in type 2 diabetic patients was not correlated with LDL-cholesterol decrease. However in humans there are no data regarding possible additional effects of Simvastatin on blood pressure and urinary albumin excretion beyond its capacity to lower serum cholesterol. Twenty-six microalbuminuric hypertensive type 2 diabetic patients (diastolic blood pressure - after four months wash-out from the previous antihypertensive therapy - consistently > 90 and < 100 mmHg; plasma LDL-cholesterol > 3.9 and < 6.5 mmol L-1) were enrolled in the study. In random order, these patients received Simvastatin (20 mg day-1) or Cholestyramine (6 g three times a day) for a period of 10 months and after three months of wash-out (cross-over) the sequence was reversed for an additional 10 months. Blood pressure, lipid parameters, glycated haemoglobin and urinary albumin excretion were measured during the study. Additionally, in eight patients, urinary glycosaminoglycan excretion (GAG) was also measured during the study. Simvastatin and Cholestyramine were equally effective in reducing total and LDL cholesterol. Only during Simvastatin treatment a significant reduction in diastolic blood pressure and both 24 h urinary albumin and GAG excretion rates were observed, while no significant changes were seen with Cholestyramine treatment. Our results clearly show for the first time that the reduction of blood pressure, together with 24 h urinary albumin excretion rate - two established cardiovascular risk factors, obtained during Simvastatin therapy in hypertensive type 2 diabetic patients - is in large part independent from the reduction of LDL Cholesterol.",2001.0,0,0 571,11115225,Enhancing drug compliance in lipid-lowering treatment.,J H LaRosa; J C LaRosa,"Hyperlipidemia and the atherosclerotic conditions that result from it are well recognized as major contributors to coronary heart disease (CHD). Fortunately, several large-scale clinical trials have shown that there are effective treatments that can substantially lower atherogenic lipid levels and thereby reduce the risk of CHD mortality and morbidity. However, duplication of these dramatic trial results can be negatively affected in ""real life"" clinical practice by an important issue: compliance. No medications will work if patients do not take them. Unfortunately, patients who need lipid-lowering therapy are likely to need it long-term, perhaps for a lifetime. Yet, many do not adhere to the prescribed medication regimen. This article reviews some major studies of compliance for lipid-lowering drugs. The reasons why patients do not take them as prescribed vary: poor education, lack of understanding, cost, provider indifference, and others. Achieving compliance requires a multifaceted approach. It can be enhanced by encouraging patients to talk openly about their medication habits and by convincing them of the long-term benefits of reaching and maintaining target low-density lipoprotein cholesterol levels. Although more studies focusing on compliance specifically regarding CHD are needed, the current literature does provide some guidance. Arch Fam Med. 2000;9:1169-1175",2001.0,0,0 572,11121593,Effects of HMG-CoA reductase inhibitor on hemostasis.,K K Koh,"Clinical trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy have demonstrated improvement in coronary atherosclerosis progression and reduction in risk of cardiovascular events. However, improvement in cardiovascular end-points is incompletely explained by the baseline or treated LDL cholesterol level. The beneficial effects of statins on clinical events may involve nonlipid mechanisms that modify hemostasis. Local activation of platelets and thrombus formation adjacent to atheromatous plaques, especially where ruptured or eroded, are now recognized to be of pathophysiological importance in the acute and chronic clinical expression of coronary heart disease. Thus, favorable effects of statins on hemostasis may be relevant to decreasing or delaying the progression and clinical manifestations of atherosclerosis.",2001.0,0,0 573,11122685,Reducing atherothrombotic events in high-risk patients: recent data on therapy with statins and fatty acids.,C M Ballantyne,"Traditional treatment of atherosclerotic coronary heart disease by cardiovascular specialists, which has focused on ""critical"" stenoses, may be less effective in reducing morbidity and mortality than therapies that stabilize plaques and reduce thrombosis and sudden death. Recent data from clinical trials of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy and modification of dietary fat composition demonstrate that both these approaches can reduce clinical events. Although revascularization therapy is effective in reducing angina caused by high-grade stenotic lesions, this therapy is incomplete because the more-numerous ""smaller"" plaques that typically cause clinical events remain untreated. Two recent trials suggest that statin therapy may have benefits on stabilizing plaques in high-risk patients within a year. Additional benefit may also be provided by increasing dietary consumption of monounsaturated or omega-3 polyunsaturated fatty acids. Both statin therapy and diets high in monounsaturated or omega-3 fatty acids appear to improve morbidity and mortality by modifying the underlying atherothrombotic disease process.",2001.0,0,0 574,11122690,The Air Force/Texas Coronary Atherosclerosis Prevention Study: implications for preventive cardiology in the general adult US population.,E Whitney,"Atherosclerotic cardiovascular diseases are the most common causes of death in the United States. Fibrous plaques develop in 77% to 78% of men before age 30. The mean low-density lipoprotein-cholesterol (LDL-C) level in men aged 25 to 30 years is 117 mg/dL. In the Air Force/Texas Coronary Atherosclerosis Prevention Study, lovastatin therapy was associated with a 40% reduction in risk of fatal and nonfatal myocardial infarction. The reduction in risk of myocardial infarction was independent of baseline LDL-C level with baseline LDL-C levels as low as 125 mg/dL. The National Cholesterol Education Program guidelines should be simplified by recommending that LDL-C levels be less than 100 mg/dL in all adults in the United States.",2001.0,0,0 575,11122719,Lipid modulation and atherosclerotic events: extending the clinical spectrum with fibrates and statins.,E A Stein,"Two recently published clinical endpoint trials, Veterans Affairs Cooperative Studies Program High-density Lipoprotein Intervention Trial (VA-HIT) and Atorvastatin Versus Revascularization Treatment (AVERT), studied lipid populations and clinical subgroups not previously evaluated in prior trials. VA-HIT, which used gemfibrozil, resurrected the potential benefits of fibrates in atherosclerotic subjects after previous trials either showed nonsignificant reductions in coronary artery disease (CAD) events or raised questions regarding non-CAD events. This study also raised intriguing questions about mechanisms and reinvigorated the triglyceride-atherothrombotic debate. The latest statin trial, AVERT, helped move the potential use of statins in two directions, addressing whether more LDL-cholesterol reduction is better, and whether lipid lowering offers an alternative to revascularization in certain subgroups. Finally, the design or initiation of a number of innovative and potentially landmark statin, fibrate, or combination studies has been published, or their results made public. The focus is on current gaps in our knowledge as we move toward evidence-based medicine. These include primary and secondary prevention of CAD in the elderly, primary prevention of CAD in persons with diabetes, and primary prevention of stroke.",2001.0,0,0 576,11122746,Pleiotropic effects of statins.,J A Farmer,"The advent of statin therapy has revolutionized the ability of the clinician to manage patients at risk for the development of an ischemic event due to dyslipidemia. Large-scale clinical trials involving thousands of patients in both primary and secondary prevention have clearly demonstrated that statin therapy will reduce cardiovascular mortality across a broad spectrum of patient subgroups. Additionally, in adequately powered trials, total mortality has been successfully decreased by the use of statin therapy. However, the precise mechanism underlying the benefit of statin therapy has been controversial due to the multiplicity of potential benefits that statins have demonstrated in addition to pure lipid lowering. The causal theory of pharmacologic benefit reiterates the lipid hypothesis, which states that dyslipidemia is central to the process of atherosclerosis and the clinical benefit which accrues from statin therapy is a function of the degree of lipid lowering. The noncausal theory supports the premise that clinical benefits are related primarily to pleiotropic effects of statins (endothelial function, inflammation, coagulation and plaque vulnerability) as being the major modulators of clinical benefit. This review will focus on the potential beneficial effects of statin therapy on a number of the pleiotropic effects of statins and the potential role that these activities play in the reduction of risk for ischemic events.",2001.0,0,1 577,11122756,Percutaneous coronary intervention versus medical therapy for coronary heart disease.,D J Maron,"Medical therapy reduces myocardial infarction and death in patients with stable coronary heart disease (CHD). In contrast, there is little evidence available to evaluate the impact of percutaneous coronary intervention (PCI) on hard endpoints in such patients. Four randomized, controlled trials have compared PCI with medical therapy. These studies have demonstrated that PCI results in an improvement in angina and exercise tolerance compared with medical therapy, but they also suggest that medical therapy may be preferable to PCI with respect to the risk of cardiac events. Interpretation of these studies has been limited by small sample size, exclusion of high-risk subjects, no or reduced use of stents, lack of a cost- effectiveness evaluation, and absence of risk factor intervention (except for Atorvastatin versus Revascularization Treatment, which used aggressive low-density lipoprotein lowering with atorvastatin in the medical group only). The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial will permit better definition of the role of PCI in the treatment of stable or recently stabilized patients with CHD.",2001.0,0,0 578,11123452,Clinical trial: the safety of terbinafine in patients over the age of 60 years: a multicenter trial in onychomycosis of the feet.,E B Smith; L F Stein; D P Fivenson; E S Atillasoy,"Thirty patients completed this open-label, multicenter prospective study performed to evaluate the efficacy and safety of terbinafine treatment of onychomycosis of the feet in elderly patients. Inclusion criteria included an age of 60 years or older, a diagnosis of onychomycosis confirmed by positive potassium hydroxide (KOH) preparation at baseline, and toenails capable of regrowth. Patients were excluded from the study if they had received any systemic antifungal therapy within the previous 3 months or topical antifungal therapy within 1 week prior to the start of the study; had psoriasis; had toenail abnormalities interfering with normal toenail appearance; were immunosuppressed or immunodeficient; or had serum hepatic enzyme (serum glutamic-oxaloacetic transaminase, SGOT; serum glutamic-pyruvic transaminase, SGPT) values greater than 1.5 times the upper limit of normal at baseline. Following baseline evaluations, eligible patients received a 12-week supply of oral terbinafine (250 mg/day) for self-administration. Compliance was assessed by tablet counts at each visit and defined as the use of at least 80% of the medication prescribed at the first two visits. Follow-up evaluations were conducted for the next 60 weeks, for a total study period of 72 weeks. These visits occurred at weeks 6, 12, 24, 36, 48, and 72. All follow-up visits included: (i) the reporting of adverse effects; (ii) assessment of efficacy by KOH preparation, mycologic culture, and investigator evaluation; and (iii) physician and patient global assessments of various quality of life parameters (except for the visit at week 36). Safety and tolerance were assessed by physical examination at baseline and week 12, by laboratory evaluations (hematology, blood chemistry, and urinalysis) at baseline, week 6 and week 12, and by reporting and evaluation of adverse events throughout the entire study. Investigators assessed the extent of involvement of the target toenail and recorded global assessments of therapeutic efficacy at all visits. Mycologic evaluation was conducted by KOH preparation and a mycologic culture of the target toenail. Because of discrepancies in KOH results between the investigator sites and the central laboratory in early analyses, we chose to use the mycologic culture results to evaluate efficacy. Because all 30 subjects were treated with terbinafine, the entire group was considered for safety evaluation.",2001.0,0,0 579,11123842,,,,,0,1 580,11123843,New statins and new doses of older statins.,E A Stein,"The need for greater reductions in LDL cholesterol, although remaining to be proven as clinically beneficial, continues to drive the development of either higher doses of currently approved and marketed statins or the development of new, more effective agents.",2001.0,0,0 581,11123844,"Diabetes: statins, fibrates, or both?",M Farnier; S Picard,"Cardiovascular disease is the leading cause of mortality in patients with type 2 diabetes. Among the many factors that are involved in the pathogenesis of atherosclerosis in diabetic patients, dyslipidemia plays a major role. It is characterized by an increase in triglycerides, a decrease in high-density lipoprotein cholesterol and normal or mildly elevated low-density lipoprotein cholesterol. The management of patients with diabetic dyslipidemia is difficult because we lack studies specifically designed for diabetic patients. Thus, strategy has to rely on post hoc analyses of landmark intervention trials, which usually include only a small number of diabetic patients, or on rare trials enrolling small cohorts of diabetic patients. When lifestyle changes fail, monotherapy should be tried first with either a statin or a fibrate, depending on triglyceride level. If lipid target values are not reached, a combination therapy can then be initiated, with close follow-up of potential side effects.",2001.0,0,0 582,11123846,"Statins, hormones, and women: benefits and drawbacks for atherosclerosis and osteoporosis.",D M Herrington; K Potvin Klein,"Clinical trials have shown that 3-hydoxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, known as statins, significantly reduce the risk of both primary and secondary coronary heart disease events. Although these trials have included few women, the evidence suggests that statins are as effective in women as in men. The addition of hormone replacement therapy to statin therapy augments lowering of low- density lipoprotein cholesterol, but may not increase the favorable effects on clinical events achieved with statins alone. Finally, new data suggest that statins may also reduce the risk of osteoporotic fractures, a provocative finding still in need of verification by clinical trials.",2001.0,0,0 583,11126839,Risks of coronary heart disease in women: current understanding and evolving concepts.,T S Tsang; M E Barnes; B J Gersh; S N Hayes,"The population of older individuals in the United States is growing rapidly. Because women generally live longer than men and make up the majority of this aging population, the elucidation of health issues related to older women is important. Cardiovascular disease is the leading cause of death and disability for women and claims the lives of more women than the next 14 causes combined. The majority of these deaths are due to atherosclerotic coronary heart disease, with nearly 250,000 women dying of myocardial infarction each year. There is evidence that women with suspected or established cardiovascular disease have not benefited fully from recent advances in the detection and management of coronary heart disease. Regardless of the mechanism and extent of the effect that sex differences have on approaches to cardiovascular disease, women appear to benefit from proven efficacious therapies, and the longer-term outcomes associated with these treatments are positive. The data regarding women and coronary heart disease are rapidly evolving and sometimes conflicting. The intent of this article is to summarize the most current understanding of coronary heart disease risks in women, highlighting the impact of prevention, and to discuss the latest novel findings that may become important in our armamentarium for prevention of coronary heart disease.",2001.0,0,0 584,11127936,Associations between change in C-reactive protein and serum lipids during statin treatment.,T E Strandberg; H Vanhanen; M J Tikkanen,"Hypolipidaemic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) treatment reduces cardiovascular risk and is also associated with the reduction of C-reactive protein (CRP) concentrations. However, there is scant data concerning the relationship between CRP and lipid changes during statin treatment. We studied 60 hypercholesterolaemic coronary patients who participated in the Treat to Target (3T) study comparing atorvastatin and simvastatin. Serum lipids and CRP (with a sensitive method) were measured before treatment at baseline and after 12 months of statin treatment. Low-density lipoprotein (LDL) cholesterol was substantially decreased and high-density lipoprotein (HDL) cholesterol increased during statin treatment. CRP decreased significantly (sign test P = 0.03) during treatment, and the changes of CRP were significantly associated with changes in HDL cholesterol (r = -0.45; P < 0.001) and apolipoprotein A1 (r = -0.40; P < 0.001) but not with changes in LDL cholesterol or triglycerides. The change in HDL cholesterol explained 20% of the change in CRP during statin treatment. The results are in line with previous suggestions that HDL has anti-inflammatory properties.",2001.0,0,0 585,11128187,Prevention.,J S Forrester,,2001.0,0,0 586,11128243,Determination of lovastatin in human plasma using reverse-phase high-performance liquid chromatography with UV detection.,L Y Ye; P S Firby; M J Moore,"The authors have developed a simple, rapid HPLC assay with ultraviolet (UV) detection for the analytical determination of lovastatin and its acid in human plasma for a concentration range of 100-5,000 ng/mL. Sample clean-up involved the use of C10 solid-phase extraction cartridges. Our limit of quantitation was 100 ng/mL. Standard curves were linear from 100 to 5,000 ng/mL, with a correlation coefficient (r2) of 0.999 +/- 0.0002. Stored samples were stable at -70 degrees C for up to 4 months prior to reversed-phase HPLC analysis. This assay was able to measure steady-state lovastatin concentration (Css) at the initial dose level in a phase I trial of lovastatin as a modulator of apoptosis.",2001.0,0,0 587,11129127,Cerivastatin: a review of its pharmacological properties and therapeutic efficacy in the management of hypercholesterolaemia.,G L Plosker; C I Dunn; D P Figgitt,"Cerivastatin is an HMG-CoA reductase inhibitor used for the treatment of patients with hypercholesterolaemia. The lipid-lowering efficacy of cerivastatin has been demonstrated in a number of large multicentre, randomised clinical trials. Earlier studies used cerivastatin at relatively low dosages of < or =0.3mg orally once daily, but more recent studies have focused on dosages of 0.4 or 0.8 mg/day currently recommended by the US Food and Drug Administration (FDA). Along with modest improvements in serum levels of triglycerides and high density lipoprotein (HDL)-cholesterol, cerivastatin 0.4 to 0.8 mg/day achieved marked reductions in serum levels of low density lipoprotein (LDL)-cholesterol (33.4 to 44.0%) and total cholesterol (23.0 to 30.8%). These ranges included results of a pivotal North American trial in almost 1000 patients with hypercholesterolaemia. In this 8-week study, US National Cholesterol Education Program (Adult Treatment Panel II) [NCEP] target levels for LDL-cholesterol were achieved in 84% of patients randomised to receive cerivastatin 0.8 mg/day, 73% of those treated with cerivastatin 0.4 mg/day and <10% of placebo recipients. Among patients with baseline serum LDL-cholesterol levels meeting NCEP guidelines for starting pharmacotherapy, 75% achieved target LDL-cholesterol levels with cerivastatin 0.8 mg/day. In 90% of all patients receiving cerivastatin 0.8 mg/day, LDL-cholesterol levels were reduced by 23.9 to 58.4% (6th to 95th percentile). Various subanalyses of clinical trials with cerivastatin indicate that the greatest lipid-lowering response can be expected in women and elderly patients. Cerivastatin is generally well tolerated and adverse events have usually been mild and transient. The overall incidence and nature of adverse events reported with cerivastatin in clinical trials was similar to that of placebo. The most frequent adverse events associated with cerivastatin were headache, GI disturbances, asthenia, pharyngitis and rhinitis. In the large pivotal trial, significant elevations in serum levels of creatine kinase and transaminases were reported in a small proportion of patients receiving cerivastatin but not in placebo recipients. As with other HMG-CoA reductase inhibitors, rare reports of myopathy and rhabdomyolysis have occurred with cerivastatin, although gemfibrozil or cyclosporin were administered concomitantly in most cases. Postmarketing surveillance studies in the US have been performed. In 3 mandated formulary switch conversion studies, cerivastatin was either equivalent or superior to other HMG-CoA reductase inhibitors, including atorvastatin, in reducing serum LDL-cholesterol levels or achieving NCEP target levels. Pharmacoeconomic data with cerivastatin are limited, but analyses conducted to date in the US and Italy suggest that cerivastatin compares favourably with other available HMG-CoA reductase inhibitors in terms of its cost per life-year gained. Cerivastatin is a well tolerated and effective lipid-lowering agent for patients with hypercholesterolaemia. When given at dosages currently recommended by the FDA in the US, cerivastatin achieves marked reductions in serum levels of LDL-cholesterol, reaching NCEP target levels in the vast majority of patients. Thus, cerivastatin provides a useful (and potentially cost effective) alternative to other currently available HMG-CoA reductase inhibitors as a first-line agent for hypercholesterolaemia.",2001.0,0,0 588,11129129,Management of type 2 diabetes mellitus and cardiovascular risk: lessons from intervention trials.,H Yki-Järvinen,"Although the diagnosis of type 2 (noninsulin-dependent) diabetes mellitus is made when blood glucose levels exceed values which increase the risk of microvascular complications, macrovascular disease is the major complication of type 2 diabetes mellitus. Both epidemiological and prospective data have demonstrated that treatment of hyperglycaemia is markedly effective in reducing the risk of microvascular disease but is less potent in reducing that of myocardial infarction, stroke and peripheral vascular disease. Treatment of other cardiovascular risk factors, although by definition less prevalent than hyperglycaemia, appears to be more effective in preventing macrovascular disease than treatment of hyperglycaemia. In recent years, data from intervention trials have suggested that greater benefits with respect to the prevention of macrovascular disease can be achieved by effective treatment of hypertension and hypercholesterolaemia, and by the use of small doses of aspirin (acetylsalicylic acid) than by treating hyperglycaemia alone. On the other hand, the UK Prospective Diabetes Study (UKPDS), which examined the impact of intensive glucose and blood pressure (BP) control on micro- and macrovascular complications, is the only intervention trial to include only patients with type 2 diabetes mellitus. The UKPDS data, the epidemic increase in the number of patients with type 2 diabetes mellitus and their high cardiovascular risk have, however, initiated several new trials addressing, in particular, the possible benefits of treatment of the most common form of dyslipidaemia (high serum triglyceride and low high density lipoprotein cholesterol levels) in these patients. Type 2 diabetes mellitus is thus a disease associated with a high vascular risk, where the majority of patients need, and are likely to benefit from, pharmacological treatment of several cardiovascular risk factors provided treatment targets have not been achieved by life-style modification.",2001.0,0,0 589,11130218,The low-density lipoprotein cholesterol-lowering effect of pravastatin and factors associated with achieving targeted low-density lipoprotein levels in an African-American population.,P H Chong; P J Tzallas-Pontikes; J D Seeger; T D Stamos,"To describe the low-density lipoprotein cholesterol (LDL)-lowering effect of pravastatin in African-American patients and to identify factors associated with achieving National Cholesterol Education Program (NCEP)-defined target levels. Retrospectively defined cohort study. Large, government-owned, teaching hospital. Eighty-four African-American patients starting therapy with pravastatin in October-November 1997. None. Whether or not target LDL concentrations were achieved was used to measure efficacy. Stepwise logistic regression identified the target LDL, baseline LDL, and baseline high-density lipoprotein cholesterol (HDL) as significant predictors of achieving the target. The proportion of patients achieving their target LDL when that target was below 160, below 130, and 100 mg/dl or below was 64%, 32%, and 13% (p=0.004), respectively. Medical record review identified the reasons for not achieving target as incorrect drug regimen, inadequate lipid monitoring, and noncompliance. These results indicate that substantial numbers of patients receiving lipid-lowering therapy are not meeting NCEP-defined targets and that with increased drug monitoring and compliance, improvements in achieving NCEP target LDL levels could be realized.",2001.0,0,1 590,11130382,Effects of pravastatin in 3260 patients with unstable angina: results from the LIPID study.,A M Tonkin; D Colquhoun; J Emberson; W Hague; A Keech; G Lane; S MacMahon; J Shaw; R J Simes; P L Thompson; H D White; D Hunt,"The LIPID study is a major trial of secondary prevention of coronary-heart-disease events that includes hospital admission with unstable angina (as well as myocardial infarction) as a qualifying event. In this substudy of LIPID, we compared subsequent cardiovascular risks and the effects of pravastatin in patients with previous unstable angina or previous myocardial infarction. 3260 patients diagnosed with unstable angina and 5754 with acute myocardial infarction 3-36 months previously were randomly assigned 40 mg pravastatin daily or placebo over a mean of 6.0 years. The risk reduction of a range of cardiovascular events was estimated by means of the hazard ratio in Cox's proportional hazards model. Among patients assigned placebo, survival in the two diagnosis groups was similar. The relative risk reduction for mortality with pravastatin was 20.6% in the myocardial infarction group and 26.3% in the unstable angina group (p=0.55). Pravastatin significantly reduced the rates of all prespecified coronary endpoints in the myocardial infarction group. In patients with previous unstable angina, coronary heart disease mortality, total mortality, myocardial infarction, a need for coronary revascularisation, the number of admissions to hospital, and the number of days in hospital were significantly lower with pravastatin. Overall, hospital admission for unstable angina was the most common endpoint (24.6% of the placebo group; 22.3% of the pravastatin group). Patients who have survived acute myocardial infarction or unstable angina have a similar long-term prognosis, a high occurrence of subsequent unstable angina, and benefit similarly from therapy with pravastatin.",2001.0,0,0 591,11130523,"Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration.",B Neal; S MacMahon; N Chapman; Blood Pressure Lowering Treatment Trialists' Collaboration,"This programme of overviews of randomised trials was established to investigate the effects of angiotensin-converting-enzyme (ACE) inhibitors, calcium antagonists, and other blood-pressure-lowering drugs on mortality and major cardiovascular morbidity in several populations of patients. We did separate overviews of trials comparing active treatment regimens with placebo, trials comparing more intensive and less intensive blood-pressure-lowering strategies, and trials comparing treatment regimens based on different drug classes. The hypotheses to be investigated, the trials to be included, and the outcomes to be studied were all selected before the results of any participating trial were known. Individual participant data or group tabular data were provided by each trial and combined by standard statistical techniques. The overview of placebo-controlled trials of ACE inhibitors (four trials, 12,124 patients mostly with coronary heart disease) revealed reductions in stroke (30% [95% CI 15-43]), coronary heart disease (20% [11-28]), and major cardiovascular events (21% [14-27]). The overview of placebo-controlled trials of calcium antagonists (two trials, 5520 patients mostly with hypertension) showed reductions in stroke (39% [15-56]) and major cardiovascular events (28% [13-41]). In the overview of trials comparing blood-pressure-lowering strategies of different intensity (three trials, 20,408 patients with hypertension), there were reduced risks of stroke (20% [2-35]), coronary heart disease (19% [2-33]), and major cardiovascular events (15% [4-24]) with more intensive therapy. In the overviews comparing different antihypertensive regimens (eight trials, 37,872 patients with hypertension), several differences in cause-specific effects were seen between calcium-antagonist-based therapy and other regimens, but each was of borderline significance. Strong evidence of benefits of ACE inhibitors and calcium antagonists is provided by the overviews of placebo-controlled trials. There is weaker evidence of differences between treatment regimens of differing intensities and of differences between treatment regimens based on different drug classes. Data from continuing trials of blood-pressure-lowering drugs will substantially increase the evidence available about any real differences that might exist between regimens.",2001.0,0,0 592,11134659,Pravastatin down-regulates inflammatory mediators in human monocytes in vitro.,O Grip; S Janciauskiene; S Lindgren,"There is experimental evidence that pravastatin, which is designed to inhibit the rate-limiting enzyme of cholesterol synthesis, can affect cell metabolism and proliferation. We therefore studied the effects of pravastatin on the generation of inflammatory mediators in non-stimulated and stimulated primary human monocytes in vitro. In our experimental model, pravastatin induced a dose-dependent inhibition of monocyte cholesterol synthesis (up to 67%), up-regulation of low density lipoprotein receptor mRNA (by about 35%) and reduction in intracellular cholesterol accumulation. In parallel, exposure of non-stimulated monocytes to various doses of pravastatin resulted in inhibition of monocyte chemoattractant protein-1 protein expression (up to 15-fold), reduction of tumour necrosis factor alpha (TNF-alpha) levels (up to 2.4-fold) and a total loss of metalloproteinase-9 activity in stimulated cells. Pravastatin at concentrations of 5, 100 and 500 microM caused an inhibition of TNF-alpha-induced cellular oxygen consumption from 2. 4- to 5.5-fold. These data extend the findings of potential anti-inflammatory actions of statins and also suggest the possibility for pravastatin use in a broader spectrum of inflammatory situations.",2001.0,0,0 593,11134806,"Effects of cerivastatin on lipid profiles, lipid peroxidation and platelet and endothelial activation in renal transplant recipients.",S Caillard; C Leray; K Kunz; C Gachet; M Offner; M L Wiesel; T Hannedouchte; J P Cazenave; B Moulin,,2001.0,0,0 594,11137095,Effects of initial and long-term lipid-lowering therapy on vascular wall characteristics.,F L Ubels; J H Muntinga; J J van Doormaal; W D Reitsma; A J Smit,"Several studies have demonstrated the beneficial effects of 3 hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on vascular properties, but little is known about treatment intensification. We compared patients in whom statins were started (INITIAL, n=30) for hypercholesterolaemia (>6.5 mmol l(-1)) with a matched patient group of long-time statin users, with similar baseline characteristics for lipids, intima-media thickness (IMT), and pulse wave velocity, in whom treatment with statins was intensified (LONG-TERM, n=54). At baseline and after 1 year, lipid profile, IMT of the carotid and femoral arteries, aortic distensibility using pulse-wave velocity and various properties of the peripheral vascular bed using a recently developed bio-impedance method were measured. After 1 year the relative changes in lipid profile were significantly better in the INITIAL compared with the LONG-TERM-group. The relative changes in IMT of the mean internal carotid and common femoral arteries significantly differed between the INITIAL and LONG-TERM-group (-8 and +11%, -11 and +22%, respectively). After 1 year, in both groups, most other vascular wall characteristics were unaltered compared with baseline. In conclusion, the beneficial structural alterations of the vascular wall were greater after starting than after intensifying already existing lipid-lowering treatment. This suggests that other effects of HMG-CoA reductase inhibitors than lipid-lowering alone must be involved in vascular changes.",2001.0,0,0 595,11137513,Diphenylpyraline-responsive parkinsonism in cerebrotendinous xanthomatosis: long-term follow up of three patients.,T Ohno; S Kobayashi; M Hayashi; M Sakurai; I Kanazawa,"A long-term follow-up study was made of three patients with cerebrotendinous xanthomatosis (CTX) associated with parkinsonism, two of whom were siblings. Besides typical CTX symptoms, all three patients showed severe parkinsonism. This observation has been rarely reported in CTX. The fact that the two siblings showed parkinsonism strongly suggests the genetic propensity to parkinsonism in these CTX patients. Positron emission tomography studies of the two patients revealed presynaptic dysfunction of the nigro-striatal dopaminergic system. Treatment with the reductase inhibitor hydroxymethyl glutaryl coenzyme successfully corrected the serum cholestanol level in the early stage of the disease, which, however, did not arrest the progression of clinical symptoms, particularly their parkinsonism. Clinically, levodopa had a little effect on parkinsonism, whereas an antihistamine drug, diphenylpyraline hydrochloride (DPP) had excellent effects on all three patients throughout the long-term follow up. The mechanism of the action of DPP on parkinsonism is unclear, however, the drug seems to be a therapeutic choice for treating parkinsonism in CTX.",2001.0,0,0 596,11137806,Preoperative lipid control with simvastatin reduces the risk for graft failure already 1 year after myocardial revascularization.,J T Christenson,"Hypercholesterolemia is a recognized risk factor for development of atherosclerosis in both native coronary arteries and bypass grafts. Lipid-lowering therapy with statins is effective. Few data are available for studies on bypass grafts. The influence of hypercholesterolemia on development of bypass graft disease was studied. Clinical and angiographic follow up 1yr after CABG of patients with a preoperative cholesterol >6.2mmol/l, with a preoperative lipid control (group 2) or controls (group 1) and patients with cholesterol <4.7mmol/l (group 3) were studied. Patient demographics, angiography and operation data were the same in all the groups. Group 1 patients had significantly higher incidence of graft lesions, requiring more interventions than Group 2. Sequential vein bypass grafts showed superior features compared to single vein grafts. Preoperative lipid control with statins is strongly recommended, since uncontrolled hypercholesterolemia has a direct impact on the outcome of CABG procedure. It significantly reduces the development of vein graft obstructive disease.",2001.0,0,1 597,11137829,Usefulness of Nisoldipine for prevention of restenosis after percutaneous transluminal coronary angioplasty (results of the NICOLE study). NIsoldipine in COronary artery disease in LEuven.,J A Dens; W J Desmet; P Coussement; I K De Scheerder; K Kostopoulos; P Kerdsinchai; C Supanantaroek; J H Piessens,"The NIsoldipine in COronary artery disease in LEuven (NICOLE) study investigates (1) whether nisoldipine, a dihydropyridine calcium antagonist, reduces the progression of minor coronary arterial lesions in the long term, and (2) whether it reduces the restenosis rate after successful percutaneous transluminal coronary angioplasty (PTCA). The NICOLE study is a single-center, randomized, double-blind trial in 826 patients, who underwent a successful PTCA. Nisoldipine 40 mg coat-core or placebo was started the morning after the procedure and continued for 3 years. All coronary arterial segments were measured on preprocedural angiogram and on the second follow-up angiogram at 3 years. On the first follow-up angiogram at 6 months only the dilated segments were measured. Although the study is still ongoing until the primary end point is reached, we report in this study the angiographic restenosis data as well as the clinical events observed at 6-month follow-up. The per-protocol population consisted of 646 patients. Restenosis, defined as a > or =50% loss of the initial gain (National Heart, Lung, and Blood Institute criterion IV) occurred in 49% and 55% of the 308 nisoldipine-treated and the 338 placebo-treated patients, respectively (p = NS). At follow-up, the rates of death and myocardial infarction were low and similar in both groups, but in the nisoldipine group, less patients required early coronary angiography (18% vs 26%, p = 0.006) and subsequent revascularization procedures (32% vs 41%, p = 0.057). Thus, nisoldipine did not significantly reduce the angiographic restenosis rate after PTCA, but reduced the number of repeat revascularization procedures, which may be due to its antianginal action.",2001.0,0,0 598,11137832,"Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia.",R J Frost; C Otto; H C Geiss; P Schwandt; K G Parhofer,"Diabetic dyslipoproteinemia characterized by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and often elevated low-density lipoprotein (LDL) cholesterol with predominance of small, dense LDL is a strong risk factor for atherosclerosis. It is unclear whether fibrate or statin therapy is more effective in these patients. We compared atorvastatin (10 mg/day) with fenofibrate (200 mg/day), each for 6 weeks separated by a 6-week washout period in 13 patients (5 men and 8 women; mean age 60.0+/-6.8 years; body mass index 30.0+/-3.0 kg/m2) with type 2 diabetes mellitus (hemoglobin A1c 7.3+/-1.1%) and mixed hyperlipoproteinemia (LDL cholesterol 164.0+/-37.8 mg/dl, triglycerides 259.7+/-107 mg/dl, HDL cholesterol 48.7+/-11.0 mg/dl) using a randomized, crossover design. Lipid profiles, LDL subfraction distribution, fasting plasma viscosity, red cell aggregation, and fibrinogen concentrations were determined before and after each drug. Atorvastatin decreased all LDL subfractions (LDL cholesterol, -29%; p <0.01) including small, dense LDL. Fenofibrate predominantly decreased triglyceride concentrations (triglycerides, -39%; p <0.005) and induced a shift in LDL subtype distribution from small, dense LDL (-31%) to intermediate-dense LDL (+36%). The concentration of small, dense LDL was comparable during therapy to both drugs (atorvastatin 62.8+/-19.5 mg/dl, fenofibrate 63.0+/-18.1 mg/dl). Both drugs induced an increase in HDL cholesterol (atorvastatin +10%, p <0.05; fenofibrate +11%, p = 0.06). In addition, fenofibrate decreased fibrinogen concentration (-15%, p <0.01) associated with a decrease in plasma viscosity by 3% (p <0.01) and improved red cell aggregation by 15% (p <0.05), whereas atorvastatin did not affect any hemorheologic parameter. We conclude that atorvastatin and fenofibrate can improve lipoprotein metabolism in type 2 diabetes. However, the medications affect different aspects of lipoprotein metabolism.",2001.0,0,0 599,11139091,Clinical trials of coronary revascularization for chronic stable angina: medical treatment versus coronary revascularization.,A F Parisi,"For patients with chronic stable angina, several randomized trials have been performed comparing medical management with surgery, medical management with angioplasty, and angioplasty with surgery. Data from the medical versus revascularization trials (either surgery or angioplasty) support the following contentions: For patients with multivessel disease, particularly involving the proximal left anterior descending coronary artery, survival is superior to surgical treatment. Symptom relief with either type of revascularization is superior to medical management. The subsequent rate of myocardial infarction is not affected by the initial treatment strategy, whether medical, angioplasty, or surgery. In individual patients the potential benefits of any revascularization strategy must be weighed against its initial risks. Further study is needed, particularly with multifaceted pharmacologic therapy and with updated angioplasty techniques, to evaluate relative survival benefits in these patients. The studies supporting these conclusions are highlighted in this paper.",2001.0,0,0 600,11141142,Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials.,M F Muldoon; S B Manuck; A B Mendelsohn; J R Kaplan; S H Belle,"To investigate the association between cholesterol lowering interventions and risk of death from suicide, accident, or trauma (non-illness mortality). Meta-analysis of the non-illness mortality outcomes of large, randomised clinical trials of cholesterol lowering treatments. 19 out of 21 eligible trials that had data available on non-illness mortality. INTERVENTIONS REVIEWED: Dietary modification, drug treatment, or partial ileal bypass surgery for 1-10 years. Deaths from suicides, accidents, and violence in treatment groups compared with control groups. Across all trials, the odds ratio of non-illness mortality in the treated groups, relative to control groups, was 1.18 (95% confidence interval 0.91 to 1.52; P=0.20). The odds ratios were 1.28 (0.94 to 1.74; P=0.12) for primary prevention trials and 1.00 (0.65 to 1.55; P=0.98) for secondary prevention trials. Randomised clinical trials using statins did not show a treatment related rise in non-illness mortality (0.84, 0.50 to 1.41; P=0.50), whereas a trend toward increased deaths from suicide and violence was observed in trials of dietary interventions and non-statin drugs (1.32, 0.98 to 1.77; P=0.06). No relation was found between the magnitude of cholesterol reduction and non-illness mortality (P=0.23). Currently available evidence does not indicate that non-illness mortality is increased significantly by cholesterol lowering treatments. A modest increase may occur with dietary interventions and non-statin drugs.",2001.0,0,0 601,11144997,Reduction of LDL cholesterol in patients with primary hypercholesterolemia by SCH 48461: results of a multicenter dose-ranging study.,C A Dujovne; H Bays; M H Davidson; R Knopp; D B Hunninghake; E A Stein; A C Goldberg; P Jones; L J Lipka; C Cuffie-Jackson,"SCH 48461, an inhibitor of gastrointestinal absorption of cholesterol, was evaluated for its effects on lipid parameters in patients with primary hypercholesterolemia in a multicenter, double-blind, randomized, parallel-group study. Following the baseline phase, which consisted of a 2- to 10-week drug washout and dietary stabilization phase and a 4-week placebo lead-in (placebo baseline phase), 190 patients were randomized to an 8-week double-blind active drug (SCH 48461 1, 6.25, 25, 100, 200, or 400 mg) or 40 mg lovastatin once daily each morning or placebo treatment phase. By week 2, patients who received SCH 48461 6.25 to 400 mg or lovastatin demonstrated greater reduction from baseline in directly measured low-density lipoprotein cholesterol (LDL-C) levels than patients in the placebo group (p < or = 0.03). Overall, the percent reductions in LDL-C from baseline increased as the dose of SCH 48461 increased, with 0.6% to 15.5% reductions from the minimum dose of 1 mg to the maximum dose of 400 mg. Lovastatin 40 mg/day reduced LDL-C by 30.7% (p < 0.01). Statistically significant decreases were also seen for total cholesterol and apolipoprotein B (apo B) with doses of 25 mg to 400 mg of SCH 48461 and lovastatin. SCH 48461 was well tolerated. There was a similar incidence of adverse events in each SCH 48461- or lovastatin-treated group compared to placebo. This study demonstrated a clinically and statistically significant cholesterol-lowering effect of SCH 48461 in patients with primary hypercholesterolemia.",2001.0,0,0 602,11152019,Delavirdine: a review of its use in HIV infection.,L J Scott; C M Perry,"Delavirdine, a bisheteroarylpiperazine derivative, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that allosterically binds to HIV-1 reverse transcriptase, inhibiting both the RNA- and DNA-directed DNA polymerase functions of the enzyme. Delavirdine in combination with nucleoside reverse transcriptase inhibitors (NRTIs) produced sustained reductions in plasma viral loads and improvements in immunological responses in large randomised, double-blind, placebo-controlled studies of 48 to 54 weeks' duration. In patients with advanced HIV infection, triple therapy with delavirdine, zidovudine and lamivudine, didanosine or zalcitabine for 1 year significantly prolonged the time to virological failure compared with dual therapy (delavirdine plus zidovudine or 2 NRTIs; p < 0.0001). After 50 weeks' treatment, plasma HIV RNA levels were below the limit of detection (LOD; <50 copies/ml) for 40% of patients receiving triple therapy but for only 6% of those receiving dual NRTI therapy. Preliminary results suggest that delavirdine also has beneficial effects on surrogate markers as a component of protease inhibitor-containing triple or quadruple regimens. At 16 to 48 weeks, the minimum mean reduction in plasma viral load from baseline was 2.5 log10 copies/ml and mean CD4+ counts increased by 100 to 313 cells/microl. The proportion of patients with plasma HIV RNAlevels below the LOD (usually 200 to 500 copies/ml) ranged from 48 to 100% after > or = 16 weeks. Delavirdine was also effective as a component of saquinavir soft gel capsule-containing salvage regimens. Since delavirdine shares a common metabolic pathway (cytochrome P450 3A pathway) with other NNRTIs, HIV protease inhibitors and several drugs used to treat opportunistic infections in patients infected with HIV, the drug is associated with a number of pharmacokinetic interactions. Some of these drug interactions are clinically significant, necessitating dosage adjustments or avoidance of co-administration. Delavirdine is not recommended for use with lovastatin, simvastatin, rifabutin, rifampicin, sildenafil, ergot derivatives, quinidine, midazolam, carbamazepine, phenobarbital or phenytoin. Importantly, the drug favourably increases the plasma concentration of several protease inhibitors. Delavirdine is generally well tolerated. Skin rash is the most frequently reported adverse effect, occurring in 18 to 50% of patients receiving delavirdine-containing combination therapy in clinical trials. Although a high proportion of patients developed a rash, it was typically mild to moderate in intensity, did not result in discontinuation or adjustment of treatment in most patients and resolved quickly. The occurrence of Stevens-Johnson syndrome was rare (1 case in 1,000 patients). A retrospective analysis of pooled clinical trial data indicated that there was no significant difference in the incidence of liver toxicity, liver failure or noninfectious hepatitis between delavirdine-containing and non-delavirdine-containing antiretroviral treatment groups. In addition, the incidence of lipodystrophy, metabolic lipid disorders, hyperglycaemia and hypertriglyceridaemia was not significantly different between these 2 treatment groups. In combination with NRTIs. delavirdine produces sustained improvements in surrogate markers of HIV disease and prolongs the time to virological failure in adult patients with HIV infection. Preliminary data of delavirdine as a component of protease inhibitor-containing triple or quadruple highly active antiretroviral therapy regimens indicate that patients achieve marked improvements in virological and immunological markers. The drug is generally well tolerated, with a transient skin rash, typically of mild to moderate intensity, being the most common adverse effect. Delavirdine is an effective component of recommended antiretroviral treatment strategies for adult patients with HIV infection and, in combination with 2 NRTIs as a first-line therapy, the drug has the advantage of sparing protease inhibitors for subsequent use. Since delavirdine favourably increases plasma concentrations of several protease inhibitors, the drug may also be beneficial as a component of salvage therapy in combination with protease inhibitors.",2001.0,0,0 603,11152850,Effectiveness of high doses of simvastatin as monotherapy in mixed hyperlipidemia.,M Miller; C Dolinar; W Cromwell; J D Otvos,"Twenty subjects with mixed hyperlipidemia participated in a 3-arm crossover trial to evaluate the effectiveness of high-dose simvastatin as monotherapy. Significant reductions were observed in atherogenic lipids and lipoproteins. The highest dose of simvastatin also resulted in significant increases in high-density lipoprotein cholesterol (21%) with a comparable increase in large, protective high-density lipoprotein particles.",2001.0,0,0 604,11153749,Is ST segment elevation non-Q-wave myocardial infarction after thrombolytic therapy a new clinical entity that requires an invasive management strategy?,B R Chaitman; S R Bitar,,2001.0,0,0 605,11157682,Do interventions to reduce coronary heart disease reduce the incidence of type 2 diabetes? A possible role for inflammatory factors.,S M Haffner,,2001.0,0,0 606,11157683,Statins for stroke: the second story?,J Plutzky; P M Ridker,,2001.0,0,0 607,11157685,Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.,D J Freeman; J Norrie; N Sattar; R D Neely; S M Cobbe; I Ford; C Isles; A R Lorimer; P W Macfarlane; J H McKillop; C J Packard; J Shepherd; A Gaw,"We examined the development of new diabetes mellitus in men aged 45 to 64 years during the West of Scotland Coronary Prevention Study. Our definition of diabetes mellitus was based on the American Diabetic Association threshold of a blood glucose level of >/=7.0 mmol/L. Subjects who self-reported diabetes at baseline or had a baseline glucose level of >/=7.0 mmol/L were excluded from the analyses. A total of 5974 of the 6595 randomized subjects were included in the analysis, and 139 subjects became diabetic during the study. The baseline predictors of the transition from normal glucose control to diabetes were studied. In the univariate model, body mass index, log triglyceride, log white blood cell count, systolic blood pressure, total and HDL cholesterol, glucose, and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, body mass index, log triglyceride, glucose, and pravastatin therapy were retained as predictors of diabetes in this cohort. We concluded that the assignment to pravastatin therapy resulted in a 30% reduction (P:=0.042) in the hazard of becoming diabetic. By lowering plasma triglyceride levels, pravastatin therapy may favorably influence the development of diabetes, but other explanations, such as the anti-inflammatory properties of this drug in combination with its endothelial effects, cannot be excluded with these analyses.",2001.0,0,0 608,11157690,Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) Project.,R P Byington; B R Davis; J F Plehn; H D White; J Baker; S M Cobbe; J Shepherd,"Stroke is a leading cause of death and disability. Although clinical trials of the early lipid-lowering therapies did not demonstrate a reduction in the rates of stroke, data from recently completed statin trials strongly suggest benefit. The effect of pravastatin 40 mg/d on stroke events was investigated in a prospectively defined pooled analysis of 3 large, placebo-controlled, randomized trials that included 19 768 patients with 102 559 person-years of follow-up. In all, 598 participants had a stroke during approximately 5 years of follow-up. The 2 secondary prevention trials (CARE [Cholesterol And Recurrent Events] and LIPID [Long-term Intervention with Pravastatin in Ischemic Disease]) individually demonstrated reductions in nonfatal and total stroke rates. When the 13 173 patients from CARE and LIPID were combined, there was a 22% reduction in total strokes (95% CI 7% to 35%, P:=0.01) and a 25% reduction in nonfatal stroke (95% CI 10% to 38%). The beneficial effect of pravastatin on total stroke was observed across a wide range of patient characteristics. WOSCOPS (West of Scotland Coronary Prevention Study, a primary prevention trial in hypercholesterolemic men) exhibited a similar, although smaller, trend for a reduction in total stroke. Among the CARE/LIPID participants, pravastatin was associated with a 23% reduction in nonhemorrhagic strokes (95% CI 6% to 37%), but there was no statistical treatment group difference in hemorrhagic or unknown type. Pravastatin reduced the risk of stroke over a wide range of lipid values among patients with documented coronary disease. This effect was due to a reduction in nonfatal nonhemorrhagic strokes.",2001.0,0,1 609,11158224,Comparative effects of cerivastatin and fenofibrate on the atherogenic lipoprotein phenotype in proteinuric renal disease.,C J Deighan; M J Caslake; M McConnell; J M Boulton-Jones; C J Packard,"Patients with nephrotic-range proteinuria have impaired clearance of triglyceride-rich lipoproteins. This results in the atherogenic lipoprotein phenotype (mild hypertriglyceridemia, low high-density lipoproteins [HDL], and excess small, dense low-density lipoproteins [LDLIII]). Excess remnant lipoproteins (RLP) are linked to hypertriglyceridemia and may contribute to the atherogenicity of nephrotic dyslipidemia. A randomized crossover study compared the effects of a statin (cerivastatin) and a fibrate (fenofibrate) on LDLIII and RLP in 12 patients with nephrotic-range proteinuria. Cerivastatin reduced cholesterol (21%, P: < 0.01), triglyceride (14%, P: < 0.05), LDL cholesterol (LDL-C; 23%, P: < 0.01), total LDL (18%, P: < 0.01), and LDLIII concentration (27% P: < 0.01). %LDLIII, RLP-C, and RLP triglyceride (RLP-TG) were unchanged. Plasma LDLIII reduction with cerivastatin treatment correlated with LDL-C reduction (r(2) = 34%, P: < 0.05). Fenofibrate lowered cholesterol (19%), triglyceride (41%), very low-density lipoprotein cholesterol (52%), LDLIII concentration (49%), RLP-C (35%), and RLP-TG (44%; all P: < 0.01). Fenofibrate also reduced %LDLIII from 60 to 33% (P: < 0.01). HDL-C (19%, P: < 0.01) increased with fenofibrate treatment; LDL-C and total LDL were unchanged. The reduction in LDLIII concentration and RLP-C with fenofibrate treatment correlated with plasma triglyceride reduction (LDLIII r(2) = 67%, P: < 0.001; RLP cholesterol r(2) = 58%, P: < 0.005). Serum creatinine increased with fenofibrate treatment (14%, P: < 0.01); however, creatinine clearance was unchanged. LDLIII concentration was 187 +/- 85 mg/dl after cerivastatin treatment and 133 +/- 95 mg/dl after fenofibrate treatment. Cerivastatin and fenofibrate reduce LDLIII concentration in nephrotic-range proteinuria. However, atherogenic concentrations of LDLIII remain prevalent after either treatment. Fenofibrate but not cerivastatin reduces remnant lipoproteins. The two treatments seem to reduce LDLIII by different mechanisms, suggesting a potential role for combination therapy to optimize lowering of LDLIII and RLP.",2001.0,0,0 610,11159815,Diabetes and endothelial dysfunction: a clinical perspective.,J Calles-Escandon; M Cipolla,"The main etiology for mortality and a great percent of morbidity in patients with diabetes mellitus is atherosclerosis. A hypothesis for the initial lesion of atherosclerosis is endothelial dysfunction, defined pragmatically as changes in the concentration of the chemical messengers produced by the endothelial cell and/or by blunting of the nitric oxide-dependent vasodilatory response to acetylcholine or hyperemia. Endothelial dysfunction has been documented in patients with diabetes and in individuals with insulin resistance or at high risk for developing type 2 diabetes. Factors associated with endothelial dysfunction in diabetes include activation of protein kinase C, overexpression of growth factors and/or cytokines, and oxidative stress. Several therapeutic interventions have been tested in clinical trials aimed at improving endothelial function in patients with diabetes. Insulin sensitizers may have a beneficial effect in the short term, but the virtual absence of trials with cardiovascular end-points preclude any definitive conclusion. Two trials offer optimism that treatment with ACE inhibitors may have a positive impact on the progression of atherosclerosis. Although widely used, the effect of hypolipidemic agents on endothelial function in diabetes is not clear. The role of antioxidant therapy is controversial. No data have been published regarding the effects of hormonal replacement therapy on endothelial dysfunction in postmenopausal women with type 2 diabetes.",2001.0,0,0 611,11161942,The post myocardial infarction exercise test: still worthy after all of these years.,E A Ashley; V Froelicher,,2001.0,0,0 612,11163746,"Clinical trials update: highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure.",S D Thackray; K K Witte; A Khand; A Dunn; A L Clark; J G Cleland,"This article continues a series of reports summarising recent research developments pertinent to the topic of heart failure. This is a summary of presentations made at scientific sessions of the American Heart Association in November 2000. Clinical studies of particular interest to people caring for patients with heart failure include Val-HeFT, AMIOVIRT and V-MAC. New data from beta-blockers trials are reviewed, highlights from some important developments in post-infarction care, including MIRACL and FLORIDA, discussed and results of some early studies of gene therapy reported.",2001.0,0,0 613,11165421,Operational aspects of terminating the doxazosin arm of The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).,S L Pressel; B R Davis; J T Wright; T S Geraci; C Kingry; C E Ford; L B Piller; J Bettencourt; B Kimmel; C Lusk; H Parks; L M Simpson; C Nwachuku; C D Furberg; ALLHAT Collaborative Research Group,"The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, practice-based trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI). The double-blind, active-controlled component of ALLHAT was designed to determine whether the rate of the primary outcome-a composite of fatal coronary heart disease and nonfatal myocardial infarction-differs between diuretic (chlorthalidone) treatment and each of three other classes of antihypertensive drugs: a calcium antagonist (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin) in high-risk hypertensive persons ages 55 years and older. In addition, 10,377 ALLHAT participants with mild to moderate hypercholesterolemia were also enrolled in a randomized, open-label trial designed to determine whether lowering serum LDL cholesterol with an HMG CoA reductase inhibitor (pravastatin) will reduce all-cause mortality as compared to a control group receiving ""usual care."" In January 2000, an independent data review committee recommended discontinuing the doxazosin treatment arm. The NHLBI director promptly accepted the recommendation. This article discusses the steps involved in the orderly closeout of one arm of ALLHAT and the dissemination of trial results. These steps included provisional preparations; the actual decision process; establishing a timetable; forming a transition committee; preparing materials and instructions; informing 65 trial officers and coordinators, 628 active clinics and satellite locations, 313 institutional review boards, over 42,000 patients, and the general public; reporting detailed trial results; and monitoring the closeout process. Control Clin Trials 2001;22:29-41",2001.0,0,0 614,11165956,Usefulness of in-hospital prescription of statin agents after angiographic diagnosis of coronary artery disease in improving continued compliance and reduced mortality.,J B Muhlestein; B D Horne; T L Bair; Q Li; T E Madsen; R R Pearson; J L Anderson,"Despite well-documented clinical benefit of the use of statins in patients with coronary artery disease (CAD) and even mild lipid elevations, studies have documented the presence of a significant ""treatment gap"" between those patients in whom treatment is indicated and those patients who actually receive it. It has been proposed that a prescription for statin therapy given to indicated patients at the time of initial angiographic diagnosis of CAD has the potential to improve long-term medication compliance, but this requires further evaluation. We prospectively followed 600 patients with angiographically demonstrated CAD (diameter stenosis > or = 70%) who met the National Cholesterol Education Project (NCEP) guidelines for statin therapy for an average of 3.0 years (range 2.0 to 4.6). Patients were an average of 65 years of age, 78% were men, 77% presented initially with acute ischemic syndrome, and 64 (10.7%) died during follow-up. Overall, 105 patients (18%) were discharged from the initial hospitalization with a statin prescription. At long-term follow-up, the number of patients taking statins had increased to 47%. However, long-term statin compliance was significantly higher among patients initially discharged with a statin prescription than those who were not (77% vs 40%; p < 0.0001). Additionally, those patients discharged with a statin prescription had significantly reduced mortality rate at long-term follow-up (5.7% vs 11.7%; p = 0.05). Cox hazard regression analysis, controlling for all known clinical baseline variables, confirmed the absence of a prehospital discharge statin prescription to be an independent predictor of increased mortality (hazard ratio 2.4) with a statistical trend (p = 0.06). Thus, this study demonstrates that after angiographic diagnosis of CAD, prescription of appropriate statin therapy at the time of hospital discharge improves long-term statin compliance and may significantly enhance survival.",2001.0,0,0 615,11165973,Fibrinogen response with simvastatin versus atorvastatin in familial hypercholesterolemia.,A S Wierzbicki; P J Lumb; G Chik; M A Crook,"The clinical and biochemical determinants of the fibrinogen response to simvastatin or atorvastatin therapy were assessed in 130 patients with severe polygenic or familial hypercholesterolemia treated in a randomized open-trial format design. Hyperfibrinogenemia was associated with atorvastatin, baseline fibrinogen, and initial concentration and change in concentration of apolipoprotein B or low-density lipoprotein cholesterol.",2001.0,0,0 616,11166775,Homocysteine and lipid lowering agents. A comparison between atorvastatin and fenofibrate in patients with mixed hyperlipidemia.,P Giral; E Bruckert; N Jacob; M J Chapman; M J Foglietti; G Turpin,"Hyperhomocysteinemia is a risk factor for cardiovascular disease. Elevation in homocysteine levels has recently been demonstrated during lipid lowering treatment with fibrates. We compared the effect of a statin and a fibrate (atorvastatin and fenofibrate) on plasma levels of homocysteine and other thiol compounds in hyperlipidemic patients. The study was of open randomized, parallel design with a preliminary screening phase, and a 6 week placebo period. After the placebo period, patients were allocated randomly to atorvastatin or fenofibrate for a 6 month period. Plasma thiols were assayed by high pressure liquid chromatography with fluorescence detection. There were 29 patients in the fenofibrate group and 24 in the atorvastatin group. Fenofibrate induced a significant increase in both homocysteine and cysteine plasma levels (+35.8 and +18%, respectively, P<0.0001); by contrast, cysteinylglycine remained stable. There were no significant changes in any thiol compounds in the atorvastatin group. Both treatments induced a significant decrease in uric acid, although fenofibrate was noticeably more effective than atorvastatin (-22.8 and -6.4%, respectively). Fenofibrate induced a non-significant increase in creatinine (12%) while atorvastatin reduced it (4.7%, NS). Our study confirms that the induction of elevations in plasma homocysteine and cysteine levels are a distinct feature of the pleiotropic effects of fibrates. Further studies are needed not only to investigate the potential deleterious effects of this modification, but also to define the specific mechanism which underlies such fibrate-mediated action.",2001.0,0,1 617,11166784,Effect of simvastatin on micropulmonary red cell mass in patients with hyperlipoproteinemia.,I Pintaric; D Eterović; J Tocilj; Z Reiner; I Lusić,"The purpose of this study was to compare the macrocirculatory and microcirculatory effects of simvastatin in hyperlipemic patients. In vitro measurements of lipoprotein levels and macrocirculatory hemorheology were complemented by in vivo measurements of the pulmonary capillary red cell volume (RCVpc) before and after 6 weeks of treatment with 40 mg of simvastatin daily in 30 male patients with hyperlipoproteinemia type IIa. RCVpc was assessed from the vascular component of the lung diffusing capacity for carbon monoxide, using the modification of the Roughton-Forster's method. RCVpc was increased in patients (60.9+/-9 versus 40+/-9 ml in healthy controls) and it decreased to 47+/-6 ml after treatment (P=5x10(-11)). The decreases in RCVpc correlated to concomitant decreases in peripheral hematocrit (R=0.68) and serum total cholesterol (-34% on average; R=0.59). Membrane diffusing capacity was normal in patients and not affected by the therapy; suggesting that increased RCVpc was due to increased micropulmonary hematocrit. Thus, it appears that viscosity in microcirculation is greatly increased in hyperlipemic patients and that simvastatin is able to normalize it. Since microcirculatory conditions can only partly be inferred from in vitro measurements the use of lung diffusional parameters was advocated, which enable in vivo assessment of hemorheology in microcirculation.",2001.0,0,0 618,11169596,Interim monitoring of clinical trials based on long-term binary endpoints.,I C Marschner; S L Becker,"This paper discusses interim analysis of randomized clinical trials for which the primary endpoint is observed at a specific long-term follow-up time. For such trials subjects only yield direct information on the primary endpoint once they have been followed through to the long-term follow-up time, potentially eliminating a large proportion of the accrued sample from an interim analysis of the primary endpoint. We advocate more efficient interim analysis of long-term endpoints by augmenting long-term information with short-term information on subjects who have not yet been followed through to the long-term follow-up time. While retaining the long-term endpoint as the subject of the analysis, methods of jointly analysing short- and long-term data are discussed for reversible binary endpoints. It is shown theoretically and by simulation that the use of short-term information improves the efficiency with which long-term treatment differences are assessed based on interim data. Sequential analysis of treatment differences is discussed based on spending functions, and is illustrated with a numerical example from a cholesterol treatment trial.",2001.0,0,0 619,11171785,Common hepatic lipase gene promoter variant determines clinical response to intensive lipid-lowering treatment.,A Zambon; S S Deeb; B G Brown; J E Hokanson; J D Brunzell,"The common -514 C-->T polymorphism in the promoter region of the hepatic lipase (HL) gene affects HL activity. The C allele is associated with higher HL activity, more dense and atherogenic LDL, and lower HDL(2) cholesterol. Intensive lipid-lowering therapy lowers HL activity, increases LDL and HDL buoyancy, and promotes coronary artery disease (CAD) regression. We tested the hypothesis that subjects with the CC genotype and a more atherogenic lipid profile experience the greatest CAD regression from these favorable effects. Forty-nine middle-aged men with dyslipidemia and established CAD who were undergoing intensive lipid-lowering therapy were studied. Change in coronary stenosis was assessed by quantitative angiography, HL polymorphism by polymerase chain reaction amplification, HL activity by (14)C-labeled substrate, and LDL buoyancy by density-gradient ultracentrifugation. The response to lipid-lowering therapy was significantly different among subjects with different HL promoter genotypes. Subjects with the C:C genotype had the greatest decrease in HL activity (P<0.005 versus TC and TT by ANOVA) and the greatest improvement in LDL density (P<0.005) and HDL(2)-C (P<0.05) with therapy. These subjects had the greatest angiographic improvement, with 96% of them experiencing CAD regression, compared with 60% of TC and none of the TT patients (P:<0.001). -In middle-aged men with established CAD and dyslipidemia, the HL gene -514 C-->T polymorphism significantly predicts changes in coronary stenosis with lipid-lowering treatment that appear to involve an HL-associated effect on LDL metabolism. This study identifies a gene polymorphism that strongly influences the lipid and clinical response to lipid-lowering drugs.",2001.0,0,0 620,11173182,Beneficial effects of pravastatin in peri- and postmenopausal hyperlipidemic women: a 5-year study on serum lipid and sex hormone levels.,T Ushiroyama; A Ikeda; M Ueki,"The aims of the present study are to assess the 5 year effects of pravastatin on serum lipids and lipoproteins in women around the menopause and to assess the effects of pravastatin on serum gonadotropins and sex steroid levels over a long-term period. We evaluated the long-term efficacy of pravastatin on serum lipid levels (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride) in 121 patients (47 premenopausal and 74 postmenopausal women) suffering from primary hypercholesterolemia. The effects of this lipid-lowering drug on serum gonadotropins and sex steroids (estradiol, estrone, and testosterone) are also reported. Pravastatin produced a remarkable reduction in the serum total cholesterol level of 19.2+/-9.3% (P<0.0001) and 18.9+/-11.8% (P<0.0001), and in LDLl-cholesterol of 25.1+/-18.7% (P<0.0001) and 24+/-18.0% (P<0.0001) after 24 and 60 months' treatment, respectively. In hypertriglyceridemia, pravastatin also produced a remarkable reduction in triglyceride of 29.3+/-27.3% (P<0.0001) and 39.9+/-20.4% (P<0.0001) after 24 and 60 months of treatment, respectively. We found that serum gonadotropins and sex steroid levels changed naturally as a function of age from pre-therapy levels in the premenopausal patients after 60 months of treatment. Pravastatin was well tolerated over 5 years and was a very effective lipid-lowering agent for both hypercholesterolemia and hypertriglyceridemia with no effect on the biosynthesis of sex steroids. These findings suggest that pravastatin can be used in the treatment of hypercholesterolemia with/without high triglyceride levels in women around the menopause.",2001.0,0,0 621,11176209,Bimonthly update. Therapy and clinical trials.,P S Bachorik,,2001.0,0,1 622,11176731,Use of the statins in patients after acute myocardial infarction: does evidence change practice?,C A Jackevicius; G M Anderson; L Leiter; J V Tu,"To compare the use of lipid-lowering agents in 42 628 elderly patients (aged > or =65 years) after acute myocardial infarction, before and after the publication of the Scandinavian Simvastatin Survival Study (4S), using the Ontario Myocardial Infarction Database. Multivariate regression models were created to estimate changes in the rate of statin use over time in monthly cohorts of elderly patients after acute myocardial infarction in Ontario from April 1, 1992, to March 31, 1997. Changes in the rate of statin use over time were estimated using patient and prescriber characteristics. We found a 3.6-fold significant increase in the monthly rate of statin use after the publication of 4S compared with before the publication of 4S (P<.001); specifically, the rate of increase in simvastatin and pravastatin sodium use was higher after the publication of 4S (P<.001 for each). Before the publication of 4S, the rate of increase in statin use in younger patients (aged 65-74 years) was 2.7 times higher than in older patients (aged > or =75 years) (P =.02), while after the publication of 4S, the rate of increase in statin use was only 1.8-fold higher in the younger group (P<.001). After the publication of 4S, there was a 1.6-fold higher rate of increase in statin use in male compared with female patients (P =.006). Also after the publication of 4S, specialists (cardiologists and internists) had a 2-fold higher rate of increased use of the statins than did generalists (P<.001). It is possible to shift practice if the evidence of benefit is strong, the intervention is easy to implement, and the intervention is marketed aggressively.",2001.0,0,0 623,11177154,The practice of evidence-based medicine in an acute medical ward: retrospective study.,A C Hui; J Mak; S M Wong; M Fu; K S Wong; R Kay,"To review the practice of evidence-based medicine with respect to drug treatment given to medical in-patients. Retrospective study. Teaching hospital, Hong Kong. Medical records of 129 consecutive patients who were admitted to the acute adult general medical ward from 1 September 1998 to 30 September 1998 were reviewed. Primary diagnoses, drug treatments prescribed, and the level of evidence (based on a literature search of randomised controlled trials and relevant studies) that supported the treatment given. For the 129 patients studied, 91 drug interventions had been prescribed on 312 occasions. Treatment that was supported by randomised controlled trials was prescribed in 162 (52.9%) cases. In 121 (38.8%) cases, patients were given standard and commonly used drugs that were not supported by evidence from clinical trials, and in 29 (9.3%) cases, the treatments given had no substantial supporting evidence. The management of some frequently encountered medical conditions was not based on trial data, because the relevant studies had not been conducted. Basing treatment on comparative efficacy results is a worthwhile goal, but there are limitations in conducting literature searches to identify relevant trials and studies. Evidence-based medical practice is not applicable in a large number of commonly encountered conditions.",2001.0,0,0 624,11177653,Coronary artery reactivity after treatment with simvastatin.,J A Vita; A C Yeung; M Winniford,,2001.0,0,0 625,11179260,The statin era: in search of the ideal lipid regulating agent.,J Shepherd,,2001.0,0,0 626,11179541,Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia.,M L Wolfe; S F Vartanian; J L Ross; L L Bansavich; E R Mohler; E Meagher; C A Friedrich; D J Rader,"Niaspan, when added to a stable dose of a statin in 66 subjects, was found to be safe and highly effective in improving lipid parameters. Subgroup analyses demonstrated its effectiveness in lowering low-density lipoprotein cholesterol in persons not at the National Cholesterol and Education Program low-density lipoprotein cholesterol target and in raising high-density lipoprotein cholesterol in persons with levels < 40 mg/dl.",2001.0,0,0 627,11181465,"Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization.",M Crisby; G Nordin-Fredriksson; P K Shah; J Yano; J Zhu; J Nilsson,"The clinical benefits of lipid lowering with statins are attributed to changes in plaque composition leading to lesion stability, but supporting clinical data from human studies are lacking. Therefore, we investigated the effect of 3 months of pravastatin treatment on composition of human carotid plaques removed during carotid endarterectomy. Consecutive patients with symptomatic carotid artery stenosis received 40 mg/d pravastatin (n=11) or no lipid-lowering therapy (n=13; control subjects) for 3 months before scheduled carotid endarterectomy. Carotid plaque composition was assessed with special stains and immunocytochemistry with quantitative image analysis. Plaques from the pravastatin group had less lipid by oil red O staining (8.2+/-8.4% versus 23.9+/-21.1% of the plaque area, P<0.05), less oxidized LDL immunoreactivity (13.3+/-3.6% versus 22.0+/-6.5%, P<0.001), fewer macrophages (15.0+/-10.2% versus 25.3+/-12.5%, P<0.05), fewer T cells (11.2+/-9.3% versus 24.3+/-13.4%, P<0.05), less matrix metalloproteinase 2 (MMP-2) immunoreactivity (3.6+/-3.9% versus 8.4+/-5.3%, P<0.05), greater tissue inhibitor of metalloproteinase 1 (TIMP-1) immunoreactivity (9.0+/-6.2% versus 3.1+/-3.9%, P<0.05), and a higher collagen content by Sirius red staining (12.4+/-3.1% versus 7.5+/-3.5%, P<0.005). Cell death by TUNEL staining was reduced in the pravastatin group (17.7+/-7.8% versus 32.0+/-12.6%, P<0.05). -Pravastatin decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in human carotid plaques, confirming its plaque-stabilizing effect in humans.",2001.0,0,1 628,11182189,Anti-inflammatory effects of simvastatin in subjects with hypercholesterolemia.,J Musial; A Undas; P Gajewski; M Jankowski; W Sydor; A Szczeklik,"Beneficial effects of statins in preventing cardiovascular events may depend, at least in part, on their anti-inflammatory action. The aim of the study was to assess the influence of simvastatin and aspirin on serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in hypercholesterolemic subjects. In 33 asymptomatic men with total cholesterol (TC) >6.5 mmol l(-1) and in 25 men with coronary heart disease and borderline-high cholesterol levels (between 5.2 and 6.5 mmol l(-1)) chronically treated with low-dose aspirin (75 mg/d), serum levels of CRP, TNF-alpha, IL-6, and IL-8 were determined before and after a 3-month simvastatin therapy (20-40 mg daily). In the former group, these markers of inflammation were also measured before and after a 2-week treatment with aspirin (300 mg/d), implemented prior to and in combination with simvastatin. A distinct reduction of CRP and TNF-alpha was found in both groups; IL-6 levels were decreased only in subjects with marked hypercholesterolemia. Aspirin had no effect on the anti-inflammatory action of simvastatin. In men with hypercholesterolemia simvastatin treatment lowers serum levels of CRP and proinflammatory cytokines. Low-dose aspirin does not add to the anti-inflammatory action of simvastatin.",2001.0,0,0 629,11185669,Effects of cholestyramine on vitamin E levels in patients treated with statins.,F Kersting; A Selenka; S Walch,"The aim of this study was to investigate the effects of cholestyramine in combination with statins on vitamin E levels and their concentration related to LDL-cholesterol (LDL-C) in patients with hyperlipidemia. In an open-label, randomized study of 25 patients with elevated LDL-C, 12 received cholestyramine (12 g/d) in addition to chronic statin therapy, which had been started at least 8 weeks prior to the study in all patients. At the start and end of the 12-week study period, vitamin E concentrations were measured by high-performance liquid chromatography and cholesterol and triglycerides enzymatically in all patients. Vitamin E levels remained virtually unchanged within normal range before (11.90 +/- 0.71 mg/l) and after 12 weeks (11.69 +/- 0.82 mg/l) of concomitant therapy with cholestyramine. However, the ratio of vitamin E/LDL-C increased from 7.48 +/- 0.56 to 8.58 +/- 0.75 (x 10(-2)) (p < 0.09) in the cholestyramine group but not in the control group. LDL-C concentrations decreased from 162.00 +/- 5.98 to 144.33 +/- 12.48 mg/dl. The authors conclude that cholestyramine 12 g/d given for 12 weeks in addition to chronic statin therapy did not lower vitamin E levels in hyperlipemic patients. However, antioxidant status (vitamin E/LDL-C ratio) seems to be improved by a cholestyramine-associated LDL-C decrease.",2001.0,0,0 630,11187857,Additive effects of another kind of HMG-CoA reductase inhibitor with different pharmacokinetics in the treatment of heterozygous familial hypercholesterolemia.,T Nozue; A Nohara; T Higashikata; A Inazu; H Mabuchi; K Kajinami; J Koizumi,,2001.0,0,0 631,11191718,The association of low serum cholesterol with depression and suicidal behaviours: new hypotheses for the missing link.,R Manfredini; S Caracciolo; R Salmi; B Boari; A Tomelli; M Gallerani,"Several observational studies indicate that reduction of serum cholesterol levels is related to an increase in violent deaths and suicide but the nature of this possible relationship remains unclear. Many confounding factors, e.g. poor health, depression and loss of appetite may play a role in the apparent relationship between serum cholesterol levels and suicide. Two separate phenomena should be considered: lowering total cholesterol and low total cholesterol. This review considers the evidence from epidemiological studies on serum cholesterol lowering and psychiatric disturbances. The available evidence does not seem to substantiate the view that large-scale intervention to reduce cholesterol concentrations could lead to more violent and aggressive behaviour, and generally greater unhappiness. In recent trials using statin treatment, there were slightly fewer deaths from accidents and suicide in the treated group compared with the placebo group. We believe that clinicians should not be deterred from prescribing cholesterol-lowering drugs, to reduce the risk of death from coronary heart disease, when they are indicated.",2001.0,0,0 632,11194239,,,,,0,0 633,11195599,"Diabetes, hypertension, and cardiovascular disease.",C R Conti,,2001.0,0,0 634,11195601,Right ventricular involvement in hypertrophic cardiomyopathy: a case report and literature review.,D Mozaffarian; J H Caldwell,"Although hypertrophic cardiomyopathy (HCM) is classically considered a disease of the left ventricle, right ventricular (RV) abnormalities have also been reported. However, involvement of the right ventricle in HCM has not been extensively characterized. The literature regarding prevalence, genetics, patterns of involvement, histologic findings, symptoms, diagnosis, and treatment of RV abnormalities in HCM is reviewed. To highlight the salient points, a case is presented of apical HCM with significant RV involvement, with an RV outflow tract gradient and near obliteration of the RV cavity, in the absence of a left intraventricular gradient. Right ventricular involvement in HCM appears to be as heterogeneous as that of the left ventricle. The spectrum extends from mild concentric hypertrophy to more unusual severe, obstructive disease. While in some cases the extent of RV involvement correlates with left ventricular (LV) involvement, predominant RV disease can be seen as well. While the genetics of RV involvement have not been well characterized, histologic findings appear to be similar to those in the left ventricle, suggesting similar pathogenesis. Significant RV involvement may result in RV outflow obstruction and/or reduced RV diastolic filling, with potentially increased incidence of severe dyspnea, supraventricular arrhythmias, and pulmonary thromboembolism. The optimal treatment for patients with significant RV disease is unknown. Medical and surgical therapies have been attempted with variable success; experience with newer techniques such as percutaneous catheter ablation has not been reported. Further characterization of RV involvement in HCM is necessary to elucidate more clearly the clinical features and optimal treatments of this manifestation of HCM.",2001.0,0,0 635,11198621,Lipid lowering and coronary bypass graft surgery.,L Campeau,"This article reviews the rationale for lipid lowering in patients who have coronary heart disease, and specifically for post-bypass patients. It has been well demonstrated that after coronary artery bypass graft surgery, atherosclerosis continues to progress in the native circulation and develops at an accelerated rate in saphenous vein bypass grafts. During the last decade, numerous clinical trials based on angiographic or clinical outcomes have clearly shown the beneficial effect of lipid lowering in coronary heart disease. Three trials (CLAS, post-CABG, and CARE) have demonstrated delayed progression of atherosclerosis in SVGs and/or a reduction of cardiac deaths, nonfatal MI, and the need for revascularization after lowering LDL-cholesterol. The recommended target of LDL cholesterol level of more than 100 mg/dl can be safely reached with diet and monotherapy using one of the statin drugs (HMG-CoA reductase inhibitors). Despite this widely-circulated information, there appears to be inadequate public and professional awareness of the importance of properly managing hyperlipidemia after coronary artery bypass graft surgery.",2001.0,0,1 636,11198624,Emerging concepts in metabolic abnormalities associated with coronary artery disease.,J Plutzky,"To an increasing degree, cardiology and endocrinology are finding a broadening interface. There is little doubt that atherosclerosis is in many ways a metabolic disorder, just as it is becoming increasingly clear that diabetes is a vascular disease. Framing such notions is evidence of diabetes as a risk equivalent for coronary disease, and clinical cardiovascular trials demonstrate the impact of altering lipid metabolism. Although the focus has been on statins and LDL, data continues to emerge for other therapies for triglycerides and HDL. These issues are discussed, as are future directions for metabolic therapeutic interventions for vascular disease.",2001.0,0,0 637,11199329,"A prospective study of genetic markers of susceptibility to infection and inflammation, and the severity, progression, and regression of coronary atherosclerosis and its response to therapy.",H Elghannam; S Tavackoli; L Ferlic; A M Gotto; C M Ballantyne; A J Marian,"Inflammation plays a key role in susceptibility to coronary atherosclerosis and response to therapy. A diverse array of factors modulates inflammation, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and CD14 receptors on the surface of macrophages. Genes encoding for inflammatory markers have variants that regulate their expression and are potential risk factors for atherosclerosis. We prospectively analyzed the possible association of CD14 -260C/T, TNF-alpha -308G/A, and IL-6 -174G/C variants, located in the promoter regions, with the severity, progression, and response to therapy of coronary atherosclerosis in a well-characterized cohort. We studied 375 subjects enrolled in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping. Fasting plasma lipids and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. Distributions of genotypes were--for CD14: 100 CC, 184 CT, and 86 TT; IL-6: 152 GG, 153 GC, and 62 CC; and TNF-alpha: 244 GG, 110 GA, and 17 AA. The CD14 CC genotype was associated with incidence of new coronary occlusion (P=0.026); TNF-alpha AA genotype with history of myocardial infarction (MI, P=0.04), and A allele with total occlusions at baseline (P=0.027), and systolic blood pressure (P=0.046); and IL-6-174 CC genotype with baseline minimum lumen diameter (P=0.043) and reduction in lipoprotein(a) with fluvastatin (P=0.03). Otherwise, no association between the genotypes and the biochemical, angiographic, and clinical phenotypes was detected, and neither were genotype-treatment interactions. Functional variants of CD14 -260C/T, TNF-alpha -308G/A, and IL-6 -174G/C, implicated in the susceptibility to infection, are unlikely to confer major risk for susceptibility to coronary atherosclerosis and its progression or response to therapy in the LCAS population.",2001.0,0,0 638,11200090,Comparison of LDL trap assay to other tests of antioxidant capacity; effect of vitamin E and lovastatin treatment.,K Malminiemi; A Palomäki; O Malminiemi,"Oxidized low density lipoprotein (LDL) has a major impact in the development of atherosclerosis. Risk for oxidative modification of LDL is usually determined indirectly by measuring the capability of LDL to resist radical insult. We compared three different methods quantifying the antioxidative capacity of LDL ex vivo in dyslipidemic patients with coronary heart disease. Plasma samples were obtained from two double-blinded cross-over trials. The duration of all interventions (placebo, lovastatin 60 mg/day, RRR-alpha-tocopherol 300 mg/day and lovastatin + RRR-alpha-tocopherol combined) was 6 weeks. The total radical capturing capacity of LDL (TRAP) in plasma was determined using 2,2-azo-bis(2,4-dimethyl-valeronitrile) (AMVN) -induced oxidation, and measuring the extinction time of chemiluminescence. TRAP was compared to the variables characterizing formation of conjugated dienes in copper-induced oxidation. Also the initial concentrations and consumption times of reduced alpha-tocopherol (alpha-TOH) and ubiquinol in AMVN-induced oxidation were determined. Repeatability of TRAP was comparable to that of the lag time in conjugated diene formation. Coefficient of variation within TRAP assay was 4.4% and between TRAP assays 5.9%. Tocopherol supplementation produced statistically significant changes in all antioxidant variables except those related to LDL ubiquinol. TRAP increased by 57%, the lag time in conjugated diene formation by 34% and consumption time of alpha-TOH by 88%. When data of all interventions were included in the analyses, TRAP correlated with the lag time (r = 0.75, p < 10(-6)), with LDL alpha-TOH (r = 0.50, p < 0.001) and with the consumption time of alpha-TOH (r = 0.58, p < 0.0001). In the baseline data, the associations between different antioxidant variables were weaker. TRAP correlated with the lag time (r = 0.55, p < 0.001) and alpha-TOH consumption time (r = 0.48, p < 0.05), and inversely with apolipoprotein Al (r = -0.51, p < 0.05). Lag time at the baseline did not correlate with ubiquinol or tocopherol parameters, or with any plasma lipid or lipoprotein levels analyzed. Lovastatin treatment did not significantly affect the antioxidant capacity of LDL. In conclusion, TRAP reflects slightly different properties of LDL compared to the lag time. Thus, LDL TRAP assay may complement the other methods used to quantify the antioxidant capacity of LDL. However, TRAP and the lag time react similarly to vitamin E supplementation.",2001.0,0,0 639,11202535,Projecting future drug expenditures--2001.,B Mehl; J Santell,"Drug cost projections for 2001 and factors that are likely to influence drug costs are discussed. The year 2000 introduced many new factors into the decision-making process for drug pricing and raised new considerations regarding drug therapy, distribution, and costs. It is anticipated that drug costs will continue to increase at a rate of 11-15% in 2001. Research and development expenditures for new drugs continue to grow and are estimated to be $26.4 billion in 2000, but the number of new drug approvals, especially for new entities, has not increased significantly. The generic drug industry has been expanding, and sales of generics are expected to increase to $20 billion by 2005. Drug costs also keep rising, and sales may reach $243 billion by 2008; this amounts to 12.6% of total health care spending, compared with 8.1% in 1999. There is a trend toward increasing the rate of conversion of prescription drugs to nonprescription status; this may reduce drug budgets somewhat. 2001 will see new systems of drug distribution and pricing, a federal prospective pricing system for ambulatory care patients covered by Medicare, drug imports from foreign manufacturers, and states taking legal action to reduce prescription drug costs. Drug costs in 2001 are expected to continue to increase at double-digit rates. The increase in costs is due to increased utilization, to new products replacing older products, and to price increases for drugs currently on the market.",2001.0,0,0 640,11202630,Antithrombotic drugs for the secondary prevention of ischemic stroke.,G G Nenci; S Goracci,"On the assumption that antithrombotic drugs are able to reduce the incidence of any vascular event independently of where it first occurs, they are used for the secondary prevention of arterial vascular disease in different locations. The Antiplatelet Trialists' Collaboration meta-analysis has shown that the net benefit of antiplatelet drugs in the prevention of stroke, acute myocardial infarction and vascular death is about the same for patients with prior stroke or prior myocardial infarction. Most of the trials included in the Antiplatelet Trialists' Collaboration meta-analysis used aspirin, which was shown to lower the risk of stroke, myocardial infarction, and vascular death in patients with a history of transient ischemic attack or stroke. Aspirin should be given to patients operated on for symptomatic carotid stenosis and should be considered for asymptomatic patients. In a comparative study ticlopidine (500 mg) vs aspirin (650 mg), ticlopidine reduced the relative risk of vascular events by 9% and of recurrent stroke by 21%. When clopidogrel (75 mg) was compared with aspirin (325 mg), a 7.3% relative risk reduction was seen in the stroke group (6431 patients) of the CAPRIE study; a reduction in hemorrhagic events, especially in gastrointestinal bleeding, was also seen. At variance with previous studies, the ESPS-2 showed an advantage when dipyridamole (400 mg) was added to aspirin (50 mg). Oral anticoagulants are more effective than aspirin in the prevention of cardioembolic stroke in patients with atrial fibrillation. The higher efficacy of indobufen with respect to aspirin in this particular setting needs confirmation. Inhibition of thrombosis may be one of the mechanisms explaining the effect of statins in reducing both stroke and cardiac events in high-risk patients.",2001.0,0,0 641,11204308,Systolic and pulse blood pressures (but not diastolic blood pressure and serum cholesterol) are associated with alterations in carotid intima-media thickness in the moderately hypercholesterolaemic hypertensive patients of the Plaque Hypertension Lipid Lowering Italian Study. PHYLLIS study group.,A Zanchetti; G Crepaldi; M G Bond; G V Gallus; F Veglia; A Ventura; G Mancia; G Baggio; L Sampieri; P Rubba; S Collatina; E Serrotti,"The Plaque Hypertension Lipid Lowering Italian Study (PHYLLIS), is the first study in patients with hypertension (diastolic blood pressure (DBP) 95-115 mmHg; systolic blood pressure (SBP) 150-210 mmHg), moderate hypercholesterolaemia (LDL-cholesterol 4.14-5.17 mmol/l (160-200 mg/dl) and initial carotid artery alterations (maximum intima-media thickness (IMT) Tmax > or = 1.3 mm). The primary objective of PHYLLIS is investigating whether in these patients administration of an angiotensin converting enzyme inhibitor, fosinopril, and a statin, pravastatin, is more effective than administration of a diuretic and a lipid-lowering diet in retarding or regressing alterations in carotid IMT. While the study is in progress, baseline data are here reported to clarify the association of various risk factors with carotid IMT in these medium-high risk hypertensive patients. Patients numbering 508 have been randomized to PHYLLIS by 13 peripheral units, in Italy. Age was (mean +/- SD) 58.4 +/- 6.7 years, males were 40.2%, current smokers 16.5%, means +/- SD of serum total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol and triglycerides concentrations were 6.79 +/- 0.67, 4.69 +/- 0.51, 1.37 +/- 0.38, 1.59 +/- 0.64 mmol/l (262.4 +/- 25.8, 181.3 +/- 19.8, 53.0 +/- 14.6, 141.0 +/- 56.7 mg/ dl). Means +/- SD of clinic sitting SBP/DBP were 159.8 +/- 9.0/98.3 +/- 4.2 mmHg. 483 of the 508 patients also had 24 h ambulatory BP monitoring, edited and read at a centralized unit (mean +/- SD 24 h SBP/DBP averages 136.3 +/- 14.1/84.0 +/- 10.0 mmHg). Quantitative B-mode ultrasound (Biosound 2000 II 5A, Biosound, Indianapolis, Indiana, USA) recordings of carotid arteries were taken by certified sonographers in the peripheral units and tracings were all read at a central unit. CBMmax (mean IMT of eight sites at common carotids and bifurcations) was 1.21 +/- 0.17; Mmax (mean of 12 sites also including internal carotids) 1.16 +/- 0.17, and Tmax (single maximum) 1.85 +/- 0.48 mm. Ambulatory SBP and pulse pressure (PP) (24 h, daytime, night-time averages) and their variability indices (24 h SD) were always significantly correlated with CBMmax and Mmax (P0.01 -0.001), and the correlations remained significant after adjustment for age, gender and smoking. No measurement of DBP was ever associated with any IMT measurement. Likewise, no lipid variable was found associated with any IMT measurement. Baseline data from PHYLLIS indicate that in this population of hypertensive patients with moderate hypercholesterolaemia, SBP and PP are with age among the most significant factors associated with carotid artery alterations. However, the narrow range of inclusion LDL-cholesterol and DBP values may have obscured an additional role of these variables.",2001.0,0,0 642,11208246,Hypertriglyceridemia and coronaryheart disease risk.,R S Rosenson,"Several angiographic-based trials have established that triglyceride remnant particles are associated with progression of coronary stenosis, and a recent prospective study has shown that triglycerides are associated with coronary heart disease (CHD), even after adjustment for high-density lipoprotein cholesterol. The importance of plasma triglycerides in CHD risk must be interpreted within the context of other plasma lipoproteins, as well as the fasting and postprandial triglyceride levels. Recommendations for triglyceride lowering are empiric because of the lack of randomized clinical trial data that evaluate triglyceride-lowering therapies and CHD prevention. This article presents a clinical approach to the management of hypertriglyceridemia.",2001.0,0,0 643,11211013,"Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials.",R Collins; S MacMahon,"This two-part review is intended principally for practising clinicians who want to know why some types of evidence about the effects of treatment on survival, and on other major aspects of chronic disease outcome, are much more reliable than others. Although there are a few striking examples of treatments for serious disease which really do work extremely well, most claims for big improvements turn out to be evanescent. Unrealistic expectations about the chances of discovering large treatment effects could misleadingly suggest that evidence from small randomised trials or from non-randomised studies will suffice. By contrast, the reliable assessment of any more moderate effects of treatment on major outcomes--which are usually all that can realistically be expected from most treatments for most common serious conditions--requires studies that guarantee both strict control of bias (which, in general, requires proper randomisation and appropriate analysis, with no unduly data-dependent emphasis on specific parts of the overall evidence) and strict control of random error (which, in general, requires large numbers of deaths or of some other relevant outcome). Past failures to produce such evidence, and to interpret it appropriately, have already led to many premature deaths and much unnecessary suffering.",2001.0,0,0 644,11213855,Factors associated with the risk of liver enzyme elevation in patients with type 2 diabetes treated with a thiazolidinedione.,J V St Peter; K L Neafus; M A Khan; J T Vessey; M S Lockheart,"To characterize frequency of liver enzyme elevation in patients with type 2 diabetes mellitus receiving troglitazone. Retrospective study. Hospital-affiliated medical center. Two hundred ninety-one patients with type 2 diabetes mellitus. Data from patients with an average troglitazone exposure of 412.7 +/- 255.6 days were studied. Enzyme elevations more than 1.5 times the upper limit of normal (ULN) occurred in 17 patients (5.8%) and more than 3-fold elevations in 6 (2.1%). The relationship among enzyme elevation events, demographic factors, duration of troglitazone exposure, frequency of monitoring, and concurrent drugs (limited to glucose and lipid-lowering agents) was assessed by multiple logistic regression. Age was an independent predictor of risk (p=0.009), and concurrent insulin therapy approached statistical significance (p=0.051) for 1.5-fold ULN elevation in liver enzymes. Age and concurrent therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were the only significant predictors of 3-fold ULN elevations (p=0.03 and p=0.04, respectively). Several factors appear to increase the risk of enzyme elevation events in patients treated with troglitazone.",2001.0,0,0 645,11213860,,,,,0,0 646,11214768,Efficacy of combination of atorvastatin and micronised fenofibrate in the treatment of severe mixed hyperlipidemia.,D N Kiortisis; H Millionis; E Bairaktari; M S Elisaf,"In patients with mixed lipid disorders, monotherapy may not effectively control all lipid abnormalities. We undertook this study to assess the efficacy of fenofibrate in combination with atorvastatin in patients with severe mixed dyslipidemia. This was an 18-week, open-label study conducted in our lipid clinic. After a 6-week dietary baseline phase, patients received 200 mg/day micronised fenofibrate for 6 weeks. At the end of this period the subjects discontinued this treatment and received 40 mg/day atorvastatin for 6 weeks. Finally 200 mg/day of micronised fenofibrate was added to the statin therapy. Administration of micronised fenofibrate reduced serum triglycerides (P < 0.01) and total cholesterol and low-density lipoprotein (LDL) cholesterol (P < 0.05 for both parameters), while it evoked a significant increase in serum high-density lipoprotein (HDL) cholesterol levels (P < 0.05). Atorvastatin monotherapy induced a more pronounced decrease of total and LDL cholesterol. However, plasma triglycerides, although significantly lower than baseline values (P < 0.05), were higher than the values observed during treatment with fenofibrate. Moreover, serum HDL cholesterol concentrations were higher during fibrate therapy than during the statin one. During the combination therapy, the decrease in triglycerides was greater than that observed with fenofibrate alone, while the decrease in LDL cholesterol was more pronounced than that observed with atorvastatin alone. The combination of atorvastatin with micronised fenofibrate in patients with severe mixed dyslipidemia may have a favourable effect on some major coronary artery disease risk factors.",2001.0,0,0 647,11216330,Professional advice and readiness to change behavioral risk factors among members of a managed care organization.,P J O'Connor; W A Rush; J O Prochaska; N P Pronk; R G Boyle,"To ascertain factors related to readiness to change behavioral risk factors in members of a managed care organization (MCO). Cross-sectional study. A telephone survey reached 4667 (73%) of 6409 adult members of a Minnesota MCO attending 2 primary care clinics. Of these, 3826 members (82%) completed an interview designed to identify behavioral risk factors (smoking, consuming a high-fat diet, and physical inactivity) and readiness to change these behaviors. Among MCO members consuming a high-fat diet, those most ready to change were older, were women, used more preventive services, and reported receiving professional advice about diet. For physical inactivity, those most ready to change were younger, women, and more educated; used more preventive services; and reported receiving professional advice about physical activity. Among smokers, those with higher readiness to change smoked fewer than 15 cigarettes a day, had higher self-efficacy, had no other smokers in the household, and reported receiving professional advice about smoking. After controlling for demographic variables and for use of preventive services, greater readiness to change for smoking (beta = 0.336, odds ratio [OR] = 1.40, P = .056), physical activity (beta = 0.651, OR = 1.92, P < .001), and diet (beta = 0.532, OR = 1.70, P < .001) was associated with having received professional advice to change these behaviors. Levels of readiness to change behaviors in MCO members who smoke, are inactive, or consume high-fat diets are similar to those reported in other populations. The association of professional advice to change behaviors with increased readiness to change for smoking, physical activity, and diet suggests that receiving professional advice on these topics might assist patients in changing adverse health-related behaviors.",2001.0,0,0 648,11218969,[Cost-effectiveness of atorvastatin against simvastatin as hypolipemic treatment in hypercholesterolemic patients in primary care].,P J Tárraga López; A Celada Rodríguez; M Cerdán Oliver; J Solera Albero; J M Ocaña López; J de Miguel Clavé,"To perform an economics evaluation of lipid-lowering therapy with atorvastatin and simvastatin in patients with hypercholesterolemia in primary care setting. Cost-effectiveness analysis (CEA) has been carried out by means of an open, random, prospective, ""real world"" study, with hypercholesterolemic patients (total cholesterol [TC] > 240 mg/dl and cLDL > 160 mg/dl). A total of 92 patients were included (44.8% males), with a mean age of 64.9 +/- 9.4 years old (mean +/- standard deviation). 41.4% were diabetics, 62.1% hypertensives and 16.1% smokers. Patients were allocated to simvastatin 20 mg/day (44) and atorvastatin. 10 mg/day (48) for 6 months. ASSESSMENT AND MAIN RESULTS: Both therapies reduced significantly cLDL, TC and triglycerides at the end of the study. Atorvastatin reduced lipids faster than simvastatin at 3 months (p < 0.05), but significant differences could not be observed at 6 months. Atorvastatin reduced cLDL levels by 21.5 +/- 13.2% and 23.8 +/- 13.9% at 3 and 6 months, respectively, versus 16.4 +/- 14.2% and 22.8 +/- 10.8% with simvastatin. By these reductions, 54.2% of patients treated with atorvastatin and 50.0% of those allocated to simvastatin reached therapeutic goals of cLDL control. Atorvastatin 10 mg was more cost-effective than simvastatin 20 mg; 95,406 versus 101,335 pts per patient reaching therapeutic goals, respectively, which means that simvastatin need an extra cost of 24,833 pts per patient reaching therapeutic goals to be as efficient as atorvastatin. Sensitivity analysis to control for uncertainty confirmed the results of cost-effectiveness analysis. Both statins were effective as lipid-lowering agents. However, atorvastatin 10 mg was more efficient than simvastatin 20 mg due to a better cost-effectiveness ratio.",2001.0,0,0 649,11219479,Comparison of the efficacy and tolerability of fluvastatin extended-release and immediate-release formulations in the treatment of primary hypercholesterolemia: a randomized trial.,A G Olsson; P Pauciullo; V Soska; C Luley; R E Pieters; G Broda; B Palacios; Fluvastatin Study Group,"A new extended-release (ER) formulation of fluvastatin 80 mg has been developed for once-daily treatment of primary hypercholesterolemia. The purpose of this study was to compare the lipid-lowering efficacy and tolerability of fluvastatin ER (80 mg once daily) versus fluvastatin immediate-release (IR) (40 mg once or twice daily). Following a 4-week placebo/dietary run-in period, patients with primary hypercholesterolemia type IIa or IIb (low-density lipoprotein cholesterol ILDL-C] > or = 160 mg/dL and triglycerides [TG] < or = 400 mg/dL) were randomized (2:1:1) to receive fluvastatin ER 80 mg once daily at bedtime (QPM), fluvastatin IR 40 mg QPM, or fluvastatin IR 40 mg BID for 24 weeks. Patients who had homozygous familial hypercholesterolemia; type I, III, IV, V, or secondary hyperlipoproteinemia; diabetes; or evidence of liver or renal impairment were excluded. At weeks 0, 2, 4, 8, 12, 16, 20, and 24 of the active-treatment period, levels of LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, and total cholesterol (TC) were measured. Of the 1183 patients enrolled, 695 were randomly assigned to treatment--346 to fluvastatin ER 80 mg QPM, 174 to fluvastatin IR 40 mg QPM, and 175 to fluvastatin IR 40 mg BID. Patients were well matched between groups, with a mean age of approximately 56 years and body mass index of 27 kg/m2; 56.0% of patients (389/695) were female and 97.7% (679/695) were white. Fluvastatin ER 80 mg QPM lowered LDL-C levels significantly more than did fluvastatin IR 40 mg QPM (33.7% vs 24.4%; P < 0.001) and as effectively as fluvastatin IR 40 mg BID (33.9%). More than half of the patients administered fluvastatin ER 80 mg QPM and IR 40 mg BID achieved reductions in LDL-C levels of > or = 35%; more than half of those administered fluvastatin IR 40 mg QPM experienced reductions in LDL-C levels of > or = 25%. The mean reductions in LDL:HDL ratio, TC, and apolipoprotein B levels in the fluvastatin ER 80 mg QPM group were significantly greater than the reductions in the IR 40 mg QPM group (P < 0.001). In patients with mixed dyslipidemia, fluvastatin ER 80 mg reduced triglycerides by 21.8% (median 28%) and increased HDL-C by 14.5%. Fluvastatin ER 80 mg QPM was well tolerated, with incidences of clinically notable elevations in alanine aminotransferase, aspartate aminotransferase, and creatine kinase levels and musculoskeletal adverse events comparable to those in the IR 40 mg QPM group. The ER 80-mg formulation of fluvastatin is effective and well tolerated as a once-daily starting and maintenance treatment for primary hypercholesterolemia.",2001.0,0,0 650,11220455,Aggressive treatment of dyslipidemia: a review of supporting evidence.,E A Stein,"Clinical trial data are now sufficient to support aggressive treatment of dyslipidemia. Cholesterol-lowering therapy is known to reduce the risk of clinical events across a wide range of lipid levels, even in patients with ""normal"" levels. Current data support lowering low-density lipoprotein cholesterol (LDL-C) levels at least to those recommended by the National Cholesterol Education Program, but perhaps even more aggressively in some patients. Of the available cholesterol-lowering agents, statins produce the greatest reductions in LDL-C levels and coronary events and are currently the best treatment option for most patients.",2001.0,0,0 651,11220553,Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus.,K Fujioka; T B Seaton; E Rowe; C A Jelinek; P Raskin; H E Lebovitz; S P Weinstein; Sibutramine/Diabetes Clinical Study Group,"To determine the efficacy and tolerability of sibutramine hydrochloride in obese patients whose type 2 diabetes was poorly controlled on diet alone or with an oral antidiabetic agent. This study was a 24-week, double-blind, multicentre trial following a 5-week placebo run-in period. One hundred and seventy-five obese (body mass index (b.m.i.) > or =27 kg/m2) patients with poorly controlled type 2 diabetes mellitus were randomized either to sibutramine (n = 89; mean age 53.5 years; mean weight 99.3 kg) or placebo (n = 86; mean age 55 years; mean weight 98.2 kg) at 16 participating centres. To achieve moderate calorie restriction (deficit > or = 250-500 kcal/day), individual dietary counselling was accompanied by either placebo or sibutramine (initial dosage of 5 mg/day titrated up by 5 mg biweekly through week 6, and maintained at 20 mg through week 24). The main outcome measures included changes in weight, b.m.i., waist and hip circumference, glycaemic control, lipid profile, and quality of life, and evaluation of reported adverse events. Sixty-seven per cent of sibutramine patients and 71% of placebo patients completed the study. At week 24 when comparing those who completed the course, sibutramine compared with placebo patients showed significantly greater (p < 0.001) absolute (-4.3 vs. -0.4 kg) and percentage (-4.5% vs. -0.5%) weight loss. Weight loss > or =5% or 10% was achieved by 33% and 8% of sibutramine patients, respectively, but no placebo patients (p < 0.03 or better). Improvement in glycaemic control was correlated with weight loss (p < 0.001). In 5% and 10% weight-loss responders, mean treatment differences were -0.53% and -1.65% (p < or = 0.05), respectively, for HbA1c, and -1.4 mmol/l (p < or =0.05) and -3.8 (p < or =0.05) mmol/l for fasting plasma glucose. Sibutramine patients also showed improvements in fasting insulin, triglycerides, HDL cholesterol, and quality-of-life assessments. Overall, sibutramine was well tolerated compared with the placebo. Sibutramine treatment was associated with small mean increases in blood pressure (BP) and pulse, although an increase in BP was not seen in sibutramine-treated patients who lost > or = 5% of their weight. Sibutramine produced statistically and clinically significant weight loss when used in combination with recommendations for moderate caloric restriction. This weight loss was associated with improvements in metabolic control and quality of life, and sibutramine was generally well tolerated in obese patients with type 2 diabetes.",2001.0,0,0 652,11221271,Statins early in acute coronary syndromes.,G Jackson,,2001.0,0,0 653,11223435,Effects of simvastatin treatment on sICAM-1 and sE-selectin levels in hypercholesterolemic subjects.,M A Sardo; M Castaldo; M Cinquegrani; M Bonaiuto; A Maesano; F Schepis; M C Zema; G M Campo; F Squadrito; A Saitta,"This study was performed to determine whether the levels of soluble intercellular adhesion molecule-1 (sICAM-l) and soluble endothelial molecule-1 (sE-selectin) were elevated in subjects with hypercholesterolemia who presented with no other risk factors or evidence of atherosclerosis. The effects of administration of an HMG-CoA reductase inhibitor on the serum levels of these molecules were also examined. Forty hypercholesterolemic subjects (HCh) (19 males and 21 females), without hypertension or cardiovascular disease, received placebo for 4 weeks. The patients were then randomized in two groups; 20 of them (simvastatin group) were treated with simvastatin (20 mg/day) and the other 20 (placebo group) continued placebo administration. After 12 and 24 weeks of either simvastatin or placebo treatment, sICAM-1 and sE-selectin levels were measured. The same parameters were measured in 20 control subjects (C) with normal cholesterol levels, matched for sex and age. HCh had sICAM-1 basal values higher than C (352.4+/-57.9 ng/ml versus 114.9+/-89.6 ng/ml; P<0.001); however, sE-selectin basal values were not different in the two groups. No correlation was observed between HCh sICAM-1 levels and cholesterol levels (total and low-density lipoprotein). Furthermore, cholesterol-lowering treatment with simvastatin did not significantly diminish sICAM-1 levels. Our findings would support the hypothesis that patients with isolated hypercholesterolemia and without clinical atherosclerosis may be silent carriers of arterial subendothelial inflammation, expressed as an increase of sICAM-1.",2001.0,0,0 654,11223444,Levels of expression of Fcgamma receptor IIA (CD32) are decreased on peripheral blood monocytes in patients with severe atherosclerosis.,J R Pfeiffer; P S Howes; M A Waters; M L Hynes; P P Schnurr; E Demidenko; F R Bech; P M Morganelli,"To obtain information in vivo concerning the role of Fcgamma receptors (FcgammaR) in atherosclerosis, we used quantitative flow cytometry to measure the levels of expression of FcgammaRI and FcgammaRIIA on peripheral monocytes in patients with severe atherosclerosis. Expression of several other markers was also measured. We found that differences in the levels of expression of FcgammaRI were not statistically significant when compared between patients and control subjects. For FcgammaRIIA, levels of expression were decreased in the patient group, a difference that was statistically significant. Levels of expression of CD14 and CD36 were also significantly decreased in the patient group. The decrease in expression of FcgammaRIIA was statistically significant when the effects of current cigarette smoking status or medication use, including statins, were taken into account. There was also a positive and statistically significant correlation between high-density lipoprotein-cholesterol and levels of expression of FcgammaRIIA for all subjects. In contrast, decreased levels of expression of CD14 and CD36 were strongly associated with current smoking status or statin use. In summary, levels of expression of FcgammaRIIA on peripheral blood monocytes were significantly decreased in patients with clinical atherosclerosis. Additional studies are warranted to determine if levels of expression of FcgammaRIIA have utility as a phenotypic marker for assessing relative risk of atherosclerotic disease.",2001.0,0,0 655,11223448,Simvastatin improves arterial compliance in the lower limb but not in the aorta.,H Shige; A Dart; P Nestel,"Several cardiovascular risk factors adversely affect arterial compliance or the distensibility of large arteries. The role of raised low-density lipoproteins (LDL) cholesterol is uncertain, most studies having shown little effect. We, therefore, investigated whether lowering LDL would improve arterial compliance. Twenty hypercholesterolemic subjects (LDL cholesterol 4.95+/-1.11 mmol/l) were randomized to simvastatin (20 or 40 mg daily) or placebo, each for 4 weeks. Arterial function was assessed at the end of the placebo and simvastatin periods, systemic arterial compliance (SAC) and pulse wave velocities (PWV) centrally (aorto-femoral) and peripherally (femoral-posterior tibial). Lipoproteins (LDL) cholesterol was reduced similarly with 20 and 40 mg simvastatin (ten subjects each dose) and data were pooled. Lipoproteins (LDL) cholesterol fell 39%, plasma triglyceride fell 18% and high-density lipoprotein (HDL) cholesterol rose 12%, all significant. Systemic arterial compliance (SAC) and central PWV did not change significantly but peripheral PWV showed evidence of greater compliance after simvastatin (10.1+/-1.3 vs. 9.4+/-1.3 m/s with placebo and simvastatin, P<0.03), distensibility being inversely related to PWV. Improvement in PWV was greatest in those with poorest baseline values, r=0.50; P<0.02. Peripheral PWV was alone improved with LDL lowering probably because of the muscularity of that arterial bed; central PWV and SAC (in the elastic aorta) were not influenced.",2001.0,0,0 656,11223999,"Assessing hypertension management in the community: trends of prevalence, detection, treatment, and control of hypertension in the MONICA Project, Augsburg 1984-1995.",C Gasse; H W Hense; J Stieber; A Döring; A D Liese; U Keil,"To assess trends in prevalence and detection, treatment and control of hypertension in a German population between 1984 and 1995. Independent random samples of the population were examined in cross-sectional surveys with identical methods in 1984/85 (age range 25 to 64 years, n = 4022 participants), 1989/90 (age range 25 to 74 years, n = 4940) and 1994/95 (age range 25 to 74 years, n = 4856). Prevalence of hypertension and proportions of hypertensives detected, treated and controlled. Hypertension was defined as blood pressure above 140/90 mm Hg or taking antihypertensive medication. The prevalence of hypertension did not change significantly over the 10 years (25--64 years, age-standardised 1984/85: 37.8% in men and 24.6% in women; 1994/95: 39.3% and 24.8%, respectively). Rates of detection, treatment and control of hypertension did not change much either. Of all hypertensives in 1994/95, 54% were detected in men and 64% in women, the treatment rates were 23% and 32%, and the proportions of those with controlled hypertension (below 140/90 mm Hg with treatment) were as low as 7% and 13%, respectively. Rates were higher in the older age groups, however, control rates never exceeded 20% at any age. Despite considerable changes in the pharmacological treatment of hypertension there was a disappointing stagnation with regard to the management of this important risk factor in the community. The reasons for this unfavourable trend need clarification and appropriate public health action. Journal of Human Hypertension (2001) 15, 27-36",2001.0,0,0 657,11224003,Improvement of patients' knowledge by a single educational meeting on hypertension.,C Cuspidi; L Sampieri; G Macca; I Michev; V Fusi; M Salerno; B Severgnini; J I Rocanova; G Leonetti; A Zanchetti,"A poor therapeutic compliance is a major cause of insufficient control of hypertension. As education of patients is fundamental in order to improve their compliance, we organised two pilot educational meetings aimed at (1) assessing the support of patients to this kind of meetings, and (2) verifying the impact on patient's education. We invited 225 consecutive patients referred to our Hypertension Clinic (some of them regularly followed up and some referred for the first time) to participate to an educational meeting on hypertension. Patients were divided in two groups, for organising reasons each attending a single meeting. Each meeting included four sessions: (1) the first session included a multiple choice questionnaire (nine questions, with answers collected by an interactive electronic system) in order to evaluate the degree of patient's information about hypertension (definition, prevalence, aetiology, complications and treatment), (2) a traditional teaching session, (3) an interactive phase aimed to assess the improvement of knowledge in which the same questions as in the first session have been asked again, and (4) a general discussion session. A total of 144 patients (mean age 54 +/- 12 years; 76 M, 68 F) of the 225 invited attended the meeting. The answers to our questions in the initial session were correct in a percentage ranging from 60% to 80%. During the third phase immediately after the teaching session, the percentage of correct answers increased significantly (range: 75--98%, P < 0.05 at least in all questions). This study shows: (1) a satisfactory adherence of patients to this educational initiative; (2) a positive impact of a single educational meeting on patient's knowledge about issues related to hypertension. The potential role of improving patient's education on clinical outcomes such as blood pressure levels and the rate of blood pressure control requires future controlled studies. Journal of Human Hypertension (2001) 15, 57-61",2001.0,0,0 658,11225741,Implications of cardiovascular risk in patients with type 2 diabetes who have abnormal lipid profiles: is lower enough?,A J Garber,"Patients with type 2 diabetes are at high risk for coronary heart disease (CHD); frequently, these patients have abnormal lipid profiles, placing them at even greater risk. A syndrome of insulin resistance, hyperinsulinaemia, hypertension, and high levels of fibrinogen and plasminogen activator inhibitor contributes to cardiovascular risk, which is not sufficiently decreased by glycaemic control alone. In several large interventional trials, CHD risk in patients with diabetes was substantially reduced by aggressive lipid-lowering therapy. In patients with diabetes, CHD, low high-density lipoprotein levels, and normal low-density lipoprotein levels, gemfibrozil reduced fatal and non-fatal CHD events. For lipid-lowering in patients with diabetes and CHD, pravastatin and simvastatin are the only HMG-CoA reductase inhibitors shown to reduce fatal and non-fatal CHD events. Of these, pravastatin has less potential for drug-drug interactions and may be safer to use, particularly for combination therapy with fibric acid derivatives, as may now be important for CHD prevention in mixed dyslipidaemias.",2001.0,0,0 659,11227051,New pharmacological agents under clinical investigation for treating disorders of lipoprotein regulation leading to atherosclerosis.,E Gallup; C Dujovne,"Coronary heart disease (CHD), whose primary aetiology is atherosclerosis, is the leading cause of mortality and a major cause of morbidity in the industrialised world [1]. Serum lipoprotein levels are aetiologically related to the risk of atherosclerosis and CHD [2]. The liver and the gastrointestinal system are the major protagonists involved in regulation of lipoprotein biochemical-physiological mechanisms and the development of hypercholesterolaemia. Furthermore, specific lipoprotein receptors are being discovered as targets for pharmacological intervention to correct lipoprotein disorders. Agents that target lipoprotein regulation in the liver, gastrointestinal-biliary and atherosclerotic tissues resulting in improved serum lipoprotein levels and/or control of primary and secondary dyslipidaemic disorders including diabetes, are currently undergoing clinical trials. The most novel promising compounds, after the greatly effective newest HMG-CoA reductase inhibitors, are drugs that affect peroxisome proliferator-activated receptors, PPARalpha and PPARgamma receptors, bile acid transport mechanisms, cholesterol absorption and cholesterol acyltransferase and other biochemical targets of lipoprotein regulation. Current knowledge and ongoing trials with these agents are described here within the boundaries of investigator confidentiality agreements.",2001.0,0,0 660,11228031,Lipid-lowering update 2001. Aggressive new goals.,T K Fenske,"To review the central role of cholesterol in coronary artery disease (CAD), underscore the need for identifying patients at high risk of CAD, and discuss treatment of dyslipidemias. Current literature (1995-2000) was searched via MEDLINE using the MeSH headings ""cholesterol,"" ""risk reduction,"" and ""statins."" Recommendations in this paper are based mainly on the results of large randomized controlled trials. Preference was given to more recent articles, clinically relevant articles, and landmark clinical trials. Lipid lowering, and specifically low-density lipoprotein lowering, has been repeatedly shown in large clinical trials to improve survival dramatically and reduce cardiac events in both primary and secondary prevention. Identifying those at highest risk for future cardiac events is critical because these patients will benefit most from aggressive modification of risk factors. The definition of high risk has been expanded to include patients with diabetes mellitus and peripheral vascular disease, as well as those with established CAD. A full lipid profile is required for these patients to assess risk and develop a lipid-lowering strategy with proven effectiveness. With the advent of powerful, efficacious, and well tolerated cholesterol-modifying therapies, lipid normalization should be a mandate for all physicians caring for patients with established CAD and patients at risk of developing CAD.",2001.0,0,1 661,11228171,Cardiac risk factors and the use of cardioprotective medications in patients with chronic renal insufficiency.,M Tonelli; C Bohm; S Pandeya; J Gill; A Levin; B A Kiberd,"Cardiovascular disease (CVD) is a major cause of morbidity and mortality among patients with chronic renal insufficiency (CRI). beta-Adrenergic blockers, acetylsalicylic acid (ASA), angiotensin-converting enzyme (ACE) inhibitors, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) all reduce CVD mortality, but little is known about the extent to which these medications are used in patients with CRI. This study, a prospective cross-sectional study of consecutive patients seen by nephrologists in four Canadian centers for follow-up of progressive CRI in 1999, was performed to investigate the prevalence of coronary risk factors and use of cardioprotective medications among patients with CRI. Patients had creatinine clearances of 75 mL/min or less but were not on dialysis therapy. Three hundred four consecutive patients meeting the inclusion criteria were enrolled. Mean age was 60.8 +/- 15.7 years, mean creatinine clearance was 30.3 +/- 18 mL/min, and the case mix of kidney diseases was similar to that in the Canadian Organ Replacement Registry data. One hundred seventeen of 304 patients (38.5%) had a history of previous CVD, and the prevalence of CVD was greater in patients with more severe CRI. Two hundred forty-three patients (79.9%) had a history of hypertension, 132 patients (43.4%) had hyperlipidemia, 114 patients (37.5%) had diabetes mellitus, and 71 patients (27.3%) were smokers. Thirty-five percent of the patients with CVD had blood pressures greater than 140/90 mm Hg; 103 patients (33.9%) were administered beta-blockers; 196 patients (64.5%), ACE inhibitors or angiotensin-receptor blockers; 83 patients (27.3%), ASA; and 56 patients (18.4%), statins. Patients with diabetes were not more likely than those without diabetes to be prescribed cardioprotective medications. CVD is common in the predialysis population, and its prevalence increases with more severe kidney failure. Despite this, the use of cardioprotective medications is relatively low, and many patients had suboptimal blood pressure control. Given the high burden of disease in these patients, beta-blockers and ACE inhibitors should be used to control hypertension and/or for cardioprotection, and the increased use of ASA and statins should be considered.",2001.0,0,0 662,11229669,Effect of pravastatin on frequency of fracture in the LIPID study: secondary analysis of a randomised controlled trial. Long-term Intervention with Pravastatin in Ischaemic Disease.,I R Reid; W Hague; J Emberson; J Baker; A Tonkin; D Hunt; S MacMahon; N Sharpe,"Statins inhibit the same biochemical pathway as aminobisphosphonates, therefore these cholesterol-lowering agents may have a beneficial effect on osteoporosis. This possibility has been supported by the finding that some statins also stimulate bone formation, and by observational studies suggesting that patients using statins have higher bone densities and lower fracture rates than controls. To assess whether statins have clinically significant effects on bone, we studied the frequency of fractures in a large randomised controlled trial of these agents. 9014 patients (17% women, median age 62 years) with ischaemic heart disease were randomly assigned pravastatin 40 mg daily or placebo and followed up for a mean of 6.0 years. Fractures were ascertained from adverse-event reports. 101 patients in the placebo group were admitted to hospital for fracture compared with 107 in the pravastatin group (hazard ratio 1.05 [95% CI 0.80-1.37]). When patients with fractures not necessitating hospital admission were added, the total number of patients having a fracture was 183 in the placebo group and 175 in the pravastatin group (0.94 [0.77-1.16]). Separate analyses for women alone and for individuals aged 65 years and over gave similar results. These findings offer no support for the hypothesis that statins have a significant effect on fracture risk. However, this study was not of an osteoporotic population, and fracture rate, although clinically important, is an insensitive index of effects on bone. Statins should not be used to prevent osteoporosis until there is evidence for their efficacy based on randomised controlled trials.",2001.0,0,0 663,11230838,Comparison of efficacy and safety of atorvastatin (10mg) with simvastatin (10mg) at six weeks. ASSET Investigators.,W Insull; S Kafonek; D Goldner; F Zieve,"The 6-week efficacy and safety of atorvastatin versus simvastatin was determined during a 54-week, open-label, multicenter, parallel-arm, treat-to-target study. In all, 1,424 patients with mixed dyslipidemia (triglyceride 200 to 600 mg/dl [2.26 to 6.77 mmol/L]) were stratified to 1 of 2 groups (diabetes or no diabetes). Patients were then randomized to receive either atorvastatin 10 mg/ day (n = 730) or simvastatin 10 mg/day (n = 694). Efficacy was determined by measuring changes from baseline in lipid parameters including low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and apolipoprotein B. Compared with simvastatin, atorvastatin produced significantly greater (p < 0.0001) reductions from baseline in LDL cholesterol (37.2% vs 29.6%), total cholesterol (27.6% vs 21.5%), triglycerides (22.1% vs 16.0%), the ratio of LDL cholesterol to high-density lipoprotein (HDL) cholesterol (41.1% vs 33.7%), and apolipoprotein B (28.3% vs 21.2%), and a comparable increase from baseline in HDL cholesterol (7.4% vs 6.9%). Atorvastatin was also significantly (p < 0.0001) more effective than simvastatin at treating the overall patient population to LDL cholesterol goals (55.6% vs 38.4%). Fewer than 6% of patients in either treatment group experienced drug-attributable adverse events, which were mostly mild to moderate in nature. Diabetic patients treated with either statin had safety characteristics similar to nondiabetics, with atorvastatin exhibiting superior efficacy to simvastatin. In conclusion, atorvastatin, at a dose of 10 mg/day, is more effective than simvastatin 10 mg/day at lowering lipids and reaching LDL cholesterol goals in patients with mixed dyslipidemia. Both statins are well tolerated with safety profiles similar to other members of the statin class.",2001.0,1,1 664,11230855,Effect of simvastatin in preventing progression of carotid artery stenosis.,O Hegland; K Dickstein; J P Larsen,This study examines the effect of simvastatin on progression of carotid artery stenosis and shows that the drug substantially reversed the anticipated disease development. This finding indicates that treatment with simvastatin may reduce the risk for stroke in patients with known carotid artery disease.,2001.0,0,0 665,11231429,Design and rationale of the ARBITER trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol)--a randomized trial comparing the effects of atorvastatin and pravastatin on carotid artery intima-media thickness.,T T Markwood; S M Kent; L C Coyle; P J Flaherty; P G O'Malley; A J Taylor,"As a class, statins are remarkably effective in reducing low-density lipoprotein (LDL) cholesterol, and several of these drugs have now been shown to reduce coronary heart disease morbidity and mortality. However, several important controversies in the use of statins remain to be answered by clinical trials. For example, it is controversial whether marked cholesterol reduction to levels below 100 mg/dL would further reduce the incidence of coronary heart disease. Furthermore, concerns about differences among statins for nonlipid effects has raised the concern that the assumption of a class effect is premature until head-to-head clinical trials are completed. Arterial Biology for the Investigation for the Treatment Effects of Reducing Cholesterol (ARBITER) is a single-center, randomized, active-controlled study comparing the efficacy of high-dose atorvastatin (80 mg/d) and pravastatin (40 mg/d) in patients being treated for either the primary or secondary prevention of coronary heart disease. This trial will enroll up to 200 patients for the primary end point of the mean change in intima-media thickness of the common carotid artery. This effect will be evaluated over a treatment duration of 12 months. Secondary end points include the effects of statin therapy on inflammatory and hemostatic markers (C-reactive protein and fibrinogen). ARBITER will provide important data on the role of marked LDL reduction and the ""class effect"" theory of statin therapy in cardiovascular medicine.",2001.0,0,0 666,11238162,"Premature discontinuation of clinical trial for reasons not related to efficacy, safety, or feasibility.",M Lièvre; J Ménard; E Bruckert; J Cogneau; F Delahaye; P Giral; E Leitersdorf; G Luc; L Masana; P Moulin; P Passa; D Pouchain; G Siest,,2001.0,0,0 667,11238259,,,,,0,0 668,11238289,High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease.,N Rifai; P M Ridker,"Coronary heart disease remains the leading cause of morbidity and mortality in the industrialized world. Clinical and laboratory studies have shown that inflammation plays a major role in the initiation, progression, and destabilization of atheromas. C-Reactive protein (CRP), an acute phase reactant that reflects low-grade systemic inflammation, has been studied in a variety of cardiovascular diseases. Findings from prospective clinical trials were examined to determine the prognostic utility of CRP in acute coronary syndromes, and observations from epidemiological studies were reviewed to determine the ability of CRP to predict future first coronary events. The analytical considerations of CRP measurement in these clinical applications were also examined. In patients with established coronary disease, CRP has been shown to predict adverse clinical events. In addition, prospective studies have consistently shown that CRP is a strong predictor of future coronary events in apparently healthy men and women. The relative risk associated with CRP is independent of other cardiovascular disease risk factors. High-sensitivity CRP (hs-CRP) assays are needed for risk assessment of cardiovascular disease. Such assays are currently available but may require further standardization because patients' results will be interpreted using population-based cutpoints. Preventive therapies to attenuate coronary risk in individuals with increased hs-CRP concentrations include aspirin and statin-type drugs. hs-CRP has prognostic utility in patients with acute coronary syndromes and is a strong independent predictor of future coronary events in apparently healthy subjects.",2001.0,0,0 669,11238469,Clinical review 123: Anabolic therapy for osteoporosis.,C J Rosen; J P Bilezikian,"All currently available, approved therapies for osteoporosis inhibit bone resorption. By acting at this site in the bone remodeling cycle, estrogens, selective estrogen receptor modulators, calcitonin, and the bisphosphonates all have the capacity to increase bone mineral density and to reduce the risk of new fractures. There can be no doubt that these agents have had an enormous impact on our diagnostic and therapeutic approach to osteoporosis. Despite their great value, the antiresorptives are generally not associated with dramatic increases in bone mass, and their action to reduce fracture risk, although highly significant, is rarely more than 50% of the baseline risk. Another approach is anabolic therapy, in which bone formation is directly stimulated. In this review we will summarize the anabolic agents that have been studied and present a current view of their current standing. Fluoride, GH, insulin-like growth factor I, the statins, and PTH will be reviewed. Although still in development, approaches to combination therapy with antiresorptives and anabolic agents are also promising.",2001.0,0,0 670,11239793,Direct vascular effects of HMG-CoA reductase inhibitors.,U Laufs; J K Liao,"The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, or statins, are potent inhibitors of cholesterol synthesis and large clinical trials have demonstrated that these agents reduce cholesterol and the incidence of cardiovascular diseases. Recent evidence, however, suggests that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels. Because statins also inhibit the synthesis of isoprenoid intermediates in the cholesterol biosynthetic pathway, they may have pleiotropic effects on vascular wall cells. In particular, the small GTP-binding protein, Rho, whose membrane localization and activity are affected by post-translational isoprenylation, may play an important role in mediating the direct vascular effects of statins.",2001.0,0,0 671,11242427,,,,,0,0 672,11244205,Advantages of lipid-lowering therapy in cerebral ischemia: role of HMG-CoA reductase inhibitors.,A C Gil-Núñez; J A Villanueva,"Dyslipemia as a risk factor for ischemic stroke and indications for statins in the prevention of ischemic stroke are revised. The role of cholesterol levels as a risk factor for ischemic stroke is controversial. This could be due to failures in the design of early epidemiological studies. Recent studies, however, do suggest a clearer risk relationship between cholesterol levels and ischemic stroke. Studies conducted on the prevention of ischemic heart disease (IHD) with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), using pravastatin and simvastatin, unequivocally show reductions in overall mortality, cardiovascular mortality, acute myocardial infarction and other coronary events. These studies show a reduction in the risk of ischemic stroke, and although relative risk reduction is great, absolute risk reduction is low; the reasons for this are analyzed. Apart from lipid mechanisms, statins act on the atheroma plaque; they have antithrombotic and possibly neuroprotecting properties. Statins reduce the number of strokes due to the decrease of atherothrombotic strokes, cardioembolic strokes secondary to IHD, and lacunar strokes related to atherothrombosis and probably to microatheromas. Although there are currently no specific studies available on the secondary prevention of stroke with statins, which are required to clarify certain points, according to European and American guidelines for prevention, statins would be indicated in the secondary prevention of atherothrombotic stroke, and in cardioembolic and lacunar stroke associated with clinical or silent atherosclerosis (IHD, peripheral artery disease). Patients with ischemic stroke of other etiologies, except for stroke in the young or other unusual causes, are patients with a high vascular risk (cardiac and cerebral) owing to the stroke itself, age and other vascular risk factors, and they should also be treated with statins, at least from the point of view of primary prevention of IHD. Natural statins (pravastatin and simvastatin) play an essential part in secondary prevention of ischemic stroke, together with antiaggregants, anticoagulants, angiotensin-converting enzyme inhibitors and the treatment of other vascular risk factors.",2001.0,0,1 673,11245405,Prevention of disease with pharmaceuticals.,H Vainio; F Bianchini,"The idea that diseases such as cardiovascular disease and cancer can be prevented by taking a 'pill' is attractive to many people. Chemoprevention is an established method in the primary and secondary prevention of cardiovascular disease such as myocardial infarct and stroke. Clinical trials have demonstrated beyond reasonable doubt that both fatal and non-fatal coronary events and strokes can be prevented. Antihypertensive drugs have been shown to be effective through clinical trials in preventing myocardial infarctions, stroke and other cardiovascular morbidity and mortality. Statins are commonly used to lower the blood cholesterol concentration, and aspirin is widely used to prevent occlusive vascular disease. Aspirin and other non-steroidal antiinflammatory agents have shown promise in the chemoprevention of colorectal cancer. While observational epidemiological studies have consistently suggested that diets rich in antioxidants such as beta-carotene might be useful in preventing coronary heart disease and cancer, the published reports of randomized trials clearly indicate that beta-carotene supplements are of no value in persons of high risk for such conditions. Although the chemoprevention of cancer is decades behind that of cardiovascular disease, there is no reason to believe that progress in cancer chemoprevention will differ substantially from that in cardiovascular disease. Better understanding of the molecular steps critical to carcinogenesis should open new avenues for cancer chemoprevention.",2001.0,0,0 674,11245504,Normocholesterolaemic dyslipidaemia: is there a role for fibrates?,G F Watts; S B Dimmitt; P J Barter,,2001.0,0,0 675,11249510,Pharmacotherapy of hypercholesterolaemia: statins in clinical practice.,M H Moghadasian; G B Mancini; J J Frohlich,"The objective of this article is to evaluate the roles of the lipid-lowering class of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in reducing cardiovascular events and to review their mechanism of action based on in vitro and in vivo studies. The clinical outcome of 15 major clinical trials has been critically reviewed and summarised; all showed a high degree of efficacy and safety. Statins, either in active or prodrug forms, are potent inhibitors of HMG-CoA reductase, have good absorption rate and their bioavailability depends on their lipophobicity and concomitant use with meals. Abdominal discomfort is the most commonly reported adverse effect. Although the incidence is low, myopathy with or without rhabdomyolysis may be considered a serious adverse effect of statins. A combination of a statin with gemfibrozil seems to increase the risk of this adverse event, particularly in patients with renal impairment. Combination therapy with several other agents, frequently administered to cardiovascular patients, has also been reviewed. Statin therapy is considered highly cost effective in secondary prevention, but it is less cost effective in primary prevention. This factor may underline the rationale for developing other safe and effective agents with an improved cost effectiveness profile. The pleiotropic non-lipid lowering effects of statins may include their anti-oxidant and antithrombotic potential as well as restoration of endothelial function. Statins may also be beneficial in the treatment of osteoporosis. Fewer studies have investigated statins' effects on the quality of lipoprotein particles, the activities of cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase as well as their possible synergistic effects with n-3 fatty acids, anti-oxidants and aspirin in reducing cardiovascular events.",2001.0,0,0 676,11249778,"Technology evaluation: Valspodar, Novartis AG.",H L Tai,"Valspodar (PSC-833) is a derivative of cyclosporin but devoid of the immunosuppressive and nephrotoxic properties seen in cyclosporin A. It exhibited high affinity binding to Mdr1 P-glycoprotein (P-gp) and demonstrated multidrug resistance-reversing activity superior to cyclosporin A and verapamil both in vitro and in vivo. Preclinical and phase I/II clinical data have indicated that plasma levels of PSC-833 with multidrug resistance-reversing activities are achievable. Potent inhibition of intestinal, hepatobiliary and blood-brain barrier P-gp function has been demonstrated. Since valspodar is also a substrate of cytochrome P450 3A (CYP3A), dual interactions of this compound with P-gp and CYP3A are the basis for the pharmacokinetic interactions seen in preclinical and clinical studies. A new formulation of the drug has recently been developed with better oral bioavailability (60%) and less interindividual variability. The toxicity profiles of valspodar are acceptable and dose-limited by transient and reversible cerebellar ataxia. It has shown multidrug resistance-modulating activities towards acute myeloid leukemia, multiple myeloma and ovarian cancer in phase I/II clinical trials. Phase III studies with respect to these three diseases are ongoing.",2001.0,0,0 677,11249916,Effect of pravastatin on plasma markers of inflammation and peripheral endothelial function in male heart transplant recipients.,T Holm; A K Andreassen; T Ueland; J Kjekshus; S S Frøland; E Kjekshus; S Simonsen; P Aukrust; L Gullestad,"Statins appear to have several biologic effects beyond those of lipid metabolism, and we hypothesized that immunomodulating effects of statins are important for the beneficial effects of these medications after heart transplantation. Our findings suggest that pravastatin treatment reduces plasma markers of inflammation and improves peripheral endothelial function in heart transplant recipients, possibly contributing to the observed clinical benefits of statin treatment in these patients.",2001.0,0,0 678,11252110,Cardiovascular disease and dyslipidemia in women.,F K Welty,"Cardiovascular disease, primarily coronary heart disease (CHD), outnumbers the next 16 causes of death in women combined. However, the long-held belief that heart disease in women has a more benign prognosis than in men has resulted in less aggressive diagnosis and management patterns. Appreciation of the differences between men and women in CHD risk factors and presentation can assist in treatment decisions. Although estrogen replacement offers substantial beneficial effects on lipid levels in postmenopausal women, the first 2 randomized trials of estrogen alone and estrogen plus progestin, the Heart and Estrogen/Progestin Replacement Study and Estrogen Replacement and Atherosclerosis Study, observed no benefit in reducing risk of CHD death and nonfatal myocardial infarction and angiographic progression of CHD, respectively, in women with CHD. Available data show that lipid-lowering therapy reduces women's CHD risk and mortality but also indicate that a considerable proportion of women remains untreated or undertreated. Randomized trials of statins for primary and secondary prevention of coronary heart disease suggest that these agents are at least as effective for lowering coronary disease risk in women as in men. Therefore, statin drugs should be the drug of first choice for women with established CHD. Hypercholesterolemic postmenopausal women who require estrogen for menopausal symptoms may derive further reductions in low-density lipoprotein cholesterol and reductions in trigyceride levels with the addition of a statin drug.",2001.0,0,0 679,11253464,Elderly patients at risk for coronary heart disease or stroke: selecting an ideal product for lipid lowering.,C E Rackley,"Coronary heart disease is an affliction of the elderly: 84% of those who die from the disease are over 65 years of age. In patients over 55 years, the incidence of stroke more than doubles with each decade of life. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have been shown to lower cholesterol and lipids in both middle-aged and elderly patients in large clinical trials. Some statins have been shown to improve endothelial function and vasodilation and to normalize thrombin formation, which may be among the mechanisms involved in both coronary event and stroke prevention.",2001.0,0,0 680,11254756,Cholesterol metabolism in primary biliary cirrhosis during simvastatin and UDCA administration.,M Del Puppo; M Galli Kienle; A Crosignani; M L Petroni; B Amati; M Zuin; M Podda,"Little is known about the effects of cholesterol-lowering agents in hypercholesterolemic patients with primary biliary cirrhosis (PBC). The aim of this study was to compare the changes induced by simvastatin and ursodeoxycholic acid (UDCA) on cholesterol metabolism in patients with PBC and preserved liver function. Six patients with PBC were administered simvastatin (40 mg/day) for 30 days and, after a washout period of 30 days, ursodeoxycholic acid (600 mg/day) for 30 days. Serum levels of lathosterol, campesterol, 7 alpha-hydroxycholesterol, and 27-hydroxycholesterol were measured by gas chromatography-mass spectrometry. During simvastatin administration, reduction of cholesterol levels (34% in 30 days) was paralleled by the decrease of lathosterol (55%), whereas concentrations of campesterol and of the two hydroxysterols were not substantially modified. During ursodeoxycholic acid administration, a trend toward a decrease of serum cholesterol concentrations was observed after only one year of treatment, and these changes were paralleled by the decrease of campesterol serum levels. Both simvastatin and UDCA were well tolerated, and a reduction of serum liver enzyme levels occurred with the latter. Simvastatin proved to be safe and effective in reducing serum cholesterol levels in patients with PBC by an inhibitory effect on cholesterol synthesis occurring within 24 h. --Del Puppo, M., M. Galli Kienle, A. Crosignani, M. L. Petroni, B. Amati, M. Zuin, and M. Podda. Cholesterol metabolism in primary biliary cirrhosis during simvastatin and UDCA administration. J. Lipid Res. 2001. 42: 437--441.",2001.0,0,0 681,11254910,Fluvastatin therapy improves microcirculation in patients with hyperlipidaemia.,E Haak; C Abletshauser; S Weber; C Goedicke; N Martin; N Hermanns; K Lackner; K Kusterer; K H Usadel; T Haak,"The purpose of this study was to investigate the effect of fluvastatin on the microcirculation of patients with hyperlipidaemia (low-density lipoprotein cholesterol > 160 mg/dL, triglycerides < 350 mg/dl) inadequately controlled by diet. After a dietary run-in of 4 weeks, patients were randomised in a double-blind study to receive fluvastatin 40 mg twice daily (n = 24) or placebo (n = 24) for 12 weeks. The effect on microcirculation was assessed using capillary microscopy and laser Doppler fluxmetry at the nailfold at baseline and at 6 and 12 weeks after initiation of therapy. Capillaroscopy showed that fluvastatin improved microcirculation, i.e. time to peak flow during postocclusive reactive hyperaemia dropped from 19.7 +/- 7.2 s at baseline to 12.3 +/- 9.5 s at week 6 (P < 0.01) and 10.6 +/- 6.5 s at week 12 (P < 0.0001). These results were confirmed using laser Doppler fluxmetry to study microcirculation in thermoregulatory capillaries at the same site. A significant decrease in total and LDL-cholesterol was achieved during fluvastatin therapy. In conclusion, fluvastatin therapy improves microcirculation in nutritive as well as thermoregulatory capillaries in hypercholesterolaemic patients within 6 weeks.",2001.0,0,0 682,11254911,Oxidized LDL and thickness of carotid intima-media are associated with coronary atherosclerosis in middle-aged men: lower levels of oxidized LDL with statin therapy.,T Vasankari; M Ahotupa; J Toikka; J Mikkola; K Irjala; P Pasanen; K Neuvonen; O Raitakari; J Viikari,"We investigated the relation between serum lipids including oxidized LDL and the severity of coronary atherosclerosis. Serum lipids and oxidized LDL was measured in 62 men (33-66 years), who underwent diagnostic coronary angiography and sonography to measure the carotid intima-media thickness. LDL oxidation was found in chemical analyses to be due to conjugated fatty acids in cholesteryl esters and triglycerides. Regression analysis indicated that the carotid intima-media thickness and the ratio of LDL diene conjugation to LDL cholesterol (the ox-LDL:LDL ratio) were the only factors associated independently with the severity of coronary atherosclerosis. The patients with multi-vessel disease who did not use lipid lowering therapy had a 50% thicker carotid intima media (P = 0.030) and a 41% higher ox-LDL:LDL ratio (P = 0.020) than patients with normal vessels. Further, patients with multi-vessel disease on statin therapy had a 24% lower ox-LDL:LDL ratio than the subjects with multi-vessel disease who did not use lipid lowering drugs (P = 0.027), although the concentration of LDL cholesterol did not differ between the groups. This study supports the hypothesis that lipid oxidation plays a role in the development of atherosclerosis.",2001.0,0,0 683,11254918,Comparative study of HMG-CoA reductase inhibitors on fibrinogen.,R S Rosenson; C C Tangney; E J Schaefer,"Statins have a variable response on fibrinogen, and these changes may have implications on cardiovascular events. In this randomized placebo-controlled crossover study, we evaluated whether changes in fibrinogen levels were different between atorvastatin and other statin-treated patients. Adult coronary heart disease (CHD) patients aged 39-83 years with LDL cholesterol levels > or = 130 mg/dl were randomized to atorvastatin 80 mg (n = 84) and one of the following statins: fluvastatin 80 mg (n = 23), lovastatin 80 mg (n = 20), pravastatin 40 mg (n = 22) or simvastatin 40 mg (n = 20) each for 12 weeks in either order. Fibrinogen was analyzed by an automated method of Clauss. Three independently acquired samples were obtained within 1 min of tourniquet application, and each specimen was measured in duplicate. Statistical analyses were performed using a mixed model repeated measures analysis of variance procedure with SAS version 6.12. There were no significant changes in fibrinogen between treatment groups. This study evaluated changes in fibrinogen with established pre-analytical and analytical procedures known to minimize variability in fibrinogen measurement, and we did not observe any differences in fibrinogen levels in the treatment groups.",2001.0,0,0 684,11257264,"A prospective study of paraoxonase gene Q/R192 polymorphism and severity, progression and regression of coronary atherosclerosis, plasma lipid levels, clinical events and response to fluvastatin.",S Turban; F Fuentes; L Ferlic; R Brugada; A M Gotto; C M Ballantyne; A J Marian,"Human serum paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated enzyme that is responsible for the protective effect of HDL against oxidation of low-density lipoprotein (LDL). PON1 has a Glu to Arg polymorphism at codon 192 (CGA-->CAA) which is designated R/Q192. The R/Q192 polymorphism has been associated with coronary artery disease (CAD) in several, but not all, case-control studies. We prospectively studied the association of the Q/R192 genotypes with the severity, progression and regression of CAD, plasma lipid levels, clinical events and response to treatment with fluvastatin in a well-characterized cohort. Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping with AlwI enzyme in 356 subjects in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. A total of 177 (50%), 142 (40%) and 37 (10%) subjects had Q/Q, Q/R and R/R genotypes, respectively. Baseline and final plasma levels of HDL, LDL, triglyceride and other lipoproteins, lesion-specific minimum lumen diameters (MLD), mean MLD, number of coronary lesions and total occlusions at baseline and follow-up and clinical event rates were not significantly different among the genotypes. There was no genotype-treatment interaction with respect to plasma lipid levels and angiographic indices of CAD. The Q/R192 variants of PON1 are not associated with severity, progression or regression of coronary atherosclerosis, plasma lipid levels, clinical events, or response to treatment with fluvastatin. Thus, the Q/R192 polymorphism is not a major risk factor in susceptibility to CAD in the LCAS population.",2001.0,0,0 685,11257816,"[Great discrepancies between European, Dutch and Belgian criteria for the use of statins in the prevention of primary cardiovascular disease in family practice].",E Van Diest; E Stoffelen; L Wydooghe; D Van Duppen; L Seuntjens; P Van der Stuyft,"To determine the differences in prescribing advice for statines in primary cardiovascular prevention, applying different protocols, in a first-line setting. In February-March 2000, at the general practice 'Medicine for the People' in Deurne-Antwerp, Belgium, all contacts with patients known with at least one cardiovascular risk factor and no signs of cardiovascular disease were included in the study. The absolute risk of developing cardiovascular disease in the next 10 years was calculated per patient according to the protocols of the 'European Society of Cardiology' (ESC) and the Dutch College of General Practitioners (NHG) and it was determined whether these protocols advised prescription of statines. It was also determined if the Belgian criteria for repayment of statines, developed by the Rijksinstituut voor Ziekte- en Invaliditeitsverzekering (RIZIV) were met. The study group comprised 143 patients with a mean age of 66 years, of which 51 (36%) were men. According to the RIZIV criteria 75 (52%) patients of these 143 were eligible for the repayment of statines. The NHG protocol advised to prescribe statines for 4 (3%) patients and the ESC protocol for 69 (48%) patients. Of the 75 patients who were considered for repayment, 34 (45%) according to the ESC protocol and 74 (99%) according to the NHG protocol did not need statines. Also, in the whole study population, 28 (20%) patients needed statines according to ESC and 3 (2%) patients according to NHG, but they could not get repayment for statines according to the RIZIV. The ESC protocol estimated the risk per patient on average 8.5% (95% confidence interval: 7.1-9.8; p < 0.0001) higher than the NHG protocol. The NHG protocol estimated the risk significantly and markedly lower than the European protocol, although they are both based on the same Framingham data. There also existed a weak concordance between both protocols. The RIZIV criteria were not 'evidence-based'. They incited to an irrational and wasting prescribing behaviour. There is a need for an integrated guideline for primary cardiovascular prevention and for the adjustment of the RIZIV criteria.",2001.0,0,0 686,11258146,Are patients' chief complaints generally specific to one organ system?,A B Fleischer; E F Gardner; S R Feldman,"The coordinator of care function is one of the most important roles played by primary care physicians. This role is essential for efficient delivery of healthcare to patients with unfocused medical problems. To identify which chief complaints are unfocused and to determine how often visits to office-based physicians are for unfocused chief complaints. Retrospective review of National Ambulatory Medical Care Survey data. We defined an unfocused chief complaint as one for which fewer than 95% of the office visits for the top 10 diagnoses associated with that chief complaint were related to a single organ system or specialty area. We analyzed data from the 1990-1994 National Ambulatory Medical Care Survey to determine the frequency of new patient visits to physicians for different chief complaints and to determine the frequency with which common chief complaints yield diagnoses in a single organ system. The 3 most common chief complaints in each of 12 symptom categories accounted for 80 million (32%) of the 250 million new patient office visits made during the survey period. Unfocused conditions accounted for 26% of visits for these chief complaints. The unfocused chief complaints included musculoskeletal conditions (back pain, knee pain, low back pain), mental/nervous system conditions (anxiety/nervousness, smoking problems, headaches, vertigo/dizziness), abnormal pulsations, swollen glands, and abdominal pain. Patients' chief complaints and the resulting diagnoses are often within the same organ system. We found that a coordinator of care role for primary care physicians is appropriate for common neurologic, rheumatologic, and general complaints. A coordinator of care is not needed for specific specialty areas, including ophthalmology, dermatology, obstetrics/gynecology, urology, and otolaryngology, because patients typically can accurately self-refer to these specialists. Our study did not address reasons to use primary care physicians as coordinators of care, such as preventive care, patient preference, or cost effectiveness of care.",2001.0,0,0 687,11259136,Good medicines for bad genes.,A Kastrati; A Schömig,,2001.0,0,0 688,11259143,Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries; principal results from EUROASPIRE II Euro Heart Survey Programme.,EUROASPIRE II Study Group,"The principal aim of the second EUROASPIRE survey was to determine in patients with established coronary heart disease whether the Joint European Societies' recommendations on coronary prevention are being followed in clinical practice. This survey was undertaken in 1999-2000 in 15 European countries: Belgium, Czech Republic, Finland, France, Germany, Greece, Hungary, Ireland, Italy, the Netherlands, Poland, Slovenia, Sweden, Spain and the U.K., in selected geographical areas and 47 centres. Consecutive patients, men and women < or =70 years were identified retrospectively with the following diagnoses: coronary artery bypass graft, percutaneous transluminal coronary angioplasty, acute myocardial infarction and myocardial ischaemia. Data collection was based on a review of medical records and interview and risk assessment at least 6 months after hospital admission. 8181 medical records (25% women) were reviewed and 5556 patients (adjusted participation rate 76%) interviewed. Recording of risk factor history and risk factor measurement in hospital notes was incomplete, particularly for discharge documents. At interview (median time 1.4 years after hospital discharge), 21% of patients smoked cigarettes, 31% were obese, 50% had raised blood pressure (systolic blood pressure > or =140 mmHg and/or diastolic blood pressure > or =90 mmHg), 58% had elevated serum total cholesterol (total cholesterol > or =5 mmol x l(-1)) and 20% reported a medical history of diabetes. Glucose control in these diabetic patients was poor with 87% having plasma glucose >6.0 mmol x l(-1)and 72% > or =7.0 mmol x l(-1). Among the patients interviewed the use of prophylactic drug therapies on admission, at discharge and at interview was as follows: aspirin or other antiplatelets drugs 47%, 90% and 86%; beta-blockers 44%, 66% and 63%; ACE inhibitors 24%, 38% and 38%; and lipid-lowering drugs 26%, 43% and 61%, respectively. With the exception of antiplatelet drugs, wide variations in the use of prophylactic drug therapies exist between countries. This European survey of coronary patients shows a high prevalence of unhealthy lifestyles, modifiable risk factors and inadequate use of drug therapies to achieve blood pressure and lipid goals. There is considerable potential throughout Europe to raise the standard of preventive cardiology through more effective lifestyle intervention, control of other risk factors and optimal use of prophylactic drug therapies in order to reduce coronary morbidity and mortality.",2001.0,0,0 689,11259146,Statin therapy is associated with reduced restenosis rates after coronary stent implantation in carriers of the Pl(A2)allele of the platelet glycoprotein IIIa gene.,D H Walter; V Schächinger; M Elsner; S Mach; S Dimmeler; W Auch-Schwelk; A M Zeiher,"Aims Platelets play a central role in the restenosis process by inducing neointimal proliferation after coronary interventions. Glycoprotein IIb/IIIa Pl(A2)polymorphism has been associated with the occurrence of acute coronary syndromes and increased restenosis rates. Statins have been shown to exert potent antiproliferative, antiinflammatory and antithrombotic properties, thereby potentially interfering with the major processes of in-stent restenosis. Therefore, we sought to find out whether statin therapy interferes with restenosis and clinical outcome at 6 months following successful coronary stent implantation in the presence or absence of the Pl(A2)allele. Methods and Results Six hundred and fifty consecutive patients were followed for 6 months after coronary stent insertion. Carriers of the Pl(A2)allele demonstrated a significantly increased restenosis rate, which was abrogated by statin therapy (50.9% vs 28.6%, P=0.01). Moreover, statin therapy was associated with a significant reduction (28.2% vs 49.3%, P<0.01) in the occurrence of major adverse coronary events (myocardial infarction, cardiac death, target vessel revascularization) in the 6 months after the intervention in patients with the Pl(A2)allele. Conclusion Statin therapy reduces increased stent restenosis rates and improves clinical outcome following coronary stent implantation in patients bearing the Pl(A2)allele, suggesting that statins interfere with the functional consequence of a genetically determined platelet-mediated risk factor associated with Pl(A2)polymorphism.",2001.0,0,0 690,11259687,Age and gender bias in statin trials.,S Bandyopadhyay; A J Bayer; M S O'Mahony,"Cardiovascular disease is strongly age-related, and is the leading cause of death in older people. Several well-publicized trials have recently reported that statin drugs (HMG CoA reductase inhibitors) are effective in lowering cholesterol and in reducing the risk of myocardial infarction and stroke. In order to determine whether the results of these trials are relevant to our ageing population, we examined the representation of older people and women in randomized controlled trials of statin drugs. A systematic search of the medical literature from 1990 to 1999 was done to identify randomized placebo-controlled trials of statin drugs which evaluated clinical end-points-myocardial infarction, stroke or death. We identified 19 trials: 15 secondary prevention and four primary prevention. The mean age, age range and gender of the participants in these trials were determined. In the secondary prevention trials, the total number of patients randomized was 31683, with a combined mean age of 58.1 years. No trial enrolled people beyond the age of 75 years, and only 23% of the trial population was female. The four primary prevention trials randomized a combined total of 14 557 subjects with a mean age of 56.9 years. Only 10% of study participants were female. Statin drug trials have suffered from age and gender bias, having been mainly conducted in middle-aged male populations. The extrapolation of evidence from these trials to older people and women needs further evaluation.",2001.0,0,1 691,11259986,The effects of lacidipine on the steady/state plasma concentrations of simvastatin in healthy subjects.,L Ziviani; L Da Ros; L Squassante; S Milleri; M Cugola; L E Iavarone,"Lacidipine, a long acting 2, 4-dihydropyridine calcium channel antagonist is frequently administered with cholesterol lowering agents, particularly in elderly populations. The effects of lacidipine on the pharmacokinetics of simvastatin were investigated, since they share the CYP3A4 pathway for metabolism. The study was an open, randomised, two-way crossover design, with at least 7 days washout. Eighteen healthy subjects received simvastatin, 40 mg once daily, alone and together with lacidipine, 4 mg once daily, for 8 days. The pharmacokinetics of simvastatin were studied on the eighth day. Analysis was made of total simvastatin acid concentrations (naive simvastatin acid plus that derived from alkaline hydrolysis of the lactone). Lacidipine increased the maximum concentration of simvastatin (Cmax) by approximately 70% (P=0.016) and the area under the plasma concentration-time curve AUC(0,24 h) by approximately 35% (P=0.001). The mean Cmax and AUC(0,24 h) of simvastatin (95% confidence interval) when given alone were 8.76 (6.72-11.41) ng ml(-1) and 60.36 (47.15-77.28) ng ml(-1) h. During treatment with lacidipine they were, respectively, 14.89 (10.77-20.58) ng ml(-1) and 80.96 (64.62-101.44) ng ml(-1) h. No significant differences were observed in either time to peak concentration (tmax was 1.0 h for simvastatin alone and 1.5 h for the combination) or in the half-life (t1/2,z was 8.5 h in both cases). The combination was safe and well tolerated. The observed increased exposure to simvastatin 40 mg following coadministration of lacidipine is unlikely to be of clinical relevance.",2001.0,0,0 692,11260410,Effect of fluvastatin on endothelium-dependent brachial artery vasodilation in patients after renal transplantation.,M Hausberg; M Kosch; F Stam; S Heidenreich; K Kisters; K H Rahn; M Barenbrock,"Hypercholesterolemia may affect both endothelial function and arterial distensibility (DC). Renal transplant recipients (NTX) exhibit advanced structural and functional alterations of arterial vessel walls. The aim of this double-blind, randomized trial was to evaluate the effects of fluvastatin (FLU) on brachial artery flow-mediated vasodilation (FMD) and DC in hypercholesterolemic NTX. Eighteen NTX received FLU 40 mg/day and 18 NTX placebo (PLA). Before and after six months of treatment, the brachial artery diameter and DC at rest were measured by a Doppler frequency analysis in the M mode, and then changes in diameter during reactive hyperemia (to assess endothelial-dependent FMD) and after 400 microg sublingual nitroglycerin (to assess endothelium-independent vasodilation-NMD). FLU, but not PLA, treatment resulted in significant decreases in total (from 288 +/- 10 to 239 +/- 8 mg/dL, P < 0.05) and low-density lipoprotein cholesterol (from 182 +/- 779 to 138 +/- 8 mg/dL, P < 0.05). Blood pressure did not differ between FLU- and PLA-treated patients and was not affected by either treatment. Also, the brachial artery baseline diameter was not different between groups and was not affected by FLU or PLA. Brachial artery flow at rest and during reactive hyperemia as measured by pulsed Doppler did not differ between groups. Brachial artery FMD increased with FLU from 0.23 +/- 0.08 to 0.54 +/- 0.08 mm (P < 0.05), whereas PLA did not alter FMD (0.22 +/- 0.07 vs. 0.14 +/- 0.05 mm at baseline and after six months of PLA treatment, respectively, P = NS). In contrast, NMD did not change significantly with either treatment (0.76 +/- 0.13 vs. 0.83 +/- 0.15 mm at baseline and after 6 months of FLU treatment, respectively, P = NS, and 0.64 +/- 0.09 vs. 0.66 +/- 0.10 mm at baseline and after 6 months of PLA treatment, respectively, P = NS). Also, brachial artery DC was not altered by FLU (6.4 +/- 1.0 vs. 5.8 +/- 0.6 x 10-3/kPa, P = NS) or PLA treatment (5.8 +/- 0.6 vs. 6.8 +/- 0.8 x 10-3/kPa, P = NS). In hypercholesterolemic NTX, the HMG-CoA reductase inhibitor FLU significantly improves brachial artery FMD as a measure of endothelial function after six months of treatment. In contrast, FLU does not have a beneficial effect on brachial artery DC.",2001.0,0,0 693,11260433,Psychosocial factors in dialysis patients.,P L Kimmel,,2001.0,0,0 694,11261530,Orlistat--a novel weight loss therapy.,K H Lucas; B Kaplan-Machlis,"To review the pharmacology, pharmacokinetics, clinical safety and efficacy, drug interactions, and therapeutic issues related to the use of orlistat for treatment of obesity. English-language articles were identified from MEDLINE (1966-July 2000), Roche Laboratories, organizational guidelines, National Institutes of Health and Food and Drug Administration Web sites, and Doctor's Guide online. Key words included obesity, orlistat, and lipase inhibitors. References were also identified from reference sections of published articles. Prospective, randomized, double-blind, placebo-controlled, human trials were selected for review and discussion. Orlistat is the first agent in the lipase inhibitor class of antiobesity drugs. Orlistat is minimally absorbed and has been shown to reduce body weight by inhibiting absorption (by approximately 30%) of ingested dietary fat. Safety and efficacy have been established in one- and two-year double-blind, placebo-controlled trials; adverse effects were primarily, and almost exclusively, gastrointestinal. Due to its ability to block fat absorption, orlistat also has the capability to inhibit absorption of fat-soluble vitamins. Therefore, a daily multiple vitamin is recommended while taking orlistat. By inhibiting fat absorption, orlistat offers a new treatment modality for weight loss and maintenance. Preliminary data from clinical trials suggest that orlistat may be beneficial in patients with comorbid conditions related to obesity, such as diabetes and hyperlipidemia. However, further studies during postmarketing surveillance are needed to fully establish orlistats long-term benefits and safety. Orlistat should be considered a useful adjunctive therapy for weight loss and maintenance in obese patients (i.e., body mass index > or = 30 kg/m2 or > or = 27 kg/m2 if other risk factors are present) committed to lifestyle changes including diet, exercise, and behavioral modification.",2001.0,0,0 695,11263601,"Coronary artery bypass graft or percutaneous coronary interventions in patients with diabetes: another nail in the coffin or ""too close to call?"".",S B King,,2001.0,0,0 696,11263847,Making the most of cholesterol-lowering margarines.,J K Avery,"Used as a substitute for normal dietary intake of saturated fatty acids, margarines containing plant sterols can cause a modest reduction in serum total cholesterol and low-density lipoprotein cholesterol levels. They have been shown effective in patients with mild hypercholesterolemia, but they are also useful in the general population.",2001.0,0,0 697,11267254,"Safety and efficacy of simvastatin for hyperlipidemia in renal transplant recipients: a double-blind, randomized, placebo-controlled study.",A F Santos; E Keitel; A E Bittar; J Neumann; F D Fuchs; J C Goldani; N A Fonseca; V C Prates; D Zaffan; C Voegeli; L Kroth; G Steffenello; D Saitovitch; V D Garcia,,2001.0,0,0 698,11267373,Tacrolimus or cyclosporine for immunosuppression after cardiac transplantation: which treatment reveals more side effects during long-term follow-up?,J Groetzner; B M Meiser; J Schirmer; J Koglin; W vScheidt; V Klauss; P Cremer; H Reichenspurner; B Reichart,,2001.0,0,0 699,11270314,Prescription and adherence to statins of patients with coronary artery disease and hypercholesterolemia.,A P Mansur; A P Mattar; C E Tsubo; D T Simão; F R Yoshi; K Daci,"Statins have proved to be safe and effective in the secondary prevention of coronary artery disease, but the level of prescription and the reasons for nonadherence to treatment in many coronary diseases treatment centers has not been determined. The purpose of this study was to identify reasons for nonadherence to statin therapy. We analyzed 207 consecutive patients with coronary artery disease and hypercholesterolemia (total cholesterol > or = 200 mg/dL or LDL-cholesterol > or = 130 mg/dL). Patients' average age was 61.7 +/- 10 year; 111 (53.6 %) male were and 94 (46.6 %) were female. We analyzed the level of prescription and adherence to treatment with statins. Statins were prescribed for 139 (67 %) patients, but only 85 (41 %) used the drug. In spite of being indicated, statins were not prescribed in 68 (33 %) patients. Of 54 (26 %) patients, nonadherent to statins, 67 % did not use the drug due to its high cost, 31 % due to the lack of instruction, and only 2 % due to side effects. Total cholesterol (260.3 +/- 42.2 vs 226.4 +/- 51.9; p < 0.0001) and LDL cholesterol (174.6 +/- 38.1 vs 149.6 +/- 36.1; p < 0.0001) were lower in patients on medication. HDL-cholesterol increased from 37.6 +/- 9.6 to 41.5 +/- 12.9 mg/dL (p = 0.02), and triglycerides were not modified in patients using statins. The prescription of statins in patients with coronary artery disease and dyslipidemia is high; however, its adherence is far from satisfactory, due to the high cost of the medication. Reduction in total cholesterol and LDL cholesterol levels did not reach the targets recommended by the Brazilian Consensus on Dyslipidemia.",2001.0,0,0 700,11270938,Safety profiles for the HMG-CoA reductase inhibitors: treatment and trust.,M H Davidson,"Hypercholesterolaemia is a chronic condition that often requires life-long treatment, making the safety of lipid-lowering drugs a critical issue. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ('statins') are commonly used as the pharmacotherapeutic treatment of choice for patients with hypercholesterolaemia. These agents have consistently demonstrated a positive safety and tolerability profile, and are recommended by the US National Cholesterol Education Program guidelines and by the European Joint Task Force for Prevention of Coronary Heart Disease to be used after, or in addition to, a first-line approach with diet. Several large-scale clinical trials have shown HMG-CoA reductase inhibitors to be efficacious and well tolerated, and to be associated with a low rate of treatment withdrawal due to adverse events. These studies included mortality and morbidity end-points, and comprised both primary- and secondary-prevention trials. Hepatic, renal and muscular systems are rarely affected during HMG-CoA reductase inhibitor therapy and the few drug interactions that can occur with concomitantly administered drugs are well documented. There is no conclusive evidence linking HMG-CoA reductase inhibitors to the development of cancer in humans. In long term studies with various HMG-CoA reductase inhibitors, there was no increase in cancer rates compared with placebo. Thus, it can be concluded that HMG-CoA reductase inhibitors are well tolerated, effective treatments for hypercholesterolaemia.",2001.0,1,1 701,11274247,Treating IgA nephropathy.,J J Dillon,,2001.0,0,0 702,11276395,Recent clinical trial highlights in hypertension.,F C Luft,"Clinical trials continue to guide patient management. However, the hypotheses generally come from observational studies. Studies on women continue to be too little and too few, particularly in light of the fact that most elderly hypertensive patients are likely to be women. Attention has been drawn to the possibility that hypertension per se may engender symptoms such as headache for example, in addition to harder endpoints such as death. The MICROHOPE study, which was not a blood pressure-lowering study, showed that angiotensin converting enzyme inhibition with ramipril in diabetic patients provided the same beneficial effects previously published for the HOPE study. The doxazosin arm of the ALLHAT study was terminated by the data monitoring and safety board because the doxazosin-treated patients developed congestive heart failure at a greater rate than diuretic-treated patients. Two extensive studies testing two different classes of calcium antagonists against primarily diuretic-based treatment showed that the calcium antagonists were no less effective in terms of preventing hard endpoints. A small, but impressive cross-over study testing the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin, against placebo showed that statin treatment lowers blood pressure in hypercholesterolemic patients with hypertension. Meta- analyses emphasized the value of blood pressure reduction in the elderly and added to the controversy and confusion about the role of calcium antagonists in the first-line treatment of hypertension. The point may be moot since with the current recommendations few hypertensive patients will be adequately treated with a single agent.",2001.0,0,0 703,11277469,Heart failure management: 25 years of progress.,N Sharpe,,2001.0,0,0 704,11277825,Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.,G G Schwartz; A G Olsson; M D Ezekowitz; P Ganz; M F Oliver; D Waters; A Zeiher; B R Chaitman; S Leslie; T Stern; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators,"Patients experience the highest rate of death and recurrent ischemic events during the early period after an acute coronary syndrome, but it is not known whether early initiation of treatment with a statin can reduce the occurrence of these early events. To determine whether treatment with atorvastatin, 80 mg/d, initiated 24 to 96 hours after an acute coronary syndrome, reduces death and nonfatal ischemic events. A randomized, double-blind trial conducted from May 1997 to September 1999, with follow-up through 16 weeks at 122 clinical centers in Europe, North America, South Africa, and Australasia. A total of 3086 adults aged 18 years or older with unstable angina or non-Q-wave acute myocardial infarction. Patients were stratified by center and randomly assigned to receive treatment with atorvastatin (80 mg/d) or matching placebo between 24 and 96 hours after hospital admission. Primary end point event defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization. A primary end point event occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group (relative risk [RR], 0.84; 95% confidence interval [CI], 0.70-1.00; P =.048). There were no significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the atorvastatin group and the placebo group, although the atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency rehospitalization (6.2% vs 8.4%; RR, 0.74; 95% CI, 0.57-0.95; P =.02). Likewise, there were no significant differences between the atorvastatin group and the placebo group in the incidence of secondary outcomes of coronary revascularization procedures, worsening heart failure, or worsening angina, although there were fewer strokes in the atorvastatin group than in the placebo group (12 vs 24 events; P =.045). In the atorvastatin group, mean low-density lipoprotein cholesterol level declined from 124 mg/dL (3.2 mmol/L) to 72 mg/dL (1.9 mmol/L). Abnormal liver transaminases (>3 times upper limit of normal) were more common in the atorvastatin group than in the placebo group (2.5% vs 0.6%; P<.001). For patients with acute coronary syndrome, lipid-lowering therapy with atorvastatin, 80 mg/d, reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring rehospitalization.",2001.0,1,1 705,11279658,Reversible sideroblastic anemia associated with the tetracycline analogue COL-3.,M A Rudek; M Horne; W D Figg; W Dahut; V Dyer; J M Pluda; E Reed,"Eight of 35 patients with cancer receiving COL-3, a tetracycline derivative with antiangiogenic properties, developed anemia while on treatment. All of these patients were enrolled on an approved Phase I clinical trial at the National Cancer Institute. Three of these patients had bone marrow examinations that revealed ringed sideroblasts. This paper describes these cases. Am. J. Hematol. 67:51-53, 2001. Published 2001 Wiley-Liss, Inc.",2001.0,0,0 706,11281812,Experimental approaches and drugs in development for the treatment of dementia.,M Emre; N Qizilbash,"Treatment of dementia can be divided as symptomatic treatment of cognitive or non-cognitive symptoms and the treatment of underlying pathology. In the last decade the thrust of symptomatic treatment of Alzheimer's disease (AD) has been enhancement of cholinergic transmission. Besides the acetycholinesterase inhibitors (AChE-I) currently in use, cholinergic agonists and enhancers are in development. Other therapeutic approaches directed towards neurotransmitter substitution or modulation include serotoninergic, noradrenergic substances, neuropeptides and those acting via excitatory amino acid receptors, such as ampakines or NMDA antagonists. Introduction of atypical neuroleptics represents the most recent development in the treatment of behavioural symptoms. Efforts to treat the underlying pathology are based on modulation of APP processing in order to decrease the accumulation of beta-amyloid, those to decrease tau hyperphosphorylation, use of nerve growth factors and those based on Apo-E modulation. Potential use of oestrogens and NSAIDs are also under investigation. Recently, vaccination with amyloid-beta peptide has been reported to be effective in an animal model of AD, this putative vaccine is now in clinical trials. Likewise, recent studies suggest that some statins may have a prophylactic effect.",2001.0,0,0 707,11281851,Current therapies and emerging targets for the treatment of diabetes.,A S Wagman; J M Nuss,"Concurrent with the spread of the western lifestyle, the prevalence of all types of diabetes is on the rise in the world's population. The number of diabetics is increasing by 4-5% per year with an estimated 40-45% of individual's over the age of 65 years having either type II diabetes or impaired glucose tolerance. Since the signs of diabetes are not immediately obvious, diagnosis can be preceded by an extended period of impaired glucose tolerance resulting in the prevalence of beta-cell dysfunction and macrovascular complications. In addition to increased medical vigilance, diabetes is being combatted through aggressive treatment directed at lowering circulating blood glucose and inhibiting postprandial hyperglycemic spikes. Current strategies to treat diabetes include reducing insulin resistance using glitazones, supplementing insulin supplies with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of small molecules are being investigated which exhibit improved efficacy and safety profiles. Promising biological targets are also emerging such as (1) insulin sensitizers including protein tyrosine phosphatase-1B (PTP-1B) and glycogen synthase kinase 3 (GSK3), (2) inhibitors of gluconeogenesis like pyruvate dehydrogenase kinase (PDH) inhibitors, (3) lipolysis inhibitors, (4) fat oxidation including carnitine palmitoyltransferase (CPT) I and II inhibitors, and (5) energy expenditure by means of beta 3-adrenoceptor agonists. Also important are alternative routes of glucose disposal such as Na+-glucose cotransporter (SGLT) inhibitors, combination therapies, and the treatment of diabetic complications (eg. retinopathy, nephropathy, and neuropathy). With may new opportunities for drug discovery, the prospects are excellent for development of innovative therapies to effectively manage diabetes and prevent its long term complications. This review highlights recent (1997-2000) advances in diabetes therapy and research with an emphasis on small molecule drug design (275 references).",2001.0,0,0 708,11282901,Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: Main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS).,B Hedblad; J Wikstrand; L Janzon; H Wedel; G Berglund,"Statins reduce cardiovascular events and progression of carotid intima-media thickness (IMT). beta-Blockers are also known to reduce cardiovascular events, but less is known about their effects on carotid IMT. We conducted a randomized, double-blind, placebo-controlled, single-center trial to compare the effects of low-dose metoprolol CR/XL (25 mg once daily) and fluvastatin (40 mg once daily) on the progression of carotid IMT during 36 months of treatment in 793 subjects who had carotid plaque but no symptoms of carotid artery disease. Changes in mean IMT in the common carotid artery and maximal IMT in the bulb were the main outcome variables. Death and cardiovascular events were monitored. Progression of IMT(max) in the carotid bulb at both 18 and 36 months was reduced by metoprolol CR/XL (-0.058 mm/y; 95% CI, -0.094 to -0.023; P=0.004; and -0.023 mm/y; 95% CI, -0.044 to -0.003; P=0.014, respectively). Incidence of cardiovascular events tended to be lower in metoprolol CR/XL-treated patients (5 versus 13 patients, P=0.055). Rate of IMT(mean) progression in the common carotid at 36 months was reduced by fluvastatin (-0.009 mm/y; 95% CI, -0.015 to -0.003; P=0.002). Women in the fluvastatin group had increased frequency of transiently high liver enzymes. This is the first randomized trial to show that a beta-blocker can reduce the rate of progression of carotid IMT in clinically healthy, symptom-free subjects with carotid plaque. This suggests that beta-blockers may have a favorable effect on atherosclerosis development.",2001.0,0,0 709,11282915,High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease.,P M Ridker,"Inflammation plays a major role in atherothrombosis, and measurement of inflammatory markers such as high-sensitivity C-reactive protein (HSCRP) may provide a novel method for detecting individuals at high risk of plaque rupture. Several large-scale prospective studies demonstrate that HSCRP is a strong independent predictor of future myocardial infarction and stroke among apparently healthy men and women and that the addition of HSCRP to standard lipid screening may improve global risk prediction among those with high as well as low cholesterol levels. Because agents such as aspirin and statins seem to attenuate inflammatory risk, HSCRP may also have utility in targeting proven therapies for primary prevention. Inexpensive commercial assays for HSCRP are now available; they have shown variability and classification accuracy similar to that of cholesterol screening. Risk prediction algorithms using a simple quintile approach to HSCRP evaluation have been developed for outpatient use. Thus, although limitations inherent to inflammatory screening remain, available data suggest that HSCRP has the potential to play an important role as an adjunct for global risk assessment in the primary prevention of cardiovascular disease.",2001.0,0,0 710,11285042,Cardiovascular disease in type 2 diabetes: challenge for treatment and prevention.,M Laakso,"Type 2 diabetes increases the risk of cardiovascular disease (CVD) two- to fourfold compared with the risk in non-diabetic subjects. Although type 2 diabetes is associated with a clustering of risk factors (small, dense low-density lipoprotein [LDL] particles, low high-density lipoprotein [HDL] cholesterol, high triglycerides, elevated blood pressure, obesity, central obesity, hyperinsulinaemia, hyperglycaemia, etc.), the cause for an excess risk of CVD remains unknown. Recent drug treatment trials have indicated that the lowering of total and LDL cholesterol and blood pressure is similarly beneficial in diabetic and non-diabetic subjects. The treatment of hyperglycaemia reduces micro- and macrovascular complications in type 2 diabetic patients. Beta-blocking agents, angiotensin-converting enzyme inhibitors, aspirin, and thrombolytic therapy are also effective in the treatment of CVD amongst diabetic patients.",2001.0,0,0 711,11285716,The benefit of aggressive lipid lowering.,W V Brown,"The beneficial effects of lipid-lowering therapy for the primary and secondary prevention of coronary heart disease (CHD) have been conclusively demonstrated in large-scale clinical trials. Does more aggressive lipid lowering provide even greater clinical benefit? The post coronary artery bypass graft (post-CABG) study was the first angiographic trial to show that aggressive lipid-lowering therapy was more effective at reducing disease progression than conventional approaches to cholesterol management. Recently, the results of the atorvastatin versus revascularization treatments (AVERT) trial have also shown significant benefit on clinical events with aggressive lipid lowering. A total of 341 patients with stable CHD were randomly assigned to receive medical therapy with atorvastatin 80 mg/day plus conventional treatment or angioplasty followed by usual care. Atorvastatin therapy resulted in a 46% reduction in the mean low-density lipoprotein cholesterol level compared with an 18% decrease for patients in the angioplasty/usual care group. Patients treated with atorvastatin had fewer ischemic events compared with those who had angioplasty (13 vs. 21%, P = 0.048) and a significantly greater time to first ischemic event (P = 0.027). AVERT is the first clinical study demonstrating that patients with stable CHD achieve significant cardiovascular benefit by aggressively lowering cholesterol levels with atorvastatin. It would therefore appear that an aggressive approach to lipid-lowering therapy is beneficial in patients with existing CHD.",2001.0,0,0 712,11286151,Clinical relevance of statins: instituting treatment early in acute coronary syndrome patients.,P L Thompson,"The efficacy of statins in lowering the total and low-density lipoprotein cholesterol and reducing the risk of cardiac events is now well established. The secondary prevention studies started treatment several months after the acute event. However, the greatest risk of recurrence is shortly after the index event. Recent evidence from small-scale clinical trials shows that standard doses of statins can be both safe and effective when given early after an acute coronary event, including early after thrombolytic therapy for myocardial infarction. Angiographic studies have shown beneficial effects of pravastatin on coronary stenosis when initiated after a coronary event. While none of these studies have been powered to demonstrate an effect on outcome, each has shown a reduction in major cardiovascular events. Two large observational studies have shown a reduction in 6- and 12-month risk-adjusted mortality among post-MI patients treated early with statins. Large-scale trials of all statins are now in progress to evaluate further the efficacy of early initiation of statin therapy in acute coronary syndromes. The largest of these is the Australian Pravastatin Acute Coronary Treatment (PACT) study, which will compare early outcomes in patients treated with pravastatin versus placebo prescribed within the first 24 h of an acute coronary event.",2001.0,0,0 713,11286152,Clinical relevance of statins: their role in secondary prevention.,A M Tonkin,"Five large randomized clinical trials show the benefits of lipid lowering with statins on cardiac morbidity and mortality. Three of these were secondary-prevention trials--the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, Cholesterol and Recurrent Events (CARE), and Scandinavian Simvastatin Survival Study (4S). The CARE and LIPID studies, performed with pravastatin, comprise populations that are representative of the majority of patients with coronary disease in that they included subjects with 'average' cholesterol levels. The 4S study, using simvastatin, comprised a patient population with elevated lipid levels. Pooled data from three trials, CARE, LIPID, and the West of Scotland Coronary Prevention Study (WOSCOPS), were examined in the Pravastatin Pooling Project (PPP). Individual patient data from these three event trials were pooled into a single database, permitting subgroup analyses and providing increased power. In the PPP, pravastatin-treated patients had significantly lower all-cause mortality (7.9, vs. 9.8% in those receiving placebo, a relative risk reduction of 20%). Pravastatin treatment was associated with a significant 24% reduction in CHD mortality and a nonsignificant difference in other vascular deaths (17%) and noncardiovascular deaths (12%). However, the reductions in absolute risk were much larger in those with a history of coronary heart disease than in those without. In the combined analysis of CARE and LIPID, there was also a uniform relative risk reduction in both men and women. In high-risk groups such as diabetics, smokers, hypertensives, and the elderly, there were also significant risk reductions in clinical end points. Finally, in the 598 participants, who had a stroke (90% of which were non-fatal), CARE and LIPID individually demonstrated reductions in non-fatal and total stroke. These data confirm that benefits of treatment in secondary prevention of coronary heart disease encompasses prevention of stroke as well as coronary heart disease events. The benefits are found in those who have had unstable angina as well as myocardial infarction. These findings strengthen even further the case for much more widespread use of statins in secondary prevention.",2001.0,0,0 714,11286153,Changing the practice of cardiovascular medicine.,E Braunwald,"Five large randomized trials of statins in primary and secondary prevention show the benefits of lipid-modifying therapy on cardiac morbidity and mortality. Evidence is beginning to accumulate showing that early and aggressive treatment of patients with acute coronary syndromes (acute myocardial infarction or unstable angina) can result in reduced mortality and morbidity and imparts a variety of mechanistic benefits. Nevertheless, recent surveys of coronary heart disease prevention in Europe and the US indicate that current evidence-based management of risk factors such as hypercholesterolemia is not uniformly employed. In fact, in Europe, only about a third of patients discharged from the hospital after an acute coronary syndrome are receiving prescriptions for statins. In US, more than a fourth of adults are eligible for treatment according to national guidelines but two thirds of them do not receive it. Among those treated, a considerable number do not reach their target levels. Therefore, strategies are needed to improve prescribing patterns among physicians and compliance among patients. It is essential that clinicians be aware of the evidence base supporting early and aggressive treatment of patients with acute coronary syndromes and that this is communicated to all clinicians involved in their care of patients with acute coronary syndromes.",2001.0,0,1 715,11286466,Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial.,S Kawata; E Yamasaki; T Nagase; Y Inui; N Ito; Y Matsuda; M Inada; S Tamura; S Noda; Y Imai; Y Matsuzawa,"Chemotherapy is not effective for hepatocellular carcinoma (HCC). HMG-CoA redutase inhibitors have cytostatic activity for cancer cells, but their clinical usefulness is unknown. To investigate whether pravastatin, a potent HMG-CoA reductase inhibitor, prolongs survival in patients with advanced HCC, this randomized controlled trial was conducted between February 1990 and February 1998 at Osaka University Hospital. 91 consecutive patients <71 years old (mean age 62) with unresectable HCC were enroled in this study. 8 patients were withdrawn because of progressive liver dysfunction; 83 patients were randomized to standard treatment with or without pravastatin. All patients underwent transcatheter arterial embolization (TAE) followed by oral 5-FU 200 mg(-1)d for 2 months. Patients were then randomly assigned to control (n = 42) and pravastatin (n = 41) groups. Pravastatin was administered at a daily dose of 40 mg. The effect of pravastatin on tumour growth was assessed by ultrasonography. Primary endpoint was death due to progression of HCC. The duration of pravastatin administration was 16.5 +/- 9.8 months (mean +/- SD). No patients in either group were lost to follow-up. Median survival was 18 months in the pravastatin group versus 9 months in controls (P = 0.006). The Cox proportional hazards model showed that pravastatin was a significant factor contributing to survival. Pravastatin prolonged the survival of patients with advanced HCC, suggesting its value for adjuvant treatment.",2001.0,0,0 716,11286949,Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia.,H H Knapp; H Schrott; P Ma; R Knopp; B Chin; J M Gaziano; J M Donovan; S K Burke; M H Davidson,"To examine the efficacy and safety of colesevelam hydrochloride, a novel, nonsystemic, lipid-lowering agent, when coadministered with starting doses of simvastatin in a multicenter, randomized, double-blind, placebo-controlled trial. Subjects with hypercholesterolemia (plasma low density lipoprotein [LDL] cholesterol level > 160 mg/dL and triglyceride level < or = 300 mg/dL) were randomly assigned to receive daily doses of placebo (n = 33), colesevelam 3.8 g (recommended dose, n = 37), simvastatin 10 mg (n = 35), colesevelam 3.8 g with simvastatin 10 mg (n = 34), colesevelam 2.3 g (low dose, n = 36), simvastatin 20 mg (n = 39), or colesevelam 2.3 g with simvastatin 20 mg (n = 37), for 6 weeks. Mean LDL cholesterol levels decreased relative to baseline in the placebo group (P < 0.05) and in all active treatment groups (P < 0.0001). For groups treated with combination therapy, the mean reduction in LDL cholesterol level was 42% (-80 mg/dL; P < 0.0001 compared with baseline), which exceeded the reductions for simvastatin 10 mg (-26%, -48 mg/dL) or 20 mg (-34%, -61 mg/dL) alone, or for colesevelam 2.3 g (-8%, -17 mg/dL) or 3.8 g (-16%, -31 mg/dL) alone (P < 0.001). The effects of combination therapy on serum HDL cholesterol and triglyceride levels were similar to those for simvastatin alone. Side effects were similar among treatment groups, and there were no clinically important changes in laboratory parameters. Coadministration of colesevelam and simvastatin was effective and well tolerated, providing additive reductions in LDL cholesterol levels compared with either agent alone.",2001.0,0,0 717,11288962,Angiotensin receptor blockers: evidence for preserving target organs.,P Carson; T Giles; M Higginbotham; N Hollenberg; W Kannel; H M Siragy,"Hypertension is a major problem throughout the developed world. Although current antihypertensive treatment regimens reduce morbidity and mortality, patients are often noncompliant, and medications may not completely normalize blood pressure. As a result, current therapy frequently does not prevent or reverse the cardiovascular remodeling that often occurs when blood pressure is chronically elevated. Blockade of the renin-angiotensin system (RAS) is effective in controlling hypertension and treating congestive heart failure. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) inhibit the activity of the RAS, but these two classes of antihypertensive medications have different mechanisms of action and different pharmacologic profiles. Angiotensin-converting enzyme inhibitors block a single pathway in the production of angiotensin II (Ang II). In addition, angiotensin I is not the only substrate for ACE. The ACE inhibitors also block the degradation of bradykinin that may have potential benefits in cardiovascular disease. Bradykinin is, however, the presumed cause of cough associated with ACE inhibitor therapy. Data from clinical trials on ACE inhibitors serve to support the involvement of the RAS in the development of cardiovascular disease. Angiotensin receptor blockers act distally in the RAS to block the Ang II type 1 (AT1) receptor selectively. Thus, ARBs are more specific agents and avoid many side effects. Experimental and clinical trials have documented the efficacy of ARBs in preserving target-organ function and reversing cardiovascular remodeling. In some instances, maximal benefit may be obtained with Ang II blockade using both ARBs and ACE inhibitors. This review describes clinical trials that document the efficacy of ARBs in protecting the myocardium, blood vessels, and renal vasculature.",2001.0,0,0 718,11291836,Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma.,W S Kim; M M Kim; H J Choi; S S Yoon; M H Lee; K Park; C H Park; W K Kang,"Lovastatin, an inhibitor of mevalonate synthesis, demonstrated in vitro antitumor activity against a variety of human cancer cells, especially in gastric adenocarcinoma cells at pharmacologically achievable concentrations. To determine the antitumor activity of this drug in advanced measurable gastric adenocarcinoma as well as to assess the toxicities and the pharmacokinetic features, we carried out a phase II study of high-dose lovastatin. Patients received lovastatin 35 mg/kg/day for 7 consecutive days, with ubiquinone (60 mg qid p.o.) to prevent rhabdomyolysis. The treatment was repeated every 28 days. From March 1996 to January 1997, 16 patients (median age, 57 years; range, 34-68) were entered into the study, 14 of whom were evaluated for response and toxicity. No patient achieved a response. A total of 28 cycles were administered. The median number of cycles was 2 (range, 1 to 4). Anorexia was the most common toxicity (64%), but decreased oral intake was observed only in 3 cycles. Two patients developed myalgia with elevated muscle enzyme. When used in this dosage and schedule, lovastatin does not appear to be effective for patients with advanced gastric adenocarcinoma.",2001.0,0,0 719,11293392,Statin-fibrate combinations in patients with combined hyperlipedemia.,V G Athyros; A A Papageorgiou; A G Kontopoulos,,2001.0,0,0 720,11293393,High-dose simvastin (80 mg/day) decreases plasma concentrations of total homocyst(e)ine in patients with hypercholesteromia.,D Lüftjohann; J I Sigit; S Locatelli; K von Bergmann; H H Schmidt,,2001.0,0,0 721,11293552,Efficacy and tolerability of fluvastatin extended-release delivery system: a pooled analysis.,C M Ballantyne; F Pazzucconi; X Pintó; J P Reckless; E Stein; J McKenney; M Bortolini; Y T Chiang,"At high doses, the pharmacokinetics of fluvastatin immediate-release (IR) are nonlinear, possibly due to saturation of hepatic uptake. Fluvastatin delivery to the liver in a slower but sustained fashion would be expected to avoid hepatic saturation without elevating systemic drug levels. This pooled analysis compared the efficacy and tolerability of extended-release (XL) 80-mg and IR 40-mg formulations of fluvastatin in lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and raising high-density lipoprotein cholesterol (HDL-C) levels in patients with hypercholesterolemia. Data were pooled from 3 double-blind, randomized, active-controlled, multicenter, parallel-group studies that compared changes in lipid and apolipoprotein levels with fluvastatin XL 80 mg at bedtime (HS) with changes in fluvastatin IR 40 mg HS or BID in patients aged > or =18 years with primary hypercholesterolemia (consistently elevated LDL-C level [> or =160 mg/dL] and plasma TG levels < or =400 mg/dL). The primary efficacy variable was percent change in LDL-C from baseline. The pooled analysis provided an intent-to-treat efficacy study population of 1674 patients. At 4 weeks, fluvastatin XL 80 mg HS reduced LDL-C levels by a mean of 36.3% (median 38%), significantly greater than a mean reduction of 25.9% (median 27%) seen with fluvastatin IR 40 mg HS, and an incremental additional mean reduction in LDL-C of 10.4% (P < 0.001). At 4 and 24 weeks, fluvastatin XL 80 mg HS provided an LDL-C reduction equivalent to fluvastatin IR 40 mg BID (P < 0.001 for noninferiority). Significant, dose-related changes in HDL-C, LDL-C:HDL-C ratio, total cholesterol, TG, and apolipoprotein A-I and apolipoprotein B levels also occurred. Mean HDL-C level increased by 8.7% and median TG level decreased by 19% with fluvastatin XL 80 mg HS (P < 0.001 and P < 0.05 vs fluvastatin IR 40 mg HS, respectively). Maximum mean increases in HDL-C level (21%) and median decreases in TG level (31%) with fluvastatin XL 80 mg HS occurred in patients with type IIb dyslipidemia and the highest baseline TG. Adverse events were mild, with similar frequency in all treatment groups. Once-daily administration of fluvastatin XL 80 mg provides enhanced efficacy with an additional 10.4% reduction in LDL-C levels compared with fluvastatin IR 40 mg HS, and superior increases in HDL-C levels, particularly in patients with elevated TG levels (P < 0.05 vs fluvastatin IR 40 mg HS). Fluvastatin XL 80 mg HS has a good tolerability profile and is effective as starting and maintenance lipid-lowering treatment in patients with type II hypercholesterolemia.",2002.0,0,1 722,11293560,Cost-minimization analysis of simvastatin versus atorvastatin for maintenance therapy in patients with coronary or peripheral vascular disease.,E Attanasio; P Russo; S E Allen,"Previous health economic studies have demonstrated the cost-effectiveness of simvastatin in the treatment of coronary heart disease (CHD) based on clinical results of the Scandinavian Simvastatin Survival Study. A prior analysis evaluated the ""cost of getting to goal,"" but ignored all costs after titration. However, when evaluating the cost-effectiveness of long-term therapies, it is important to consider the maintenance costs as well. The purpose of this study was to evaluate the maintenance costs of treatment with simvastatin versus that of treatment with another more recently available statin, atorvastatin, in a European context. We assessed the long-term maintenance cost of simvastatin versus atorvastatin in terms of the cost of reducing low-density lipoprotein cholesterol (LDL-C) levels to the recommended goals based on a previously published clinical trial in patients with CHD. The analysis focused on the patients in the original clinical trial who were randomized to treatment with simvastatin or atorvastatin. Patients began therapy with 10 mg of simvastatin or atorvastatin; the dose of study drug was titrated every 12 weeks up to 40 mg simvastatin or 80 mg atorvastatin, with the addition of up to 8 g/d of cholestyramine until a modified European Atherosclerosis Society LDL-C goal (<2.84 mmol/L) was reached. As there was no significant difference between the 2 groups in resource utilization for adverse events, only drug costs were included. The calculated average annual maintenance cost was based on the distribution of the final daily dosing regimens and the public drug prices for each regimen. Individual country analyses were conducted using each local currency. There was no significant difference between groups in the percentage of patients reaching their LDL-C goal over the study period (80% for simvastatin-treated pa- tients vs 89% for atorvastatin-treated patients, P = 0.135). However, the cost of maintaining a similar percentage of patients at their appropriate LDL-C levels was significantly lower in the simvastatin group compared with the atorvastatin group in 13 of the 17 countries assessed. In the remaining 4 countries, there was a cost advantage for simvastatin, but it did not reach statistical significance. Across Europe there was a significant reduction in the cost of maintaining patients at their appropriate LDL-C levels with simvastatin versus atorvastatin. The results of this analysis, along with the proven clinical benefits of simvastatin, support the use of this drug as the treatment of choice in the secondary prevention of CHD.",2002.0,0,1 723,11293642,Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries. EUROASPIRE I and II Group. European Action on Secondary Prevention by Intervention to Reduce Events.,EUROASPIRE I and II Group; European Action on Secondary Prevention by Intervention to Reduce Events,"Patients with coronary heart disease (CHD) are the top priority for preventive cardiology. The first EUROASPIRE survey among patients with established CHD in nine countries in 1995-96 showed substantial potential for risk reduction. A second survey (EUROASPIRE II) was done in 1999-2000 in the same countries to see whether preventive cardiology had improved since the first. We compared the proportion of patients in both studies who achieved the lifestyle, risk-factor, and therapeutic goals recommended by the Joint European Societies report on coronary prevention. The surveys were undertaken in the same selected geographical areas and hospitals in the Czech Republic, Finland, France, Germany, Hungary, Italy, the Netherlands, Slovenia, and Spain. Consecutive patients (men and women < or = 70 years of age) were identified after coronary-artery bypass graft or percutaneous transluminal coronary angioplasty, or a hospital admission with acute myocardial infarction or ischaemia, and were interviewed at least 6 months later. 3569 and 3379 patients were interviewed in the first and second surveys, respectively. The prevalence of smoking remained almost unchanged at 19.4% vs 20.8%. The prevalence of obesity (body-mass index > or = 30 kg/m2) increased substantially from 25.3% to 32.8%. The proportion with high blood pressure (> or = 140/90 mm Hg) was virtually the same (55.4% vs 53.9%), whereas the prevalence of high total cholesterol concentrations (> or = 5.0 mmol/L) decreased substantially from 86.2% to 58.8%. Aspirin or other antiplatelet therapy was as widely used in the second survey as the first (83.9% overall), and reported use of beta-blockers, angiotensin-converting-enzyme inhibitors, and especially lipid-lowering drugs increased. The adverse lifestyle trends among European CHD patients are a cause for concern, as is the lack of any improvement in blood-pressure management, and the fact that most CHD patients are still not achieving the cholesterol goal of less than 5 mmol/L. There is a collective failure of medical practice in Europe to achieve the substantial potential among patients with CHD to reduce the risk of recurrent disease and death.",2001.0,0,0 724,11295953,Primary prevention of coronary heart disease: where do we go from here?,A M Gotto,,2001.0,0,1 725,11295957,Applicability of cholesterol-lowering primary prevention trials to a general population: the framingham heart study.,D M Lloyd-Jones; C J O'Donnell; R B D'Agostino; J Massaro; H Silbershatz; P W Wilson,"Four large trials have shown cholesterol-reduction therapy to be effective for primary prevention of coronary heart disease (CHD). To determine the generalizability of these trials to a community-based sample, we compared the total cholesterol and high-density lipoprotein cholesterol (HDL-C) distributions of patients in the 4 trials with those of Framingham Heart Study subjects. Lipid profiles that have not been studied were identified. Twelve-year rates of incident CHD were compared between subjects who met eligibility criteria and those who did not. The Framingham sample included 2498 men and 2870 women aged 30 to 74 years. Among Framingham men, 23.4% to 42.0% met eligibility criteria for each of the 4 trials based on their lipid levels; 60.2% met eligibility criteria for at least 1 trial. For the 1 trial that included women, 20.2% of Framingham women met eligibility criteria. In general, subjects with desirable total cholesterol levels and lower HDL-C levels and subjects with average total cholesterol levels and average to higher HDL-C levels have not been included in these trials. Among subjects who developed incident CHD during follow-up, 25.1% of men and 66.2% of women would not have been eligible for any trial. Most ineligible subjects who developed CHD had isolated hypertriglyceridemia (>2.25 mmol/L [>200 mg/dL]). In our sample, 40% of men and 80% of women had lipid profiles that have not been studied in large trials to date. We observed a large number of CHD events in ""ineligible"" subjects in whom hypertriglyceridemia was common. Further studies are needed to define the role of lipid-lowering therapy vs other strategies for primary prevention in the general population.",2001.0,0,0 726,11295958,"Dose discrepancies between the Physicians' Desk Reference and the medical literature, and their possible role in the high incidence of dose-related adverse drug events.",J S Cohen,"Adverse drug events (ADEs) are a major cause of morbidity and mortality, and even minor ADEs may adversely affect patients' compliance with treatment. Because most ADEs are dose-related phenomena, adjusting drug dosages to account for individual patients' needs and tolerances is fundamental to good therapeutics. To determine whether the Physicians' Desk Reference (PDR), the leading source of drug information for physicians, provides the full range of effective drug doses, especially the lowest, least ADE-prone doses of medications, for physicians to consider in treating patients. Review of dosage guidelines and dose-response information in the PDR. Comparison with dose-response data obtained from articles listed in MEDLINE from 1966 to 2000. For many types of medications, physicians are frequently advised to use the lowest effective doses of drugs, especially initially. Yet, effective low doses determined in prerelease studies or in postrelease work are often omitted from the PDR, even when they have been recommended by expert panels. Optimal therapeutics depends on the availability of comprehensive information. However, the PDR contains only the limited dose information from package inserts. Because the PDR was originally developed as a promotional device, there is no mechanism by which all clinically relevant dose-response data or important postrelease discoveries are regularly and rapidly incorporated into it. Thus, a gap exists in the availability of current and comprehensive dose information for physicians. This article provides information on lower, effective doses for 48 major medications, with an extensive reference list-a compilation of low-dose information not previously published, to our knowledge, in the medical literature. Physicians must have a readily accessible source of current and complete dose-response information to individualize drug therapy and minimize the risks of ADEs.",2001.0,0,0 727,11296612,Treatment of hyperlipidemia in HIV-infected patients.,S M Geletko; A R ZuWallack,"The treatment of hyperlipidemia in patients infected with HIV is discussed. Hyperlipidemia is common in HIV-infected patients receiving antiretroviral therapy, especially protease inhibitors and stavudine. The recommendations of the National Cholesterol Education Program (NCEP) may not entirely apply to HIV-infected patients. The pathogenesis of hyperlipidemia in these patients may make them refractory to traditional pharmacotherapy, and NCEP's emphasis on diet and exercise may be unrealistic. Other factors that may complicate treatment of hyperlipidemia include metabolism of many antiretroviral drugs by the cytochrome P-450 isoenzyme system, polypharmacy, and drug-food interactions. A patient's cardiac risk should first be assessed. Nonpharmacologic measures, such as a low-fat diet, weight reduction, and exercise, should be considered. Drug therapy is indicated for patients with familial combined hyperlipidemia that is associated with atherogenesis and for patients with triglyceride concentrations exceeding 1000 mg/dL. Drug therapy for hyperlipidemia involves niacin and statins, in addition to fibric acid derivatives and probucol. Switching among antiretroviral agents when one is found to cause hyperlipidemia should be done cautiously because of the risk for viral rebound and disease progression. NCEP guidelines recommend monitoring low-density-lipoprotein cholesterol levels four to six weeks after the start of lipid-lowering therapy and then at three months; more frequent monitoring may be necessary in HIV-infected patients. The treatment of hyperlipidemia in HIV-infected patients is complicated by their need for antiretroviral drugs, which can themselves contribute to lipid disorders.",2001.0,0,1 728,11300446,Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks.,S John; C Delles; J Jacobi; M P Schlaich; M Schneider; G Schmitz; R E Schmieder,"We investigated whether improvement of endothelial dysfunction in hypercholesterolemia can be achieved with short-term lipid-lowering therapy. Impaired endothelium-dependent vasodilation plays a pivotal role in the pathogenesis of atherosclerosis and acute coronary syndromes. In a randomized, double-blind, placebo-controlled trial, we studied 37 patients (52 +/- 11 yrs) with low density lipoprotein cholesterol > or = 160 mg/dl (196 +/- 44 mg/dl) randomly assigned to either cerivastatin (0.4 mg/d) or placebo. Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh 12, 48 microg/min) and endothelium-independent vasodilation by intra-arterial infusion of nitroprusside (3.2, 12.8 microg/min). Low density lipoprotein cholesterol decreased after two weeks of treatment (cerivastatin -33 +/- 4% vs. placebo + 2 +/- 4%, x +/- SEM, p < 0.001). Endothelium-dependent vasodilation improved after two weeks of therapy with cerivastatin compared with baseline (ACh 12 microg/min: + 22.3 +/- 5.2 vs. + 11.2 +/- 1.9 ml/min/100 ml, p < 0.01; ACh 48 microg/min: +31.2 +/- 6.3 vs. +19.1 +/- 3.1 ml/min/100 ml, p < 0.05). In contrast, changes in forearm blood flow to ACh were similar before and after therapy in the placebo group (ACh 12 microg/min: + 12.9 +/- 3.6 vs. + 9.0 +/- 1.9 ml/min/100 ml, NS; ACh 48 microg/min: +20.7 +/- 3.7 vs. 19.4 +/- 2.9 ml/min/100 ml, NS). Endothelium-dependent vasodilation improved in comparison with placebo (ACh 48 microg/min: +203 +/- 85% [cerivastatin] vs. -26 +/- 71% [placebo], p < 0.05). This improvement in endothelium-dependent vasodilation was no longer observed when the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine was coinfused (ACh 48 microg/min + N(G)-monomethyl-L-arginine 4 micromol/min -48 +/- 85% [cerivastatin]). Short-term lipid-lowering therapy with cerivastatin can improve endothelial function and NO bioavailability after two weeks in patients with hypercholesterolemia.",2001.0,0,0 729,11302109,Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico).,,"The aim of this study was to test the efficacy of a low-dose pravastatin regimen (20 mg daily) in patients with myocardial infarction. GISSI Prevenzione (GISSI-P) is an open trial on secondary coronary heart disease prevention: 4271 recent acute myocardial infarction patients (< or = 6 months) with total blood cholesterol > or = 200 mg/dl were randomized to low-dose cholesterol-lowering treatment (pravastatin 20 mg daily) or no treatment. GISSI-P was started in 1993 and its story was crossed by the publication of the results of similarly designed clinical trials. The publication of 4S results in 1994 prompted the Data Safety and Monitoring Board (DSMB) and the Steering Committee (SC) to change the protocol so that only patients whose total blood cholesterol was < 250 mg/dl could be randomized whilst patients with total blood cholesterol > 250 mg/dl who had already been enrolled in the study had to be re-evaluated and, if appropriate, pharmacologically treated. The DSMB and the SC agreed to stop randomization prematurely in late 1996 after the publication of CARE results. Mean follow-up time was 23.0 +/- 6.7 months (median 24.3 months). The two treatment groups were well matched at baseline. Pharmacological interventions recommended by the protocol were widely prescribed (antiplatelet agents > 90%, beta-blockers 42.7%, and ACE-inhibitors 40.2%). Mainly because of the on-course modification of the study protocol, 402/2133 (18.8%) patients in the control group started a cholesterol-lowering treatment during follow-up. Conversely, 296/2138 (13.8%) patients permanently stopped taking their tablets. Side effects, however, were the reason for discontinuing therapy in 57 (2.7%) patients in the pravastatin group, and patient reluctance to continue accounted for most of the remainder. After excluding control patients who had started a cholesterol-lowering treatment during follow-up, the following changes of median lipid concentrations in the control group over the whole course were observed: total cholesterol -1.9%; LDL cholesterol -2.9%; triglycerides -2.0%; HDL cholesterol +1.4%. The analysis carried out excluding patients randomized to pravastatin treatment and actually not assuming the drug clearly indicated the cholesterol-lowering efficacy of low-dose pravastatin (total cholesterol -12.5%; LDL cholesterol -18.8%; triglycerides -7.9%; HDL cholesterol +3.4%). During the study 256 (6.0%) patients either died or had a non-fatal stroke or a myocardial infarction, 136 (6.4%) in the control group and 120 (5.6%) in the pravastatin group (relative risk 0.90, 95% confidence interval 0.71-1.15, p = 0.41); 160 patients died, 88 (4.1%) in the control group and 72 (3.4%) in the pravastatin group (relative risk 0.84, 94% confidence interval 0.61-1.14, p = 0.26). The few (n = 28) non-cardiovascular deaths were balanced: 16 (0.8%) in the control group and 15 (0.6%) in the pravastatin group. The reduction of cardiovascular events was more evident in the by-treatment analysis, with coronary heart disease deaths being significantly decreased (relative risk 0.60, 95% confidence interval 0.38-0.96, p = 0.04). The overall frequency of adverse events was similar in the two groups. No significant difference between treatment groups was found for total cases of cancer or at any particular site. Despite the decreased statistical power due to its premature stopping, the results of the GISSI-P suggest that a low-dose treatment with pravastatin (20 mg daily) is effective in reducing blood lipids, and underline the importance of long-term compliance with treatments in the search for a maximal effective dosage. Furthermore, the effects of a statin on total and coronary mortality quantified for the first time in a population exposed to Mediterranean dietary and lifestyle habits are markedly consistent with those obtained in different settings.",2001.0,0,0 730,11302410,Slowing the progression of renal disease in diabetic patients.,E M Vivian; M L Goebig,"To review recent clinical trials that evaluate the most appropriate therapeutic options for delaying the progression of nephropathy in type 2 diabetic patients. Primary and review articles were retrieved through a MEDLINE search (January 1990-January 2000). All studies related to attenuating the progression of nephropathy in diabetic patients were evaluated and included in this review. Clinical trials with angiotensin-converting enzyme inhibitors (ACEI) have consistently demonstrated a decrease in the progression of renal disease in diabetic patients. The angiotensin-2 receptor blocker (ARB) losartan has been shown to reduce microalbuminuria to the same extent as the ACEI enalapril. The nondihydropyridine calcium-channel blockers (NCCBs) verapamil and diltiazem have also been shown to decrease urinary albumin excretion. Clinical literature suggests that if monotherapy with an ACEI or ARB does not provide an adequate response, an NCCB should be added to the regimen. ACEIs should be considered first-line therapy for diabetic patients with nephropathy. ARBs should be considered as an alternative for patients who are unable to tolerate an ACE inhibitor due to adverse effects. If blood pressure goals are not achieved with an ACEI or ARB, then the addition of an NCCB should be considered.",2001.0,0,0 731,11302415,Alternate-day dosing of HMG-CoA reductase inhibitors for cholesterol reduction.,C A Metz; K H Lucas,"Assess efficacy, safety, and cost of alternate-day dosing with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (HRIs). International Pharmaceutical Abstracts and MEDLINE (English-language clinical trials, 1966-April 2000) were searched. Established efficacy of HRIs is based on daily administration. Many patients who could benefit from these agents are unable to afford them; therefore, alternate-day dosing may be a solution for reducing expense without decreasing therapy benefits. Studies addressing alternate-day HRI therapy are evaluated to determine the usefulness of this option for cholesterol reduction. Although limited studies imply a trend toward benefit with alternate-day HRI therapy, large, controlled, randomized trials are needed before making this a standard recommendation.",2001.0,0,0 732,11303007,An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.,P N Durrington; D Bhatnagar; M I Mackness; J Morgan; K Julier; M A Khan; M France,"Omega-3 fatty acids, such as those present in fish oil, have been reported to prolong life in myocardial infarction survivors. These fatty acids can decrease serum triglyceride concentrations, but so far the doses used in trials examining their effects on coronary end points have had only minimal triglyceride lowering effects. To examine the triglyceride lowering effectiveness, safety, and tolerability of Omacor, a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil (84% of the total as opposed to an average of 35% in fish oil) over one year in patients with established coronary heart disease (CHD) and persisting hypertriglyceridaemia, despite receiving simvastatin in doses similar to those employed in the Scandinavian simvastatin survival study. 59 patients with CHD, receiving simvastatin 10-40 mg daily with serum triglycerides > 2.3 mmol/l, were randomised to receive Omacor 2 g twice a day or placebo for 24 weeks in a double blind trial. Forty six patients accepted the offer of active treatment for a further 24 weeks in an open phase of the trial. There was a sustained significant decrease in serum triglycerides by 20-30% (p < 0.005) and in very low density lipoprotein (VLDL) cholesterol by 30-40% (p < 0.005) in patients receiving active Omacor at three, six, and 12 months compared either to baseline or placebo. Omacor did not have any deleterious effect on low density or high density lipoprotein cholesterol or on biochemical and haematological safety tests. There was no adverse effect on glycaemic control in patients with diabetes, who showed a decrease in serum triglyceride, which was at least as great as in non-diabetic patients. One patient receiving placebo died of acute myocardial infarction. Three patients withdrew from the trial (two on placebo and one on active treatment). Omacor was generally well tolerated. Omacor was found to be a safe and effective means of lowering serum triglycerides over one year in patients with CHD and combined hyperlipidaemia, whose triglycerides remained elevated despite simvastatin treatment.",2001.0,0,0 733,11303693,Lessons learned from statin trials.,J Auer; R Berent; B Eber,This article aims to review lessons learned about lipid lowering and statins in the past decade and to consider what developments the future may hold. Results from a series of landmark clinical trials confirm that statins significantly reduce cardiovascular morbidity and mortality in patients with and without previous coronary artery disease. The potential of this drug class has yet to be fully explored. Studies currently under way will answer many of the outstanding questions.,2001.0,0,1 734,11305526,C-reactive protein: risk assessment in the primary prevention of atherosclerotic disease. Has the time come for including it in the risk profile?,W Koenig,"About half of patients presenting with myocardial infarction do not have the ""classic"" risk factors. This has stimulated a search for other factors that may be responsible and, when present, may help to predict which patients are at greatest risk for myocardial infarction and other cardiovascular events. With improved understanding of the pathogenesis of ischemic cardiovascular disease, we have gleaned new insights into potential markers of underlying atherosclerosis and cardiovascular risk. In recent years, data suggesting that certain markers of inflammation--both systemic and local--play a key role in the development and progression of atherosclerosis, and in its final clinical complications have accumulated. Specifically, elevated levels of one systemic marker of inflammation, C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease events. Among several markers of systemic inflammation, CRP shows the strongest associations with vascular events, and the addition of CRP to total cholesterol dramatically improves risk prediction. CRP fulfils most of the requirements needed to serve as a new risk factor, but still several issues await further confirmation and clarification before this marker can ultimately be included in the routine risk profile. Moreover, potentially important associations have been established between elevated CRP levels and increased efficacy of established therapies, in particular lipid-lowering therapy with statins; CRP testing may enable us to tailor expensive cardiovascular medication to the individual patient. Such an improved prescription strategy might be especially valuable in the primary care setting where the absolute cardiovascular risk is considerably lower compared to that in secondary prevention.",2001.0,0,0 735,11305529,Medical-economical aspects of high sensitivity C-reactive protein assay for the prediction of coronary heart disease. An analysis in Germany and Italy.,S M Ess; T D Szucs,"Elevated plasma concentrations of C-reactive protein (CRP) are associated with increased cardiovascular risk. We studied the cost-effectiveness of CRP determination in primary and secondary prevention settings in two European countries: Germany and Italy. Using a decision analytic model we evaluated the costs and consequences of testing or not testing using a high sensitivity (hs)-CRP assay. In a primary prevention model we analyzed a hypothetical cohort of 300000 apparently healthy men divided into three age groups (35-44, 45-54 and 55-64 years). Individuals with CRP levels > 3 mg/l were administered either aspirin or statins according to lipid levels. The cohort was followed for 5 years. In the secondary prevention model hs-CRP testing was evaluated in a cohort of 10000 patients with total cholesterol levels < 4.52 mmol/l and a history of myocardial infarction or unstable angina. The two strategies tested were: 1) administer pravastatin only to those with high CRP values, and 2) treat all patients. The analysis was performed from the societal perspective. Event rates were obtained from epidemiological studies and clinical trials. In the primary prevention model, strategies including testing showed, for men aged 45 years and older, cost-effectiveness ratios between each life year saved (LYS) and cost savings in Germany equal to 10217euro and between each LYS and savings in Italy equal to 16950euro In the age group 35-44 years, therapy with aspirin showed cost-effectiveness ratios of 5318euro and 11203euro per LYS in Germany and in Italy respectively. The widespread use of statins showed an unfavorable cost-effectiveness profile: 44630euro per LYS in Germany and 36270euro per LYS in Italy. In the secondary prevention model, hs-testing for CRP can reduce the cost-effectiveness of pravastatin from 16400 to 6830euro per quality adjusted life year gained. Sensitivity analysis performed on the variables test price and costs of cardiovascular events resulted in minimal changes of the cost-effectiveness ratios. Both in the primary and the secondary prevention settings, hs-testing for CRP can better target individuals at higher risk, thus improving outcomes and resulting in a more cost-effective strategy.",2001.0,0,0 736,11305530,Determinants of C-reactive protein concentration in blood.,M P de Maat; C Kluft,"C-reactive protein (CRP) is a very strong acute phase protein. During the acute phase of disease the CRP concentration can increase up to a thousand-fold. However, a higher CRP concentration is also observed during chronic stages of disease, for example in subjects with chronic bronchitis, periodontal disease or subjects with increased titers of Helicobacter pylori or Chlamydia pneumoniae. The concentration of CRP is also reported to be associated with age, sex, race, smoking, obesity, consumption of coffee and alcohol, stress, physical training, lipid levels, and blood pressure. Statins decrease the CRP concentration whereas estrogen increases it. With regard to most other drugs no consistent relationship has been reported.",2001.0,0,0 737,11305994,Lipid lowering and weight reduction by home-delivered dietary modification in coronary heart disease patients taking statins.,E J Schaefer; J L Augustin; J R McNamara; L J Seman; K L Bourdet; M M Meydani; S Holay,,2001.0,0,0 738,11306519,Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels.,I Jialal; D Stein; D Balis; S M Grundy; B Adams-Huet; S Devaraj,"Prospective studies indicate that baseline levels of C-reactive protein (CRP), the prototypic marker of inflammation, are associated with an increased risk for cardiovascular events. Limited studies have examined therapies that influence high-sensitive CRP (hs-CRP) levels, especially in hyperlipidemic patients. Thus, we tested the effects of 3 hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), simvastatin (20 mg/d), pravastatin (40 mg/d), and atorvastatin (10 mg/d), on levels of hs-CRP in a randomized, double-blind, crossover trial of 22 patients with combined hyperlipidemia (LDL cholesterol >130 mg/dL and triglycerides of 200 to 600 mg/dL). After 6 weeks of an American Heart Association Step 1 diet, fasting blood samples were drawn at baseline and after 6 weeks of therapy with each drug. hs-CRP levels were significantly decreased after treatment with all 3 statins compared with baseline (median values: baseline, 2.6 mg/L; atorvastatin, 1.7 mg/L; simvastatin, 1.7 mg/L; and pravastatin, 1.9 mg/L; P<0.025). The reductions obtained with the 3 statins were similar. In addition, there was no significant effect on either plasma interleukin-6 or interleukin-6 soluble receptor levels. There was no relationship between reductions in hs-CRP and LDL cholesterol. Pravastatin, simvastatin, and atorvastatin significantly decreased levels of hs-CRP. These data support an anti-inflammatory effect of these drugs.",2001.0,0,0 739,11306521,Fluvastatin lowers atherogenic dense low-density lipoproteins in postmenopausal women with the atherogenic lipoprotein phenotype.,W März; H Scharnagl; C Abletshauser; M M Hoffmann; A Berg; J Keul; H Wieland; M W Baumstark,"Although HMG-CoA reductase inhibitors (HMGRIs) are effective lipid-lowering agents, it remains controversial whether these agents also lower dense LDL (dLDL), a predominance of which is considered to contribute to the atherogenicity of the metabolic syndrome. In a multicenter, double-blind, randomized, placebo-controlled study, we determined the effect of the HMGRI fluvastatin on lipids, apolipoproteins, and LDL subfractions (by equilibrium density gradient ultracentrifugation). A total of 52 postmenopausal women with combined hyperlipidemia and increased dLDL were treated with either fluvastatin 40 mg/d (n=35) or placebo (n=17). After 12 weeks' treatment, significant reductions (P<0.001) in total cholesterol (-19%), IDL cholesterol (-35%), LDL cholesterol (-23%), apolipoprotein B (-21%), and apolipoprotein B in dLDL (-42%) were apparent among fluvastatin recipients. No significant changes in triglycerides or HDL cholesterol were observed. The effect of fluvastatin on dLDL was correlated with baseline values. There was no consistent relationship, however, between the effect of fluvastatin on triglycerides and the decrease in dLDL. Fluvastatin lowers total and LDL cholesterol and the concentration of dLDL. This profile may contribute to an antiatherogenic effect for fluvastatin that is greater than expected on the basis of changes in lipids and apolipoproteins.",2001.0,0,0 740,11307620,"Lovastatin and phenylacetate induce apoptosis, but not differentiation, in human malignant glioma cells.",F Schmidt; P Groscurth; M Kermer; J Dichgans; M Weller,"Induction of differentiation is an attractive approach to the management of infiltrative tumors such as malignant glioma. Here, we report that lovastatin and phenylacetate induce apoptosis, but fail to induce differentiation, in malignant glioma cell lines and untransformed rat astrocytes. Lovastatin and phenylacetate promote p21 accumulation but fail to induce cell cycle arrest. BCL-2 gene transfer inhibits apoptosis induced by lovastatin but not apoptosis induced by phenylacetate. Wild-type p53 gene transfer promotes lovastatin-induced apoptosis in p53 wild-type LN-229 cells but not in p53 mutant T98G cells. Phenylacetate-induced apoptosis is attenuated by wild-type p53 gene transfer in both cell lines. Neither lovastatin nor phenylacetate modulate glioma cell sensitivity to CD95 ligand-induced apoptosis or cancer chemotherapy. Thus, this study provides no rationale for clinical trials of lovastatin or phenylacetate in the differentiation therapy of malignant glioma. We conclude that neoplastic glioma cells as well as untransformed rat astrocytes are refractory to the induction of differentiation by lovastatin and phenylacetate.",2001.0,0,0 741,11309029,Bexarotene capsules and gel for previously treated patients with cutaneous T-cell lymphoma: results of the Australian patients treated on phase II trials.,H M Prince; C McCormack; G Ryan; C Baker; H Rotstein; J Davison; R Yocum,"Bexarotene (Targretin, LGD1069) is a novel synthetic retinoid analogue that binds selectively to retinoid X receptors. We describe eight previously treated patients who entered phase II international multicentre studies examining the role of bexarotene in cutaneous T-cell lymphoma. Patients received either the oral formulation (n = 7) or the topical gel (n = 1). Of the seven patients who received 300 mg/m2 per day capsules, five (71%) achieved a partial response, with mean time to onset of response of 27 days (range, 20-29) with responses persisting for a mean of 92 days (range, 57-115). The single patient receiving the topical preparation (stage IB) remains in partial response at 31 months. The major toxicity with oral administration was hypertriglyceridaemia requiring therapy. Bexarotene capsules and gel are active and generally well-tolerated agents in patients with cutaneous T-cell lymphoma and studies examining its role in previously untreated patients or as part of combination therapy are warranted.",2001.0,0,0 742,11310195,Achieving control of diabetic risk factors in primary care settings.,A G Bertoni,,2001.0,0,0 743,11310513,Therapeutic change of HMG-CoA reductase inhibitors in patients with coronary artery disease.,D E Hilleman; R L Wurdeman; T L Lenz,"To evaluate short-term outcomes when atorvastatin was substituted for pravastatin or simvastatin in patients with coronary artery disease. Open-label, fixed-dosage, one-way crossover from pravastatin and simvastatin to atorvastatin. University-affiliated hospital and outpatient clinics. Eighty patients with coronary artery disease with a minimum baseline low-density lipoprotein (LDL) above 130 mg/dl: 20 were treated with pravastatin 20 mg/day, 20 with pravastatin 40 mg/day, 20 with simvastatin 20 mg/day, and 20 with simvastatin 40 mg/day for a minimum of 6 months, with a prescription refill rate of 80% or greater. Intervention. Before crossover, patients had a fasting lipid profile determined and were questioned about side effects of pravastatin and simvastatin. All patients were switched to atorvastatin 10 mg/day. After 12 weeks of atorvastatin therapy, a repeat fasting lipid profile was obtained and patients were questioned about side effects with the drug. Baseline demographic and clinical characteristics of the treatment groups were not significantly different with the exception of a lower baseline LDL in patients receiving pravastatin 20 mg/day. Baseline LDL values were as follows: pravastatin 20 mg/day, 158+/-26 mg/dl; pravastatin 40 mg/day, 176+/-22 mg/dl; simvastatin 20 mg/day, 177+/-27 mg/dl; and simvastatin 40 mg/day, 177+/-27 mg/dl. Reductions in LDL after treatment with pravastatin or simvastatin were as follows: pravastatin 20 mg/day, 22%; pravastatin 40 mg/day, 32%; simvastatin 20 mg/day, 33%; and simvastatin 40 mg/day, 38%. Patients achieving LDL goal with initial therapy were as follows: pravastatin 20 mg/day, 5%; pravastatin 40 mg/day, 5%; simvastatin 20 mg/day, 20%; and simvastatin 40 mg/day, 30%. After the switch to atorvastatin 10 mg/day, reductions in LDL were as follows: pravastatin 20 mg/day, 39% (p<0.001); pravastatin 40 mg/day, 38% (p<0.01); simvastatin 20 mg/day, 39% (p=0.04); and simvastatin 40 mg/day, 38% (p=0.83). Patients achieving LDL goals with atorvastatin 10 mg/day were as follows: pravastatin 20 mg/day, 60%; pravastatin 40 mg/day, 30%; simvastatin 20 mg/day, 25%; and simvastatin 40 mg/day, 30%. The frequency of side effects was similar for all three statins. Based on annual average wholesale price, atorvastatin 10 mg/day was more cost-effective than all pravastatin and simvastatin regimens. Therapeutic interchange from pravastatin 20 and 40 mg/day and simvastatin 20 mg/day to atorvastatin 10 mg/day was associated with both cost savings and significant reductions in LDL. The change from simvastatin 40 mg/day to atorvastatin 10 mg/day was associated with cost savings and an equivalent reduction in LDL.",2001.0,0,0 744,11311587,Vascular effects of hormones.,P Collins,,2001.0,0,0 745,11315826,Baseline characteristics of the diabetic participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).,J I Barzilay; C L Jones; B R Davis; J N Basile; D C Goff; J O Ciocon; M E Sweeney; O S Randall; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Collaborative Research Group,"Hypertension (HTN) is a major risk factor for cardiovascular disease (CVD) in the setting of diabetes. There is no consensus on how best to treat hypertension among those with diabetes. Here we describe the characteristics of a cohort of hypertensive adults with diabetes who are part of a large prospective blood pressure study. This study will help clarify the treatment of HTN in the setting of diabetes. The Antihypertensive and Lipid-Lowering high-risk hypertensive participants, ages > or = 55 years, designed to determine whether the incidence of fatal and nonfatal coronary heart disease (CHD) and combined cardiovascular events (fatal and nonfatal CHD, revascularization surgery, angina pectoris, congestive heart failure, and stroke) differs between diuretic (chlorthalidone) treatment and three alternative antihypertensive therapies: a calcium channel blocker (amlodipine), an ACE inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin). The planned follow-up is an average of 6 years, to be completed March 2002. There are 15,297 diabetic individuals in the ALLHAT study (36.0% of the entire cohort). Of these individuals, 50.2% are male, 39.4% are African-American, and 17.7% are Hispanic. Demographic and laboratory characteristics of the cohort are similar to those of other studies of the U.S. elderly population with HTN. The sample size has 42 and 93% confidence, treatments for the two study outcomes. The diabetic cohort in ALLHAT wil be able to provide valuable information about the treatment of hypertension in older diabetic patients at risk for incident CVD.",2001.0,0,0 746,11317474,Effects of fluvastatin on biliary lipids in subjects with an elevated cholesterol saturation index.,M Porsch-Ozçürümez; P D Hardt; H Schnell-Kretschmer; K von Bergmann; C Darui; J Nonhoff; C Abletshauser; H U Klör,"3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been suggested as agents to reduce the biliary cholesterol saturation index (CSI) in duodenal bile and therefore might be supportive in primary or secondary prevention of gallstones. However, the efficiency of the therapy seems to depend on both the HMG-CoA reductase inhibitor used and the study population selected. We therefore investigated the effect of a high-dose application of fluvastatin on biliary lipid composition in 21 subjects exhibiting mild hypercholesterolaemia and a history of current gallstones or cholecystectomy due to gallstone disease. Subjects were treated either with 40 mg fluvastatin twice per day over a 3-month period (n = 14) or with placebo (n = 7). Bile samples were aspirated during endoscopy after intravenous ceruletid stimulation before and after therapy. Both groups were comparable in CSI (mean +/- SD) at baseline (1.78 +/- 0.2 placebo vs. 1.97 +/- 0.4 verum). CSI significantly decreased in the verum group to 1.45 +/- 0.4 (P = 0.003) mainly due to increased phospholipid levels, whereas no difference was observed in the placebo group (1.85 +/- 0.7, n.s.). In addition, the verum group exhibited a significant reduction of hydrophobic deoxycholic acid, which has been reported to induce cholesterol crystal precipitation, and an increase of hydrophilic cholic acid. Fluvastatin might decrease the risk of cholesterol gallstone formation in patients with elevated biliary CSI during long-term treatment by reduction of biliary cholesterol saturation and percentage change in deoxycholic acid content.",2001.0,0,0 747,11317478,"Influence of gender on the pharmacokinetics, safety, and tolerability of cerivastatin in healthy adults.",J Isaacsohn; M Zinny; A Mazzu; J Lettieri; A H Heller,"The pharmacokinetics, safety, and tolerability of cerivastatin, a synthetic HMG-CoA reductase inhibitor were studied in 49 healthy volunteers. In this double-blind, parallel group, multiple-dose study, volunteers were randomized as age-matched, male-female pairs and stratified into younger (18-65 years, premenopausal females) or older (65-85 years, postmenopausal females) groups. Thirty-two (16 female, 16 male) subjects received 0.2 mg cerivastatin daily for 7 days; 17 received placebo. Between all males and females, no differences in cerivastatin pharmacokinetics were observed. The AUCnorm in older females was 21% higher than in older males, while the AUCnorm in younger females was 26% lower than in younger males. The Cmax in older females was 30% higher than in age-matched males or younger males and females. All other pharmacokinetic parameters, including half-life, tmax, accumulation ratios, and steady state plasma levels were similar in all treatment groups. The most common adverse events, including headache (4), dyspepsia (4), and rash (4), were equally distributed between groups. Treatment-emergent elevations (< 2 x ULN) in creatine kinase occurred in one subject. Transaminase elevations occurred in nine subjects, most were less than 3 x ULN, and were equally distributed between groups. In conclusion, cerivastatin was well tolerated. The minor differences in the pharmacokinetics of cerivastatin 0.2 mg between genders does not require modification of dosage.",2001.0,0,0 748,11317483,Are users of lipid-lowering drugs at increased risk of peripheral neuropathy?,D Gaist; L A García Rodríguez; C Huerta; J Hallas; S H Sindrup,"To estimate the risk of peripheral neuropathy associated with use of lipid-lowering drugs. Population-based dynamic cohort study based on data from general practices in the United Kingdom from 1991 to 1997. Three cohorts of individuals aged 40-74 years were identified: a cohort of 17,219 persons who received at least one prescription for lipid-lowering drugs in the period; a second cohort of patients with a hyperlipidaemia diagnosis who had not been prescribed lipid-lowering drugs (n = 28,974) and a third cohort comprised of 50,000 individuals from the general population. The incidence rates of peripheral neuropathy in the three cohorts were calculated and the relative risk of peripheral neuropathy in users of lipid-lowering drugs was compared with non-users from the general population cohort. The incidence rate of idiopathic peripheral neuropathy in users of lipid-lowering drugs was higher [0.73 per 10,000 person-years, 95% confidence interval (CI) 0.01-2.62] than in the hyperlipidaemia non-treated cohort (0.40 per 10,000 person-years, CI 0.05-1.46) and the general population cohort (0.46 per 10,000 person-years, CI 0.13-1.18). The raised risk of idiopathic peripheral neuropathy in users of lipid-lowering drugs was confined to current users of statins (relative risk 2.5, CI 0.3-14.2). These figures suggest one excess case of neuropathy for every 14,000 person-years of statin treatment. Because of the wide CIs, these results are inconclusive and should be interpreted with caution. However, although peripheral neuropathy as an adverse effect of the use of lipid-lowering drugs cannot be excluded, the magnitude of this untoward effect appears to be small.",2001.0,0,1 749,11318080,"A comparison of the efficacy and tolerability of titrate-to-goal regimens of simvastatin and fluvastatin: a randomized, double-blind study in adult patients at moderate to high risk for cardiovascular disease.",M J van Dam; H J Penn; F R den Hartog; H A Kragten; M D Trip; R J Buirma; J J Kastelein; MUST Study Group,"Use of cholesterol-lowering regimens has been shown to reduce the risk of coronary heart disease (CHD), both in primary and secondary prevention. However, there have been few studies of the relative benefits and risks of the various cholesterol-lowering agents in patient groups with specific risk factors for CHD. The primary goal of this study was to compare the proportions of adult patients with primary hypercholesterolemia and a moderate to high risk for CHD achieving National Cholesterol Education Program low-density lipoprotein cholesterol (LDL-C) goals with titrate-to-goal regimens of simvastatin and fluvastatin. This was a multicenter, prospective, randomized, double-blind, parallel-group study enrolling adult patients with type IIa or IIb primary hypercholesterolemia, LDL-C levels <6.0 mmol/L (<232.0 mg/dL), and triglyceride levels <4.5 mmol/L (<398.6 mg/dL), and either CHD or other atherosclerotic disease (the CHD, or high-risk, group), or multiple risk factors for CHD (the MRF, or moderate-risk, group). After a 6-week washout period, patients were randomized to 18 weeks of treatment at an initial dosage of simvastatin 10 mg once daily or fluvastatin 20 mg once daily. At 6- and 12-week titration visits, the dosage in patients who had not acheived the LDL-C goal could be increased to simvastatin 20 mg once daily and then 40 mg once daily, or to fluvastatin 40 mg once daily and then 40 mg twice daily. Lipid profiles were obtained at each titration visit and at the end of treatment. In addition to the comparison between treatments, secondary comparisons were made between the CHD and MRF subgroups within each treatment group. Statistical significance was assessed using analysis of variance. A total of 478 patients were enrolled, 237 in the simvastatin group and 241 in the fluvastatin group. There were no significant between-group differences in patients' characteristics at baseline. At the end of the study, 60.8% (135/222) of patients in the simvastatin group had reached target LDL-C goals, compared with 35.1% (76/216) in the fluvastatin group (P < 0.001). In the simvastatin CHD and MRF subgroups, 49% and 73%, respectively, reached the LDL-C target, compared with 19% and 50% in the corresponding fluvastatin subgroups (P < 0.001). The proportion of patients requiring titration was higher in the fluvastatin group than in the simvastatin group (87.1% and 64.1%, respectively; P = 0.001). The incidence of adverse events was similar between groups. In this study, more patients with primary hypercholesterolemia and CHD or multiple risk factors for CHD reached LDL-C goals with simvastatin treatment and required less titration than those who received fluvastatin treatment.",2001.0,0,1 750,11320358,Aggressive versus moderate lipid-lowering therapy in postmenopausal women with hypercholesterolemia: Rationale and design of the Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES) trial.,P Raggi; T Q Callister; M Davidson; F K Welty; G A Bachmann; R Laskey; D Pittman; S Kafonek; R Scott,"Electron beam tomography (EBT) is a noninvasive technique that allows the study of the entire coronary artery tree during a brief imaging session without the injection of any contrast media. Atherosclerosis is identified vicariously through the visualization of coronary calcific deposits. Quantitative assessments of calcium burden, such as calcium volume scores, have been shown to be a useful means to assess treatment-related changes in the extent of atherosclerotic plaques. Historically, the elderly female population has received less medical recognition regarding the risk and severity of coronary heart disease (CHD). In the BELLES (Beyond Endorsed Lipid Lowering with EBT Scanning) trial, the presence of asymptomatic CHD in 600 postmenopausal women will be assessed by EBT. In this 1-year, multicenter, randomized, double-blind, parallel-group study, aggressive lipid-lowering treatment will be compared with moderate lipid-lowering treatment in postmenopausal women with hypercholesterolemia. The hypothesis we will test is that aggressive lipid-lowering therapy with 80 mg/d atorvastatin can produce greater reductions in atherosclerotic plaque burden as assessed by volumetric calcium scores than a moderate treatment with 40 mg/d pravastatin. The primary outcome measure will be the percent change from baseline in total CVS determined by EBT at 12 months. The results of the BELLES trial will help assess the actual incidence of CHD in postmenopausal women and the relative ability of two different lipid-lowering therapies to halt its progression.",2001.0,0,0 751,11320359,Cost-effectiveness of pravastatin therapy for survivors of myocardial infarction with average cholesterol levels.,J Tsevat; K M Kuntz; E J Orav; M C Weinstein; F M Sacks; L Goldman,"The objective of this study was to assess the cost-effectiveness of pravastatin therapy in survivors of myocardial infarction with average cholesterol levels. We performed a cost-effectiveness analysis based on actual clinical, cost, and health-related quality-of-life data from the Cholesterol and Recurrent Events (CARE) trial. Survival and recurrent coronary heart disease events were modeled from trial data in Markov models, with the use of different assumptions regarding the long-term benefit of therapy. Pravastatin therapy increased quality-adjusted life expectancy at an incremental cost of $16,000 to $32,000 per quality-adjusted life-year gained. In subgroup analyses, the cost-effectiveness of pravastatin therapy was more favorable for patients >60 years of age and for patients with pretreatment low-density lipoprotein cholesterol levels >125 mg/dL. Results were sensitive to the cost of pravastatin and to assumptions about long-term survival benefits from pravastatin therapy. The cost-effectiveness of pravastatin therapy in survivors of myocardial infarction with average cholesterol levels compares favorably with other interventions.",2001.0,0,0 752,11320369,ADEPT: Addition of the AT1 receptor antagonist eprosartan to ACE inhibitor therapy in chronic heart failure trial: hemodynamic and neurohormonal effects.,D R Murdoch; T A McDonagh; R Farmer; J J Morton; J J McMurray; H J Dargie,"Persistent activation of the renin-angiotensin-aldosterone-system (RAAS) is known to occur in patients with chronic heart failure (CHF) despite treatment with angiotensin-converting enzyme inhibitor (ACE) therapy. When added to ACE inhibitors, angiotensin II type 1 (AT1) antagonists may allow more complete blockade of the RAAS and preserve the beneficial effects of bradykinin accumulation not seen with AT1 receptor blockade alone. Thirty-six patients with stable New York Heart Association class II-IV CHF receiving ACE inhibitor therapy were randomly assigned in a double-blind manner to receive either eprosartan, a specific competitive AT1 receptor antagonist (400 to 800 mg daily, n = 18) or placebo (n = 18) for 8 weeks. The primary outcome measure was left ventricular ejection fraction (LVEF) as measured by radionuclide ventriculography, and secondary measures were central hemodynamics assessed by Swan-Ganz catheterization and neurohormonal effects. There was no change in LVEF with eprosartan therapy (mean relative LVEF percentage change [SEM] +10.5% [9.3] vs +10.1% [5.0], respectively; difference, 0.4; 95% confidence interval [CI], -20.8 to 21.7; P =.97). Eprosartan was associated with a significant reduction in diastolic blood pressure and a trend toward a reduction in systolic blood pressure compared with placebo (-7.3 mm Hg [95% CI, -14.2 to -0.4] diastolic; -8.9 mm Hg [95% CI, -18.6 to 0.8] systolic). No significant change in heart rate or central hemodynamics occurred during treatment with eprosartan compared with placebo. A trend toward an increase in plasma renin activity was noted with eprosartan therapy. Eprosartan was well tolerated, with an adverse event profile similar to placebo, whereas kidney function remained unchanged. When added to an ACE inhibitor, eprosartan reduced arterial pressure without increasing heart rate. There was no change in LVEF after 2 months of therapy with eprosartan.",2001.0,0,0 753,11320381,International differences in cardiovascular clinical trials.,J C O'Shea; R M Califf,,2001.0,0,0 754,11321864,Is a statin a statin?,A S Wierzbicki,,2001.0,0,0 755,11322858,Postmenopausal oestrogen replacement therapy and atherosclerosis: can current compounds provide cardiovascular protection?,M Barton,"The natural oestrogen, 17 beta-oestradiol, has been implicated in protection from atherosclerosis, a chronic systemic vascular disease with an inflammatory component accounting for the majority of morbidity and mortality in Western countries. Despite the protective effects of 17 beta-oestradiol in premenopausal women and experimental evidence demonstrating inhibitory effects of oestrogen on atherosclerosis progression, it is currently unclear whether hormone replacement therapy can affect cardiovascular morbidity and mortality in postmenopausal women. The recent advances in understanding the mechanisms of oestrogen action demonstrated roles for different oestrogen receptors and oestrogen metabolites in the pathogenesis of vascular injury and endothelial cell dysfunction. However, their respective role in the process of atherogenesis remains yet to be elucidated. Moreover, the availability of novel drugs with tissue- and/or receptor-specific actions will help to understand the role of oestrogen in cardiovascular diseases. Several ongoing large-scale clinical trials using opposed or unopposed replacement therapy with natural or synthetic oestrogens, or selective oestrogen receptor modulators (SERMs) will resolve the question whether the drugs currently available have therapeutic potential to interfere with the progression of atherosclerosis and its complications.",2001.0,0,0 756,11324372,Effects of fluvastatin on cardiac events in renal transplant patients: ALERT (Assessment of Lescol in Renal Transplantation) study design and baseline data.,H Holdaas; B Fellström; I Holme; G Nyberg; P Fauchald; A Jardine; C Grönhagen-Riska; S Madsen; H H Neumayer; E Cole; B Maes; T Weinreich; A G Olsson; T R Pedersen; R Benghozi; A Hartmann; ALERT Study Group. Assessment of Lescol in Renal Transplantation,"Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors ('statins') reduces morbidity and mortality from coronary heart disease in diverse patient populations. The aim of the present ALERT (Assessment of Lescol in Renal Transplantation) study is to determine whether renal transplant recipients would also benefit from statin therapy. ALERT is a multicentre, randomized, double-blind, placebo-controlled trial to assess the effect of fluvastatin in renal transplant recipients with mild-to-moderate hypercholesterolaemia. The primary objective is to investigate the effects of fluvastatin on major adverse cardiac events (MACE). In addition, the effects on cardiovascular and all-cause mortality, as well as renal function, will be addressed. The study population contains patients with functioning renal allografts of more than 6 months' duration, recruited from 75 centres in Northern Europe and Canada. Patients of both sexes, aged 30-75 years, with a total cholesterol level of 4.0-9.0 mmol/l (155-348 mg/dl) were included, except for those with a history of myocardial infarction, where the upper limit for inclusion was 7.0 mmol/l (270 mg/dl). A total of 2100 patients were recruited by the end of October 1997 and will be followed for up to 6 years. This report presents the design features of the study (recruitment, follow-up, sample size, data analysis and study organization), along with baseline results. ALERT is the first large-scale prospective, randomized, double-blind study to address the prevention of cardiovascular mortality in renal transplant patients receiving an HMGCoA reductase inhibitor.",2001.0,0,0 757,11324679,Review of macrolides and ketolides: focus on respiratory tract infections.,G G Zhanel; M Dueck; D J Hoban; L M Vercaigne; J M Embil; A S Gin; J A Karlowsky,"The first macrolide, erythromycin A, demonstrated broad-spectrum antimicrobial activity and was used primarily for respiratory and skin and soft tissue infections. Newer 14-, 15- and 16-membered ring macrolides such as clarithromycin and the azalide, azithromycin, have been developed to address the limitations of erythromycin. The main structural component of the macrolides is a large lactone ring that varies in size from 12 to 16 atoms. A new group of 14-membered macrolides known as the ketolides have recently been developed which have a 3-keto in place of the L-cladinose moiety. Macrolides reversibly bind to the 23S rRNA and thus, inhibit protein synthesis by blocking elongation. The ketolides have also been reported to bind to 23S rRNA and their mechanism of action is similar to that of macrolides. Macrolide resistance mechanisms include target site alteration, alteration in antibiotic transport and modification of the antibiotic. The macrolides and ketolides exhibit good activity against gram-positive aerobes and some gram-negative aerobes. Ketolides have excellent activity versus macrolide-resistant Streptococcus spp. Including mefA and ermB producing Streptococcus pneumoniae. The newer macrolides, such as azithromycin and clarithromycin, and the ketolides exhibit greater activity against Haemophilus influenzae than erythromycin. The bioavailability of macrolides ranges from 25 to 85%, with corresponding serum concentrations ranging from 0.4 to 12 mg/L and area under the concentration-time curves from 3 to 115 mg/L x h. Half-lives range from short for erythromycin to medium for clarithromycin, roxithromycin and ketolides, to very long for dirithromycin and azithromycin. All of these agents display large volumes of distribution with excellent uptake into respiratory tissues and fluids relative to serum. The majority of the agents are hepatically metabolised and excretion in the urine is limited, with the exception of clarithromycin. Clinical trials involving the macrolides are available for various respiratory infections. In general, macrolides are the preferred treatment for community-acquired pneumonia and alternative treatment for other respiratory infections. These agents are frequently used in patients with penicillin allergies. The macrolides are well-tolerated agents. Macrolides are divided into 3 groups for likely occurrence of drug-drug interactions: group 1 (e.g. erythromycin) are frequently involved, group 2 (e.g. clarithromycin, roxithromycin) are less commonly involved, whereas drug interactions have not been described for group 3 (e.g. azithromycin, dirithromycin). Few pharmacoeconomic studies involving macrolides are presently available. The ketolides are being developed in an attempt to address the increasingly prevalent problems of macrolide-resistant and multiresistant organisms.",2001.0,0,0 758,11327196,The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein.,Y Zhang; L Z Benet,"Intestinal phase I metabolism and active extrusion of absorbed drug have recently been recognised as major determinants of oral bioavailability. Cytochrome P450 (CYP) 3A, the major phase I drug metabolising enzyme in humans, and the multidrug efflux pump, P-glycoprotein, are present at high levels in the villus tip of enterocytes in the gastrointestinal tract, the primary site of absorption for orally administered drugs. The importance of CYP3A and P-glycoprotein in limiting oral drug delivery is suggested to us by their joint presence in small intestinal enterocytes, by the significant overlap in their substrate specificities, and by the poor oral bioavailability of joint substrates for these 2 proteins. These proteins are induced or inhibited by many of the same compounds. A growing number of preclinical and clinical studies have demonstrated that the oral bioavailability of many CYP3A and/or P-glycoprotein substrate drugs can be increased by concomitant administration of CYP3A inhibitors and/or P-glycoprotein inhibitors. We believe that further understanding the physiology and biochemistry of the interactive nature of intestinal CYP3A and P-glycoprotein will be important in defining, controlling, and improving oral bioavailability of CYP3A/P-glycoprotein substrates.",2001.0,0,0 759,11329860,HMG-CoA reductase inhibitors.,D R Illingworth; J A Tobert,,2001.0,0,0 760,11336101,"Safety, tolerability, and pharmacokinetics of an extended-release formulation of fluvastatin administered once daily to patients with primary hypercholesterolemia.",H Sabia; P Prasad; H T Smith; R R Stoltz; P Rothenberg,"Fluvastatin sodium (Lescol, Novartis Pharmaceutical Corp., East Hanover, NJ, U.S.A.), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitor that limits cholesterol biosynthesis, is available as a 40-mg immediate-release formulation capsule. An extended-release formulation for once-daily administration has been developed for patients with primary hypercholesterolemia who may benefit from doses higher than 40 mg/day. This phase I study evaluated the safety, tolerability, and pharmacokinetics of a new fluvastatin extended-release formulation at doses ranging from 80-640 mg/day in 40 hypercholesterolemic patients. After a 2-week dietary stabilization phase, patients (Fredrickson type IIa/IIb), 18-55 years of age, were randomly assigned to four groups to receive oral fluvastatin extended-release (80, 160, 320, or 640 mg) or matching placebo once daily for 13 days. Fluvastatin extended-release was generally safe and well tolerated at doses of 80-320 mg/day. Within this dose range, linear pharmacokinetics was observed after single and multiple dosing. At 640 mg, fluvastatin extended-release was not well tolerated. Six of the seven actively treated patients at this dose experienced adverse events, including diarrhea, headache, and clinically relevant elevations in serum transaminase concentrations. In addition, nonlinear pharmacokinetics, possibly due to saturation of first-pass metabolism, was observed at this dose, causing higher than expected serum drug concentrations. Once-daily administration of fluvastatin extended-release at doses of 80-320 mg/day was generally safe and well tolerated in patients with primary hypercholesterolemia over a 13-day dosing period.",2001.0,0,0 761,11336576,Pharmacology and clinical experience with simvastatin.,D C Hess; S C Fagan,"Simvastatin (Zocortrade mark, Merck) is a safe and effective 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Simvastatin potently lowers total and low density lipoprotein (LDL) cholesterol. Simvastatin was the first cholesterol-lowering agent that reduced total mortality in a randomised clinical trial. Simvastatin is effective at reducing total mortality, myocardial infarction, coronary mortality and the incidence of stroke or transient ischemic attack in patients with coronary heart disease and hypercholesterolemia. Simvastatin, like other statins, also has non-lipid mechanisms of action. These include anti-inflammatory effects, antiproliferative effects on smooth muscle cells and an upregulation of endothelial nitric oxide synthase. Overall, simvastatin has an excellent safety profile. Simvastatin, along with other statins, has made a significant impact on the morbidity and mortality from coronary heart disease.",2002.0,0,0 762,11336596,Lipids and atherosclerosis: clinical management of hypercholesterolaemia.,J P Chin-Dusting; J A Shaw,"Hypercholesterolaemia is a major risk factor for the development of atherosclerosis which, in turn, underlies most ischaemic heart disease (IHD). This review deals briefly with the pathophysiology of lipids in humans and follows with a discussion of current lipid-lowering therapies. In those patients with a history of myocardial infarction (MI) or unstable angina, appropriate lipid-lowering therapy has been convincingly shown to reduce not only cardiac events but also overall mortality. The advent of the HMG CoA reductase inhibitors in the late 1980s has had a revolutionary impact in the clinical management of hypercholesterolaemia, not only because of their efficacy but especially because they are well-tolerated. The use of other treatments such as the fibrates and bile acid resins are also discussed. Given the successful use of the statins, it is felt that an emergence of a different class of LDL-cholesterol lowering compound is unlikely in the near future and rather that compounds which can increase HDL-cholesterol while lowering LDL will be of greater impact. There may also be a shifting trend towards such naturally occurring compounds as plant stanols and phytoestrogens.",2002.0,0,0 763,11336617,Clinical review of glimepiride.,A L McCall,"This article reviews the pharmacological and clinical aspects of glimepiride, the latest second-generation sulfonylurea for treatment of Type 2 diabetes mellitus (DM). Glimepiride therapy ameliorates the relative insulin secretory deficit found in most patients with Type 2 DM. It is a direct insulin secretagogue; indirectly, it also increases insulin secretion in response to fuels such as glucose. Its action to augment insulin secretion requires binding to a high affinity sulfonylurea receptor, which results in closure of ATP-sensitive potassium channels in the beta-cells of the pancreas. The question has been raised whether insulin secretagogues by acting on vascular or myocardial potassium channels may prevent ischaemic preconditioning, a physiological adaptation that could affect the outcome of coronary heart disease, but there is evidence against this concern being applicable to glimepiride. Glimepiride's antihyperglycaemic efficacy is equal to other secretagogues. It has pharmacokinetic properties that make it less prone to cause hypoglycaemia in renal dysfunction than some other insulin secretagogues, particularly glyburide (also known as glibenclamide in Europe). Its convenient once daily dosing may enhance compliance for diabetic patients who often also require medications for other co-morbid conditions, such as hypertension, hyperlipidaemia and cardiac disease. Glimepiride is approved for monotherapy, for combination with metformin and with insulin. Clinically, its reduced risk of hypoglycaemia makes it preferable to some other insulin secretagogues when attempting to achieve recommended glycaemic control (haemoglobin A(1c) (HgbA(1c)) 7%). Using suppertime neutral protamine Hagedorn (NPH) and regular insulin with morning glimepiride in overweight diabetic patients achieves glycaemic goals more quickly than insulin alone and with lower insulin doses.",2002.0,0,0 764,11336625,Atorvastatin.,A S Wierzbicki,"Atorvastatin (Lipitor, Pfizer) is a safe and effective 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin). It is the most potent currently available statin in terms of lowering low-density lipoprotein (LDL) and total cholesterol levels. It was the first statin shown to lower triglycerides in patients with isolated hypertriglyceridaemia. It has a good safety profile. In common with other statins, it has non-lipid-lowering effects including improving endothelial function, antiproliferative actions on smooth muscle and reducing platelet aggregation. It also has anti-inflammatory effects and may reduce plasma glucose levels. Clinical trial evidence with this statin is currently limited. It did slightly reduce events in the AVERT trial comparing patients receiving coronary angioplasty with those receiving high-dose atorvastatin therapy and in the MIRACL study reduced ischemia in patients with acute coronary syndromes. Other end point trials are in progress.",2002.0,0,0 765,11336628,Trimetazidine for stable angina pectoris.,H R Cross,"Stable angina pectoris, a symptom of coronary heart disease (CHD), manifests as stress-induced ischaemic episodes resulting in severe chest pain. Therapeutic aims are to improve quality of life by decreasing anginal attacks and to prevent myocardial infarction (MI) and death. Current anginal medications include beta-blockers and calcium antagonists, which decrease ischaemic severity by reducing cardiac workload, and nitrates, which increase coronary blood flow. A new therapeutic approach is the use of metabolic agents, such as trimetazidine, which are cytoprotective during ischaemia. Results of several clinical trials demonstrated that trimetazidine, at the standard dose of 20 mg t.i.d., increased exercise capacity, decreased anginal incidence and decreased left-ventricular (LV) dysfunction compared to placebo. Trimetazidine was also as effective as propranolol (120 - 160 mg/day) and nifedipine (40 mg/day) in decreasing anginal episodes and improving exercise parameters. Trimetazidine improved anginal frequency and symptoms in patients in which treatment with diltiazem, nifedipine, propranolol, pindolol, oxprenolol or long-acting nitrates had failed. Trimetazidine was also more effective than isosorbide dinitrate (30 mg/day) as an adjunct to propranolol. Despite efficacy being equivalent to that of beta-blockers and calcium antagonists, trimetazidine does not depress cardiac function and, correspondingly, is not contraindicated in any condition. Adverse effects of trimetazidine are mild and infrequent. In summary, clinical data indicate that trimetazidine is a safe, effective treatment for the symptoms of stable angina pectoris when used either as a monotherapy or an adjunctive therapy. Longer-term trials are necessary to determine whether trimetazidine will be effective in reducing rates of mortality and MI.",2002.0,0,0 766,11342472,"Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation.",A Undas; K E Brummel; J Musial; K G Mann; A Szczeklik,"The mechanism of the antithrombotic action of statins is unclear. The aim of this study was to evaluate the effects of simvastatin on the coagulation process at sites of microvascular injury. Tissue factor-initiated coagulation was assessed in blood samples collected every 30 seconds from bleeding-time wounds of 17 patients who had advanced coronary artery disease and total cholesterol levels of 224.6+/-11.8 mg/dL (mean+/-SEM). Quantitative Western blotting for time courses of fibrinogen depletion and activation of prothrombin, factor V, and factor XIII was performed before and after 3 months of simvastatin treatment (20 mg/d). Simvastatin induced reductions in total cholesterol (23%) and LDL-cholesterol (36%), which were accompanied by significant decreases in the rates of prothrombin activation (16.2+/-2.1%; P=0.004), formation of alpha-thrombin B-chain (27.4+/-1.8%; P=0.001), generation of factor Va heavy chain (29.7+/-3.1%; P=0.007) and factor Va light chain (18.9+/-1.2%; P=0.02), factor XIII activation (19.8+/-1.3%; P=0.001), and fibrinogen conversion to fibrin (72.2+/-3%; P=0.002). Posttreatment fibrinopeptides A and B concentrations, determined by using high-performance liquid chromatography, were reduced within the last 30 seconds of bleeding. The 30-kDa fragment of the factor Va heavy chain (residues 307 to 506), produced by activated protein C, and the 97-kDa fragment of the factor Va heavy chain (residues 1 to 643) were released more rapidly after simvastatin treatment. The antithrombotic actions of simvastatin showed no relationship to its cholesterol-lowering action. Simvastatin treatment depresses blood clotting, which leads to reduced rates of prothrombin activation, factor Va generation, fibrinogen cleavage, factor XIII activation, and an increased rate of factor Va inactivation. These effects are not related to cholesterol reduction.",2001.0,0,0 767,11342801,"Associations of homocysteine, C-reactive protein and cardiovascular disease in patients with renal disease.",J W Eikelboom; G J Hankey,"In the past year, evidence from epidemiological studies in patients with renal disease has confirmed associations between both elevated plasma total homocysteine concentrations and the inflammatory marker C-reactive protein with an increased risk of arteriosclerotic vascular disease. However, it remains to be determined whether lowering total homocysteine or reducing inflammation will prevent 'hard' clinical outcome events such as stroke, myocardial infarction, and vascular death. Randomized trials of homocysteine lowering are currently ongoing and should further clarify the nature of the observed association between elevated total homocysteine and cardiovascular risk in patients with or without renal disease, and whether it is causal and modifiable. There are currently no known therapeutic interventions that specifically lower C-reactive protein levels in individuals or the prevalence of elevated C-reactive protein in the population but randomized trials of anti-inflammatory therapy (e.g. using selective cyclo-oxygenase-2 inhibitors) aimed at preventing cardiovascular disease are currently being planned.",2001.0,0,0 768,11343673,Effects of 1-year treatment with fluvastatin or pravastatin on bone.,S Watanabe; S Fukumoto; Y Takeuchi; H Fujita; T Nakano; T Fujita,,2001.0,0,0 769,11344588,Comparative trials in registration files of cardiovascular drugs: comparator drugs and dosing schemes.,N F Wieringa; R Vos; P A de Graeff,"Registration files of 13 cardiovascular drugs were analysed with respect to the number of double-blind phase-III clinical trials, the use of placebo and active comparator drugs and their dosing schemes. Half of the 146 double-blind trials used active comparator drugs. The majority of files included first-choice reference drugs, but we also found trials in three files with lower dosing schemes of comparator drugs and four files which included only placebo or active controlled double-blind trials. To allow a better interpretation of the information provided in European Public Assessment Reports, which are published for every product approved for marketing in the European Union, uniform reporting is recommended on basic details of trial design, such as comparator drugs used and dosing schemes.",2001.0,0,0 770,11348605,Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS): additional perspectives on tolerability of long-term treatment with lovastatin.,J R Downs; M Clearfield; H A Tyroler; E J Whitney; W Kruyer; A Langendorfer; V Zagrebelsky; S Weis; D R Shapiro; P A Beere; A M Gotto,"This study presents the long-term safety data from AFCAPS/TexCAPS, the first primary prevention trial to demonstrate that men and women with average levels of low-density lipoprotein cholesterol (LDL-C) and below average levels of high-density lipoprotein cholesterol (HDL-C) can significantly benefit from long-term treatment to lower LDL-C; lovastatin 20 to 40 mg/day reduced the risk of a first acute major coronary event (fatal or nonfatal myocardial infarction, unstable angina, or sudden death) by 37% (p = 0.00008). This double-blind randomized, placebo-controlled trial, in 6,605 generally healthy middle-aged and older men and women, had prespecified end point and cancer analyses. All analyses were intention-to-treat. Safety monitoring included history, physical examination, and laboratory studies (including hepatic transaminases and creatine phosphokinase [CPK]). All participants, even those who discontinued treatment, were contacted annually for vital status, cardiovascular events, and cancer history. After an average of 5.2 years of follow-up, there were 157 deaths (80 receiving lovastatin and 77 receiving placebo; relative risk [RR] 1.04; 95% confidence interval [CI] 0.76 to 1.42; p = 0.82); of which 115 were noncardiovascular (RR 1.21; CI 0.84 to 1.74; p = 0.31), and of these, 82 were due to cancer (RR 1.41; CI 0.91 to 2.19; p = 0.13). There were no significant differences between treatment groups in overall cancer rates, discontinuations for noncardiovascular adverse experiences, or clinically important elevations of hepatic transaminases or CPK. Among those who used cytochrome P450 isoform (CYP3A4) inhibitors, there were no treatment group differences in the frequency of clinically important muscle-related adverse events. Treatment with lovastatin 20 to 40 mg daily for primary prevention of coronary heart disease was well tolerated and reduced the risk of first acute coronary events without increasing the risk of either noncardiovascular mortality or cancer.",2001.0,0,0 771,11349008,,,,,0,0 772,11349614,[Statins do not prevent restenosis after coronary angioplasty: where to go from here?].,M Horlitz; U Sigwart; J Niebauer,"Despite the use of intracoronary stents, approximately 15-20% of patients who undergo percutaneous transluminal coronary angioplasty (PTCA) experience symptomatic restenosis. Known mechanisms of restenotic lesion formation are smooth muscle cell proliferation, extracellular matrix production, remodeling and decreased programmed cell death (apoptosis). Experimental observations suggest that HMG-CoA reductase inhibitors (""statins"") reduce the risk of restenosis. The activity of statins limits the rate of synthesis, not only of cholesterol, but also of a range of other molecules involved in cellular function. Their benefits in primary and secondary prevention of atherosclerosis have been widely recognized. Clinical trials using different types of statins were designed to evaluate their ability to influence the incidence of restenosis after successful conventional PTCA. The results clearly demonstrated that statins reduce lipid levels but do not prevent restenosis. Experimental evidence has failed to translate into clinical effect. The underlying pathological reasons for this shortcoming as well as promising alternative approaches including vascular gene therapy and brachytherapy will be discussed in this review.",2001.0,0,0 773,11350107,Cost-effectiveness of HMG coenzyme reductase inhibitors; whom to treat?,B A van Hout; M L Simoons,"Treatment guidelines have been developed for both ""primary"" and ""secondary"" prevention of coronary heart disease. These should consider both the efficacy as well as the costs of such treatment, particularly the costs of treatment with HMG co-enzyme A reductase inhibitors (statins). In the context of guideline development in The Netherlands, the cost effectiveness of treatment with statins was analysed. Following a modelling approach, cost effectiveness was analysed as a function of a patient's initial risk for new coronary heart disease events, combining results from 4S, CARE, LIPID, WOSCOPS and AFCAPS with Dutch cost data. For each sex and age group, an estimate was made of the level of cardiovascular risks that might correspond to a cost-effectiveness ratio under NLG 40 000 (Euro 18 151) per life year gained. If the 10-year risk of myocardial infarction, stroke or cardiovascular death was estimated at 9% (AFCAPS/TexCAPS), 20% (WOSCOPS), 36% (CARE) 36% (LIPID) and 47% (4S), cost effectiveness was estimated at Euro 51 400, Euro 26 013, Euro 9970, Euro 8028 and Euro 6695. The arbitrary threshold of NLG 40 000 (approximately Euro 18 000) was achieved at a 10 year coronary heart disease event risk ranging from 19% to 26% for different age groups. Assuming the effectiveness of statin treatment decreased with age, a 10-year risk, corresponding to Euro 18 000, varied from 11% (under age 30) to 41% (over age 80). Patients at higher risk levels should be considered for statin therapy. Treatment costs for primary or secondary prevention are determined predominantly by the costs of statin drugs. The developed model allows comparison of cost effectiveness of statin therapy across a wide range of subjects with or without coronary heart disease. The consensus committee in the Netherlands postulated that drug therapy should be considered in subjects with or without coronary heart disease in which cost-effectiveness is similar. Such groups can be identified using the presented model. When cost effectiveness ratios up to Euro 18 000 per life year gained are deemed acceptable, statin treatment should be considered in most patients with known cardiovascular disease (secondary prevention), and in a limited group of subjects who are at high risk of developing coronary heart disease (primary prevention).",2001.0,0,0 774,11352694,Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: Results from the LIPID trial.,D Hunt; P Young; J Simes; W Hague; S Mann; D Owensby; G Lane; A Tonkin,"The effect of cholesterol-lowering therapy on death from coronary heart disease in older patients with previous coronary heart disease and average cholesterol levels is uncertain. To compare the relative and absolute effects of pravastatin on cardiovascular disease outcomes in patients with coronary heart disease who are 65 years of age or older with those in patients 31 to 64 years of age. Subgroup analysis of a randomized, placebo-controlled trial. 87 centers in Australia and New Zealand. 3514 patients 65 to 75 years of age, chosen from among 9014 patients with previous myocardial infarction or unstable angina and a baseline plasma cholesterol level of 4.0 to 7.0 mmol/L (155 to 271 mg/dL). Pravastatin, 40 mg/d, or placebo. Major cardiovascular disease events over 6 years. Older patients were at greater risk than younger patients (31 to 64 years of age) for death (20.6% vs. 9.8%), myocardial infarction (11.4% vs. 9.5%), unstable angina (26.7% vs. 23.2%), and stroke (6.7% vs. 3.1%) (all P < 0.001). Pravastatin reduced the risk for all cardiovascular disease events, and similar relative effects were observed in older and younger patients. In patients 65 to 75 years of age, pravastatin therapy reduced mortality by 21% (CI, 7% to 32%), death from coronary heart disease by 24% (CI, 7% to 38%), coronary heart disease death or nonfatal myocardial infarction by 22% (CI, 9% to 34%), myocardial infarction by 26% (CI, 9% to 40%), and stroke by 12% (CI, -15% to 32%). For every 1000 older patients treated over 6 years, pravastatin prevented 45 deaths, 33 myocardial infarctions, 32 unstable angina events, 34 coronary revascularization procedures, 13 strokes, or 133 major cardiovascular events, compared with 22 deaths and 107 major cardiovascular events per 1000 younger patients. Among older patients, the numbers needed to treat were 22 (CI, 17 to 36) to prevent one death from any cause, 35 (CI, 24 to 67) to prevent one death from coronary heart disease, and 21 (CI, 17 to 31) to prevent one coronary heart disease death or nonfatal myocardial infarction. In older patients with coronary heart disease and average or moderately elevated cholesterol levels, pravastatin therapy reduced the risk for all major cardiovascular events and all-cause mortality. Since older patients are at greater risk than younger patients for these events, the absolute benefit of treatment is significantly greater in older patients.",2001.0,0,0 775,11356390,Plasma vascular endothelial growth factor and its receptor Flt-1 in patients with hyperlipidemia and atherosclerosis and the effects of fluvastatin or fenofibrate.,A D Blann; F M Belgore; J Constans; C Conri; G Y Lip,"Increased vascular endothelial cell growth factor (VEGF) may be important in cardiovascular pathophysiology (perhaps relating to angiogenesis and collateral vessel development) and binds target endothelium via receptors such as Flt-1. We hypothesized that there would be increased levels of plasma VEGF and Flt-1 in patients with atherosclerosis and others with hyperlipidemia compared with controls, and a reduction in these factors with 3 months of lipid-lowering therapy. Twenty patients with uncomplicated hyperlipidemia but no atherosclerosis, 20 patients with hyperlipidemia plus clear atherosclerosis, and 40 matched controls were studied. Plasma VEGF was higher in patient groups than in healthy controls (p <0.01), but Flt-1 was not significantly altered. After lipid-lowering therapy, patients with uncomplicated hyperlipidemia had significantly reduced total cholesterol and VEGF (all p <0.05) but no significant change in Flt-1. Lack of a significant correlation between the von Willebrand factor and VEGF suggests the latter is unrelated to endothelial damage. Plasma VEGF that increases in patients with uncomplicated hyperlipidemia free of major underlying atherosclerosis and in patients with hyperlipidemia plus established atherosclerosis is reduced by successful lipid-lowering treatment. These findings may have implications for the pathophysiology and treatment of hyperlipidemia and atherosclerosis, and suggest an alternative mechanism (i.e., modulation of angiogenesis) by which lipid-lowering therapy may reduce cardiovascular events beyond lipid reduction alone.",2001.0,0,0 776,11356393,Hypertriglyceridemia: new insights and new approaches to pharmacologic therapy.,H N Ginsberg,,2001.0,0,1 777,11356400,Status of secondary prevention in patients undergoing coronary revascularization.,J K Allen; R S Blumenthal; S Margolis; D R Young,,2001.0,0,0 778,11356401,"Using both ""relative risk reduction"" and ""number needed to treat"" in evaluating primary and secondary clinical trials of lipid reduction.",P M Moriarty,,2001.0,0,0 779,11357922,The efficacy of atorvastatin in treating patients with hypercholesterolaemia to target LDL-cholesterol goals: the LIPI-GOAL trial.,E Muls; G De Backer; C Brohet; F Heller; LIPI-GOAL investigators,"LIPI-GOAL is a multicentre, open-label, non-comparative treat-to-target study, conducted from March 1998 to May 1999, that assessed the percentage of patients reaching 1992 European Atherosclerosis Society (EAS) low-density lipoprotein cholesterol (LDL-C) targets with atorvastatin 10-80 mg/day in subjects with hypercholesterolaemia, defined as LDL-C > 160 mg/dl after a 12-week step I diet. Patients were treated towards the following LDL-C goals: < 135 mg/dl in patients with atherosclerotic disease present and/or coronary heart disease (CHD) risk >40%/10 years, or LDL-C < 155 mg/dl in all others. All subjects started treatment with atorvastatin 10 mg/day for 6 weeks. The dose was doubled every 6 weeks, to 20, 40, or 80 mg/day at weeks 12, 18, and 24, respectively, if targets were not reached. Of 587 patients screened for participation, 473 were enrolled and 419 (59% male; mean age 61 years) were available for efficacy evaluation. Fifty-five percent had atherosclerotic disease and/or CHD risk >40%/10 years. Dose titration was not needed in 303 patients (72%) who reached LDL-C target with atorvastatin 10 mg/day. Among 116 patients who were subsequently treated with higher atorvastatin dosages, 47 reached LDL-C target with 20 mg/day, 15 with 40 mg/day, and 6 with 80 mg/day. Therefore, 88.5% of subjects reached LDL-C goal in an intention-to-treat analysis. In general, atorvastatin was well tolerated. Most patients at high risk for CHD reached LDL-C goals with atorvastatin 10-80 mg/day. Seventy-two % of patients reached target with atorvastatin 10 mg/day, which may simplify clinical management and should encourage better adherence to recommendations.",2001.0,0,0 780,11358645,Effects of bezafibrate and simvastatin on plasma lipoproteins in hypercholesterolemia resistant to hormone replacement therapy.,M Ohmichi; H Ikegami; H Kurachi; K Node; K Morishige; Y Nishio; K Adachi; K Matumoto; J Hayakawa; K Tasaka; C Azuma; Y Murata,"Estrogen replacement therapy has favorable effects on serum lipoprotein levels in postmenopausal women with hypercholesterolemia. However, there are some patients who fail to respond to hormone replacement therapy (HRT) to lower the serum cholesterol level. In these cases, a conventional lipid-lowering therapy will be applied in addition to HRT, while the effects of these drugs are not well understood. In this study, we studied the effects of simvastatin and bezafibrate administered in addition to HRT. Patients who were hypercholesterolemic even after HRT were randomly assigned to three treatment groups: HRT only (control group, n=10), HRT+simvastatin (10 mg/day, n=10), or HRT+bezafibrate (400 mg/day, n=10). Serum lipids and lipoprotein levels were measured throughout 12 weeks. The serum triglyceride levels were decreased by 24+/-28 and 38+/-13% in the HRT+simvastatin and HRT+bezafibrate groups, respectively. HRT+simvastatin decreased the total cholesterol (21+/-10%) and low-density lipoprotein cholesterol (28+/-12%) levels without affecting the high-density lipoprotein cholesterol (HDL-C) level, while HRT+bezafibrate increased the HDL-C level (12+/-11%). Treatment with simvastatin or bezafibrate in addition to HRT should be considered in cases of postmenopausal hypercholesterolemia in which HRT alone fails to lower the serum lipoprotein levels.",2001.0,0,0 781,11359190,How much do we pay for a benefit? A descriptive cost analysis of the use of statins. The need for a national cost-effectiveness analysis.,J L Vieira; V L Portal; E H Moriguchi,,2001.0,0,0 782,11361054,Interactions between simvastatin and troglitazone or pioglitazone in healthy subjects.,T Prueksaritanont; J M Vega; J Zhao; K Gagliano; O Kuznetsova; B Musser; R D Amin; L Liu; B A Roadcap; S Dilzer; K C Lasseter; J D Rogers,"Two randomized, two-period crossover studies were conducted to evaluate the effects of repeat oral dosing of troglitazone (Study I) and pioglitazone (Study II) on the pharmacokinetics of plasma HMG-CoA reductase inhibitors following multiple oral doses of simvastatin and of simvastatin on the plasma pharmacokinetics of troglitazone (Study I) in healthy subjects. In both studies, each subject received two treatments. Treatment A consisted of once-daily oral doses of troglitazone 400 mg (Study I) or pioglitazone 45 mg (Study II) for 24 days with coadministration of once-daily doses of simvastatin 40 mg (Study I) or 80 mg (Study II) on Days 15 through 24. Treatment B consisted of once-daily oral doses of simvastatin 40 mg (Study I) or 80 mg (Study II) for 10 days. In Study I, the area under the plasma concentration-time profiles (AUC) and maximum plasma concentrations (Cmax) of HMG-CoA reductase inhibitors in subjects who received both troglitazone and simvastatin were decreased modestly (by approximately 30% for Cmax and approximately 40% for AUC), but time to reach Cmax (tmax) did not change, as compared with those who received simvastatin alone. Simvastatin, administered orally as a 40 mg tablet daily for 10 days, did not affect the AUC or tmax (p > 0.5) but caused a small but clinically insignificant increase (approximately 25%) in Cmax for troglitazone. In Study II, pioglitazone, at the highest approved dose for clinical use, did not significantly alter any of the pharmacokinetic parameters (AUC, Cmax, and tmax) of simvastatin HMG-CoA reductase inhibitory activity. For all treatment regimens, side effects were mild and transient, suggesting that coadministration of simvastatin with either troglitazone or pioglitazone was well tolerated. The modest effect of troglitazone on simvastatin pharmacokinetics is in agreement with the suggestion that troglitazone is an inducer of CYP3A. The insignificant effect of simvastatin on troglitazone pharmacokinetics is consistent with the conclusion that simvastatin is not a significant inhibitor for drug-metabolizing enzymes. The lack of pharmacokinetic effect of pioglitazone on simvastatin supports the expectation that this combination may be used safely.",2001.0,0,0 783,11368702,"Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).","Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults",,2001.0,1,1 784,11368705,Updated guidelines for cholesterol management.,M S Lauer; P B Fontanarosa,,2001.0,0,0 785,11369681,Coronary heart disease in the first 30 years of the 21st century: challenges and opportunities: The 33rd Annual James B. Herrick Lecture of the Council on Clinical Cardiology of the American Heart Association.,G A Beller,,2001.0,0,0 786,11372014,Medical treatment of peripheral arterial disease and claudication.,W R Hiatt,,2001.0,0,0 787,11374422,Reassuring effect of pravastatin on natural killer cell activity in stable renal transplant patients.,L M Vaessen; P P van Miert; T van Gelder; J N Ijzermans; W Weimar,"Administration of pravastatin soon after transplantation successfully lowers cholesterol levels, whereas a reduced number of acute rejection episodes is accompanied by a decrease in natural killer (NK) cell activity. As a consistent low NK cell activity caused by pravastatin might impair tumor surveillance leading to cancer, we studied the effect of pravastatin on NK cell activity in stable renal transplant patients. From 14 cyclosporine (CsA)-treated and 11 azathioprine (AZA)-treated patients with hypercholesterolemia, more than 1 year after kidney transplantation, we determined NK cell number and cytotoxic activity before, and at 6 and 12 weeks after, initiating pravastatin treatment. Additionally, cholesterol levels and liver and kidney function parameters were assessed. During pravastatin treatment, total cholesterol and low-density lipoprotein-cholesterol levels decreased significantly in both patient groups. In the CsA group, the number and cytotoxic activity of the NK cells at 12 weeks after institution of pravastatin was in the same range as before pravastatin. Additionally, in the AZA group, pravastatin did not influence the number of NK cells. However, in the AZA group, both the number of NK cells and their cytotoxic activity were significantly (<0.002) lower compared to the values in the CsA group. In contrast to previous reports on decreased NK cell cytotoxicity caused by pravastatin treatment early after transplantation, we cannot confirm these results in stable kidney recipients. In our hands, NK cell cytotoxicity during pravastatin treatment was within the same range as in the absence of pravastatin. Thus, in view of the potential role of NK cells in tumor surveillance, these data are reassuring.",2001.0,0,0 788,11375257,"A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid.",T J Stalker; A M Lefer; R Scalia,"Recent studies have reported that hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have vasculoprotective effects independent of their lipid-lowering properties, including anti-inflammatory actions. We used intravital microscopy of the rat mesenteric microvasculature to examine the effects of rosuvastatin, a new HMG-CoA reductase inhibitor, on leukocyte-endothelium interactions induced by thrombin. Intraperitoneal administration of 0.5 and 1.25 mg kg(-1) rosuvastatin 18 h prior to the study, significantly and dose-dependently attenuated leukocyte rolling, adherence, and transmigration in the rat mesenteric microvasculature superfused with 0.5 u ml(-1) thrombin. This protective effect of rosuvastatin was reversed by intraperitoneal injection of 25 mg kg(-1) mevalonic acid 18 h before the study. Immunohistochemical detection of the endothelial cell adhesion molecule P-selectin showed a 70% decrease in endothelial cell surface expression of P-selectin in thrombin-stimulated rats given 1.25 mg kg(-1) rosuvastatin. In addition, rosuvastatin enhanced release of nitric oxide (NO) from the vascular endothelium as measured directly in rat aortic segments. Moreover, rosuvastatin failed to attenuate leukocyte-endothelium interactions in peri-intestinal venules of eNOS(-/-) mice. These data indicate that rosuvastatin exerts important anti-inflammatory effects via inhibition of endothelial cell adhesion molecule expression, and that this protective action of rosuvastatin requires release of nitric oxide by the vascular endothelium. These data also demonstrate that the mechanism of the non-lipid lowering actions of HMG-CoA reductase inhibitors in vivo may be due to reduced formation or availability of mevalonic acid within endothelial cells.",2001.0,0,0 789,11376298,"PRINCE's prospects: statins, inflammation, and coronary risk.",R R Azar; D D Waters,,2001.0,0,0 790,11376301,The pravastatin inflammation CRP evaluation (PRINCE): rationale and design.,M A Albert; J Staggers; P Chew; P M Ridker; PRINCE Investigators,"Randomized, controlled trials demonstrate that HMG CoA reductase inhibition reduces coronary event rates in both primary and secondary prevention. In addition to reducing cholesterol levels, laboratory evidence suggests that statins also have anti-inflammatory activity, a property that may be critical for maintaining plaque stability. Recently, the inflammatory marker high-sensitivity C-reactive protein (hs-CRP) has been shown to predict vascular risk in individuals with and without hyperlipidemia. Furthermore, in the Cholesterol and Recurrent Events (CARE) trial, the relative efficacy of pravastatin in reducing events was greatest among those with elevated levels of hs-CRP. However, the time course and magnitude of this effect in both primary and secondary prevention is controversial. PRavastatin Inflammation CRP Evaluation (PRINCE) is an investigator-initiated, multicenter, community-based trial that will evaluate the effects of pravastatin on hs-CRP in up to 1182 individuals with coronary artery disease and up to 1702 individuals without coronary artery disease. Lipid profiles and hs-CRP levels will be obtained at baseline, 12 weeks, and 24 weeks in all study participants. Patients with known coronary artery disease will receive 40 mg/d pravastatin, whereas those without coronary artery disease will be randomly assigned to receive placebo or 40 mg/d pravastatin. The potential clinical impact of the PRINCE trial is substantial because nearly 50% of myocardial infarctions in the United States occur in persons with normal cholesterol levels, and inflammatory markers such as hs-CRP may provide a means to detect such individuals at high risk who do not currently qualify for statin therapy. The PRINCE trial will determine the time course of effect of this statin on hs-CRP and whether any observed effect on hs-CRP is independent of pravastatin-induced changes in low-density lipoprotein cholesterol.",2001.0,0,0 791,11376309,Efficacy of atorvastatin in achieving National Cholesterol Education Program low-density lipoprotein targets in women with severe dyslipidemia and cardiovascular disease or risk factors for cardiovascular disease: The Women's Atorvastatin Trial on Cholesterol (WATCH).,R McPherson; C Angus; P Murray; J Genest; WATCH Investigators,"Recent studies have demonstrated that women at high risk for cardiovascular disease (CVD) benefit from cholesterol lowering to an extent similar to that of men. The ability to achieve established treatment goals for low-density lipoprotein cholesterol (LDL-C) in women with clearly defined risk factors has not been examined in detail. We have determined the efficacy and frequency of achieving target levels for LDL-C with atorvastatin on the basis of National Cholesterol Education Program Adult Treatment Panel II recommendations in 318 women according to the presence of CVD (198 women) or risk factors for CVD (120 women) and the presence of mixed dyslipidemia with obesity with or without CVD (72 women). Mean baseline LDL-C concentrations for women with established CVD were in the upper 10% of the distribution for age-matched North American women and, for those without CVD, were also extremely elevated and were in the top 5% of the LDL-C distribution for age-matched women in this population. The majority of participants without CVD (63%) reached LDL-C targets (LDL-C or=2 CVD risk factors) with 10 mg atorvastatin and 79% reached targets with up to 20 mg of atorvastatin. For women with established CVD, 34% achieved an LDL-C or =65 years with stable angina, to compare the profiles to local guidelines and to explore the determinants of these profiles, in a cross-sectional study. We identified 11 141 individuals from the Quebec provincial out-patient pharmaceutical database for the period 1 June 1996 to 31 May 1997, and examined the percentage of these patients with and without associated co-morbidities receiving antiplatelet, beta-blocker and lipid-lowering medications. We used hierarchical modelling to examine the role of patient and physician characteristics in explaining the variation in the use of these medications. Calcium-channel blockers were the class of anti-ischaemic drugs most prescribed (63%). Beta-blockers were prescribed in 52.1% of patients. Antiplatelet and lipid-lowering drugs were prescribed to 56.8% and 32.6%, respectively. Increasing age and female gender made patients less likely to be prescribed these treatments. General practitioners were less likely than cardiologists to prescribe beta-blockers and lipid-lowering drugs (OR 0.79, CI 95% 0.68-0.91 and OR 0.77, CI 95% 0.66-0.91, respectively). There is a general under-use of antiplatelet, beta-blocker and lipid-lowering medications in the treatment of stable angina pectoris patients, possibly leading to adverse patient outcomes.",2001.0,0,0 802,11391041,The challenge of rejection and cardiac allograft vasculopathy.,W G Cotts; M R Johnson,"Since the first human heart transplantation was performed in 1967, the field of heart transplantation has advanced to the point where survival and acceptable quality of life are commonplace. Despite remarkable progress in the clinical management of rejection, rejection continues to limit survival and quality of life in the heart transplant population. This review will discuss the biologic processes involved in hyperacute rejection, acute rejection, and humoral (vascular) rejection. The development of endomyocardial biopsy techniques represented a significant advancement in the diagnosis of cardiac rejection, and endomyocardial biopsy remains the 'gold standard' in the diagnosis of cellular rejection. To date, no noninvasive parameters will diagnose rejection with adequate sensitivity and specificity. Biopsy frequency and immunosuppressive therapies may be tailored to the risk of rejection. Immunosuppression for cardiac transplantation can be divided into three major phases: 1) perioperative immunosuppression; 2) maintenance immunosuppression, and; 3) treatment of rejection. The strategy for treating transplant rejection should be influenced by several variables: 1) Histologic grade of rejection; 2) Evidence of hemodynamic compromise by ejection fraction or right heart catheterization; 3) Severity of previous rejection episodes and types of immunosuppressives used; and 4) Risk factors for rejection, including time after transplantation. Future rejection therapy will involve more sophisticated attempts to alter host responses toward the donor organ in a more specific and selective way. Despite considerable advances in the care of the heart transplant recipient, long-term survival is limited by cardiac allograft vasculopathy. The final section of this chapter will review the pathology, immunopathology, nonimmunologic risk factors, diagnosis, prevention and treatment of allograft vasculopathy.",2001.0,0,0 803,11393378,Alternative treatments for focal and segmental glomerular sclerosis.,C Ponticelli; P Passerini,"Corticosteroids represent the first therapeutic approach for patients with focal and segmantal glomerulosclerosis. What to do in patients who do not respond to corticostetoids is still uncertain. Cytotoxic agents have been tried. The results are usually poor when these drugs are given for short periods but almost half of patients may enter remission ir treatment is prolonged. Some decrease in proteinuria may be obtained with mycophenolav, mofetil but the available reports are still scanty and the follow ups are short. Cyclosporine has been largely used both in controlled and non controlled trials with favorable results. However, being the drug nephrotoxic caution should be recommended with its use. Plasma-exchange and lipopheresis may attempted in resistant cases.",2001.0,0,0 804,11394370,The influence of simvastatin on lipase and cholesterol esterase activity in the serum of men with coronary heart disease.,M Pioruńska-Stolzmann; A Pioruńska-Mikołajczak,"Several studies have demonstrated that any beneficial effects of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), of which simvastatin (Merck Sharp & Dohme) is an example, on coronary events are linked to their hypocholesterolemic properties. The in vivo effects of simvastatin treatment on lipase (GEH = glycerol ester hydrolase) and cholesterol esterase (CEase) activity in the serum of men with coronary heart disease (CHD) were examined. GEH and CEase activity in the serum of men with CHD, before simvastatin treatment, was lower than in the control subjects. In our study we have provided evidence that simvastatin increases GEH activity in a time-dependent manner, but has no effect on CEase activity. This suggests that simvastatin can directly affect acylglycerol metabolism by an increase in GEH activity and may therefore be suitable for the treatment of combined lipoprotein disorders characterized by elevation of triacylglycerols.",2001.0,0,0 805,11395029,Randomised controlled trial of use by hypercholesterolaemic patients of a vegetable oil sterol-enriched fat spread.,H A Neil; G W Meijer; L S Roe,"Plant sterols may be a useful additive therapy in the treatment of hypercholesterolaemic patients. The purpose of this study was to determine the effect of a fat spread enriched with vegetable oil sterols on plasma lipid, lipoprotein and apolipoprotein concentrations. A randomised double blind placebo-controlled crossover trial with two consecutive periods of 8 weeks was conducted. 30 patients with heterozygous familial hypercholesterolaemia treated concurrently with an HMG-CoA reductase inhibitor (statin) and 32 patients with type IIa primary hypercholesterolaemia with a total cholesterol concentration >6.5 mmol/l not taking lipid-lowering drug therapy were recruited from a hospital lipid clinic. The active treatment was a fortified fat spread (25 g/day) providing 2.5 g of plant sterols. The control spread was indistinguishable in taste and appearance. Comparison at the end of the two 8-week trial periods showed a statistically significant reduction in total and LDL-cholesterol with use of the fortified spread but the results were confounded by a carry-over effect, which was partly explained by changes in the background diet. Because a carry-over effect was present, further analyses were restricted to the parallel arms of the first treatment period and were conducted on an intention to treat basis. After 4 weeks, LDL-cholesterol had decreased by 0.04 mmol/l ([0.8%] 95% confidence interval -0.44-0.37 NS) in the placebo group and decreased by -0.76 mmol/l ([15.0%] 95% CI -1.03--0.48, P<0.0001) in the active treatment group. After 8 weeks, the corresponding results were 0.0 mmol/l ([0.0%] 95% CI -0.26-0.24 NS) and -0.51 mmol/l ([10.0%] 95% CI -0.73--0.29 P<0.0001). There were no significant changes in apolipoprotein AI or B concentrations in the placebo group, but there was a small but statistically significant increase in apolipoprotein AI and a decrease in apolipoprotein B in the active treatment group. HDL cholesterol and triglyceride concentrations were unchanged. There was no difference in response between patients with statin-treated familial hypercholesterolaemia and patients with type IIa hyperlipoproteinaemia. We conclude that a fortified fat spread enriched with vegetable oil sterols reduces LDL-cholesterol by 10-15% with no difference in response between hypercholesterolaemic patients prescribed statins and those not taking lipid-lowering drug therapy.",2001.0,0,0 806,11395334,Is sticky blood a treatable determinant of cognitive decline and of dementia?,G D Lowe,,2001.0,0,0 807,11397506,Current research on respiratory viral infections: Third International Symposium.,A C Schmidt; R B Couch; G J Galasso; F G Hayden; J Mills; B R Murphy; R M Chanock,,2001.0,0,0 808,11398906,Renoprotective therapy in patients with nondiabetic nephropathies.,R Pisoni; P Ruggenenti; G Remuzzi,"End-stage renal failure (ESRF) represents a major health problem. Early diagnosis and effective measures to slow or to stop renal damage are essential goals for nephrologists to prevent or delay progression to ESRF. Identifying mechanisms of progressive parenchymal injury is instrumental in developing renoprotective strategies. Protein traffic through the glomerular barrier is an important determinant of progression in chronic nephropathies and proteinuria is the best predictor of renal outcome. At the moment, ACE inhibition is the most effective treatment in patients with chronic nondiabetic proteinuric nephropathies, reducing protein traffic, urinary protein excretion rate and progression to ESRF more effectively than conventional treatment. Low sodium diet and/or diuretic treatment may help to increase the antiproteinuric effect of ACE inhibitors by maximally activating the renin-angiotensin system. Intensified blood pressure control, whatever treatment is employed, also enhances the antiproteinuric response to ACE inhibitors. However, since this is not always sufficient to normalise urinary proteins and fully prevent renal damage, additional treatments may be needed in patients poorly or not responding to ACE inhibitors. These may include angiotensin II receptor antagonists, non-dihydropyridine calcium antagonists and perhaps low doses of nonsteroidal anti-inflammatory drugs. Preliminary data on multidrug treatments including these additional antiproteinuric agents are encouraging, but additional studies in larger patient numbers are needed to better define the risk/benefit profile of this innovative approach.",2001.0,0,0 809,11401927,In-hospital initiation of lipid-lowering therapy for patients with coronary heart disease: the time is now.,G C Fonarow; C M Ballantyne,,2001.0,0,0 810,11403364,"Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. ASCOT investigators.",P S Sever; B Dahlöf; N R Poulter; H Wedel; G Beevers; M Caulfield; R Collins; S E Kjeldsen; G T McInnes; J Mehlsen; M Nieminen; E O'Brien; J Ostergren,"To test the primary hypothesis that a newer antihypertensive treatment regimen (calcium channel blocker +/- an angiotensin converting enzyme inhibitor) is more effective than an older regimen (beta-blocker +/- a diuretic) in the primary prevention of coronary heart disease (CHD). To test a second primary hypothesis that a statin compared with placebo will further protect against CHD endpoints in hypertensive subjects with a total cholesterol < or = 6.5 mmol/l. Prospective, randomized, open, blinded endpoint trial with a double-blinded 2 x 2 factorial component. Patients were recruited mainly from general practices. Men and women aged 40-79 were eligible if their blood pressure was > or = 160 mmHg systolic or > or = 100 mmHg diastolic (untreated) or > or = 140 mmHg systolic or > or = 90 mmHg diastolic (treated) at randomization. Patients received either amlodipine (5/ 10 mg) +/- perindopril (4/8 mg) or atenolol (50/ 100 mg) +/- bendroflumethiazide (1.25/2.5 mg) +K+ with further therapy as required to reach a blood pressure of < or = 140 mmHg systolic and 90 mmHg diastolic. Patients with a total cholesterol of < or = 6.5 mmol/l were further randomized to receive either atorvastatin 10 mg or placebo daily. Non-fatal myocardial infarction (MI) and fatal coronary heart disease (CHD). 19 342 men and women were initially randomized, of these 10297 were also randomized into the lipid-lowering limb. All patients had three or more additional cardiovascular risk factors. The study has 80% power (at the 5% level) to detect a relative difference of 20% in CHD endpoints between the calcium channel blocker-based regimen and the beta-blocker-based regimen. The lipid-lowering limb of the study has 90% power at the 1% level to detect a relative difference of 30% in CHD endpoints between groups.",2002.0,1,1 811,11403502,Secondary prevention antibiotic treatment trials.,C R Conti,,2001.0,0,0 812,11403509,Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia.,M H Davidson; P Toth; S Weiss; J McKenney; D Hunninghake; J Isaacsohn; J M Donovan; S K Burke,"Colesevelam hydrochloride is a novel, lipid-lowering agent that binds bile acids with high affinity. A multicenter, randomized, double-blind, placebo-controlled, parallel-design study was conducted to assess the efficacy and tolerability of combination low-dose colesevelam and lovastatin treatment in patients with primary hypercholesterolemia. Combination therapy with low doses of colesevelam and lovastatin decreases low density (LDL) cholesterol with minimal adverse events. Following a 4- to 6-week dietary lead in, 135 patients were randomized into five groups for a 4-week treatment period: placebo, colesevelam 2.3 g at dinner, lovastatin 10 mg at dinner, the combination of colesevelam and lovastatin given at dinner (dosed together), and combination treatment with colesevelam given at dinner and lovastatin administered at bedtime (dosed apart). Combination colesevelam and lovastatin treatment decreased LDL cholesterol by 34% (60 mg/dl, p < 0.0001) and 32% (53 mg/dl, p < 0.0001) when colesevelam and lovastatin were dosed together or dosed apart, respectively. Both combination therapies were superior to either agent alone (p < 0.05). Decreases in LDL cholesterol exceeded the combined decreases observed for colesevelam alone (13 mg/dl, 7%) and lovastatin alone (39 mg/dl, 22%). Both combination treatments reduced total cholesterol by 21% (p < 0.0001) and apolipoprotein B by 24% (p < 0.0001). Neither combination treatment significantly altered high-density lipoprotein cholesterol or triglycerides. Adverse side effects were not significantly different among randomized groups. Combination colesevelam and lovastatin was efficacious and well tolerated, resulting in additive decreases in LDL cholesterol levels whether or not both agents were administered simultaneously.",2001.0,0,0 813,11403756,Do statins cause cancer? A meta-analysis of large randomized clinical trials.,L M Bjerre; J LeLorier,"Although the short-term safety and tolerability of statins has been well established, their potential carcinogenicity in the long term is still debated. The goal of this study was to determine whether long-term treatment with statins is associated with an increased risk of fatal and nonfatal cancers. We searched the Medline database between January 1966 and December 1999 for randomized, controlled trials of human subjects in which monotherapy with a statin was compared with placebo. No language restrictions were applied. Only trials with a minimum treatment duration of 4 years and a minimum of 1,000 subjects were included. Studies that did not provide information on fatal or nonfatal cancers were excluded. Data on fatal and nonfatal cancers and all-cause mortality were extracted by a single nonblinded reviewer. Overall crude estimates of risk difference were computed by summing the numerators and denominators of trial-specific risk estimates. Five trials met the inclusion criteria. The estimated differences in absolute risk between treatment and placebo were as follows (negative risks indicate that treatment was safer than placebo): all nonfatal cancers, 0.0% (95% confidence interval [CI]: -0.8% to 0.8%); all fatal cancers, -0.1% (95% CI: -0.7% to 0.4%); all fatal and nonfatal cancers combined, -0.1% (95% CI: -1.0% to 0.7%); and all-cause mortality, -1.5% (95% CI: 2.8% to 0.2%). This study demonstrates no association between statin use over a 5-year period and the risk of fatal and nonfatal cancers. This conclusion is limited by the relatively short follow-up of the studies analyzed. Similar analyses of data from studies with longer follow-up periods would be valuable.",2001.0,0,0 814,11403761,,,,,0,0 815,11405194,Statins and bone formation.,I R Garrett; G Gutierrez; G R Mundy,"The main therapy needed most in the bone field is an anabolic agent for the treatment of osteoporosis. Current drugs on the market, which included bisphosphonates, calcitonin, estrogen and related compounds, vitamin D analogues trabecular microarchitecture. Therefore, it would be desirable to have a satisfactory and universally and iprifalvone, are essentially bone resorption inhibitors that mainly act to stabilize bone mass. Patients with established osteoporosis have lost more than 50% of their bone mass at critical sites in the skeleton, and more over have marked disruption of acceptable drug that would stimulate new bone formation and correct this disturbance of trabecular microarchitecture characteristic of established osteoporosis. Recently inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, which controls the first step in the biosynthesis of cholesterol, have been shown to stimulate bone formation in rodents both in vitro and in vivo. The effect is associated with an increased expression of the bone morphogenetic protein-2 (BMP-2) gene in bone cells. These statins drugs are widely used agents for lowering cholesterol and reducing heart attacks, however they are also known to elicit numerous pleiotropic effects including inhibition of proliferation and migration of smooth muscle cells, inhibition of tumor growth and anti-inflammatory activity. Some of these effects have been attributed to not only to the reduction of cholesterol synthesis by inhibition of the HMG-CoA reductase enzyme but also by the concurrent reduction in downstream metabolites of the mevalonate pathway such as mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. The findings that statins are capable of increasing bone formation and bone mass in rodents suggests a potential new action for the statins, which may be beneficial in patients with established osteoporosis where marked bone loss has occurred. Recent clinical data suggests that they may reduce the risk of fracture in patients taking these drugs. However, their precise role can only be determined by appropriate randomized clinical trials, which demonstrate their efficacy in this regard in patients.",2001.0,0,0 816,11405397,"Prognostic significance of risk stratifiers of mortality, including T wave alternans, after acute myocardial infarction: results of a prospective follow-up study.",J M Tapanainen; A M Still; K E Airaksinen; H V Huikuri,"Occurrence of sustained microvolt-level T wave alternans (TWA) at a specified heart rate has been suggested to predict life-threatening arrhythmic events, but its prognostic value has not been well established in patients who survived an acute myocardial infarction (AMI). The purpose of this prospective study was to assess the predictive significance of various noninvasive risk indicators of mortality, including TWA, in consecutive post-AMI patients with optimized medical therapy. In addition to a symptom-limited predischarge exercise test with measurement of TWA, mortality risk was assessed using heart rate variability, 24-hour ECG recordings, baroreflex sensitivity, signal-averaged ECG, QTc interval, QT dispersion, and echocardiographic wall-motion index in 379 consecutive patients. Twenty-six patients (6.9%) died during a mean follow-up of 14 +/- 8 months. Sustained TWA was found in 56 patients (14.7%), none of whom died. Several risk variables, e.g., incomplete TWA test (inability to perform the exercise test or reach the required target heart rate of 105 beats/min), increased QRS duration on signal-averaged ECG, increased QT dispersion, long QTc interval, nondiagnostic baroreflex sensitivity result, and low wall-motion index, predicted all-cause mortality in univariate analyses. In multivariate analysis, the incomplete TWA test was the most significant predictor of cardiac death (relative risk 11.1, 95% confidence interval 2.4 to 50.8; P < 0.01). Sustained TWA during the predischarge exercise test after AMI does not indicate increased risk for mortality. An incomplete TWA test and several common risk variables provided prognostic information in this post-AMI population.",2001.0,0,0 817,11405825,Statin therapy and the prevention of dementia.,E L Bollen; A Gaw; B M Buckley,,2001.0,0,0 818,11406909,A cost-effectiveness model of alternative statins to achieve target LDL-cholesterol levels.,G D Maclaine; H Patel,"An economic model was developed to estimate the relative cost-effectiveness of alternative HMG-CoA reductase inhibitors (statins)--atorvastatin, cerivastatin, fluvastatin, pravastatin and simvastatin--to achieve target low-density lipoprotein cholesterol (LDL-C) levels in a population of secondary CHD prevention patients. By using a cholesterol target as the endpoint of interest and a dose titration approach, the model assumes that the statins demonstrate a class effect through cholesterol lowering. The model was used to estimate the proportion of patients achieving target LDL-C levels (< 3 mmol/l) under each scenario tested. Total costs and incremental cost-effectiveness relative to no treatment and to the lowest cost option were estimated for each scenario. Total costs were highest for pravastatin and lowest for cerivastatin. Compared with no treatment, the incremental cost per patient treated to target LDL-C varied between 383 Pounds (atorvastatin) and 1213 Pounds (pravastatin). Incremental cost-effectiveness ratios in comparison with the lowest cost treatment (cerivastatin) were 141 Pounds per additional patient achieving target LDL-C with atorvastatin, and 275 Pounds with simvastatin. Fluvastatin and pravastatin were both less effective and more expensive than the lowest cost therapy. Although cerivastatin was associated with lowest expected costs, therapy with atorvastatin achieved the lowest cost-effectiveness ratios. Hence atorvastatin would allow the largest number of patients to be treated to target LDL-C within a fixed drug budget. Choosing between drug therapies on the basis of price alone may be misleading if the effectiveness of therapies varies.",2001.0,0,0 819,11408299,"Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study.",M Kivipelto; E L Helkala; M P Laakso; T Hänninen; M Hallikainen; K Alhainen; H Soininen; J Tuomilehto; A Nissinen,"To examine the relation of midlife raised blood pressure and serum cholesterol concentrations to Alzheimer's disease in later life. Prospective, population based study. Populations of Kuopio and Joensuu, eastern Finland. Participants were derived from random, population based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average of 21 years' follow up, a total of 1449 (73%) participants aged 65-79 took part in the re-examination in 1998. Midlife blood pressure and cholesterol concentrations and development of Alzheimer's disease in later life. People with raised systolic blood pressure (>/=160 mm Hg) or high serum cholesterol concentration (>/=6.5 mmol/l) in midlife had a significantly higher risk of Alzheimer's disease in later life, even after adjustment for age, body mass index, education, vascular events, smoking status, and alcohol consumption, than those with normal systolic blood pressure (odds ratio 2.3, 95% confidence interval 1.0 to 5.5) or serum cholesterol (odds ratio 2.1, 1.0 to 4.4). Participants with both of these risk factors in midlife had a significantly higher risk of developing Alzheimer's disease than those with either of the risk factors alone (odds ratio 3.5, 1.6 to 7.9). Diastolic blood pressure in midlife had no significant effect on the risk of Alzheimer's disease. Raised systolic blood pressure and high serum cholesterol concentration, and in particular the combination of these risks, in midlife increase the risk of Alzheimer's disease in later life.",2001.0,0,0 820,11413075,Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease.,M Vasa; S Fichtlscherer; K Adler; A Aicher; H Martin; A M Zeiher; S Dimmeler,"Therapeutic neovascularization may constitute an important strategy to salvage tissue from critical ischemia. Circulating bone marrow-derived endothelial progenitor cells (EPCs) were shown to augment the neovascularization of ischemic tissue. In addition to lipid-lowering activity, hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) reportedly promote the neovascularization of ischemic tissue in normocholesterolemic animals. Methods and Results-Fifteen patients with angiographically documented stable coronary artery disease (CAD) were prospectively treated with 40 mg of atorvastatin per day for 4 weeks. Before and weekly after the initiation of statin therapy, EPCs were isolated from peripheral blood and counted. In addition, the number of hematopoietic precursor cells positive for CD34, CD133, and CD34/kinase insert domain receptor was analyzed. Statin treatment of patients with stable CAD was associated with an approximately 1.5-fold increase in the number of circulating EPCs by 1 week after initiation of treatment; this was followed by sustained increased levels to approximately 3-fold throughout the 4-week study period. Moreover, the number of CD34/kinase insert domain receptor-positive hematopoietic progenitor cells was significantly augmented after 4 weeks of therapy. Atorvastatin treatment increased the further functional activity of EPCs, as assessed by their migratory capacity. The results of the present study define a novel mechanism of action of statin treatment in patients with stable CAD: the augmentation of circulating EPCs with enhanced functional activity. Given the well-established role of EPCs of participating in repair after ischemic injury, stimulation of EPCs by statins may contribute to the clinical benefit of statin therapy in patients with CAD.",2001.0,0,0 821,11413940,The devil is in the details.,D L DeSilvey,,2001.0,0,0 822,11417585,Statins and fractures.,A S Wierzbicki; T M Reynolds,,2001.0,0,0 823,11420583,The beneficial effects of plant sterols on serum cholesterol.,N C Wong,"Phytosterol-enriched margarines are a recent addition to the list of so-called 'functional foods'. The ingestion of phyto-sterols lowers the serum cholesterol by inhibiting intestinal uptake of the sterol. The phytosterols available in consumer products are comprised predominantly of beta-sitosterol and sitostanol. The esterified form of these phytosterols increases their solubility and enhances their residence time in the small intestine. Their ability to displace cholesterol from micelles in the small intestine underlies the mechanism that inhibits cholesterol absorption, leading to a 10% reduction in total serum cholesterol. Numerous well designed studies have documented the beneficial actions of these phytosterols on serum cholesterol.",2001.0,0,0 824,11421562,Comparison of effects of thiazolidinediones on cardiovascular risk factors: observations from a clinical practice.,C G Gegick; M D Altheimer,"To compare short-term glycosylated hemoglobin (HbA(1c)), lipid, weight, tolerability, and hepatic effects after switching patients with type 2 diabetes from troglitazone to either pioglitazone or rosiglitazone treatment. This study compared the effects of conversion from maintenance troglitazone therapy to pioglitazone versus rosiglitazone. HbA(1c), lipids, weights, adverse effects, and hepatic status were monitored, providing no other major therapeutic change had been made. Of 163 study candidates, 144 and 125 patients fulfilled the criteria for comparison of HbA(1c) and lipids, respectively. HbA(1c) decreased an absolute mean of 0.08% for each treatment group, after a mean 3.2-month observation. Mean cholesterol, triglyceride, and low-density lipoprotein (LDL) cholesterol levels decreased in the pioglitazone group by 4.7%, 11.3%, and 7.3% but increased 8.4%, 38.4%, and 8.1%, respectively, in the rosiglitazone group. Mean high-density lipoprotein (HDL) increased 2.6% with pioglitazone and decreased 6.3% with rosiglitazone therapy. Patients receiving a statin concomitantly when switched to rosiglitazone treatment had a 51.9% mean triglyceride increase versus a 25.7% increase for those not taking a statin, whereas the patients switched to pioglitazone therapy had respective decreases of 14.2% and 6.2%. Both drugs were generally well tolerated; patients in both groups had similar slight weight increases and no hepatic dysfunction. Patients switched from maintenance troglitazone treatment to either pioglitazone or rosiglitazone therapy had similar glycemic control. Conversion to pioglitazone therapy caused a trend toward improvement in all lipid variables, but switching to rosiglitazone therapy caused significantly increased levels of cholesterol, triglycerides, and LDL and a trend toward decreased HDL. Patients already receiving statins when switched to rosiglitazone therapy had particularly notable triglyceride worsening. Whether these effects will lead to changes in cardiovascular outcome or will be maintained over a longer period remains to be established.",2001.0,0,0 825,11423051,Long-term (> or =8 years) outcome after Palmaz-Schatz stent implantation.,R Choussat; C Klersy; A J Black; I Bossi; J P Laurent; C Jordan; G Guagliumi; J Fajadet; J Marco,"The purpose of this single-center study was to evaluate the long-term (> or =8 years) outcome of Palmaz-Schatz intracoronary stenting and to identify independent predictors of outcome. Although short-term results of Palmaz-Schatz intracoronary stenting have been promising, with a reduction in both angiographic restenosis and clinical cardiac events up to 3 years, longer-term follow-up has not been established. We analyzed clinical outcome in 426 consecutive patients at least 8 years after coronary stenting. Demographic, clinical, and procedural predictors of restenosis, survival, and event-free survival, defined as freedom from death, myocardial infarction (MI), and coronary revascularization (target stented site, target vessel, and any revascularization) were analyzed. Before discharge, 28 patients (6.6%) sustained at least 1 major cardiovascular event: 3 deaths (0.7%), 18 MIs (4.2%), and 17 repeat revascularizations. Surviving patients were followed for 8.9 years (interquartile range 8.4 to 9.4). After discharge, 59 patients (13.9%) died, 47 (11.1%) sustained an MI, and 188 (44.4%) underwent coronary revascularization. The 8-year event-free survival (freedom from death, freedom from death/MI/target-stented site revascularization, and freedom from death/MI/any coronary revascularization) was (mean +/- SE) 0.86 +/- 0.01, 0.62 +/- 0.03, and 0.47 +/- 0.02, respectively. Unstable angina, lower left ventricular ejection fraction, and saphenous vein graft stenting were found to be independent predictors of death during follow-up. Hypertension, unstable angina, multivessel disease, and multiple stent implantation were found to be independent predictors of the composite of death/MI/any coronary revascularization during follow-up. This study provided a useful assessment of very long-term outcome in survival, event-free survival, and predictors of major cardiac events 8 to 10 years after Palmaz-Schatz stent implantation.",2001.0,0,0 826,11423053,Effects of kaliuretic peptide on sodium and water excretion in persons with congestive heart failure.,A Nasser; J R Dietz; M Siddique; H Patel; N Khan; E K Antwi; G I San Miguel; M T McCormick; D D Schocken; D L Vesely,"Kaliuretic peptide, a 20-amino acid peptide hormone synthesized in the heart, enhances urine flow twofold, whereas atrial natriuretic peptide (ANP) enhances urine flow four- to 11-fold in healthy persons. The present investigation was designed to (1) determine whether kaliuretic peptide may have beneficial diuretic effects in persons with congestive heart failure (CHF), and (2) compare its beneficial effects with ANP in the treatment of CHF. Kaliuretic peptide (100 ng/kg body weight/min) given intravenously for 60 minutes to subjects with New York Heart Association class III CHF increased urine flow fourfold (p <0.001), which was maximal 212 hours after its infusion was stopped. Kaliuretic peptide enhanced sodium excretion threefold in subjects with CHF (p <0.01). Kaliuretic peptide increased the urinary excretion rate of potassium ion and fractional excretion of potassium 3.5- and twofold (p <0.05), respectively. ANP (same concentration) did not significantly enhance urine flow. ANP enhanced sodium excretion two- to sixfold in half of the CHF subjects, whereas it had no effect on sodium excretion in the other half. ANP did not significantly increase fractional excretion of sodium but did increase fractional excretion of potassium (p <0.05) during the first 20 minutes of its infusion. ANP-infused patients with CHF became hypotensive. None became hypotensive secondary to kaliuretic peptide. These data indicate that the diuretic properties of kaliuretic peptide in persons with CHF, as opposed to those of ANP, are not diminished (but rather are increased) compared with their effects in healthy persons. In patients with CHF, kaliuretic peptide causes a natriuresis-a feature not observed in those without sodium retention.",2001.0,0,0 827,11423054,Elevated plasma tissue plasminogen activator and anti-THP-1 antibodies are independently associated with decreased graft survival in cardiac transplant recipients.,M K Warshofsky; M Dominguez; M S Eisenberg; H S Wasserman; R Sciacca; W Wang; A D Simon; J H Morse; A Schwartz; E Anglés-Cano; L E Rabbani,"Hemostatic and immunologic factors have been implicated in future cardiac events in patients with coronary artery disease. The role of these factors and their interaction is less established in cardiac transplant recipients. We sought to characterize the role of these factors in these patients. Cardiac transplant patients who presented for surveillance coronary angiography and/or endomyocardial biopsy were eligible for enrollment. Ninety-nine consecutive patients were enrolled. Plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1, von Willebrand factor, fibrin D-dimer, and anti-t-PA antibody were determined by enzyme-linked immunosorbent assays. Anti-THP-1 cell antibodies directed against a monocytic leukemia cell line were detected by incubating patient plasma with THP-1 cells. Bound antibody was detected using goat peroxidase-labeled immunoglobulin G directed against human immunoglobulins. Lipids were measured by enzymatic methods. Multivariate analysis identified the presence of anti-THP-1 cell antibodies (risk ratio 4.41, p = 0.002), t-PA antigen (risk ratio 1.10, p = 0.033), donor age 20 to 26 years (risk ratio 8.83, p = 0.042), and donor age >36 years (risk ratio 15.53, p = 0.009) as predictors of allograft failure. Altered hemostatic function, as demonstrated by elevated plasma t-PA antigen levels, is predictive of subsequent allograft failure in cardiac transplant recipients. In addition, the presence of anti-THP-1 cell antibodies in these patients is predictive of allograft failure.",2001.0,0,0 828,11424897,Statins: new drugs for treating osteoporosis?,J F Whitfield,"Statins are widely used lipid-lowering drugs that reduce cholesterol synthesis by inhibiting 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase activity. They also strongly stimulate bone formation in rodents. If the drugs' potent bone-building activity results directly from inhibition of HMG-CoA reductase, there should be less bone fracturing in humans who have taken statins to lower their serum cholesterol and prevent heart attacks, but the data gleaned from several databases are contradictory. According to some reports the lipid-lowering doses of oral statins increased bone mineral density and more than halved the risk of fracturing various bones, while according to others, including the very large Women's Health Initiative Observational Study (WHI-OS), the drugs did not significantly affect the fracturing risk. Such contradictory data could be due in part to one of the commonly used statins, pravastatin which only targets hepatocytes, or due to bone growth being stimulated by something other than inhibition of HMG-CoA reductase. Therefore, different doses of statins may be needed to build bone or optimally lower serum cholesterol. To be able to answer the question posed by the title of this editorial, it will be necessary to carry out a controlled trial using designer statins that are less liver-oriented and thus better for assessing the optimal doses needed, specifically for osteogenicity rather than for their cholesterol-lowering ability.",2001.0,0,0 829,11425277,"Current prospects for controlling cancer growth with non-cytotoxic agents--nutrients, phytochemicals, herbal extracts, and available drugs.",M F McCarty,"In animal or cell culture studies, the growth and spread of cancer can be slowed by many nutrients, food factors, herbal extracts, and well-tolerated, available drugs that are still rarely used in the clinical management of cancer, in part because they seem unlikely to constitute definitive therapies in themselves. However, it is reasonable to expect that mechanistically complementary combinations of these measures could have a worthwhile impact on survival times and, when used as adjuvants, could improve the cure rates achievable with standard therapies. The therapeutic options available in this regard include measures that: down-regulate serum free IGF-I; suppress the synthesis of mevalonic acid and/or certain derivatives thereof; modulate arachidonate metabolism by inhibiting 5-lipoxygenase, 12-lipoxygenase, or COX-2; antagonize the activation of AP-1 transcription factors; promote the activation of PPAR-gamma transcription factors; and that suppress angiogenesis by additional mechanisms. Many of these measures appear suitable for use in cancer prevention.",2001.0,0,0 830,11428472,Lipid-lowering effect of simvastatin in patients of type 2 diabetes mellitus.,H Udawat; R K Goyal,"Dyslipidemia is an important factor in causation of macrovascular disease in type 2 diabetics. The role of simvastatin in the management of dyslipidemia in patients with type 2 diabetes mellitus is not very well elucidated, particularly in the context of the recent American Diabetes Association criteria 2001. The American Diabetes Association suggests that aggressive therapy of diabetic dyslipidemia will reduce the risk of coronary heart disease in diabetics and that optimal levels are serum low-density lipoprotein cholesterol <2.60 mmol/L (< 100 mg/dl), high-density lipoprotein cholesterol >1.1 5 mmol/L (>45 mg/dl) and triglycerides <2.30 mmol/L, (<200 mg/dl). This study was planned to compare the effect of simvastatin together with behavioral modification and behavioral modification alone, in age, sex and body mass index matched patients with type 2 diabetes mellitus with dyslipidemia, in reaching the target levels of various lipids as suggested by the American Diabetes Association criteria 2001. An open-label, prospective study was conducted on 80 patients with type 2 diabetes mellitus, who had fair to moderate glycemic control with a total glycated hemoglobin < 10%. The patients in the control group (n=40) were treated with only behavioral modifications like calorie control and daily walking for 30 minutes, and no lipid-lowering agent was given. The lipid profile was re-evaluated after 6 and 12 weeks. The patients in the test group (n=40) were advised behavioral modification and given simvastatin. The starting dose was 10 mg at bed time. After 6 weeks of simvastatin therapy, a lipid profile was done. If the goal of low-density lipoprotein cholesterol < 100 mg/dl and/or triglycerides <200 mg/dl and/or high-density lipoprotein cholesterol >45 mg/dl was not achieved, the dose of simvastatin was increased to 20 mg at bedtime for another 6 weeks. It was observed that low-density lipoprotein dyslipidemia was most prevalent. In the control group, a favorable alteration in lipid levels was brought about but none was statistically significant and the American Diabetes Association goals were not achieved in any of the patients. In the test group, there was a significant and favorable alteration in all lipid moieties, and the target levels were achieved in 80% of patients after 12 weeks. There was no significant alteration in glycemic control and liver functions. Myopathy and epigastric pain were seen in 1 patient in each group. In our study, behavioral modification alone did not achieve the target levels of various lipids in diabetic dyslipidemia as per the American Diabetes Association guidelines. Hence, pharmacological therapy with statins should be resorted to in patients with type 2 diabetes mellitus who carry a high risk of coronary heart disease. Simvastatin is a safe and efficacious lipid-lowering drug.",2001.0,0,0 831,11428488,Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACL study.,,,2001.0,0,1 832,11428539,Non-lipid effects of statin on hypercholesterolemic patients established to have coronary artery disease who remained hypercholesterolemic while eating a step-II diet.,K K Koh; J W Son; J Y Ahn; Y M Choi; D K Jin; G S Park; I S Choi; M S Sohn; E K Shin,"Results of clinical trials of statin therapy demonstrate that an improvement in incidence of cardiovascular end points and coronary stenosis can be achieved. The beneficial effects of statins on clinical events may involve nonlipid mechanisms that affect endothelial function, such as inflammatory responses, formation of thrombi, and stabilization of plaque. To investigate levels of serologic markers, which may be useful surrogates for activity of vascular disease after administration of statin. We administered 20-40 mg simvastatin daily for 14 weeks to 13 patients established to have coronary artery disease who remained hypercholesterolemic during step-II diet therapy. Administration of simvastatin significantly lowered lipoprotein levels and the low: high-density lipoprotein cholesterol level ratio and apolipoprotein B:A-I level ratio compared with pretreatment values (P < 0.01). Administration of simvastatin significantly lowered plasma levels of matrix metalloproteinase-9 (MMP-9) and monocyte chemoattractant protein-I [33+/-46 and 13+/-19%, respectively (P = 0.027 and 0.020, respectively)]. Furthermore, administration of simvastatin tended to lower plasma levels of plasminogen activator inhibitor type-1 and tumor necrosis factor-alpha [by 20+/-44 and 13+/-29%, respectively (P= 0.066 and 0.110, respectively)]. There were significant inverse correlations between pretreatment levels of MMP-9 and the degree of change in those levels after administration of simvastatin (r = -0.714, P= 0.005). However, there was no significant correlation between levels of lipoprotein and levels of MMP-9, monocyte chemoattractant protein-I, and plasminogen activator inhibitor type-1 during administration of simvastatin. Our current data support the hypothesis that nonlipid mechanisms elicited by administration of simvastatin contribute to the decrease in incidence of cardiovascular events and explain the early clinical benefit observed in clinical trials, independent of changes in levels of lipoprotein.",2002.0,0,0 833,11428822,Is a mechanical or a metabolic approach superior in the treatment of coronary disease? Results of the atorvastatin versus revascularization (AVERT) trial.,D P Mikhaildis; A S Wierzbicki; T M Reynolds,,2001.0,0,0 834,11428834,Cost-effectiveness of implantable cardioverter-defibrillators.,G Boriani; M Biffi; C Martignani; M Gallina; A Branzi,,2001.0,0,0 835,11428852,Risk factors for a major coronary event after myocardial infarction in the Scandinavian Simvastatin Survival Study (4S). Impact of predicted risk on the benefit of cholesterol-lowering treatment.,L Wilhelmsen; K Pyörälä; H Wedel; T Cook; T Pedersen; J Kjekshus,"To analyse (1) the prognostic importance of clinical findings and lipids in patients with a previous myocardial infarction and (2) the relative and absolute benefit of simvastatin in patients at low, medium and high predicted risk. The 4S was a double-blind, randomized, clinical trial of long-term treatment with simvastatin or matching placebo in patients with myocardial infarction or angina pectoris, serum total cholesterol 5.5-8.0 mmol x l(-1), and serum triglycerides /=1.1 mm representing plaque, plaque number (PN) and plaque score (PS; the sum of all plaque thicknesses) were calculated. The development of atherosclerosis was estimated by the formula Deltavalue/year=(last value-baseline value)/number of follow-up years. Multivariate linear regression analysis revealed that the log-transformed value for hs-CRP concentration was not related to baseline PN or PS but was related to DeltaPN/year and DeltaPS/year (beta=0.29 and 0.30; P<0.001 for both) independently of the effect of traditional risk factors. During the early stages of carotid atherosclerosis, the hs-CRP concentration is a marker of carotid atherosclerotic activity rather than extent of atherosclerosis.",2001.0,0,0 841,11437691,Risk factors for and management of post-transplantation cardiovascular disease.,B Fellström,"The mortality rates due to cardiovascular disease (CVD) in transplant recipients are greater than in the general population. CVD is a major cause of both graft loss and patient death in renal transplant recipients, and improving cardiovascular health in transplant recipients will presumably help to extend both patient and graft survival. Further studies are needed to better evaluate the effectiveness of risk modification on subsequent CVD morbidity and mortality. There is no reason to consider risk factors for CVD such as hyperlipidaemia, hypertension and diabetes mellitus in transplant recipients differently from in the general population. In addition, there are specific transplantation risk factors such as acute rejection episodes and the use of immunosuppressive drugs. It is obvious that several of the immunosuppressive agents used today have disadvantageous influences on risk factors for CVD such as hyperlipidaemia, hypertension and post-transplantation diabetes mellitus (PTDM), but the relative importance of immunosuppressant-induced increases in these risk factors is basically unknown. This may be a strong argument for the selective use and individual tailoring of immunosuppressive agents based upon the risk factor profile of the patient, without jeopardising the function of the graft. Hyperlipidaemia is common after transplantation, and immunosuppression with corticosteroids, cyclosporin, or sirolimus (rapamycin) causes different types of post-transplantation hyperlipidaemia. However, to date, no studies have demonstrated that lipid lowering strategies significantly reduce CVD morbidity or mortality and improve allograft survival in transplant recipients. Several studies using preventive or interventional approaches are ongoing and will be reported in the near future. Post-transplantation hypertension appears to be a major risk factor determining graft and patient survival, and immunosuppressive agents have different effects on hypertension. Controlled studies support the opinion that post-transplantation hypertension must be treated as strictly as in a population with essential hypertension, diabetes mellitus, or chronic renal failure. As increasing numbers of immunosuppressive agents become available for use, we may be in a better position to tailor immunosuppressive therapy to the individual patient, avoiding the use of diabetogenic drugs, drug combinations, or inappropriate doses in patients susceptible to PTDM. Multiple acute rejection episodes have also been demonstrated to be a risk factor for CVD - a strong argument for the use of immunosuppressive drugs to reduce acute rejection. Until we have a better understanding from ongoing landmark studies on the management of CVD, presently available therapy to reduce risk factors needs to be used together with individual tailoring of immunosuppressive therapy with the aim of reducing CVD in these patients.",2001.0,0,0 842,11438554,Gene therapy for antiangiogenesis.,H K Kleinman; G Liau,,2001.0,0,0 843,11440285,Effects of low doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol levels in patients with hypercholesterolemia.,A Branchi; A M Fiorenza; A Torri; F Muzio; C Berra; E Colombo; E Dalla Valle; A Rovellini; D Sommariva,"Simvastatin 40 to 80 mg/d has been found to increase high-density lipoprotein cholesterol (HDL-C) levels significantly more than atorvastatin at equipotent doses (ie, 20-80 mg/d). Data on the effects of lower doses of the 2 drugs on HDL-C levels are conflicting. The purpose of this study was to investigate the effects of simvastatin 20 mg/d and atorvastatin 10 mg/d on HDL-C levels in patients with hypercholesterolemia. Patients with primary hypercholesterolemia (total cholesterol [TC] >250 mg/dL) who were not taking any lipid-lowering agents and who were following a low-fat diet were randomized to receive 1 of 2 treatments: simvastatin 20 mg/d or atorvastatin 10 mg/d. Serum TC, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and HDL-C levels were measured using standard methods after 2 months of therapy. In a secondary analysis, lipids and lipoprotein cholesterol were measured after 1 year in patients who continued treatment. Of the 240 patients enrolled (108 men and 132 women; age range, 23-77 years, mean [SEM] 56.7 [0.69]), 235 completed the study. After 2 months of therapy, TC, LDL-C, and serum TG levels decreased significantly versus baseline in both groups (P < 0.001), with no significant differences between treatment groups. HDL-C levels increased by 9.0% (P < 0.001 vs baseline) in the simvastatin group and by 4.3% (P < 0.02) in the atorvastatin group. The difference between the 2 groups in the percentage increase in HDL-C was statistically significant (P < 0.05). In 113 patients who continued treatment, HDL-C levels at 1 year were still significantly higher than baseline levels in the simvastatin group (6.3%, P = 0.034), but not in the atorvastatin group (2.8%, P = 0.587). The findings from this study suggest that the HDL-C-increasing effect of simvastatin 20 mg is significantly greater than that of atorvastatin 10 mg. Since increasing HDL-C levels is thought to lower the risk for atherosclerosis and coronary heart disease, these results warrant further investigation.",2002.0,0,0 844,11440286,STATT: a titrate-to-goal study of simvastatin in Asian patients with coronary heart disease. Simvastatin Treats Asians to Target.,N Chung; S Y Cho; D H Choi; J R Zhu; K Lee; P Y Lee; S H Lee; S Lee; J J Wang; W H Yin; M S Young; K K Koh; J W Son; S Sangwatanaroj; P Panchavinnin; R Phankingthongkum; N S Cai; W F Fan,"Most published studies on the use of lipid-lowering agents to treat hypercholesterolemia have focused on Western populations, with few data on Asian populations. The Simvastatin Treats Asians to Target (STATT) study used a titrate-to-goal protocol to evaluate the efficacy and tolerability of simvastatin 20 to 80 mg/d in the treatment of Asian patients with coronary heart disease. This was a multicenter, open-label, uncontrolled, 14-week study in patients with coronary heart disease and serum low-density lipoprotein cholesterol (LDL-C) levels of 115-180 mg/dL and triglyceride levels of < or = 400 mg/dL. The dose of simvastatin was titrated from 20 to 80 mg/d to achieve the National Cholesterol Education Program (NCEP) LDL-C target of < or = 100 mg/dL. The primary efficacy measure was the percentage of patients achieving the NCEP target. Among secondary measures were the percentage of patients achieving European Society of Cardiology/European Atherosclerosis Society/European Society of Hypertension target LDL-C levels of < or = 115 mg/dL and the percentage change from baseline in lipid parameters. Tolerability was assessed in terms of the overall incidence of adverse experiences and the incidences of the most commonly reported adverse experiences. The intent-to-treat analysis included 133 Asian patients (93 men, 40 women; mean age, 59.5 years), of whom 125 completed 14 weeks of therapy. Their mean blood pressure was 130.2/79.4 mm Hg. Overall, 104 (78.2%) patients treated with simvastatin achieved LDL-C levels < or = 100 mg/dL at week 14, and 125 (94.0%) achieved this target at some point during the study. Similarly, 122 (91.7%) patients achieved an LDL-C level < or = 115 mg/dL at week 14, and 130 (97.7%) achieved this target at some point during the study. Treatment with simvastatin had favorable effects on the lipid profile, producing significant percentage changes from baseline in all parameters (P < 0.001). Simvastatin was well tolerated across the dose range. Overall, 40 patients (30.1%) had > or = 1 clinical adverse experience. Only 14 (10.5%) had adverse experiences that were possibly, probably, or definitely related to study drug; none of these experiences were considered serious. The most common adverse experiences (> or = 3% incidence) were abdominal pain (6%); chest pain (5%); dizziness (4%); and asthenia/fatigue, fibromyalgia, headache, insomnia, and upper respiratory tract infection (3% each). No new or unexpected adverse experiences were seen at the higher doses. Simvastatin was effective and well tolerated at doses of 20, 40, and 80 mg/d in Asian patients with coronary heart disease. Titration enabled the majority to achieve target LDL-C levels of < or = 100 mg/dL.",2002.0,0,1 845,11440296,The effects of postal and telephone reminders on compliance with pravastatin therapy in a national registry: results of the first myocardial infarction risk reduction program.,R M Guthrie,"Noncompliance with cardiovascular therapy and prevention initiatives is well documented. The purpose of the First Myocardial Infarction (MI) Risk Reduction Program, an open-label drug registry involving mainly primary-care patients at increased risk of a first MI, was to examine the effects of postal and telephone reminders, as well as demographic and other baseline characteristics, on patient self-reported compliance with pravastatin treatment. A second objective was to determine whether regimen adherence was associated with the adoption of other lifestyle modifications recommended to decrease the risk of coronary artery disease. Patients with risk scores of > or = 4 on a scale of -1 to +16 for men and -1 to +17 for women on the First Heart Attack Risk Test were considered to be at increased risk of a first MI and eligible for enrollment in the registry program. An elevated total cholesterol level despite dietary interventions was an additional inclusion criterion. Patients were prospectively randomized (4:1) to either an intervention involving postal and telephone reminders (about coronary risk reduction and medication compliance), which were sent during the first 2 months of pravastatin treatment, or usual care. Both groups received reminder postcards at 4 and 5 months, in addition to counseling by physicians about coronary risk reduction. At 3 and 6 months (or study discontinuation), patients completed and mailed to the program-coordinating center questionnaires concerning compliance with care, including current use of prescribed pravastatin, as well as self-reported adoption of other lifestyle modifications, such as changing eating habits, losing weight, increasing physical activity, and/or quitting smoking. Compliance with pravastatin therapy and with these coronary risk-reducing behaviors was also assessed by physicians at the 3-month follow-up visit. A total of 10,335 patients were in the intervention group, and 2765 received usual care. The 2 groups were well balanced at baseline with respect to age, race, and total cholesterol values. Neither early reminders nor baseline patient characteristics were significantly associated with reported pravastatin compliance rates, which were approximately 79% overall. However, according to self-reports at 6 months, regimen compliance was associated with the adoption of other coronary risk-reducing behaviors. The results of this study suggest that early telephone and postal reminders do not improve compliance with drug treatment or with recommended coronary risk-reducing behaviors.",2002.0,0,0 846,11440491,Multivessel coronary artery disease: current revascularization strategies.,C V Patil; E Nikolsky; M Boulos; E Grenadier; R Beyar,,2001.0,0,0 847,11440749,Use of statins in CNS disorders.,B Cucchiara; S E Kasner,"It is well established that 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors (""statins"") reduce cholesterol levels and prevent coronary heart disease (CHD). Although a causal relation between elevated cholesterol levels and stroke has not been well defined, a number of large secondary prevention studies and meta-analyses have shown that statin therapy reduces stroke in patients with CHD and hypercholesterolemia. In addition to the vascular effects of statins (stabilization of atherosclerotic plaques, decreased carotid intimal-medial thickness), there are increasing data to suggest that these agents have additional properties that are potentially neuroprotective. These include endothelial protection via actions on the nitric oxide synthase system, as well as antioxidant, anti-inflammatory and anti-platelet effects. These actions of statins might have potential uses in other neurological disorders such as Alzheimer's disease and certain types of brain tumors.",2001.0,0,0 848,11444086,The effect of fluvastatin on parameters of bone remodeling.,N H Bjarnason; B J Riis; C Christiansen,"Statins decrease the hepatic biosynthesis of cholesterol, and reduce the incidence of myocardial infarction in women who have already experienced a myocardial infarction. Statins also reduce the risk of atherosclerosis in diabetic patients, but it is unknown whether they influence the glucose tolerance. It has further been suggested that they may influence bone metabolism. Vitamin C is an antioxidant and it decreases serum cholesterol moderately. Antioxidants may also have other metabolic effects, but these are insufficiently studied. The aim of the present study was to investigate the metabolic effects of the cholesterol-lowering agent fluvastatin and the antioxidant vitamin C. Sixty-eight elderly, postmenopausal women with osteoporosis and mild hypercholesterolemia were randomly assigned to 12 weeks open treatment with either fluvastatin (40 mg daily) + 500 mg vitamin C (n = 45) or vitamin C only (n = 23). We measured biochemical markers of bone formation (serum osteocalcin and total alkaline phosphatase) and bone resorption (serum and urinary CTX), parameters related to diabetes and serum lipids and lipoproteins. Fluvastatin in combination with vitamin C had no effect on bone formation markers. We found a weak decrease in parameters of bone resorption, which was significant from baseline, but not different between the two groups. There were no significant effects on any of the other markers of either fluvastatin or vitamin C. The lipid-lowering effect of fluvastatin was confirmed with a decrease of 20% and 30% in serum total cholesterol and LDL-cholesterol, respectively. We conclude that fluvastatin given in clinically relevant doses has no influence on parameters of bone remodeling. Other statins remain to be investigated.",2001.0,0,0 849,11444576,"Role of coenzyme Q10 in chronic heart failure, angina, and hypertension.",M T Tran; T M Mitchell; D T Kennedy; J T Giles,"Coenzyme Q10 (CoQ10) has a pathophysiologic role in many disease states. The purpose of this review is to provide recommendations regarding the safety, efficacy, and dosing of CoQ10 in the management of chronic heart failure (CHF), angina, and hypertension. Literature pertaining to the safety and efficacy of CoQ10 specifically in cardiovascular indications was reviewed. We used relevant clinical trials, articles, reviews, and letters that were selected from a literature search of the MEDLINE database (1974-2000), Micromedex Healthcare Series, and the Natural Medicines Comprehensive Database. Coenzyme Q10 administered orally has favorable actions in the described cardiovascular conditions and appears to be safe and well tolerated in the adult population. Issues concerning optimum target dosages, potential interactions, monitoring parameters, and the role of CoQ10 as a monotherapeutic agent need to be investigated further. Favorable effects of CoQ10 on ejection fraction, exercise tolerance, cardiac output, and stroke volume are demonstrated in the literature; thus, the use of CoQ10 as adjuvant therapy in patients with CHF may be supported. Coenzyme Q10 therapy in angina and hypertension cannot be substantiated until additional clinical trials demonstrate consistent beneficial effects. However, CoQ10 may be recommended as adjuvant therapy in selected patients with CHE At this time, CoQ10 should not be recommended as monotherapy or first-line therapy in any disease state.",2002.0,0,0 850,11448316,Statins and dementia.,B A Golomb; B Jaworski,,2001.0,0,0 851,11448418,Effect of pravastatin in mildly hypercholesterolemic young men on serum matrix metalloproteinases.,A Kalela; R Laaksonen; T Lehtimäki; T A Koivu; M Höyhtyä; T Janatuinen; P Pöllänen; R Vesalainen; P Saikku; J Knuuti; S T Nikkari,Pravastatin decreases serum MMP-9 concentration in clinically healthy men. This may reflect reduction of nonsymptomatic chronic arterial inflammation.,2001.0,0,0 852,11448728,Metabolic complications associated with antiretroviral therapy.,R G Jain; E S Furfine; L Pedneault; A J White; J M Lenhard,"Mortality rates in the HIV-infected patient population have decreased with the advent of highly active antiretroviral therapy (HAART) for the treatment of AIDS. Due to the chronic nature of HAART, long-term metabolic complications are associated with therapy, such as hyperlipidemia, fat redistribution and diabetes mellitus. Currently, all of these symptoms are classified as the lipodystrophy (LD) syndrome(s). However, hyperlipidemia and fat redistribution occur independently, indicating there may be multiple syndromes associated with HAART. Although fat gain/loss and dyslipidemia occur in protease inhibitor (PI) naïve patients treated with nucleoside reverse transcriptase inhibitors (NRTIs), combination therapies (PI and NRTI) accelerate the syndrome. Recent clinical trials, cell culture and animal studies indicate that these effects are not drug class specific and select PIs, NRTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) can be associated with metabolic complications. Moreover, the effects can vary between various members of the same class of antiretroviral agents (i.e. not all PIs cause the same adverse reactions) and may be influenced by duration of infection, genetics and environmental factors. Although HAART increases the risk of metabolic complications, this does not outweigh the benefits of survival. In this review, we summarize the latest clinical and scientific information on these metabolic complications, examine current hypotheses explaining the syndromes and comment on the existing methods available to manage these metabolic side effects.",2001.0,0,0 853,11448925,Cerivastatin triggers tumor-specific apoptosis with higher efficacy than lovastatin.,W W Wong; M M Tan; Z Xia; J Dimitroulakos; M D Minden; L Z Penn,"The statin family of drugs inhibits 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway, and is used clinically as a safe and effective approach in the control of hypercholesterolemia. We have shown previously (Dimitroulakos, J., Nohynek, D., Backway, K. L., Hedley, D. W., Yeger, H., Freedman, M. H., Minden, M D., and Penn, L. Z. Increased sensitivity of acute myelogenous leukemias to lovastatin-induced apoptosis: a potential therapeutic approach. Blood, 93: 1308-1318, 1999) that lovastatin, a prototypic member of the statin family, can induce apoptosis of human acute myeloid leukemia (AML) cells in a sensitive and specific manner. In the present study, we evaluated the relative potency and mechanism of action of the newer synthetic statins, fluvastatin, atorvastatin, and cerivastatin, to trigger tumor-specific apoptosis. Cerivastatin is at least 10 times more potent than the other statins at inducing apoptosis in AML cell lines. Cerivastatin-induced apoptosis is reversible with the addition of the immediate product of the HMG-CoA reductase reaction, mevalonate, or with a distal product of the pathway, geranylgeranyl pyrophosphate. This suggests protein geranylgeranylation is an essential downstream component of the mevalonate pathway for cerivastatin similar to lovastatin-induced apoptosis. The enhanced potency of cerivastatin expands the number of AML patient samples as well as the types of malignancies, which respond to statin-induced apoptosis with acute sensitivity. Cells derived from acute lymphocytic leukemia are only weakly sensitive to lovastatin cytotoxicity but show robust response to cerivastatin. Importantly, cerivastatin is not cytotoxic to nontransformed human bone marrow progenitors. These results strongly support the further testing of cerivastatin as a novel anticancer therapeutic alone and in combination with other agents in vivo.",2001.0,0,0 854,11450211,Did the major clinical trials of statins affect prescribing behaviour?,M M Mamdani; J V Tu,,2001.0,0,0 855,11451296,Long-term risk stratification for survivors of acute coronary syndromes. Results from the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study. LIPID Study Investigators.,I C Marschner; D Colquhoun; R J Simes; P Glasziou; P Harris; B B Singh; D Friedlander; H White; P Thompson; A Tonkin; Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study,"We developed a prognostic strategy for quantifying the long-term risk of coronary heart disease (CHD) events in survivors of acute coronary syndromes (ACS). Strategies for quantifying long-term risk of CHD events have generally been confined to primary prevention settings. The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, which demonstrated that pravastatin reduces CHD events in ACS survivors with a broad range of cholesterol levels, enabled assessment of long-term prognosis in a secondary prevention setting. Based on outcomes in 8,557 patients in the LIPID study, a multivariate risk factor model was developed for prediction of CHD death or nonfatal myocardial infarction. Prognostic indexes were developed based on the model, and low-, medium-, high- and very high-risk groups were defined by categorizing the prognostic indexes. In addition to pravastatin treatment, the independently significant risk factors included: total and high density lipoprotein cholesterol, age, gender, smoking status, qualifying ACS, prior coronary revascularization, diabetes mellitus, hypertension and prior stroke. Pravastatin reduced coronary event rates in each risk level, and the relative risk reduction did not vary significantly between risk levels. The predicted five-year coronary event rates ranged from 5% to 19% for those assigned pravastatin and from 6.4% to 23.6% for those assigned placebo. Long-term prognosis of ACS survivors varied substantially according to conventional risk factor profile. Pravastatin reduced coronary risk within all risk levels; however, absolute risk remained high in treated patients with unfavorable profiles. Our risk stratification strategy enables identification of ACS survivors who remain at very high risk despite statin therapy.",2001.0,0,0 856,11452674,"Diabetes, statins and cardiovascular disease.",G Jackson,,2001.0,0,0 857,11452676,Pravastatin in acute ischaemic syndromes: results of a randomised placebo-controlled trial.,F R Den Hartog; P M Van Kalmthout; T T Van Loenhout; H J Schaafsma; H Rila; F W Verheugt,"Therapy with individual 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been shown conclusively to diminish coronary event rates and mortality in both primary and secondary prevention. To date, scant attention has been paid to whether initiation of such regimens in the hospital phase of acute coronary syndromes might confer cardioprotective benefits. The purpose of this study was to determine the safety and tolerability of early initiation of statin therapy in patients with acute coronary syndromes. In this randomised, double-blind, three-month, pilot study, 100 patients with acute myocardial infarction or unstable angina and low-density lipoprotein cholesterol > 3.5 mmol/l were randomly assigned to pravastatin 40 mg daily or placebo initiated within 48 hours of hospital admission. Pravastatin proved safe and well tolerated in these patients, who were well matched at baseline. No statistically significant differences in death, MI and drug-related adverse events were observed in the pravastatin group compared with control subjects. This pilot study shows that therapy with pravastatin early after an acute coronary event is safe and well tolerated. Larger, long-term studies are needed to confirm these findings.",2001.0,1,1 858,11452711,The effects of converting from simvastatin to atorvastatin on plasminogen activator inhibitor type-1.,M K Ito,"Plasminogen activator inhibitor type-1 (PAI-1) is an important regulatory component of fibrinolysis and is elevated in the presence of endothelial dysfunction. Endothelial dysfunction and PAI-1 in patients with coronary artery disease (CAD) have been demonstrated to improve following simvastatin therapy. The effect of converting from simvastatin to atorvastatin on PAI-1 has not been reported and may be an additional consideration when making a formulary medication switch. Fourteen adult patients with hypercholesterolemia and CAD who were receiving simvastatin for a minimum of 3 months were randomized to continue on simvastatin or be converted to atorvastatin. Doses were adjusted to achieve or sustain a low-density lipoprotein (LDL) cholesterol of < or = 100 mg/dL. A fasting lipid panel and PAI-1 were obtained at baseline and following 10 weeks of treatment. Mean +/- SD LDL cholesterol at baseline (95.6 +/- 13.8 vs. 87.0 +/- 12.3 dL, p = 0.24) and following 10 weeks of simvastatin or atorvastatin (96.6 +/- 8.9 vs. 87.4 +/- 20.3 mg/dL, p = 0.29) were similar. No differences in PAI-1 were observed at baseline (47.7 +/- 19.3 vs. 64.6 +/- 22.2 ng/mL, p = 0.15) or at 10 weeks (51.1 +/- 32.5 vs. 63.9 +/- 26.9 ng/mL, p = 0.44). These data suggest that the conversion from simvastatin to atorvastatin does not adversely affect PAI-1 plasma concentrations in patients with CAD.",2002.0,0,0 859,11453971,LDL-receptor gene mutations and the hypocholesterolemic response to statin therapy.,J U Brorholt-Petersen; H K Jensen; B Raungaard; N Gregersen; O Faergeman,"Studies of the cholesterol lowering effect of statin therapy as a function of low-density lipoprotein (LDL)-receptor mutation type have not produced a clear picture, possibly because they included patients with several different kinds of LDL-receptor mutations. We studied the response to treatment with fluvastatin in 28 patients with heterozygous familial hypercholesterolemia as a result of a receptor-negative mutation (Trp23-stop) and in 30 patients with a receptor-binding defective mutation (Trp66-Gly) to test the hypothesis that response to treatment depends on the type of mutation. Patients were randomized to 12 weeks of treatment with fluvastatin 40 mg daily and 12 weeks of placebo treatment, preceded by a placebo run-in period of 8 weeks in a double-blind, cross-over design. Untreated plasma concentrations of lipids and lipoproteins were similar in the two groups of patients. Plasma cholesterol and LDL cholesterol response to therapy tended to be less marked in receptor-binding defective patients, but the differences were not statistically significant. A tabulation of the results of the present and earlier studies suggests that differences in treatment response as an apparent function of LDL-receptor gene mutational type occur mainly in populations with recent genetic admixture (<400 years). In such populations, persons with the same mutation in the LDL-receptor gene are more likely to share other but undetermined genetic variations affecting the pharmacology of statins.",2001.0,0,0 860,11454008,Triglycerides and endothelial function in type 2 diabetes.,G A Rongen; C J Tack,,2001.0,0,0 861,11455241,"Database Conference January 27-30, 2000, Washington D.C.--Do existing databases answer clinical questions about geriatric cardiovascular disease and stroke?",M D Cheitlin; G Gerstenblith; W R Hazzard; R Pasternak; L P Fried; M W Rich; H M Krumholz; E Peterson; J G Reves; C McKay; S Saksena; W K Shen; M Akhtar; L M Brass; J Biller,"EXECUTIVE SUMMARY: Most randomized, controlled trials evaluating the effectiveness of pharmaceutical, surgical, and device interventions for the prevention and treatment of cardiovascular disease have excluded patients over 75 years of age. Consequently, the use of these therapies in the older population is based on extrapolation of safety and effectiveness data obtained from younger patients. However, there are many registries and observational databases that contain large amounts of data on patients 75 years of age and older, as well as on younger patients. Although conclusions from such data are limited, it is possible to define the characteristics of patients who did well and those who did poorly. The goal of this conference was to convene the principal investigators of these databases, and others in the field of geriatric cardiology, to address questions relating to the safety and effectiveness of treatment interventions for several cardiovascular conditions in the elderly. Seven committees discussed the following topics: (I) Risk Factor Modification in the Elderly; (II) Chronic Heart Failure; (III) Chronic Coronary Artery Disease: Role of Revascularization; (IV) Acute Myocardial Infarction; (V) Valve Surgery in the Elderly; (VI) Electrophysiology, Pacemaker, and Automatic Internal Cardioverter Defibrillators Databases; (VII) Carotid Endarterectomy in the Elderly. The chairs of these committees were asked to invite principal investigators of key databases in each of these areas to discuss and prepare a written statement concerning the available safety and efficacy data regarding interventions for these conditions and to identify and prioritize areas for future study. The ultimate goal is to stimulate further collaborative outcomes research in the elderly so as to place the treatment of cardiovascular disease on a more scientific basis.",2001.0,0,0 862,11455843,Pharmaco-economic impact of HMG-CoA reductase inhibitors in type 2 diabetes.,N Chaiyakunapruk; D Boudreau; S D Ramsey,"Dyslipidemia is very common in diabetics and substantially increases the risk of fatal and non-fatal cardiovascular disease. Pharmacological therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ('statins') is effective for dyslipidemia, but the cost and efficacy of individual therapies vary. Therefore, the interest in cost-effective pharmacologic interventions for the prevention of cardiovascular disease events in diabetics has increased. In this article, the literature pertaining to the epidemiology, cost and efficacy of statins in preventing cardiovascular disease in patients with type 2 diabetes mellitus, in both the primary and secondary prevention settings, is reviewed. Cost-effectiveness studies of statins in the diabetic population are detailed, along with recommendations for further research.",2002.0,0,0 863,11457739,"Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging.",R Corti; Z A Fayad; V Fuster; S G Worthley; G Helft; J Chesebro; M Mercuri; J J Badimon,"This study was designed to investigate the effects of lipid-lowering by simvastatin on human atherosclerotic lesions. Eighteen asymptomatic hypercholesterolemic patients with documented aortic and/or carotid atherosclerotic plaques were selected for the study. A total of 35 aortic and 25 carotid artery plaques were detected. Serial black-blood MRI of the aorta and carotid artery of the patients was performed at baseline and 6 and 12 months after lipid-lowering therapy with simvastatin. The effects of the treatment on atherosclerotic lesions were measured as changes in lumen area, vessel wall thickness, and vessel wall area, a surrogate of atherosclerotic burden. Simvastatin induced a significant (P<0.01) reduction in total and LDL cholesterol levels at 6 weeks that was maintained thereafter. At 6 months, no changes in lumen area, vessel wall thickness, or vessel wall area were observed. However, at 12 months, significant reductions in vessel wall thickness and vessel wall area, without changes in lumen area, were observed in both aortic and carotid arteries (P<0.001). This in vivo human study demonstrates that effective and maintained lipid-lowering therapy by simvastatin is associated with a significant regression of atherosclerotic lesions. Our observation suggests that statins induce vascular remodeling, as manifested by reduced atherosclerotic burden without changes in the lumen.",2001.0,0,1 864,11457751,Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy.,R Patel; S F Nagueh; N Tsybouleva; M Abdellatif; S Lutucuta; H A Kopelen; M A Quinones; W A Zoghbi; M L Entman; R Roberts; A J Marian,"Hypertrophic cardiomyopathy is a genetic disease characterized by cardiac hypertrophy, myocyte disarray, interstitial fibrosis, and left ventricular (LV) dysfunction. We have proposed that hypertrophy and fibrosis, the major determinants of mortality and morbidity, are potentially reversible. We tested this hypothesis in beta-myosin heavy chain-Q(403) transgenic rabbits. We randomized 24 beta-myosin heavy chain-Q(403) rabbits to treatment with either a placebo or simvastatin (5 mg. kg(-1). d(-1)) for 12 weeks and included 12 nontransgenic controls. We performed 2D and Doppler echocardiography and tissue Doppler imaging before and after treatment. Demographic data were similar among the groups. Baseline mean LV mass and interventricular septal thickness in nontransgenic, placebo, and simvastatin groups were 3.9+/-0.7, 6.2+/-2.0, and 7.5+/-2.1 g (P<0.001) and 2.2+/-0.2, 3.1+/-0.5, and 3.3+/-0.5 mm (P=0.002), respectively. Simvastatin reduced LV mass by 37%, interventricular septal thickness by 21%, and posterior wall thickness by 13%. Doppler indices of LV filling pressure were improved. Collagen volume fraction was reduced by 44% (P<0.001). Disarray was unchanged. Levels of activated extracellular signal-regulated kinase (ERK) 1/2 were increased in the placebo group and were less than normal in the simvastatin group. Levels of activated and total p38, Jun N-terminal kinase, p70S6 kinase, Ras, Rac, and RhoA and the membrane association of Ras, RhoA, and Rac1 were unchanged. Simvastatin induced the regression of hypertrophy and fibrosis, improved cardiac function, and reduced ERK1/2 activity in the beta-myosin heavy chain-Q(403) rabbits. These findings highlight the need for clinical trials to determine the effects of simvastatin on cardiac hypertrophy, fibrosis, and dysfunction in humans with hypertrophic cardiomyopathy and heart failure.",2001.0,0,0 865,11465962,The HOPE study: comparison with other trials of secondary prevention.,J E Otterstad; P Sleight,,2001.0,0,0 866,11466161,Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide.,L T Friedhoff; E I Cullen; N S Geoghagen; J D Buxbaum,"The deposition of beta-amyloid (A beta) in neuronal plaques is believed to be crucial for the initiation and progression of Alzheimer's disease (AD). Studies in vitro have shown that inhibiting cholesterol metabolism with lovastatin, or its active metabolite lovastatin acid, lowers A beta production. To examine the effects of lovastatin on A beta in vivo, human subjects who had elevated low-density lipoprotein cholesterol were treated during a double-blind, randomized, placebo-controlled study with 10, 20, 40 or 60 mg once-daily doses of a controlled-release formulation of lovastatin, or matching placebo. Serum A beta concentrations were measured before and after up to 3 months of treatment. Mean and median changes from baseline in serum A beta concentrations showed a dose-dependent decrease, and analysis of variance indicated that treatment was statistically significant (p < 0.0348). Differences between the 40- and 60-mg dose groups and placebo were statistically significant (Dunnett's p < or = 0.05).",2001.0,0,0 867,11467215,Time to look beyond just lowering the serum concentration of low density lipoprotein--high density lipoprotein levels are also important.,D R Nair; A S Wierzbicki; D P Mikhailidis,"There is convincing epidemiological evidence indicating that the serum levels of high density lipoprotein (HDL) cholesterol are inversely related to the risk of vascular events. Similarly, intervention trials, involving healthy populations and patients with coronary heart disease (CHD), have shown that raising the serum levels of HDL is associated with a significant decrease in the risk of vascular events. It follows that serum HDL levels must be considered when assessing risk and setting therapeutic goals. Some of the currently available national treatment guidelines reflect this view. The present review considers the place of serum HDL measurement in the prevention of vascular events.",2001.0,0,0 868,11467307,"Safety of drugs commonly used to treat hypertension, dyslipidemia, and type 2 diabetes (the metabolic syndrome): part 1.",A O Marcus,"The benefits of blood pressure lowering, lipid lowering, and glycemic control on morbidity and mortality have been established in major long-term clinical trials. The most extensive information is available for diuretics or beta-blockers in hypertension, hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in dyslipidemia, and insulin or sulfonylureas in diabetes. Other drug classes provide similar improvements in blood pressure, lipid profile, and glycemic control, and thereby might be expected to provide comparable long-term benefits. As a result, national guidelines advocate treating patients aggressively in order to achieve control of blood pressure low-density lipoprotein (LDL) cholesterol, and blood glucose. The risks associated with drug treatment are generally class-specific. Among antidiabetic agents, sulfonylureas and insulin are associated with risk for severe hypoglycemia, metformin with risk for lactic acidosis, and troglitazone with risk for idiosyncratic hepatocellular injury. Similarly, widely used antihypertensive and lipid-lowering agents are associated with risk for serious complications, such as angioedema with angiotensin-converting enzyme inhibitors, possible increased risk for myocardial infarction and cancer with calcium antagonists, and myositis and liver dysfunction with statins. Physicians must take an aggressive approach to patient management in order to achieve a level of disease control that optimally reduces risk for morbidity and mortality. Serious adverse events may occur rarely with most drug classes; these events can be minimized by appropriately monitoring or selecting patients for treatment.",2001.0,0,0 869,11468195,"Cerivastatin, a hydroxymethylglutaryl coenzyme a reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days.",T Tsunekawa; T Hayashi; H Kano; D Sumi; H Matsui-Hirai; N K Thakur; K Egashira; A Iguchi,"The short-term effects of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) on endothelial function at doses that do not affect plasma lipid levels are not known. We investigated the short-term effects of cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, on endothelial function and endothelium-related products in elderly diabetic patients. Twenty-seven elderly diabetic patients (aged 69.3+/-3.4 years), with or without mild hypercholesterolemia, were enrolled in this study, which tested cerivastatin treatment (0.15 mg/d) for 3 days. Endothelium-dependent flow-mediated dilatation, endothelium-independent dilatation by nitroglycerin in the brachial artery, nitric oxide-related products (nitrite/nitrate and cGMP), endothelium-related products (von Willebrand Factor, soluble vascular cell adhesion molecule-1, and soluble intercellular adhesion molecule-1), and a marker of oxidant stress (8-isoprostane) were assessed. Levels of plasma lipids were not changed before and after treatment with cerivastatin. Flow-mediated dilatation was significantly increased by cerivastatin treatment, as were plasma nitrite/nitrate levels (from 16.9+/-3.4 to 22.0+/-3.7 micromol/L, P<0.05) and cGMP values. The percent of nitroglycerin-induced dilatation was not changed. Plasma concentrations of 8-isoprostane decreased, and levels of soluble vascular cell adhesion molecule also tended to decrease with cerivastatin. Improvement of endothelial function was in line with antiatherosclerotic effects. Cerivastatin improved impaired endothelial function in the short-term without affecting lipid profiles in elderly diabetic patients. This effect may be partly due to upregulation of endothelial nitric oxide synthase.",2001.0,0,0 870,11468198,Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease.,M Schartl; W Bocksch; D H Koschyk; W Voelker; K R Karsch; J Kreuzer; D Hausmann; S Beckmann; M Gross,"We studied whether lipid-lowering therapy with atorvastatin (target LDL cholesterol [LDL-C] <100 mg/dL) compared with a moderate treatment regimen that used other lipid-lowering drugs led to a lesser progression of atherosclerosis and to different changes in plaque echogenicity in patients with coronary artery disease. This study was a 12-month, open-label, randomized, multicenter trial, which used serial 3D intracoronary ultrasound to calculate plaque volume and plaque echogenicity. After transcatheter therapy, 131 patients were randomized (atorvastatin n=65, usual care n=66). The target plaque had to be a minor lesion (ie, a diameter stenosis of <50% on angiography). After 12 months, mean LDL-C was reduced from 155 to 86 mg/dL in the atorvastatin group and from 166 to 140 mg/dL in the usual care group. Mean absolute plaque volume showed a larger increase in the usual care group compared with the atorvastatin group (usual care 9.6+/-28.1 mm(3), atorvastatin 1.2+/-30.4 mm(3); P=0.191). The hyperechogenicity index of the plaque increased to a larger extent for the atorvastatin group than for the usual care group, with a significant treatment effect for the percent change (atorvastatin 42.2%, usual care 10.1%; P=0.021). One year of lipid-lowering therapy to <100 mg/dL LDL-C most likely led to a slowdown of plaque growth of minor lesions. The significantly larger increase in plaque hyperechogenicity is most likely due to a change in plaque composition.",2001.0,0,0 871,11468643,Investigating the determinants of decreasing postmyocardial infarction mortality: an analysis of in-hospital data from 1992 and 1997.,N Daneman; P C Austin; J V Tu,"Although acute myocardial infarction (AMI) is the leading cause of mortality in the industrialized world, postmyocardial infarction mortality rates have been declining in recent decades. Two possible contributing factors toward this encouraging trend include changing patient characteristics and improved patient management. To compare temporal changes in the characteristics and management of patients with AMI at a tertiary care hospital (Sunnybrook and Women's College Health Sciences Centre) in Toronto, Ontario. Two hundred hospital charts of patients with AMI as the most responsible diagnosis were reviewed (100 from 1992 and 100 from 1997). One hundred thirty prespecified variables were extracted from each chart, with emphasis placed on baseline clinical characteristics, AMI management and survival. Between 1992 and 1997, AMI in-hospital mortality declined from 20% to 15%. Most baseline clinical characteristics (age, sex, comorbidity, cardiac history, and presenting symptoms and signs) were similar across the 1992 and 1997 patient populations. The only significant risk factor change involved an increase in the prevalence of hypercholesterolemia. In contrast, between 1992 and 1997 there was an increased in-hospital use of anticoagulants, antiplatelets, thrombolytics, beta-blockers, angiotensin-converting enzyme inhibitors and statins. Similarly, there was an increased use of coronary angioplasty and coronary bypass surgery. There was no significant change in the use of AMI therapies that are potentially harmful, including antiarrythmic agents and calcium channel blockers. AMI patient characteristics were similar between 1992 and 1997 but there were striking changes in AMI treatment patterns. The increased use of evidence-based pharmacotherapy may be the most significant contributing factor to declining postmyocardial infarction mortality.",2001.0,0,0 872,11471769,Evidence-based treatment of patients with ischemic cerebrovascular disease.,R Llinas; L R Caplan,"The results of trials that study patients with defined lesions (atrial fibrillation without valvular heart disease, various severities of carotid artery stenosis in the neck, intracranial artery stenosis) are very helpful for clinicians caring for patients with those conditions. On the other hand, trials that group all patients with brain ischemia together are not very helpful. Modern technology now makes it possible to define quickly and safely: (1) the location, nature, and severity of causative cerebrovascular, cardiac, and aortic lesions; (2) blood constituents and coagulability; and, (3) the presence, location, and severity of ischemic brain damage. As in all medicine, treatment should be aimed at the cause of disease, not the time course and severity of present damage. Clearly, more trials are needed in patients who have been studied thoroughly using modern technology. Until then, clinicians must understand the context of the trial data to determine if the results are applicable to Mr. or Ms. Jones, and the patients sitting before them in the office or in the hospital bed.",2001.0,0,0 873,11471927,The effect of atorvastatin on postprandial lipaemia in overweight or obese women homozygous for apo E3.,G Vansant; A Mertens; E Muls,"To determine the effect of atorvastatin on postprandial lipaemia in overweight or obese women with the apoprotein (apo) E3/E3 genotype. Double-blind randomised, placebo-controlled 8-week single-centre study. Twenty-two healthy women, homozygous for apo E3 with a BMI ranging from 27.6 to 41.1 kg/m2 and normal or moderately elevated fasting triglycerides (53-184 mg/dl). After a 4-week isocaloric single-blind, placebo lead-in period, subjects were randomly assigned to receive either placebo (n = 7) or atorvastatin 20 mg once daily in the evening (n = 15) for 4 weeks. Atorvastatin significantly reduces fasting total cholesterol, LDL-cholesterol and postprandial triglycerides in obese women, homozygous for apo E3 with normal or near-normal fasting triglyceride levels. No significant effect on fasting triglycerides was observed. Atorvastatin decreases postprandial hyperlipidaemia, an independent cardiovascular risk factor, in normolipidaemic obese women. This effect of atorvastatin may, therefore, represent a cardioprotective mechanism.",2002.0,0,0 874,11472705,Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels.,C M Ballantyne; T C Andrews; J A Hsia; J H Kramer; C Shear; ACCESS Study Group. Atorvastatin Comparative Cholesterol Efficacy and Safety Study,"Apolipoprotein B has been shown to be a better predictor of coronary heart disease than low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol may also be a better parameter for coronary heart disease risk assessment and as a target for therapy. Data from the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS) were used to assess the correlation between lipid and apolipoprotein B levels before and after lipid-lowering therapy and to examine the effects of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on lipids and apolipoprotein B. The 54-week study randomized 3,916 hypercholesterolemic patients to atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin, initiated at recommended starting doses with titrations as needed at weeks 6, 12, and 18 to achieve National Cholesterol Education Program LDL targets. Compared with LDL cholesterol, non-HDL cholesterol correlated better with apolipoprotein B levels at baseline (r = 0.914, p <0.0001) and at week 54 (r = 0.938, p <0.0001), and the correlation was strong across all baseline triglyceride strata. At starting doses, atorvastatin (10 mg) lowered non-HDL cholesterol by 33.3% compared with 26.6% with simvastatin (10 mg), 24.1% with lovastatin (20 mg), 17.2% with fluvastatin (20 mg), and 17.0% with pravastatin (10 mg). Atorvastatin also provided greater reductions in non-HDL cholesterol after dose titration, and a greater percentage of patients taking atorvastatin achieved non-HDL cholesterol targets. Baseline triglyceride did not affect non-HDL cholesterol reductions with any of the 5 hydroxymethylglutaryl coenzyme A reductase inhibitors. Fewer patients achieved non-HDL cholesterol targets than LDL cholesterol targets, particularly among high-risk patients, implying that if non-HDL cholesterol was used as a target for treatment, more patients would need to be treated more aggressively than National Cholesterol Education Program guidelines require.",2001.0,0,1 875,11472706,Effect of niacin and atorvastatin on lipoprotein subclasses in patients with atherogenic dyslipidemia.,J M McKenney; L S McCormick; E J Schaefer; D M Black; M L Watkins,"This study was conducted to determine the efficacy of atorvastatin and niacin on lipoprotein subfractions in patients with atherogenic dyslipidemia. This was a multicenter, randomized, open-label, parallel-design study of patients with total cholesterol >200 mg/dl, triglycerides between 200 and 800 mg/dl, and apolipoprotein B >110 mg/dl. Patients were randomly assigned to atorvastatin 10 mg or immediate release niacin 3,000 mg daily for 12 weeks following a low-fat diet stabilization period. Lipoprotein subclasses were measured by nuclear magnetic resonance spectroscopy. Atorvastatin and niacin both significantly reduced the concentrations of very low-density lipoprotein (VLDL) particles (-31% and -29%, respectively) and small low-density lipoprotein (LDL) particles (-44% and -35%, respectively). Niacin increased the concentration of large LDL (+75%). Atrovastatin reduced the number of LDL particles more than niacin (31% vs 14%). In patients with atherogenic dyslipidemia, both drugs had important effects on lipoprotein subfractions, which contributed to a reduction in coronary heart disease risk. The drugs equally reduced VLDL subclass levels. Niacin shifted the LDL subclass distribution toward the larger particles, more effectively converted patients from LDL phenotype B to phenotype A, and increased levels of the larger and perhaps more cardioprotective high-density lipoprotein particles. In contrast, atorvastatin preferentially lowered the concentration of small LDL particles without increasing levels of large LDL, and more effectively, reduced LDL particle numbers. Atorvastatin had a preferred LDL effect, whereas niacin had a preferred high-density lipoprotein effect.",2001.0,0,0 876,11472710,Pleiotropic effects of statins and their clinical significance.,J C LaRosa,,2001.0,0,0 877,11472741,Reduced levels of TNF alpha in hypercholesterolemic individuals after treatment with pravastatin for 8 weeks.,S Solheim; I Seljeflot; H Arnesen; J Eritsland; L Eikvar,"cellular adhesion molecules (CAMs) expressed on the endothelial surface play a key role in the inflammatory process of atherosclerosis, and increased expression of CAMs has been shown in hypercholesterolemic individuals. The expression of CAMs is mediated by several cytokines including tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6). The aim of the present study was to assess the influence of pravastatin 40 mg per day on selected soluble CAMs; intercellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), E-selectin, P-selectin and some circulating markers of inflammation; C-reactive protein (CRP) and the cytokines TNF alpha and IL-6. 40 non-diabetic men, age below 70 years, with serum total cholesterol 6--10 mmol/l combined with HDL-cholesterol < or =1.2 mmol/l were included. The study was randomized, double blinded, placebo controlled, cross over designed with 8 weeks intervention periods. Fasting blood samples were drawn after 8 and 16 weeks. significant reduction of total cholesterol was achieved after treatment with pravastatin (7.8 on placebo vs. 5.7 mmol/l on pravastatin). TNF alpha was significantly reduced after treatment with pravastatin (1.33 on placebo vs. 1.10 pg/ml on pravastatin, P=0.032), whereas no differences in the levels of the measured sCAMs, CRP and IL-6 were found. Subgroup analysis among smokers versus non-smokers showed a significant reduction in the level of TNF alpha only among the smokers. hypercholesterolemic individuals treated with pravastatin 40 mg per day for 8 weeks showed a statistically significant reduction in the levels of TNF alpha as compared with placebo.",2001.0,0,0 878,11472743,,,,,0,0 879,11473066,"The effect of aggressive versus standard lipid lowering by atorvastatin on diabetic dyslipidemia: the DALI study: a double-blind, randomized, placebo-controlled trial in patients with type 2 diabetes and diabetic dyslipidemia.",Diabetes Atorvastin Lipid Intervention (DALI) Study Group,"In patients with type 2 diabetes, intensive glucose regulation, although effective for microangiopathy, has not been shown to have unambiguous preventive effects on the occurrence of cardiovascular disease. Patients with diabetes show a characteristic dyslipidemia (high triglyceride level, low HDL cholesterol level). Aggressive reduction of triglycerides might be an effective method to reduce the cardiovascular risk in these patients. A double-blind, placebo-controlled, randomized study to assess the effect of 30 weeks of administration of atorvastatin 10 and 80 mg on plasma triglyceride levels in 217 patients with type 2 diabetes and fasting triglyceride levels between 1.5 and 6.0 mmol/l. Administration of atorvastatin 10 and 80 mg resulted in significant reductions (25 and 35%, respectively) of plasma triglyceride levels (both P < 0.001). The difference between 10 and 80 mg was not statistically significant (P > 0.5). Atorvastatin 10 mg provided significant reductions from baseline in total cholesterol (-30%, P < 0.001), LDL cholesterol (-40%, P < 0.001), and apolipoprotein B (-31%, P < 0.001), and significantly increased HDL cholesterol from baseline by 6% (P < 0.005). Atorvastatin 80 mg had a similar effect on HDL cholesterol (+5.2%, P < 0.005) but significantly decreased total cholesterol (-40%, P < 0.001), LDL cholesterol (-52%, P < 0.001), and apolipoprotein B (-40%, P < 0.001) more than atorvastatin 10 mg (P < 0.005). The side effects of atorvastatin 10 and 80 mg were similar and did not differ from the patients receiving placebo. Administration of 10- and 80-mg doses of atorvastatin provides similar, significant reductions from baseline in triglyceride levels in patients with type 2 diabetes. A higher dose of atorvastatin improves cholesterol-related parameters. Both doses were well tolerated in this patient population.",2001.0,0,0 880,11473096,Improvement in endothelial dysfunction with LDL cholesterol level < 80 mg/dl in type 2 diabetic patients.,W H Sheu; Y T Chen; W J Lee,,2001.0,0,0 881,11474227,Combined treatment with low-dose pravastatin and fish oil in post-renal transplantation dislipidemia.,D Grekas; E Kassimatis; A Makedou; D Bacharaki; G Bamichas; A Tourkantonis,"The most common cause of post-transplant dyslipidemia is the use of corticosteroids and cyclosporin-A (CyA). The HMG-CoA reductase inhibitors have emerged as the agents of first choice in the treatment of post-transplant hyperlipidemia in combination with low fat diet. The objective of this study was to evaluate the efficacy of combined treatment with low-dose pravastatin and fish oil in post-renal transplantation dislipidemia. Twenty-four renal transplant patients, 15 men and 9 women aged from 30 to 60 years with stable renal function were included in this study. All patients were transplanted from living related donors and were given a stable triple immunosuppressive therapy, with methylprednisolone, azathioprine and CyA. All patients were also given a standard diet containing 1 g/kg BW protein, reducing the daily fat to less than 30%, and maintaining at least a 1:1 ratio of saturated to polyunsaturated (or monounsaturated) fats. A dosage of 20 mg pravastatin (pravachol) and 1 g of fish oil (prolipid) were added to the diet after dinner, according to our protocol. Blood samples were taken after each study period for total cholesterol, LDL-cholesterol, triglycerides, Apo A(1), Apo B, Lp(a), creatinine, CPK and fibrinogen determination. At the end of the therapeutic protocol with pravastatin a significant reduction (p < 0.02) of total and LDL-cholesterol was observed, but no significant change in triglycerides, HDL, Lp(a), Apo A(1), Apo B and fibrinogen was shown. At the end of the therapeutic protocol with pravastatin and fish oil supplement significant changes were seen in TC (p < 0.02), TG (p < 0.03), LDL-C (p < 0.03), Apo A(1) (p < 0.04) and Apo B (p < 0.05) concentrations. There were no significant changes in HDL-C and Lp(a) concentrations. Renal function and cyclosporine levels were not changed during and after the study. CPK was increased only in one case. It is suggested that if the response to the diet is inadequate, the use of combined treatment with low-dose pravastatin and fish oil is a more effective strategy than the pravastatin treatment alone for changing the lipid profile after renal transplantation.",2001.0,0,0 882,11475783,[Beyond cholesterol levels: new therapeutic indications of statins].,N De Luca,"Cardiovascular diseases represent the major cause of morbility and mortality in industrialized countries, even if the incidence is quite different between each other. In the last years the knowledge of molecular mechanisms, which are responsible of progression of atherosclerosis vascular disease and of its complications such as coronary heart disease, has been particularly improved. At this regard new pharmacological compounds are introduced in clinical practice improved efficacy and effectiveness and, among these ones, thanks to statins a significative reduction in primary endpoint (i.e. reduction in incidence of stroke, total and cardiovascular mortality) has been already demonstrated. This effectiveness seems to be due by acting directly on the vascular atherosclerotic plaque independently from the reduction of blood cholesterol level which, on the contrary, may be involved in the progression of atherosclerotic vascular process.",2001.0,0,0 883,11477342,The effects of lipid-lowering agents on acute renal allograft rejection.,B L Kasiske; K L Heim-Duthoy; G G Singer; B Watschinger; M J Germain; B Bastani,"Preliminary results from clinical trials suggest that 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors may help prevent acute renal allograft rejection. However, the mechanism for this putative effect of 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors, and whether it is independent of lipid-lowering per SE are unknown. Immediately after renal transplantation we randomly allocated (proportioned 2:1:2) patients to: 1) simvastatin (10 mg/day, n=53), 2) simvastatin placebo plus gemfibrozil (dose adjusted for renal function, n=36), and 3) simvastatin placebo (n=52). Simvastatin, but not gemfibrozil, reduced total and low density lipoprotein cholesterol during the first 90 days posttransplant. There were no major adverse effects of therapy. However, there were no effects of treatment on acute rejection. Indeed, survival free of acute rejection at 90 days was 72% in the simvastatin group, 72% in the gemfibrozil group, and 77% in the placebo control group (P=0.771). A post hoc power analysis suggested that there was only a 7.5% chance that a true effect of simvastatin on acute rejection (versus placebo) was not detected, and a 2.5% chance that an effect of gemfibrozil on acute rejection (versus placebo) was not detected in this study. Lipid-lowering agents may not reduce the incidence of acute renal allograft rejection. However, additional studies are needed to confirm this observation. In the mean time, many if not most renal transplant recipients should be treated with HMG-CoA reductase inhibitors starting early posttransplant to prevent cardiovascular disease complications. The results of this study suggest that starting lipid-lowering therapy immediately after renal transplantation is both safe and effective in lowering total and low density lipoprotein cholesterol.",2001.0,0,0 884,11479456,The A-to-Z Trial: Methods and rationale for a single trial investigating combined use of low-molecular-weight heparin with the glycoprotein IIb/IIIa inhibitor tirofiban and defining the efficacy of early aggressive simvastatin therapy.,M A Blazing; J A De Lemos; C K Dyke; R M Califf; D Bilheimer; E Braunwald,"The A-to-Z Trial is an ongoing international, multicenter, randomized study designed to investigate 2 issues concerning contemporary care of patients with acute coronary syndromes (ACS). The first issue is whether the use of low-molecular-weight heparin versus unfractionated heparin affects outcomes and safety when used as a therapy adjunctive to baseline treatment with tirofiban and aspirin in patients with non-ST-elevation (nSTE) ACS. The second issue is whether early use of an aggressively dosed statin is superior to a current trial-based ""accepted care"" regimen of a lower-dose statin started 3 to 6 months after an acute event. The study is conceptually and functionally divided into 2 sequential parts-the ""A"" Aggrastat and ""Z"" Zocar phases. The primary A-phase end point is a composite of all-cause mortality, myocardial infarction (MI), and documented refractory ischemia at 7 days. Both nSTE-ACS patients from the A phase and patients with ST-elevation ACS who meet specific risk criteria are eligible to enter the subsequent ""Z"" (Zocor) chronic phase (Z phase). The primary end point of the Z phase is a composite of cardiovascular death, MI, readmission for ACS, and stroke. The trial will continue until 970 primary events have occurred in the Z-phase population. This trial is evaluating 2 temporally connected sequences of phamacotherapy for ACS. At completion, trial results will provide definitive evidence regarding efficacy and safety of early, intensive statin therapy and better define the role of low-molecular-weight heparin in patients with nSTE ACS.",2001.0,0,0 885,11479458,Pediatric issues and diseases.,R M Lauer; S P Sanders,,2001.0,0,0 886,11481566,Long-term effect of simvastatin on the improvement of impaired myocardial flow reserve in patients with familial hypercholesterolemia without gender variance.,I Yokoyama; K Yonekura; Y Inoue; K Ohtomo; R Nagai,"Impaired myocardial flow reserve (MFR) in patients with familial hypercholesterolemia (FH) without evidence of ischemia has been reported. However, it has not been clarified whether diminished MFR in such male or female patients with FH can be reversed by simvastatin. Sixteen patients with FH and 16 age-matched control subjects were studied. All patients were proved to have no evidence of exercise stress-induced myocardial ischemia. Baseline myocardial blood flow (MBF) and MBF during dipyridamole administration (MBF [DP]) were measured with positron emission tomography and nitrogen 13 ammonia; MFR was then calculated before and 9 to 15 months after therapy with simvastatin (5-10 mg/day). Total cholesterol level was significantly higher in patients with FH (277 +/- 49.0) than in control subjects (190 +/- 14.9) but was normalized after lipid-lowering therapy (205 +/- 40.3). Baseline MBF was comparable among FH patients before (77.6 +/- 11.6 mL/min/100 g) and after therapy (74.5 +/- 9.62 mL/min/100 g) and control subjects (78.5 +/- 29.9 mL/min/100 g). However, MBF (DP) in FH patients before therapy (178 +/- 50.9 mL/min/100 g) was significantly lower than that in control subjects (282 +/- 148 mL/min/100 g) and was significantly improved after therapy (228 +/- 91.6 mL/min/100 g, P <.05). In fact, there was no statistically significant difference in the MBF (DP) value in FH patients after therapy compared with that in control subjects (P =.09). MFR significantly improved after therapy in patients with FH (3.33 +/- 1.19 vs 2.27 +/- 0.625, P <.01) and was then statistically comparable to that in control subjects (3.54 +/- 1.11). Improvement of MFR was observed whether MBF (DP) before therapy was greater than or less than 200 mL/min/100 g. MFR was improved in both male and female patients with FH. There was a significant relationship between percent change in plasma total cholesterol concentration and percent change in MFR before and after lipid-lowering therapy (r = -0.57, P <.05). Diminished MFR in patients with FH without evidence of ischemia can be reversed by moderate- to long-term simvastatin therapy without gender variance.",2001.0,0,0 887,11483446,Gallstones and biliary disease.,A N Kalloo; S V Kantsevoy,"Gallstones are common in the US and western countries. This article describes the pathogenesis of gallstone formation and the clinical manifestations and current approaches to diagnosis and treatment of the most common clinical conditions caused by gallstones: biliary colic, acute cholecystitis, choledocholithiasis, and acute gallstone pancreatitis. The role of widely used imaging techniques (transabdominal ultrasound, CT scan, MR imaging, and MRCP) and diagnostic and therapeutic endoscopy (endoscopic ultrasound, ERCP) is emphasized. This article is intended mainly for general practitioners, primary care physicians, and other specialists providing medical care to patients with gallstones and their complications.",2001.0,0,0 888,11485143,Colesevelam hydrochloride: a novel bile acid-binding resin.,M A Aldridge; M K Ito,"To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of colesevelam hydrochloride, a bile acid-binding resin. MEDLINE searches (1966-June 2000) and manufacturer prescribing literature were employed to find articles on colesevelam. Additional studies and abstracts were identified from the bibliographies of reviewed literature. All articles identified from data sources were evaluated, and all information deemed relevant was included in this review. Priority was given to randomized, double-blind, placebo-controlled studies. Colesevelam HCl is a nonabsorbed hydrogel with bile acid sequestrant properties. Monotherapy using colesevelam in once-daily or two divided daily doses of 1.5-4.5 g has produced significant reductions in total cholesterol and low-density lipoprotein (LDL) cholesterol. Mean LDL cholesterol decreases to 20% have been noted when the patient is on 3.75-4.5 g/d. Increases in high-density lipoprotein (HDL) cholesterol have been observed (up to 9%), whereas triglycerides (TG) have increased significantly to 25% in some studies. In unpublished studies, combined use of colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor have produced greater reductions in LDL cholesterol than either the statin or colesevelam administered alone. The efficacy of colesevelam monotherapy is slightly less than or similar to cholestyramine or colestipol in decreasing LDL cholesterol, although colesevelam is more potent on a gram-to-gram basis. Adverse effects have been minimal with colesevelam in published studies; this suggests an advantage over cholestyramine or colestipol therapy. Colesevelam appears to be more cost-effective than the packet dosage form of the brand formulation of the older bile acid resins. Care in selection of an appropriate agent should be exercised when considering the issues of adverse effects and palatability. Colesevelam alone or combined with an HMG-CoA reductase inhibitor is effective in the reduction of total and LDL cholesterol. Since colesevelam is formulated as a tablet, problems with palatability such as with the powder formulation of the bile acid-binding resins are likely to be eliminated.",2002.0,0,0 889,11485144,Statin-fibrate combination therapy.,A Shek; M J Ferrill,"Precautionary warnings for severe myopathy and rhabdomyolysis from the coadministration of statins and fibrates have been well publicized. However, a recent cerivastatin labeling change made the combined use with fibric acid derivatives a contraindication. Practical recommendations for clinicians who care for patients with refractory mixed hyperlipidemia are needed. To provide recommendations for clinicians in the treatment of refractory mixed hyperlipidemia. A comprehensive MEDLINE (1966-July 2000) and bibliographic search was performed. Thirty-six published clinical trials and 29 case reports involving combination therapy with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and fibric acid derivatives regarding the occurrence of rhabdomyolysis or myopathy were reviewed. The literature review demonstrated that combination therapy with a statin and fibrate increases the risk of muscle damage, with an incidence of 0.12%. Risk factors that predispose patients to myopathy caused by combination statin-fibrate therapy include increased age, female gender, renal or liver disease, diabetes, hypothyroidism, debilitated status, surgery, trauma, excessive alcohol intake, and heavy exercise. Combination therapy with a statin and fibrate offers significant therapeutic advantage for the treatment of severe or refractory mixed hyperlipidemia. Although such a combination does increase the risk of myopathy, with an incidence of approximately 0.12%, this small risk of myopathy rarely outweighs the established morbidity and mortality benefits of achieving lipid goals. Nevertheless, a higher incidence of myopathy has been reported with statin monotherapy. When monotherapy with a statin fails to control mixed hyperlipidemia, combination therapy may be considered. Niacin may be added before a fibrate is considered, as it appears to have less risk of myopathy. Statin-fibrate combination therapy must be undertaken cautiously and only after careful risk-benefit analysis. Patient counseling on the risks and warning signs of myopathy is extremely important.",2002.0,1,1 890,11485701,Can early treatment with atorvastatin (Lipitor) improve the outcome of patients with acute coronary syndromes?,K Johnson; W J Breen,,2001.0,0,0 891,11487446,The use of statins in acute coronary syndromes: the mechanisms behind the outcomes.,J C Plana; P H Jones,"Lipid-lowering drugs, in particular statin treatments, have been shown to reduce the incidence of initial and recurrent coronary heart disease (CHD) events within several years of initiating therapy. This effect can be clinically detected within the first 1 to 2 years in randomized trials. Recent observational and clinical trial data suggest that lipid-lowering therapy initiated at the time of an acute coronary event can reduce recurrent events, and possibly all-cause mortality, in a much shorter period of time. The possible mechanisms by which this benefit occurs include the effect of reduced lipoprotein levels, as well as an independent effect of statins on endothelial function. Statins improve endothelial-dependent flow-mediated vasodilation by increasing the bioavailability of nitric oxide. They stabilize the plaque by modulating the inflammatory response within the vessel wall. They also decrease clot formation by decreasing the adherence of platelets to the ruptured plaque and by acting on the extrinsic coagulation cascade pathway. This review examines these effects of statins and lipoproteins on vascular function, as well as the clinical evidence supporting early treatment in acute coronary syndromes.",2001.0,0,0 892,11488782,Tacrolimus/cerivastatin interaction study in liver transplant recipients.,W Mück; D A Neal; O Boix; B Voith; R Hasan; G J Alexander,,2001.0,0,0 893,11494031,The inhibitory effect of simvastatin on growth in malignant gliomas--with special reference to its local application with fibrin glue spray in vivo.,M Murakami; T Goto; Y Saito; S Goto; M Kochi; Y Ushio,"Simvastatin is one of the competitive inhibitors of HMG-CoA reductase. During clinical trials, it has shown the ability to lower serum cholesterol. We investigated the effect of simvastatin on the growth of malignant gliomas in vitro, semi-in vivo, and in vivo. An in-vitro MTT assay revealed that human malignant glioma cell lines: U-251MG, U-373MG, and U-87MG, and rat malignant glioma cell line C6 were well inhibited in growth in a dose-dependent fashion. An anchorage-independent growth assay showed that the number of colonies (more than 100 microM in size) of human (U-373MG) and rat malignant gliomas (C6) was markedly reduced in a dose-dependent fashion. A flow cytometry analysis revealed that simvastatin treatment led U-251MG cells to accumulate in sub G0-G1. Immunostaining by TUNEL method showed that most glioma cells treated by 10 microM simvastatin had nuclear immunostaining, suggesting apoptotic changes of the treated cells. The human umbilical vein endothelial cells and human lung fibroblasts were inhibited in growth by no more than 20% of controls even with a high dose (10 microM) of simvastatin. In the semi-in vivo model, using newborn rat brain slice cultures, the rhodamine-labeled glioma cells were abolished after 7 days of local simvastatin treatment with fibrin glue probably suggesting that simvastatin led the cells to apoptosis. In rat models using subcutaneously inoculated C6, the local application of simvastatin combined with fibrin glue (spray method) was quite effective in inhibiting the growth of the tumor. These data suggest that simvastatin may be a novel anti-glioma drug, and the local application of simvastatin combined with fibrin glue (by spray method) may be a crucial new clinical strategy against glioma growth.",2001.0,0,0 894,11495047,Short-term effects of statin therapy in patients with hyperlipoproteinemia after liver transplantation: results of a randomized cross-over trial.,R Zachoval; A L Gerbes; P Schwandt; K G Parhofer,"Hyperlipoproteinemia is frequent following liver transplantation and may lead to atherosclerosis. Lipid-lowering agents may be useful, but could interfere with the function of the transplanted organ and with immunosuppression. We therefore evaluated in a prospective, randomized, open-labeled cross-over trial the effect of two frequently used 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (pravastatin 10 mg d(-1) and cerivastatin 0.1 mg d(-1)) in hyperlipoproteinemic patients after liver transplantation. Sixteen patients (6.3 +/- 2.0 years post-transplantation, cyclosporine n = 11, tacrolimus n = 5) with hyperlipoproteinemia (cholesterol 246 +/- 42, triglycerides 191 +/- 87, low-density lipoprotein (LDL)-cholesterol 161 +/- 35, high-density lipoprotein (HDL)-cholesterol 44 +/- 11 mg d(-1)) were included. Treatment periods of 6 weeks were separated by a 4-week washout period. Both medications were tolerated well, no effects on serum concentrations of liver enzymes or immunosuppressive agents were observed. Cerivastatin and pravastatin decreased (P < 0.001) cholesterol by 21 +/- 10% and 15 +/- 10%, LDL-cholesterol by 27 +/- 14% and 17 +/- 15%, respectively, while triglyceride and HDL-cholesterol concentrations did not change significantly. LDL/HDL-cholesterol markedly improved (P < 0.001) by 29 +/- 16% (cerivastatin) and 16 +/- 16% (pravastatin). Cerivastatin was more potent than pravastatin in patients receiving cyclosporine A, while there was no significant difference in patients receiving tacrolimus. Low-dose cerivastatin and pravastatin significantly improve lipid profiles following liver transplantation without affecting liver function or immunosuppression.",2002.0,0,0 895,11497338,Study of the drug-drug interaction between simvastatin and cisapride in man.,C Simard; G E O'Hara; J Prévost; R Guilbaud; R Masseé; J Turgeon,"The objective of our study was to evaluate in humans the drug-drug interaction occurring during the concomitant administration of cisapride and simvastatin, two well-known substrates of CYP3A4. Eleven healthy men aged between 20 years and 35 years gave their written informed consent to participate in the study. Each participant received repeated doses of cisapride and/or simvastatin. At first, subjects received cisapride alone, 10 mg every 8 h, for 3 days. Then, the drug was given at the same regimen during concomitant administration of simvastatin, 20 mg every 12 h for 4 days, starting on the night of day 3. Finally, cisapride was stopped and subjects received simvastatin (20 mg every 12 h) for four additional days. Simvastatin administration caused a 14 +/- 20% increase in the AUC0-8 of cisapride. In contrast, plasma concentrations of simvastatin were unaltered by the coadministration of cisapride, whereas plasma concentrations of simvastatin acid, its active metabolite, were decreased by 33 +/- 24%. The concomitant administration of the prokinetic agent cisapride and the 3-hydroxy-3-methylgluaryl CoA reductase inhibitor simvastatin resulted in altered pharmacokinetics of both drugs. Increased plasma concentrations of cisapride suggest that some patients may be at risk of toxicity while receiving both drugs, whereas the decrease in simvastatin acid plasma concentrations suggests that cholesterol lowering effects of simvastatin treatment may be blunted.",2002.0,0,0 896,11498182,The effect of simvastatin on panel-reactive antibody and crossmatch positivity.,F N Ozdemir; S Sezer; M Turan; T Colak; Z Arat; S Gülmüş; M Haberal,,2002.0,0,0 897,11500190,Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner.,J Pedro-Botet; E J Schaefer; R G Bakker-Arkema; D M Black; E M Stein; D Corella; J M Ordovas,"The response to therapy with hypolipidemic agents shows considerable individual variation. These differences may be due to the interaction of environmental and genetic factors that affect drug bioavailability, receptor function or ligand structure. Our objective was to assess the effect of apolipoprotein (apo) E genotype and gender on lipid-lowering response to the HMG CoA reductase inhibitor, atorvastatin. Genotyping was carried out on DNA from 328 male and female subjects who participated in a multicentric, double-blind clinical trial, and received 10 mg/day of atorvastatin. Our data demonstrate no significant gender differences for LDL cholesterol levels at baseline. Moreover, mean LDL-C lowering was similar in men (-36.2%, range -2.7 to -57.8%) and in women (-38.1%, range -9.5 to -58.5%) as compared to baseline. However, men carrying the epsilon2 allele had a significantly higher mean LDL-C response (-44%) than epsilon3 homozygotes (-37%) and epsilon4 carriers (-34%); P=0.01 for apoE group by treatment interaction. No such gene/treatment interactions were noted in women, with those carrying the epsilon2 allele showing a similar mean response (-34%) as epsilon3 homozygotes (-39%) and epsilon4 carriers (-34%). Mean plasma triglyceride lowering with atorvastatin was 17%. A significant apoE group by treatment interaction (P=0.010) was also observed in men, with epsilon2 carriers being more responsive (-27%) than epsilon3/3 (-13%) and epsilon4 (-22%). This interaction was not observed in women. In summary, atorvastatin treatment had similar effects on plasma lipid levels in both men and women; however, the apoE gene locus was a significant predictor of LDL-C and TG responses to atorvastatin therapy in men, but not in women.",2001.0,0,0 898,11501219,Acute coronary syndrome: are intervention and IIb/IIIa platelet inhibitors epiphenomena?,G Jackson,,2001.0,0,0 899,11501230,"Clinical rationale for rosuvastatin, a potent new HMG-CoA reductase inhibitor.",M Hanefeld,"Coronary heart disease (CHD) is the leading cause of death worldwide, and effective treatment of hyperlipidaemia can prevent development of CHD and significantly reduce the risk for cardiovascular events and mortality in this disease. The advent of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) has revolutionised the treatment of hyperlipidaemia, but many patients receiving these drugs still do not achieve their therapeutic goals. Rosuvastatin (Crestor; formerly ZD4522) is a new, potent and long-lasting inhibitor of HMG-CoA reductase that is highly selective for hepatocytes. Its pharmacokinetics permit once-daily dosing, and a lack of oxidative hepatic metabolism results in a reduced potential for drug-drug interactions. Preliminary clinical results indicate that it produces rapid dose-related reductions in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B that may exceed those achieved with other currently available statins. Increases in high-density lipoprotein cholesterol have also been observed. Rosuvastatin is also well tolerated, with no evidence of either hepato- or myotoxicity. It is hoped that new agents such as rosuvastatin may help to reduce the high global morbidity, mortality and associated costs of CHD and related vascular disorders.",2001.0,0,0 900,11502313,Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study.,I J Schatz; K Masaki; K Yano; R Chen; B L Rodriguez; J D Curb,"A generally held belief is that cholesterol concentrations should be kept low to lessen the risk of cardiovascular disease. However, studies of the relation between serum cholesterol and all-cause mortality in elderly people have shown contrasting results. To investigate these discrepancies, we did a longitudinal assessment of changes in both lipid and serum cholesterol concentrations over 20 years, and compared them with mortality. Lipid and serum cholesterol concentrations were measured in 3572 Japanese/American men (aged 71-93 years) as part of the Honolulu Heart Program. We compared changes in these concentrations over 20 years with all-cause mortality using three different Cox proportional hazards models. Mean cholesterol fell significantly with increasing age. Age-adjusted mortality rates were 68.3, 48.9, 41.1, and 43.3 for the first to fourth quartiles of cholesterol concentrations, respectively. Relative risks for mortality were 0.72 (95% CI 0.60-0.87), 0.60 (0.49-0.74), and 0.65 (0.53-0.80), in the second, third, and fourth quartiles, respectively, with quartile 1 as reference. A Cox proportional hazard model assessed changes in cholesterol concentrations between examinations three and four. Only the group with low cholesterol concentration at both examinations had a significant association with mortality (risk ratio 1.64, 95% CI 1.13-2.36). We have been unable to explain our results. These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations (<4.65 mmol/L) in elderly people.",2001.0,0,0 901,11503831,Cholesterol-lowering drugs. Some drugs with demonstrated efficacy but different benefits in primary and secondary prevention.,,"(1) In primary prevention trials, pravastatin and lovastatin prevented myocardial infarction and had a positive risk-benefit ratio in men with LDL-cholesterol values exceeding 4.5 mmol/l (1.7 g/l). Cholestyramine and gemfibrozil also prevented myocardial infarction in men with more severe hypercholesterolaemia; while clofibrate had a negative risk-benefit ratio in patients with moderate hypercholesterolaemia. These treatments have not been assessed for primary prevention in women or in patients aged over 70. (2) In trials involving patients with coronary heart disease, pravastatin and simvastatin both reduced the risk of myocardial infarction and/or mortality in patients of both sexes with LDL-cholesterol values above 3.2 mmol/l (1.2 g/l). Gemfibrozil also reduced the risk of myocardial infarction but not mortality, while clofibrate and bezafibrate had no preventive effect.",2001.0,0,0 902,11504577,Treatment of dyslipidemia in pre- and postmenopausal women with and without known atherosclerotic cardiovascular disease.,V Bittner,"Cardiovascular disease is the primary cause of death among women in the United States, in part due to a very high prevalence of dyslipidemia. Clinical trials have shown that low-density lipoprotein cholesterol-lowering therapy can decrease angiographic progression of coronary disease and decrease clinical events among women and men. Although hormone replacement therapy has beneficial effects on the lipoprotein profile, its role in cardiovascular disease prevention remains unclear. The recently released Third Report of the National Cholesterol Education Program Expert Panel provides detailed guidelines for the management of dyslipidemia in women, with a focus on low-density lipoprotein cholesterol and intensity guided by risk of cardiovascular events.",2001.0,0,0 903,11504982,Dietary advice with or without pravastatin for the management of hypercholesterolaemia associated with protease inhibitor therapy.,G J Moyle; M Lloyd; B Reynolds; C Baldwin; S Mandalia; B G Gazzard,"Therapy with a HIV protease inhibitor is associated with elevations in cholesterol and triglycerides. HMG-CoA reductase inhibitors ('statins') are the established therapy for persons with primary hypercholesterolaemia. Because of drug interactions, pravastatin may represent the preferred choice in those taking HIV protease inhibitors. A randomized, open-label comparative 24 week trial of dietary advice alone or with pravastatin in 31 male patients established on protease inhibitor-based regimens for greater than 12 weeks with viral load < 500 copies/ml and cholesterol > 6.5 mmol/l. There were no significant clinical or laboratory events and no patient discontinuation secondary to adverse effects. Viral rebound did not occur. Relative to baseline, total cholesterol at week 24 fell significantly in the pravastatin (1.2 mmol/l; 17.3%) (P < 0.05) but not in the dietary advice (0.3 mmol/l; 4%) group. The difference between the two groups approached significance at week 24 (P = 0.051). This fall was accounted for entirely by a reduction in low density lipoprotein [calculated change 1.24 mmol/l (19%) and 0.07 mmol (5.5%) in pravastatin and dietary advice groups, respectively] as high density lipoprotein rose non-significantly by 0.6 mmol/l in both groups. Weight, basal metabolic rate, fasting glucose and triglycerides did not change significantly in either group. Dietary advice plus pravastatin significantly reduced total cholesterol in HIV-positive individuals taking protease inhibitors, without significant adverse effects. The inclusion of pravastatin substantially increases the magnitude of the change, which is comparable with changes achieved in endogenous hyperlipidaemia.",2001.0,0,0 904,11505177,Lipid-lowering drugs and risk of myopathy: a population-based follow-up study.,D Gaist; L A Rodríguez; C Huerta; J Hallas; S H Sindrup,"We conducted a population-based cohort study to estimate the risk of myopathy associated with use of lipid-lowering drugs. Using data from general practices in the United Kingdom in 1991 through 1997, we identified three cohorts of individuals 40 to 74 years of age. One cohort comprised 17,219 persons who had received at least one prescription for lipid-lowering drugs in the period; a second cohort consisted of patients with a hyperlipidemia diagnosis who had not been prescribed lipid-lowering drugs (N = 28,974); and a third cohort comprised 50,000 individuals from the general population with no diagnosis of hyperlipidemia. The incidence rate of myopathy in the cohort of users of lipid-lowering drugs was 2.3 per 10,000 person-years [95% confidence interval (95% CI) = 1.2-4.4], which exceeded the incidence rates observed in the nontreated hyperlipidemia cohort [0 per 10,000 person-years (95% CI = 0.0-0.4)] and the general population [0.2 per 10,000 person-years (95% CI = 0.1-0.4)]. The relative risks of myopathy in current users of fibrates and statins compared with nonusers were 42.4 (95% CI = 11.6-170.5) and 7.6 (95% CI = 1.4-41.3), respectively. Potential risk factors other than drug use could not explain our findings in the nested case-control analysis. We conclude that use of lipid-lowering drugs is associated with a substantially greater risk of myopathy, which is most pronounced for fibrates. The absolute risk of myopathy in users of lipid-lowering drugs is, however, small.",2001.0,1,1 905,11507323,Pleiotropic effects of statins: do they matter?,A M Gotto; J A Farmer,"Treatment with the 3-hydroxy-3-methylglutaryl coenyzme A reductase inhibitors (or statins) reduces the risk for cardiovascular events across a broad spectrum of patient profiles, as evidenced by both primary prevention and secondary prevention trials. Improved survival by way of reduced deaths from coronary heart disease was also reported with these agents, which are primarily indicated for substantial reduction in LDL-cholesterol levels. However, the statins are extremely complex drugs and exhibit a wide variety of vascular effects that may or may not be dependent on their lipid-modifying properties. These so-called pleiotropic effects include alterations of endothelial function, inflammation, coagulation, and plaque stability. The relative contribution of the nonlipid effects of statin therapy to the well-documented clinical benefits is currently under intense investigation.",2001.0,0,0 906,11507334,Therapy and clinical trials.,N Abate; I Jialal,,2001.0,0,0 907,11511118,"Patients, families and populations at high risk for coronary heart disease.",M Higgins,,2001.0,0,0 908,11514481,Population implications of lipid lowering for prevention of coronary heart disease: data from the 1995 Scottish health survey.,I U Haq; L E Ramsay; E J Wallis; C G Isles; L D Ritchie; P R Jackson,"To determine the proportion of the population, firstly, with cholesterol >/= 5.0 mmol/l and, secondly, with any cholesterol concentration, who might benefit from statin treatment for the following: secondary prevention of coronary heart disease (CHD); primary prevention at CHD risk 30%, 20%, 15%, and 6% over 10 years; and primary prevention at projected CHD risk 20% over 10 years (CHD risk at age 60 years if actual age < 60 years). Random stratified sample of 3963 subjects aged 35-64 years from the Scottish health survey 1995. For secondary prevention 7.8% (95% confidence interval (CI) 6.9% to 8.6%) of the population with cholesterol >/= 5.0 mmol/l would benefit from statins. For primary prevention, the prevalence of people at CHD risk 30%, 20%, 15%, and 6% over 10 years is 1.5% (95% CI 1.2% to 1.9%), 5.4% (95% CI 4.7% to 6.1%), 9.7% (95% CI 8.8% to 10.6%), and 32.9% (95% CI 31.5% to 34.4%), respectively. At projected CHD risk 20% over 10 years, 12.4% (95% CI 11.4% to 13.5%) would be treated with statins. Removing the 5.0 mmol/l cholesterol threshold makes little difference to population prevalence at high CHD risk. Statin treatment would be required for 7.8% of the population for secondary prevention. For primary prevention, among other factors, guidelines should take into account the number of patients needing treatment at different levels of CHD risk when choosing the CHD risk to target. The analysis supports a policy of targeting treatment at CHD risk 30% over 10 years as a minimum, as recommended in current British guidelines, with a move to treating at CHD risk 15% over 10 years as resources permit.",2001.0,0,0 909,11522100,Effects of angiotensin-converting enzyme inhibitor and steroid therapy on proteinuria in FSGS: a retrospective study in a single clinic.,K P Stiles; K C Abbott; P G Welch; C M Yuan,"We retrospectively evaluated the response to steroids (S) +/- angioten-sin-converting enzyme inhibitors (ACEI) vs. ACEI in nephrotic patients with FSGS seen in our clinic from 1992 - 1999. Of 48 patients with biopsy-proven FSGS, 30 had pre-therapy and follow-up evaluations of proteinuria. Of these, 22 were nephrotic (> or = 3 g protein/24 h). Twelve/22 were treated with S and 10/22 with ACEI +/- HMG-CoA reductase inhibitor (statin) alone. 92% of S patients received ACEI during follow-up, 83% concurrently with steroid treatment. The two cohorts (S vs. ACEI) were not different in age (34 +/- 12 vs. 33 +/- 12), sex (75% vs. 78% male), or ethnicity (83% vs. 83% African American). Mean follow-up time was 16 (range 4 - 61 months) vs. 23 months (range 6 - 56 months). Mean S dose was 70 mg qd (range 60 - 100 mg), with mean treatment duration of 4 months. Nephrotic patients were compared with regard to degree of proteinuria at follow-up. There were no complete remissions (proteinuria < or = 200 mg/24 h) in either group. There was no difference in partial remissions (> 200 mg to < 3 g proteinuria/24 h) between the two groups - 5/12 vs. 6/10 (p = 0.434). There was no difference in the proportion of patients progressing to ESRD. Although proteinuria decreased significantly with time in both groups, there was no significant treatment effect. There was no significant time or treatment effect on serum creatinine. Mean arterial pressure and serum cholesterol were not significantly different between the groups. Thus, treatment with S +/- ACEI is no more effective in reducing proteinuria in FSGS than treatment with ACEI alone.",2002.0,0,0 910,11523726,Drug interactions with irbesartan.,M R Marino; N N Vachharajani,"Irbesartan is an angiotensin II receptor antagonist indicated for the treatment of patients with hypertension. Although irbesartan does not require biotransformation for its pharmacological activity, it does undergo metabolism via the cytochrome P450 (CYP) 2C9 isoenzyme and negligible metabolism by the CYP3A4 isoenzyme. The long term treatment of patients with hypertension is generally required for effective management of the disease, and the use of concurrent medications is usually inevitable. This paper reviews the drug and food interaction trials involving irbesartan that have been conducted to date. Based on the available literature, no significant interactions have been identified between irbesartan and hydrochlorothiazide, nifedipine, simvastatin, tolbutamide, warfarin, magnesium and aluminum hydroxides, digoxin or food. Fluconazole did increase the steady-state peak plasma concentration (by 19%) and area under the concentration-time curve (by 63%) of irbesartan, but these increases are not likely to be clinically significant. In summary, irbesartan has demonstrated minimal potential for drug or food interactions in trials conducted to date.",2002.0,0,0 911,11524031,Do statins afford neuroprotection in patients with cerebral ischaemia and stroke?,C J Vaughan; N Delanty; C T Basson,"An emerging body of evidence indicates that beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or 'statins', provide neuroprotection in addition to reducing ischaemic stroke. Statins reduce the incidence of ischaemic stroke by stabilising atherosclerotic plaques in the precerebral vasculature and through antithrombotic actions, and the neuroprotective effects of statins may confer significant clinical benefit. Some of these neuroprotective effects are likely to be cholesterol independent and mediated by the interruption of isoprenoid biosynthesis. Therapy with statins may modulate endothelial function and preserve blood flow to regions exposed to an ischaemic insult. In particular, statin-mediated preservation of endothelial nitric oxide synthase activity in cerebral vasculature, especially in the ischaemic penumbra, may limit neurological deficit. Moreover, putative anti-inflammatory and antioxidant properties of statins may confer additional neuroprotection. Further large clinical trials are necessary to address the role of statin therapy in the primary prevention of stroke, small vessel cerebrovascular disease and vascular dementia.",2001.0,0,0 912,11524058,Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolemia.,A G Olsson; J Pears; J McKellar; J Mizan; A Raza,"Rosuvastatin is a new, synthetic, orally active statin, with marked low-density lipoprotein (LDL) cholesterol-lowering activity. We conducted 2 dose-ranging studies. In the first study, after a 6-week dietary run-in, 142 moderately hypercholesterolemic patients were randomized equally to receive double-blind placebo or rosuvastatin 1, 2.5, 5, 10, 20, or 40 mg or open-label atorvastatin 10 or 80 mg once daily for 6 weeks; in the second study, conducted to extend the rosuvastatin dose range, 64 patients were randomized to double-blind, once-daily placebo or rosuvastatin 40 or 80 mg (1:1:2 ratio) for 6 weeks. Data from both studies were combined for analysis of lipid effects. No statistical comparison of atorvastatin arms with placebo or rosuvastatin was performed. Rosuvastatin was associated with highly significant dose-dependent reductions in LDL cholesterol compared with placebo (p <0.001); decreases ranged from 34% (1 mg) to 65% (80 mg). Linear regression analysis indicated an additional 4.5% LDL cholesterol reduction for each doubling of the rosuvastatin dose. Across the dose range, approximately 90% of LDL cholesterol reduction occurred within the first 2 weeks of treatment. Significant, dose-dependent reductions in total cholesterol and apolipoprotein B with rosuvastatin were also observed (p <0.001). High-density lipoprotein cholesterol increases and triglyceride reductions were consistently observed and statistically significant at some dose levels. All lipid ratios were significantly reduced at all rosuvastatin dose levels (p <0.001). Adverse events were similar across placebo and active treatments. No significant increases in alanine aminotransferase or creatine kinase were seen in any patient. Over 6 weeks, rosuvastatin produced large, rapid, dose-dependent LDL cholesterol reductions and was well tolerated in hypercholesterolemic patients.",2001.0,0,0 913,11524554,Hormone replacement in women with a history of breast cancer.,K I Pritchard,"Estrogen used alone (estrogen replacement therapy [ERT]) or with the addition of progesterone (hormone replacement therapy [HRT]) is known to be effective in reducing menopausal symptoms including hot flashes, vaginal dryness and urinary symptoms. It has been traditionally contraindicated, however, in women with a previous diagnosis of breast cancer because of fear that it may increase the risk of recurrence. There are considerable basic scientific data but little methodologically strong observational data and none from randomized studies concerning the use of ERT in women with a prior diagnosis of breast cancer. From our knowledge of the physiology of breast cancer, however, estrogen and/or progestational agents should be used with caution in women with a previous diagnosis of breast cancer. There are currently many alternatives to ERT/HRT in the prevention of menopausal symptoms such as vitamin E, clonidine and selective serotonin reuptake inhibitor antidepressants such as venlafaxine. There are also a variety of other approaches to the prevention of osteoporosis and cardiovascular disease including bisphosphonates, diet, and exercise; and diet, exercise, and statins, respectively. Other suggested beneficial effects of estrogen such as colon cancer prevention can be approached by the use of aspirin or the non-steroidals. Several trials of ERT/HRT used for 2 years versus no therapy in menopausal women with a previous diagnosis of breast cancer are ongoing in Europe and Britain, and should give us stronger data as to the role of HRT in this setting.",2001.0,0,0 914,11526345,The continuation of the Prevention of Events With Angiotensin-Converting Enzyme Inhibition (PEACE) Trial.,M A Pfeffer; M Domanski; J Verter; M Dunlap; G C Flaker; B Gersh; J Hsia; A D Goldberg; M C Limacher; A P Maggioni; Y Rosenberg; J L Rouleau; J W Warnica; A G Wasserman; E Braunwald; PEACE Investigators,,2001.0,0,0 915,11526915,"In vitro antitumor activity of cerivastatin, a novel and potent HMG-CoA reductase inhibitor.",W Feleszko; I Mlynarczuk; D Nowis,,2001.0,0,0 916,11528008,Cholesterol lowering in the older population: time for reassessment?,N Kagansky; S Levy; Y Berner; E Rimon; H Knobler,"Hypercholesterolaemia is an established major risk factor for coronary heart disease (CHD) in the general population. In the vast majority of studies that focused on this particular age group and carefully eliminated other confounding factors such as co-morbid conditions, hypercholesterolaemia was a risk factor for CHD in the older population. Because the prevalence of CHD increases with advancing age, studies that consider not only the relative risk attributed to cholesterol but also the absolute numbers of people affected, show hypercholesterolaemia to be an even stronger risk factor in the elderly. Large primary and secondary prevention studies of HMG-CoA reductase inhibitors (statins) in the elderly have shown a reduction in major coronary events similar to that observed in the younger age group. The role of hypercholesterolaemia as a risk factor for stroke is less clear, and a major limitation is the heterogeneous nature of the disease. Nevertheless, most studies that evaluated non-haemorrhagic strokes separately showed a positive association with cholesterol levels, and statin therapy is effective in preventing stroke. These data provide a rationale for treating older hypercholesterolaemic people with statins, not only to prevent CHD, but also to prevent stroke.",2001.0,0,0 917,11529594,Response to erythropoietin in chronic myelomonocytic leukaemia.,I Kerridge; A Spencer; A Azzi; M Seldon,,2002.0,0,0 918,11529595,Diltiazem-mediated inhibition of sildenafil metabolism may promote nitrate-induced hypotension.,L Howes,,2002.0,0,0 919,11530028,Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins.,T C Andrews; C M Ballantyne; J A Hsia; J H Kramer,"Most patients fail to achieve and maintain low-density lipoprotein (LDL) cholesterol goals established by the National Cholesterol Education Program (NCEP). The Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS) was a randomized study comparing the efficacy and safety of five statins and their ability reduce LDL cholesterol to the NCEP target level. Of 7542 patients screened, 3916 hypercholesterolemic patients were randomly assigned to treatment with a statin, beginning with the lowest recommended dose (atorvastatin, pravastatin, and simvastatin, 10 mg; fluvastatin and lovastatin, 20 mg). If the NCEP target was not achieved, the dose was titrated up to the recommended maximum (atorvastatin, fluvastatin, and lovastatin, 80 mg; pravastatin and simvastatin, 40 mg). The total duration of treatment was 54 weeks. Atorvastatin achieved the greatest mean reduction in LDL cholesterol: 36% +/- 11% at 6 weeks (initial dose) and 42% +/- 13% at 54 weeks. More patients receiving atorvastatin at its initial dose (53%, 997 of 1888) achieved their NCEP target levels than patients receiving simvastatin (38%, 174 of 462), lovastatin (28%, 134 of 472), pravastatin (15%, 71 of 461), or fluvastatin (15%, 69 of 474) at the initial dose. Atorvastatin-treated patients were more likely to maintain their target levels from week 6 to week 54. The percent reduction in LDL cholesterol achieved at the initial dose correlated strongly with the proportion of patients who maintained their goals at 54 weeks (r = -0.84). For patients treated with statins, providing a greater margin between the NCEP target level and the achieved LDL cholesterol level enhances the likelihood of maintaining NCEP goal levels.",2001.0,1,1 920,11531002,"The Sixth International Lupus Conference, Barcelona 24-28 March 2001.",Y Schoenfeld; I Krause; I Krause; M Khamashta; G Hughes,,2002.0,0,0 921,11545752,The platelet Pl(A2) and angiotensin-converting enzyme (ACE) D allele polymorphisms and the risk of recurrent events after acute myocardial infarction.,P F Bray; C P Cannon; P Goldschmidt-Clermont; L A Moyé; M A Pfeffer; F M Sacks; E Braunwald,"Chromosome 17q21-23 harbors genes for platelet glycoprotein IIIa and angiotensin-converting enzyme (ACE), which are polymorphic for alleles Pl(A2) and ACE ""D."" These alleles have been independently and often associated with ischemic coronary artery disease (CAD). We sought to determine if the Pl(A2) and ACE D polymorphisms were risk factors for recurrent coronary events. In the Cholesterol And Recurrent Events (CARE) trial, 4,159 men and women with documented myocardial infarction (MI) were randomized to receive either placebo or pravastatin, and were followed prospectively for 5 years. Pl(A) and ACE genotypes were determined in 767 patients: 385 cases who had experienced a recurrent primary event (death due to coronary disease or nonfatal MI), and 382 age- and gender-matched controls. In patients receiving placebo, the Pl(A1,A2) genotype conferred a relative risk (RR) of 1.38 (confidence intervals [CI] 1.04 to 1.83; p = 0.028; adjusted RR = 1.32, CI = 0.99 to 1.76; p = 0.058]) for the primary end point. Compared with the placebo group, pravastatin reduced the excess RR of coronary disease death and recurrent MI in the Pl(A1,A2) patient population by 31% (p = 0.06). The ACE D allele appeared to have modestly additive effects on the Pl(A1,A2) risk. Among the Pl(A1,A2) patients, pravastatin had little effect on the risk of recurrent events with the ACE II genotype, but reduced the adjusted RR from 1.42 (placebo) to 0.58 for ACE ID patients, and from 1.56 (placebo) to 0.83 for ACE DD. The Pl(A1,A2) genotype was associated with an excess of recurrent coronary events in patients after MI who did not receive pravastatin, and the ACE D allele added to this risk. These data suggest that it would be important to perform a larger study to address the potential role of these genotypes in therapeutic decision making.",2001.0,0,0 922,11545771,Statin therapy and the acute inflammatory response after coronary artery bypass grafting.,D J Brull; J Sanders; A Rumley; G D Lowe; S E Humphries; H E Montgomery,,2001.0,0,0 923,11547217,,,,,0,0 924,11549708,Simvastatin increases serum osteocalcin concentration in patients treated for hypercholesterolaemia.,M H Chan; T W Mak; R W Chiu; C C Chow; I H Chan; C W Lam,"Animal studies, experimental models on cell lines, and epidemiological case-control studies have all suggested the possibility that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors have a beneficial effect on bone metabolism. However, all epidemiological studies are not prospective in nature and based on either measurement of bone mineral density or fracture risk. They also differ in recruitment criteria, definition of statin exposure, and outcome assessment. We performed a first prospective study using specific biochemical bone markers on 17 hypercholesterolaemic non-osteoporotic subjects treated with a therapeutic dose of simvastatin 20 mg daily for 4 weeks. Our results show that serum osteocalcin concentration increased significantly (p-value < 0.05) 4 weeks after therapy, whereas other bone markers including serum bone-specific alkaline phosphatase activity, urine deoxypyridinoline, and urine cross-linked N-telopeptides of type I collagen did not show any significant changes. Our data support that simvastatin causes a beneficial effect on bone metabolism as reflected by an increase in serum osteocalcin concentration. This added beneficial effect of statins on bone metabolism could potentially allow statins to become the first effective anabolic agent for the treatment of osteoporosis. We urge that priority should be given to a randomised controlled study to re-evaluate this group of drugs.",2001.0,0,0 925,11550660,Effect of atorvastatin on serum uric acid levels.,A Kakafika; V Tsimihodimos; M Elisaf,,2001.0,0,0 926,11551003,Long-term effects on cholesterol levels and the utilization of lipid-lowering drugs of a hospital-based programme for secondary prevention of coronary artery disease.,M Stagmo; L Westin; R Carlsson; B Israelsson,"The study was designed to determine whether a 1-year hospital-based secondary prevention programme would have any long-term effects on serum lipid levels and the use of lipid-lowering drugs in patients with coronary artery disease 4 years after referral to primary care facilities for follow-up. After acute myocardial infarction or coronary bypass surgery, 241 consecutive patients were randomly assigned to conventional care (CC) by the primary health care facilities or to a 1-year hospital-based secondary prevention programme (SPP) with target levels for serum cholesterol (< 5.2 mmol/l) and triglycerides (< 1.5 mmol/l). After 1 year all patients were referred to the primary care sector for a further 4-year follow-up. At the 1-year follow-up there was a significant decrease in serum cholesterol, LDL-cholesterol and triglyceride levels in the SPP group but no change in the CC group, and lipid-lowering drugs were used more frequently in the SPP group. These changes were maintained after 5 years. The proportion of patients achieving target serum cholesterol and triglyceride levels were larger in the SPP group. Initiatives regarding cholesterol lowering and drug treatment taken by specialists within a structured hospital-based SPP have long-term impact. Accordingly, drug treatment should be initiated and adjusted to adequate doses before patients are referred to primary care for follow-up.",2002.0,0,0 927,11555537,Lipid disorders: justification of methods and goals of treatment.,J B Braunstein; A Cheng; G Cohn; M Aggarwal; C M Nass; R S Blumenthal,"Dyslipidemia is a major risk factor for coronary heart disease (CHD). While some uncertainty exists about the clinical significance of improving high-density lipoprotein cholesterol and triglyceride levels, large primary- and secondary-prevention studies aimed at lowering low-density lipoprotein cholesterol levels with statins have convincingly reduced CHD events and total mortality. Despite the strong clinical evidence and widely publicized treatment guidelines, many hyperlipidemic patients receive inadequate lipid-lowering treatment. This failure to achieve clinical treatment goals may be due to poor physician adherence to treatment guidelines, patient noncompliance, and the presence of concomitant medical conditions that modify typical hyperlipidemia management. This review considers the challenges and available strategies to optimize lipid management in patients at risk for CHD.",2001.0,0,0 928,11558479,Rigorous detection and vigorous treatment of familial hypercholesterolaemia.,P N Durrington,,2001.0,0,0 929,11558482,"Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial.",T J Smilde; S van Wissen; H Wollersheim; M D Trip; J J Kastelein; A F Stalenhoef,"High LDL-cholesterol is a risk factor for atherosclerosis. We aimed to determine whether aggressive cholesterol lowering with statins was more effective than conventional statin treatment in this disease. We investigated the effect of high-dose atorvastatin on carotid atherosclerosis progression. We did a randomised, double-blind clinical trial in 325 patients with familial hypercholesterolaemia. Patients were given either atorvastatin 80 mg (n=160) or simvastatin 40 mg (n=165) daily, on an intent-to-treat basis. The primary endpoint was the change of carotid intima media thickness (IMT), as measured by quantitative B-mode ultrasound, over 2 years. The overall baseline IMT, combining the measurements of the common and internal carotid artery and the carotid bifurcation on both sides, was 0.93 mm (SD 0.22) and 0.92 mm (0.21) in the atorvastatin and simvastatin groups, respectively. After treatment with atorvastatin for 2 years, IMT decreased (-0.031 mm [95% CI -0.007 to -0.055]; p=0.0017), whereas in the simvastatin group it increased (0.036 [0.014-0.058]; p=0.0005). The change in thickness differed significantly between the two groups (p=0.0001). Atorvastatin showed greater reductions in cholesterol concentrations than did simvastatin. HDL-cholesterol concentrations increased in both groups. Both drugs were equally well tolerated. Our results show that aggressive LDL-cholesterol reduction by atorvastatin was accompanied by regression of carotid intima media thickness in patients with familial hypercholesterolaemia, whereas conventional LDL lowering was not.",2001.0,0,0 930,11559693,Cardiovascular complications of renal disease.,A G Jardine; K McLaughlin,,2001.0,0,0 931,11560203,"Lipid-lowering efficacy, safety, and costs of a large-scale therapeutic statin formulary conversion program.",A J Taylor; K Grace; J Swiecki; R Hyatt; H Gibbs; M Sheikh; P G O'Malley; S P Lowenthal; M West; J Spain; K Maneval; D L Jones,"To assess the lipid-lowering efficacy, safety, and costs of a large-scale statin formulary conversion program. Prospective, observational study. Tertiary academic medical center. A total of 980 patients consented to participate; 942 patients completed the study. Patients were converted from their current statin therapy to either cerivastatin 0.4 or 0.8 mg/day, or simvastatin 80 mg/day, using a conversion algorithm. Efficacy and safety were evaluated at baseline and after 6 weeks of therapy; costs were also measured. Overall attainment of the National Cholesterol Education Program (NCEP) goal for low-density lipoprotein cholesterol (LDL) increased from 64.8% to 74.5% of patients (p<0.001); mean LDL decreased from 115+/-30 mg/dl to 106+/-25 mg/dl (p<0.001). Adverse events occurred in 3% of patients, and included myositis (0.6%) and increased hepatic transaminases (0.1%). Overall costs were reduced by $115/patient treatment-year. Statin therapeutic interchange can improve lipid control at reduced costs. The possibility of uncommon but potentially serious adverse effects suggests that these programs require appropriate monitoring.",2002.0,0,0 932,11562276,Non-peptidic prenyltransferase inhibitors: diverse structural classes and surprising anti-cancer mechanisms.,R A Gibbs; T J Zahn; J S Sebolt-Leopold,"The development of farnesyltransferase inhibitors (FTIs) has been one of the most active areas of anticancer drug development for the past ten years. This review presents a general overview of the developments in this area, along with a critical appraisal of the anticancer activity of FTIs. A historical survey of the protein prenylation field is given, in particular to emphasize the key role played by the Ras oncoprotein in driving the discovery of prenyltransferase enzymes. The different classes of prenylated proteins will be described along with the biochemical characteristics of the key drug target--farnesyltransferase (FTase). Numerous potent farnesyltransferase inhibitors have been developed. The FTIs developed can be separated into three different categories, based on their origin and/or mechanism of action: a) natural products; b) peptidomimetics and other CAAX-competitive inhibitors; c) farnesyl pyrophosphate (FPP) mimetics or analogs and other FPP-competitive inhibitors. Along with a survey of newer FTIs in each class, the development of several representative, potent compounds will be discussed in depth as we discuss the potential advantages and liabilities of each class. Particular emphasis is given to the discovery of new, more potent FPP-competitive FTIs of several diverse structural classes. Testing of different FTIs for their ability to block the growth of various cancer cell types in animal models will be discussed. There are a number of key differences between these compounds and traditional cytotoxic cancer chemotherapeutic agents, with surprising exceptions to their expected modes of action. As some FTIs have entered human clinical trials, answers may soon become available to key mechanistic questions concerning the extent and nature of their antitumor growth properties.",2002.0,0,0 933,11563401,Pharmacological effects of HMG CoA reductase inhibitors other than lipoprotein modulation.,C M White,"The HMG CoA reductase inhibitors reduce levels of low-density lipoproteins, raise high-density lipoproteins, and lower triglycerides. However, there are other pharmacological effects derived from HMG CoA reductase inhibitor therapy. Certain HMG CoA reductase inhibitors affect atherosclerotic plaque composition, endothelial function, platelet and clotting factors, and immune functioning. The unique extrahepatic pharmacological profile of agents in this class has not been fully characterized. All of the HMG CoA reductase inhibitors studied have improved endothelium-dependent vasodilatation. Vascular smooth muscle proliferation is not significantly affected by pravastatin but is by the other agents. Of all the HMG CoA reductase inhibitors, cerivastatin is the most potent inhibitor of vascular smooth muscle proliferation. Pravastatin is the only agent proven to significantly reduce platelet-thrombus formation and fibrinogen levels. Simvastatin has no effect on platelet-thrombus formation or fibrinogen levels, while atorvastatin and lovastatin have been shown to increase fibrinogen in some studies. Plasminogen activator inhibitor-1 levels are decreased by pravastatin, are not affected by atorvastatin, and are significantly increased by lovastatin and simvastatin. Pravastatin also has clinical benefits in transplant medicine as a result of inhibiting natural killer cell function, an effect that has not been explored with other HMG CoA reductase inhibitors.",2001.0,0,0 934,11564386,Comparison of the efficacy of atorvastatin versus cerivastatin in primary hypercholesterolemia.,D Hunninghake; W Insull; R Knopp; M Davidson; L Lohrbauer; P Jones; S Kafonek,"This 6-week Prospective, Randomized, Open-label Blinded End point (PROBE) study conducted at 12 sites in the United States compared the efficacy and safety of atorvastatin with cerivastatin. In all, 215 hypercholesterolemic patients (low-density lipoprotein [LDL] cholesterol > or = 160 mg/dl [4.14 mmol/L]; triglycerides < or = 400 mg/dl [4.52 mmol/L]) were randomized to receive either atorvastatin 10 mg once daily (n = 108) or cerivastatin 0.3 mg once daily (n = 107). Efficacy was assessed by measuring changes from baseline in LDL cholesterol, total cholesterol, high-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. Atorvastatin produced significantly greater (p < 0.0001) reductions from baseline to week 6 in LDL cholesterol (37.7% vs 30.2%), total cholesterol (27.5% vs 22.2%), and apolipoprotein B (28.6% vs 21.2%), and a significantly greater (p < 0.05) increase from baseline to week 6 in high-density lipoprotein cholesterol (6.8% vs 4.3%) than cerivastatin. Atorvastatin treatment was also associated with a greater percent decrease from baseline to week 6 in triglycerides, with a trend toward statistical significance (p = 0.0982). The percentage of patients that achieved the National Cholesterol Education Program LDL cholesterol goal was greater for those receiving atorvastatin (73%) than for those receiving cerivastatin (66%). The proportion of patients experiencing drug-attributable adverse events, which were mostly mild to moderate and related to the digestive system, was significantly less (p < 0.05) with atorvastatin (5%) than with cerivastatin (14%) treatment. In conclusion, atorvastatin (10 mg/day) is more effective at lowering LDL cholesterol in hypercholesterolemic patients than cerivastatin (0.3 mg/day). Both atorvastatin and cerivastatin are well tolerated, with safety profiles similar to other members of the statin class.",2001.0,0,0 935,11564402,Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons.,W S Aronow; C Ahn; I Kronzon; M E Goldman,,2001.0,0,1 936,11569948,Apoptosis modulators as cancer therapeutics.,L Z Penn,"In the past ten years a wealth of fundamental knowledge delineating the molecular mechanism(s) of apoptosis has emerged, and can now be exploited to identify novel apoptotic modulators for the treatment of cancer. Two distinct yet complimentary classes of non-genotoxic agonists that can selectively kill tumor cells are discussed; agents that target 'classical' and 'atypical' apoptotic signaling pathways. The goal of agents targeting classical apoptosis and survival pathways is to directly modulate key apoptotic regulators such as Bcl-2, Akt/PKB, and p53. The aim of agents targeting atypical apoptotic pathways is to target signaling cascades whose inhibition remains non-lethal in normal cells, yet is suicidal in tumor cells. Such compounds presently under development include inhibitors of heat shock protein 90, histone deacetylases and HMG-CoA reductase. Both classes of apoptotic modulators have merit and identification of additional agonists of this nature will provide the many diverse cytotoxic agents that are required to combat the many diseases we call cancer.",2001.0,0,0 937,11570656,Smoking diminishes the beneficial effect of statins: observations from the landmark trials.,H J Milionis; E Rizos; D P Mikhailidis,"The landmark statin trials showed a significant reduction in morbidity and mortality associated with ischemic heart disease. However, it may not be widely appreciated that smoking had a marked adverse effect on outcome in these trials. In both the primary and secondary prevention setting, the effect of smoking was broadly similar. Smoking markedly increased the risk of events in the placebo and treatment groups. For example, in the primary prevention trials, this risk was 74-86% higher when smokers were compared with nonsmokers in the placebo groups. The corresponding figures for the secondary prevention trials were 23-61%. The risk of events in untreated nonsmokers was of a similar order to that seen in smokers taking statins. Although statin treatment was associated with a significant reduction in events in smokers, the best outcome was observed in nonsmokers treated with statins (primary prevention: lovastatin or pravastatin; secondary prevention: pravastatin or simvastatin). The highest risk of events in any group was in the smokers on placebo. This information may increase clinician and patient awareness as to the marked harmful effect of smoking relative to effective, evidence-based treatment (ie, the use of statins).",2001.0,0,0 938,11570952,Differences between primary vs secondary prevention trials regarding the stroke protective effect of antihypertensive drugs.,A Fournier; R Oprisiu; J M Achard,,2002.0,0,0 939,11571421,Current immunosuppressant regimens: considerations for critical care.,B D Kahan; S M Koch,"While current immunosuppressive drug regimens have significantly increased the rate of successful transplantation outcomes, they convey potentially serious and overlapping adverse effects. Cyclosporine and tacrolimus are the cornerstones of current immunosuppression, achieving excellent one-year renal graft survival rates. Other promising new drugs include sirolimus, which has been demonstrated to reduce efficacy failure rates among renal transplant recipients, and everolimus, which is currently undergoing clinical trials. Agents targeting novel sites in the immune response or disrupting the ischemia-reperfusion cascades are currently under development. Among them, only FTY720 is undergoing large-scale human clinical trials. With its unique mechanism of action and synergistic interactions with cyclosporine and sirolimus, it may provide the foundation for a new era in immunosuppression.",2001.0,0,0 940,11571478,"High-density lipoprotein: epidemiology, metabolism, and antiatherogenic effects.",P P Toth,,2001.0,0,0 941,11571816,Effect of pravastatin-to-simvastatin conversion on low-density-lipoprotein cholesterol.,M K Ito; J C Lin; A P Morreale; D B Marcus; R Shabetai; T R Dresselhaus; R R Henry,"The effects of a pravastatin-to-simvastatin conversion program on low-density-lipoprotein (LDL) cholesterol levels were studied. Patients receiving pravastatin at a Veterans Affairs medical center were switched to simvastatin beginning in 1997. The dosage of simvastatin was based on the additional percent reduction in LDL cholesterol needed to achieve the goal specified by the National Cholesterol Education Program. The primary endpoint was the change in the percentage of patients meeting their LDL cholesterol goal at baseline and follow-up. Changes in lipid indices, the relative risk (RR) of coronary heart disease (CHD), and program costs were also evaluated. A total of 1032 patients completed the program. The mean +/- S.D. daily doses of pravastatin and simvastatin were 25.2 +/- 11.3 and 22.7 +/- 13.3 mg, respectively. Median baseline and follow-up LDL cholesterol concentrations were 116 and 99 mg/dL, respectively (p < 0.001). Overall, 44% of the patients met their LDL cholesterol goal while taking pravastatin, compared with 69% after conversion to simvastatin (p < 0.001). The predicted mean RR of a future CHD event (based on changes in serum lipids) was 0.87 (95% confidence interval, 0.83-0.91) four years after conversion. The total cost of the program was $40,644 in the first year, and there was a net saving thereafter. Therapeutic interchange between pravastatin and simvastatin increased the number of patients meeting their LDL cholesterol goal.",2002.0,0,0 942,11572739,"Low-density lipoprotein size, pravastatin treatment, and coronary events.",H Campos; L A Moye; S P Glasser; M J Stampfer; F M Sacks,"Small low-density lipoprotein (LDL) particle size has been hypothesized to be a risk factor for coronary heart disease (CHD). Animal models link large LDL to atherosclerosis. However, the strong association between small LDL and other risk factors, particularly triglyceride levels, impedes determining whether LDL size independently predicts CHD in humans. To examine whether LDL size is an independent predictor of recurrent coronary events in patients with known CHD, as opposed to a marker for other lipid abnormalities. Prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin conducted in 1989-1996. Survivors of myocardial infarction with typical LDL concentrations (416 cases and 421 controls). Subsequent myocardial infarction or coronary death during the 5-year follow-up, analyzed by quintile of LDL particle size and by treatment group. Overall, the mean LDL size was identical in cases and controls (25.6 nm). In patients in the placebo group, large LDL predicted coronary events in models adjusted only for age (relative risk [RR], 1.79; 95% confidence interval [CI], 1.01-3.17) and for age and lipid and nonlipid risk factors (RR, 4.00; 95% CI, 1.81-8.82), comparing those in the highest (mean, 26.6 nm) and lowest (mean, 24.5 nm) quintiles of LDL size. This increased risk was not present in those taking pravastatin (age-adjusted analysis: RR, 0.98; 95% CI, 0.47-2.04; P =.046 for interaction for a difference in the effect of LDL size on coronary events between the placebo and treatment groups; multivariable analysis: RR, 1.33; 95% CI, 0.52-3.38; P =.11 for interaction). Large LDL size was an independent predictor of coronary events in a typical population with myocardial infarction, but the adverse effect was not present among patients who were treated with pravastatin. Identifying patients on the basis of LDL size may not be useful clinically, since effective treatment for elevated LDL cholesterol concentrations also effectively treats risk associated with large LDL.",2001.0,0,1 943,11574788,Triglycerides: risk factor or fellow traveler?,J S Forrester,"An unresolved issue in preventive cardiology is whether the serum triglyceride level is an independent risk factor for coronary heart disease and, as a direct practical consequence, whether it has value as a diagnostic test. Evidence published in the past year has contributed substantially to clarifying these issues. In this review, we discuss the data that bears upon the importance of triglycerides as a risk factor and the implications of recent clinical trials directed at lipid lowering. We then discuss the alternatives for triglyceride lowering therapy in the light of this new knowledge.",2002.0,0,0 944,11575709,A clinical focus on statins.,J Auer; B Eber,"Clinical trials have demonstrated that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) significantly reduce cardiovascular-related morbidity and mortality in patients with and without coronary artery disease. Furthermore, statins are currently the most potent cholesterol-lowering drugs available. Subanalyses of the LIPID study have shown that patients suffering from unstable angina pectoris had at least the same benefit from statin therapy as did patients after myocardial infarction. Studies, recently published (AVERT or MIRACL) provide more information on the topic of therapy with statins in the early phase of acute coronary syndromes.",2002.0,0,1 945,11575710,Ezetimibe (Schering-Plough).,C Q Meng,"Ezetimibe (Sch-58235) is a cholesterol absorption inhibitor being developed by Schering-Plough for the potential treatment of atherosclerosis and hypercholesterolemia. By January 2000, it was in phase III trials in the US [353762], [363364]. Schering-Plough is studying ezetimibe as a monotherapy for lowering lipid levels and, by February 2000, it was also planning combination studies with commonly used statin (HMG-CoA reductase inhibitor) therapies. The company believes that ezetimibe will have additive effects with the statins, inhibiting the absorption of cholesterol in the intestine while the statins work by inhibiting the production of cholesterol in the liver [363364]. In May 2000, Merck signed an agreement with Schering-Plough to develop and market in the US a once-daily, fixed-combination tablet with simvastatin (Zocor) [368021]. This combination has been shown to improve LDL reduction to 52% as compared to 35% with Zocor alone [375966].",2002.0,0,0 946,11575711,S-8921 (Shionogi).,M L Booker,"S-8921 is a sodium/bile acid transport inhibitor under development by Shionogi for the potential treatment of hyperlipidemia. As of June 2000, phase I trials had commenced in Japan and were planned in Europe [370602]. S-8921 acts by altering sodium-dependent transport mechanisms of the brush-borders in the intestinal mucosa, causing bile acids that re-enter the intestine to be excreted rather than reabsorbed [281476].",2002.0,0,0 947,11577798,Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus.,C R Culy; B Jarvis,"Repaglinide, a carbamoylmethyl benzoic acid derivative, is the first of a new class of oral antidiabetic agents designed to normalise postprandial glucose excursions in patients with type 2 diabetes mellitus. Like the sulphonylureas, repaglinide reduces blood glucose by stimulating insulin release from pancreatic beta-cells, but differs from these and other antidiabetic agents in its structure, binding profile, duration of action and mode of excretion. In clinical trials of up to 1-year's duration, repaglinide maintained or improved glycaemic control in patients with type 2 diabetes mellitus. In comparative, 1-year, double-blind, randomised trials (n = 256 to 544), patients receiving repaglinide (0.5 to 4mg before 3 daily meals) achieved similar glycaemic control to that in patients receiving glibenclamide (glyburide) < or = 15 mg/day and greater control than patients receiving glipizide < or = 15 mg/day. Changes from baseline in glycosylated haemoglobin and fasting blood glucose levels were similar between patients receiving repaglinide and glibenclamide in all studies; however, repaglinide was slightly better than glibenclamide in reducing postprandial blood glucose in I short term study (n = 192). Patients can vary their meal timetable with repaglinide: the glucose-lowering efficacy of repaglinide was similar for patients consuming 2, 3 or 4 meals a day. Repaglinide showed additive effects when used in combination with other oral antidiabetic agents including metformin, troglitazone, rosiglitazone and pioglitazone, and intermediate-acting insulin (NPH) given at bedtime. In 1-year trials, the most common adverse events reported in repaglinide recipients (n = 1,228) were hypoglycaemia (16%), upper respiratory tract infection (10%), rhinitis (7%), bronchitis (6%) and headache (9%). The overall incidence of hypoglycaemia was similar to that recorded in patients receiving glibenclamide, glipizide or gliclazide (n = 597) [18%]; however, the incidence of serious hypoglycaemia appears to be slightly higher in sulphonylurea recipients. Unlike glibenclamide, the risk of hypoglycaemia in patients receiving repaglinide was not increased when a meal was missed in 1 trial. In conclusion, repaglinide is a useful addition to the other currently available treatments for type 2 diabetes mellitus. Preprandial repaglinide has displayed antihyperglycaemic efficacy at least equal to that of various sulphonylureas and is associated with a reduced risk of serious hypoglycaemia. It is well tolerated in a wide range of patients, including the elderly, even if a meal is missed. Furthermore, glycaemic control is improved when repaglinide is used in combination with metformin. Thus, repaglinide should be considered for use in any patient with type 2 diabetes mellitus whose blood glucose cannot be controlled by diet or exercise alone, or as an adjunct in patients whose glucose levels are inadequately controlled on metformin alone.",2002.0,0,0 948,11578152,Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease. The Heart and Estrogen/progestin Replacement Study.,J A Simon; D B Hunninghake; S K Agarwal; F Lin; J A Cauley; C C Ireland; J H Pickar,"Animal and observational epidemiologic studies have reported that estrogens may increase the risk for gallstones. No major clinical trials have examined the effect of estrogen plus progestin therapy in postmenopausal women on the risk for biliary tract surgery. To determine the effect of estrogen plus progestin on the risk for biliary tract surgery in postmenopausal women with known coronary artery disease. Randomized, double-blind placebo-controlled trial of postmenopausal hormone therapy for coronary heart disease. 20 U.S. clinical centers. 2253 postmenopausal women with a gallbladder, 44 to 79 years of age at baseline, in the Heart and Estrogen/progestin Replacement Study (HERS). Conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, daily in one tablet or identical placebo. Documented biliary tract surgery. A total of 147 women (7%) were hospitalized for biliary tract surgery in HERS. Treatment with estrogen plus progestin resulted in a marginally significant 38% increase in the relative risk for biliary tract surgery (P = 0.05). A small absolute difference in risk suggested that for every 185 women treated with estrogen plus progestin, one additional woman had biliary tract surgery per year. After adjustment for baseline and in-study statin use, the association was attenuated further (P = 0.09). After adjustment for treatment assignment and other variables, increased body mass index, fibric acid use, and a history of nonsurgical gallbladder disease were associated with an increased risk for biliary tract surgery, whereas statin use was associated with a decreased risk (for each comparison, P < 0.05). Estrogen plus progestin therapy among postmenopausal women with known coronary disease resulted in a marginally significant increase in the risk for biliary tract surgery.",2001.0,0,0 949,11578706,Activation of CD14 on circulating monocytes in patients with acute coronary syndrome.,W H Lee; Y Lee; J O Jeong; S Y Lee; Y H Choi; J E Park,"Increasing evidence supports the involvement of inflammation in acute phase of coronary artery diseases. We analyzed the status of activation of inflammatory cells in 38 patients with acute coronary syndrome, 14 stable angina patients, and 19 control subjects by flow-cytometry. Expression levels of CD14 and the percentage of HLA-DR(+) T-lymphocytes were used as markers of monocyte and T-lymphocytes activation, respectively. The expression of CD14 on monocytes in acute coronary syndrome patients (mean fluorescence intensity+/-S.D.=158.1+/-77.1) was increased significantly in comparison to control subjects (57.1+/-8.0) and the stable angina group (63.6+/-22.0) (P<0.0001 for both). A significantly higher percentage of HLA-DR positive T-lymphocytes (20.4+/-9.0 vs. 12.7+/-3.7%, P<0.01) was observed in acute coronary syndrome patients in comparison to control subjects. Incubation of whole blood cells with bacterial lipopolysaccharide resulted in a 2.4-fold higher secretion of tumor necrosis factor-alpha in acute coronary syndrome patients than in control subjects (P<0.05). When these markers of activation were measured in acute coronary syndrome patients 6 weeks after medical treatment, a significant reduction both in monocytic CD14 expression and percentage of HLA-DR positive T-lymphocytes (P<0.05 for both) was observed. We observed markedly increased levels of monocytic CD14 expression in ACS patients, which appear to indicate the activated status of monocytes and hyper-responsiveness to external stimuli. The CD14 expression levels decreased as the patients were treated, indicating that the expression of CD14 accurately represents the activation status of monocytes during the acute phase of coronary artery diseases.",2002.0,0,0 950,11578788,Rationale and design of the St. Francis Heart Study: a randomized clinical trial of atorvastatin plus antioxidants in asymptomatic persons with elevated coronary calcification.,Y Arad; D Newstein; M Roth; A D Guerci,"Early detection of asymptomatic subjects who are at risk for future cardiovascular events may allow for earlier medical treatment in order to prevent disease progression and future events. Electron-beam computed tomography accurately identifies people with increased coronary calcification, which is correlated with increased coronary plaque mass, increased likelihood of obstructive coronary disease, and increased likelihood of future cardiovascular events. The St. Francis Heart Study is a single-center combination study of men and women 50-70 years old that includes a natural history study of the relation between calcium scores and cardiovascular events (n = 5582), the association of calcium scores with traditional and nontraditional coronary disease risk factors (n = 1160), and a randomized clinical trial designed to assess the benefit of combination treatment with atorvastatin, vitamin C, and vitamin E, as compared to placebos, in subjects with elevated age- and gender-adjusted coronary calcification (n = 1007). Mean follow-up duration will be 4 years. The study is proceeding on schedule with anticipated completion by August 2002. It should provide important information regarding the benefits of treating asymptomatic men and women who have elevated coronary artery calcium, using cholesterol reduction and antioxidant therapy. The article describes the design of the St. Francis Heart Study.",2001.0,0,0 951,11578794,Genetic and metabolic factors predicting risk of cardiovascular disease in familial hypercholesterolemia.,T J Smilde; S van Wissen; H Wollersheim; J J Kastelein; A F Stalenhoef,"Familial hypercholesterolemia is a hereditary metabolic disorder characterised by high low-density lipoprotein cholesterol levels and an extreme risk of premature cardiovascular disease. In patients with heterozygous familial hypercholesterolemia a substantial variation is seen in both the severity of the hypercholesterolemia and onset of atherosclerotic disease symptoms. We discuss the contribution of additional atherogenic risk factors of metabolic, environmental and genetic origin. Subclinical disease measurements, such as the intima media thickness (IMT), assessed by ultrasonography, may contribute to a better risk prediction of future cardiovascular disease in these patients.",2002.0,0,0 952,11582622,Management of acute myocardial infarction in Portugal. Results of a nationwide survey.,J Morais; D Ferreira; R Soares; R Ferreira,"The management of acute myocardial infarction (AMI) has improved markedly over the last decade. Large-scale trials have produced a large amount of evidence, and recommendations and guidelines have been established. Whether and to what extent these data have influenced everyday practice on a nationwide scale remains to be ascertained. The present observational prospective, registry was designed to assess current practice in in-hospital management of AMI in Portugal. For a period of 3 months (February to May, 1999), 44 centers, distributed all over the country, Atlantic islands included, enrolled 1372 cases of AMI corresponding to 1366 patients (996 male, mean age 65 +/- 13 years; 370 female, mean age 72 + 11 years; p < 0.0001). Non-ST segment elevation infarcts were present in 26% of cases. In-hospital mortality was 11.2% (154 pts, mean age 74 +/- 10 years). 519 pts (37.8%) were managed with reperfusion therapy, 413 of them with fibrinolysis (30.1%) and 106 with primary PTCA (7.7%). Besides the invasive procedures performed within the first few hours after admission, coronary angiography was performed in 327 more pts (26.1%); 143 pts were revascularized (PTCA in 117 pts and CABG in 26) and 96 more pts were discharged and referred for further revascularization. The total number of pts given or referred for a revascularization procedure (including the primary treatment) was 316 (20.6%). Besides reperfusion therapy the most commonly used drugs for secondary prevention were aspirin in 91%; ACE inhibitors in 63%; beta-blockers in 45%; and statins in 28%. Based on the results of this nationwide survey it can be concluded that the main international guidelines and recommendations for the medical management of acute myocardial infarction are generally being applied in Portugal.",2002.0,0,0 953,11583063,The role of cytochrome P450-mediated drug-drug interactions in determining the safety of statins.,C R Worz; M Bottorff,"The objectives of this review are to discuss the role of cytochrome P450 (CYP450) isoforms in drug metabolism, to explain differences in metabolism among the HMG-CoA reductase inhibitors (HMGs, statins), to review drug-drug and drug-food interaction studies dealing with the HMGs, to present case reports dealing with HMG-related myopathy, to discuss major clinical implications of these case reports and to express an opinion of use of HMGs in clinical practice.",2001.0,1,1 954,11583472,"Effects of low-dose pravastatin on plasma levels of lipids and apolipoproteins in Japanese type II hyperlipoproteinemic subjects with apolipoprotein E phenotype E3/2, E3/3, and E4/3.",T Kobayashi; Y Homma,"Effects of 12 weeks of treatment with pravastatin at a dose of 20 mg/day were compared in subjects with type II hyperlipoproteinemia with apo+(lipoprotein) E phenotype E3/2, E3/3, and E4/3. There were no differences in age, body mass index, smoking status, complications, or plasma levels of lipids and apoproteins, except the higher levels of apo E in E3/2 subjects (n = 11) than in E3/3 subjects (n = 84) and E4/3 subjects (n = 28). Plasma levels of low-density lipoprotein cholesterol (LDL-C) were reduced by 47% +/- 8% (mean +/- SD) in E3/2 subjects, 36% +/- 10% in E3/3 subjects, and 26% +/- 12% in E4/3 subjects after 12 weeks of treatment with pravastatin (all p < 0.0001). Plasma levels of apo B were decreased by 40% +/- 12% in E3/2 subjects, 27% +/- 10% in E3/3 subjects, and 18% +/- 14% in E4/3 subjects after 12 weeks of treatment with pravastatin (all p < 0.0001). The reduction in plasma levels of LDL-C and apo B was most marked in E3/2 subjects, next in E3/3 subjects, and smallest in E4/3 subjects. The authors conclude that treatment with pravastatin at a dose of 20 mg/day in Japanese subjects is equally effective as 40 mg/day in Western subjects, and apo Epolymorphism is a factor to determine the efficacy of pravastatin in Japanese subjects.",2002.0,0,0 955,11583643,Clinically relevant differences between the statins: implications for therapeutic selection.,P H Chong; J D Seeger; C Franklin,"Although the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, share a common lipid-lowering effect, there are differences within this class of drugs. The low-density lipoprotein (LDL) cholesterol-lowering efficacy, pharmacokinetic properties, drug-food interactions, and cost can vary widely, thus influencing the selection of a particular statin as a treatment option. The statins that produce the greatest percentage change in LDL cholesterol levels are atorvastatin and simvastatin. Atorvastatin and fluvastatin are least affected by alterations in renal function. Fewer pharmacokinetic drug interactions are likely to occur with pravastatin and fluvastatin, because they are not metabolized through the cytochrome P450 (3A4) system. The most cost-effective statins, based on cost per percentage change in LDL cholesterol levels, are fluvastatin, cerivastatin, and atorvastatin. Awareness of these differences may assist in the selection or substitution of an appropriate statin for a particular patient.",2002.0,0,1 956,11583720,Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively.,D Hunninghake; W Insull; P Toth; D Davidson; J M Donovan; S K Burke,"Colesevelam hydrochloride is a novel, potent, non-absorbed lipid-lowering agent previously shown to reduce low density lipoprotein (LDL) cholesterol. To examine the efficacy and safety of coadministration of colesevelam and atorvastatin, administration of these agents alone or in combination was examined in a double-blind study of 94 hypercholesterolemic men and women (baseline LDL cholesterol > or =160 mg/dl). After 4 weeks on the American Heart Association Step I diet, patients were randomized among five groups: placebo; colesevelam 3.8 g/day; atorvastatin 10 mg/day; coadminstered colesevelam 3.8 g/day plus atorvastatin 10 mg/day; or atorvastatin 80 mg/day. Fasting lipids were measured at screening, baseline and 2 and 4 weeks of treatment. LDL cholesterol decreased by 12-53% in all active treatment groups (P<0.01). LDL cholesterol reductions with combination therapy (48%) were statistically superior to colesevelam (12%) or low-dose atorvastatin (38%) alone (P<0.01), but similar to those achieved with atorvastatin 80 mg/day (53%). Total cholesterol decreased 6-39% in all active treatment groups (P<0.05). High density lipoprotein cholesterol increased significantly for all groups including placebo (P<0.05). Triglycerides decreased in patients taking atorvastatin alone (P<0.05), but were unaffected by colesevelam alone or in combination. The frequency of side effects did not differ among groups. At recommended starting doses of each agent, coadministration of colesevelam and atorvastatin was well tolerated, efficacious and produced additive LDL cholesterol reductions comparable to those observed with the maximum atorvastatin dose.",2002.0,0,0 957,11583721,Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus.,N Ichimaru; S Takahara; Y Kokado; J D Wang; M Hatori; H Kameoka; T Inoue; A Okuyama,"Hyperlipidemia is frequently developed following renal transplantation and results in worsening of the patient's prognosis. In study 1, the effects of immunosuppressants, cyclosporine (CsA) and tacrolimus on serum lipids were compared in-patients undergoing renal transplantation. The study included 32 cases of renal transplantation recipients who randomized to the CsA treatment group (15 patients) and the tacrolimus group (17 patients). Before and 1 month after the transplantation, we assessed the serum lipid levels, apolipoprotein levels, the concentrations of cholesterol in the respective lipoprotein fractions and the enzyme activities related to lipid-metabolism. The serum lipid levels in both groups were significantly increased at 1 month after renal transplantation. In the CsA group, there were significant increases in cholesterol contents in very-low-density lipoprotein (VLDL), LDL2 and HDL2 fractions, whereas, in the tacrolimus group, cholesterol content was increased in VLDL and HDL2 fractions. In study 2, 1 month after renal transplantation, 19 patients with hypercholesterolemia (total cholesterol (TC) >200 mg/dl) and hypertriglyceridemia (triglyceride (TG) >150 mg/dl) were treated with simvastatin 5-10 mg/day for 6 months. Simvastatin treatment significantly decreased serum TC (240+/-29-200+/-22 mg/dl, P<0.001), low-density lipoprotein cholesterol (LDL-C; 114+/-20-99+/-17 mg/dl, P<0.05) and TG levels (217+/-103-130+/-38 mg/dl, P<0.01). In addition, there were significant decreases in very-low-density lipoprotein cholesterol (VLDL-C; 53+/-20-34+/-15 mg/dl, P<0.001). The Cmax and AUC of simvastatin were increased about eight-fold, when simvastatin was given in combination with CsA. In contrast, no significant changes in simvastatin levels were observed when combination with tacrolimus. Although simvastatin levels were increased with CsA, there were no abnormal changes in renal and liver functions, creatinine phosphokinase (CPK) levels or in incidence of adverse effects.",2002.0,0,0 958,11583725,The influence of plasma lipoprotein (a) on angiographic restenosis and coronary events in patients undergoing planned coronary balloon angioplasty. Ancillary analysis of the Fluvastatin Angioplasty Restenosis (FLARE) trial.,G W Lloyd; G Jackson; D P Foley; E Boersma; J Shepherd; P W Serruys,"Elevated Lipoprotein (a) [Lp (a)] has been reported frequently, but not consistently, to be associated with restenosis following percutaneous transluminal coronary angioplasty (PTCA). The purpose of this study was to examine the association between Lp (a) and restenosis and clinical events in the context of a multi-centre randomised restenosis [Fluvastatin Angioplasty Restenosis (FLARE)] study of patients undergoing elective PTCA with full angiographic follow up. In the FLARE trial 40 mg fluvastatin twice daily did not influence restenosis, compared with placebo, after successful balloon angioplasty, measured as late loss in 834 patients, but did reduce the risk of death or myocardial infarction. Lp (a) was not effected by fluvastatin. Lp (a) and other biochemical details were established prior to planned PTCA. Among those undergoing successful PTCA, follow up angiography was performed at 26+/-2 weeks. Clinical follow up was complete to week 40. Included in this analysis are the 823 patients who underwent successful angioplasty and had a baseline Lp (a) performed yielding 891 lesions for quantitative coronary angiography (QCA). No association was observed between Lp (a) and either quantitative markers of restenosis or binary restenosis rates. Late loss was 0.27 (SD 0.51) in the lowest quintile (Lp (a) 0-4 g/dl) compared with 0.23 (SD 0.49) (P>0.05). Elevated Lp (a) was not associated with an increased risk of individual or combined major coronary events over 40 weeks. A major adverse cardiac event (MACE) occurred in 41 (24%) of the lowest quintile and 42 (26%) of the highest (P>0.05). In conclusion, elevated Lp (a) was not associated with restenosis or clinical events following elective coronary balloon angioplasty in this randomised clinical trial and should not be considered a risk factor for post angioplasty restenosis.",2002.0,0,0 959,11583742,Approach to symptomatic coronary disease in the elderly: TIME to change?,W S Aronow,,2001.0,0,0 960,11585023,Homocysteine-lowering treatment: an overview.,C van Guldener; C D Stehouwer,"Elevated fasting plasma concentrations of homocysteine have a high prevalence in subjects with cardiovascular disease and have also been associated with an increased risk of atherothrombosis in most, but not all, prospective studies. The most frequent causes of hyperhomocysteinaemia are genetic defects, such as cystathionine-beta-synthase (CBS) deficiency, deficiencies of folic acid and/or vitamin B12, renal failure and interference in homocysteine metabolism by drugs or metabolic alterations. In most cases, no underlying cause can be established. Subjects with CBS deficiency are treated with pyridoxine with additional folic acid and betaine if necessary. Folic acid and vitamin B12 deficiencies should be corrected by supplementation. Increases in folate intake by dietary changes or fortification can also lower plasma homocysteine in vitamin-replete subjects with normal plasma homocysteine levels. In renal failure, folic acid treatment (1-5 mg/day) ameliorates the plasma homocysteine level in most cases but hyperhomocysteinaemia persists in the majority of patients. Primary (fasting) hyperhomocysteinaemia can be treated with folic acid (0.5-5 mg/day). An abnormal methionine-loading test identifies additional patients at risk and postmethionine-loading hyperhomocysteinaemia should be treated with a combination of pyridoxine and folic acid. In the absence of dose-effect studies, a combination of pyridoxine (50 mg) and folic acid (5 mg) is advised. Large clinical trials are currently underway to establish the role of homocysteine-lowering therapy in the secondary prevention of atherothrombotic disease. In view of the effective, cheap and safe character of therapy with folic acid and pyridoxine, a policy can be accepted to screen and treat high-risk patients until these trials have been concluded.",2002.0,0,0 961,11587400,Azithromycin: an assessment of its pharmacokinetics and therapeutic potential in CAPD.,J R Kent; M K Almond; S Dhillon,"Azithromycin is an azalide antibiotic with a similar antibacterial spectrum to erythromycin but with greater gram-negative activity. Azithromycin displays a favorable pharmacokinetic profile, with improved absorption and higher sustained tissue concentrations compared with erythromycin. This results in a prolonged elimination half-life, suggesting a potential for treating continuous ambulatory peritoneal dialysis (CAPD) peritonitis. This study aimed to define the potential role of azithromycin in treating CAPD peritonitis. The pharmacokinetics and peritoneal dialysis (PD) clearance of azithromycin were studied following a single 500-mg oral dose of azithromycin. Blood and dialysate samples were taken over a 10-day period and assayed using high-pressure liquid chromatography. The study took place within the Renal Unit at Southend Hospital NHS Trust, a district general hospital in the United Kingdom. Eight patients with oliguric end-stage renal failure without peritonitis maintained on CAPD (3 x 2 L/day). Peak plasma concentrations occurred at 2-3 hours with 0.35-1.35 microg/mL (mean 0.75). The mean elimination half-life was 84.55 hrs, and plasma clearance was 21.93 L/hour. This compares with values of greater than 40 hours and 40.8 L/hour reported in healthy volunteers. After 8 hours, the mean dialysate concentration was 0.07 microg/mL; PD clearance was 0.06 L/hr. Azithromycin is not substantially removed by CAPD in the absence of peritonitis and cannot be recommended for widespread use in this setting at present. However, the successful use of azithromycin in CAPD peritonitis, due possibly to an intracellular drug transport mechanism, has been reported. Future research should address this possibility.",2002.0,0,0 962,11588412,Current concepts of pharmacotherapy in hypertension: combination calcium channel blocker therapy in the treatment of hypertension.,D A Sica,"Effective control of blood pressure is usually achieved only with the use of two or more antihypertensive medications. The treatment options for hypertension are numerous, and the number of possible combinations large. The selection of a specific combination drug regimen has often been linked to the perceived need for diuretic therapy as first- or second-step therapy; thus, the popularity of such drug combinations as an angiotensin-converting enzyme (ACE) inhibitor/diuretic, an angiotensin-receptor blocker/diuretic, or a beta blocker/diuretic. Rational alternatives exist, including an ACE inhibitor/calcium channel blocker (CCB) or a dihydropyridine CCB/b blocker combination. Traditionally, recommendations have advised against the use of combination therapy with two drugs from the same therapeutic class. However, because of the different binding and pharmacologic characteristics of CCBs, a rationale exists for combining different agents in this class in the management of hypertension and/or symptomatic coronary artery disease. In the treatment of either hypertension or angina, combination CCB therapy can prove uniquely successful.",2002.0,0,0 963,11588526,Effect of lipid-lowering therapy with pravastatin on myocardial blood flow in young mildly hypercholesterolemic adults.,T Janatuinen; R Laaksonen; R Vesalainen; O Raitakari; T Lehtimäki; P Nuutila; J Knuuti,"Serum low-density lipoprotein cholesterol concentration is an important regulator of vascular reactivity. This double-blinded study examined the effect of lipid-lowering therapy on myocardial vasodilatory function in young hypercholesterolemic but otherwise healthy men. Fifty-one men (age 35 +/- 4 years) with mild hypercholesterolemia (total cholesterol, 5.6 +/- 0.8 mM ) were randomly assigned to receive pravastatin, 40 mg/day, or placebo for 6 months. Myocardial blood flow was measured at rest and during adenosine-induced hyperemia using positron emission tomography and oxygen-15-labeled water at baseline and after treatment. Pravastatin lowered low-density-lipoprotein cholesterol by 33% from 3.77 +/- 0.76 mM (p < 0.001), whereas placebo had no effect. At baseline, resting and adenosine-induced flow values were 0.85 +/- 0.27 and 3.61 +/- 1.00 ml/min per gram in the pravastatin group and 0.83 +/- 0.18 and 3.17 +/- 0.69 ml/min per gram in the placebo group. Despite significant low-density-lipoprotein cholesterol lowering, resting and adenosine-stimulated blood flow values remained similar at follow-up: 0.86 +/- 0.23 and 3.79 +/- 1.31 vs. 0.78 +/- 0.20 and 3.20 +/- 0.86 ml/min per gram, in the pravastatin and placebo groups, respectively. An improvement in adenosine-induced flow after pravastatin, but not after placebo, was seen only in a subgroup of subjects (n = 15) with relatively low adenosine flow (<4.0 ml/min per gram) at baseline. Six months of cholesterol-lowering therapy with statin treatment has no overall significant effect on coronary vasodilator capacity in healthy subjects with mildly elevated cholesterol levels. A controlled study is needed to further test whether improvement in coronary function is obtained in subjects with initially reduced hyperemic flow response.",2002.0,0,0 964,11591618,"Vasoconstrictor effect of the angiotensin-converting enzyme-resistant, chymase-specific substrate [Pro(11)(D)-Ala(12)] angiotensin I in human dorsal hand veins: in vivo demonstration of non-ace production of angiotensin II in humans.",J E McDonald; N Padmanabhan; M C Petrie; C Hillier; J M Connell; J J McMurray,"[Pro(11)(D)-Ala(12)] angiotensin I is an ACE-resistant substrate specific for chymase. We used this peptide to determine whether a functionally significant non-ACE angiotensin (Ang) II-generating pathway exists in human dorsal hand veins. Using a modified Aellig technique, we studied the response to Ang I and [Pro(11)(D)-Ala(12)] Ang I in dorsal hand veins in vivo in patients with coronary heart disease. We measured the venoconstrictor effect of each peptide given before and after a 6.25-mg oral dose of the ACE inhibitor captopril or matching placebo. Placebo or captopril was given in a double-blind, randomized fashion. Ang I induced a mean+/-SEM venoconstrictor response of 45+/-11%, 40+/-10%, 55+/-8%, and 4+/-4% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, the response to Ang I was reproducible and was reduced significantly only after treatment with captopril (P=0.002). [Pro(11)(D)-Ala(12)] Ang I induced a mean venoconstrictor response of 42+/-9%, 49+/-9%, 48+/-10%, and 54+/-11% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, captopril had no significant effect on the response to [Pro(11)(D)-Ala(12)] Ang I. We have demonstrated that [Pro(11)(D)-Ala(12)] Ang I is able to induce venoconstriction in humans in vivo. With this specific pharmacological probe, we have shown that a non-ACE pathway capable of generating Ang II exists in human veins in vivo and is potentially functionally important. This pathway is likely to involve the enzyme chymase.",2002.0,0,0 965,11594247,Statins in acute coronary syndromes: from bench to bedside.,G Jackson,,2001.0,0,0 966,11594253,Standard cardiac rehabilitation is less effective for diabetics.,V Suresh; R A Harrison; P Houghton; N Naqvi,"To assess clinical outcomes and lifestyle modifications in diabetic patients attending a standard cardiac rehabilitation programme following myocardial infarction (MI), a retrospective longitudinal study was undertaken in a district general hospital in the north west of England. A total of 1804 patients attended the cardiac rehabilitation programme over 10 years, of whom 223 (12.4%) had diabetes mellitus. Drugs were underprescribed in all patients, aspirin and beta-blockers especially in diabetics (75.3% vs 90.3%, p < 0.0001; 38.6% vs 60.8%, p < 0.0001). Smoking cessation was poor in diabetics (54.2% vs 69.1%, p < 0.003) and diabetics were less likely to attend at least one session of physiotherapy (26.9% vs 58.6%, p < 0.0001). Diabetics had higher mortality at one year (15.7% vs 5.6%; p < 0.0001), mostly associated with cardiovascular disease (13.4% vs 5.4%, p < 0.0001). Standard cardiac rehabilitation programmes appear to be less effective for patients with diabetes mellitus. We suggest that patients presenting with an existing chronic condition need specialised programmes of rehabilitation to integrate the care of that condition with their recent MI. Aggressive drug therapy following acute MI should also be prescribed in all patients when not contraindicated by other evidence.",2001.0,0,0 967,11594254,What is the relevance of the HOPE study in general practice?,J Kennedy; C E Mogensen; S G Ball; A D Castaigne; P J Commerford; L Distiller; B M Fisher; J Gonzalez-Jaunatey; R Nosadini; A Novials; J Ostergren; J Palma-Gámiz; P Perrone-Filardi; J J Schipperheijn; J Senges; R Trevisan,"The unique findings from the HOPE (Heart Outcomes Prevention Evaluation) study strongly support extending the use of the angiotensin-converting enzyme (ACE) inhibitor ramipril as a preventive agent for patients at high risk of cardiovascular events with normal left ventricular function. In addition, ramipril provides significant benefit in diabetic patients. These findings will impact on how ramipril is used in primary care, where ACE inhibitors are currently underprescribed. Patients reflecting the inclusion criteria of the HOPE study should be considered as suitable candidates for long-term ramipril therapy as an addition to their existing drug regimen. Screening should include control of kidney function (by serum creatinine), particularly within the first two weeks of treatment, in addition to regular monitoring of serum potassium. However, the HOPE study shows that ramipril is well tolerated at high doses and over a long treatment period. The effectiveness of therapy should also be regularly reviewed and dose adjustments made where necessary. If concern remains, referral to a specialist--a cardiologist or a diabetologist--may ultimately be necessary.",2001.0,0,0 968,11599653,Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins).,M Igel; T Sudhop; K von Bergmann,"3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors (statins) are mainly considered for long-term use and often constitute part of a multiple-drug regime. Besides common adverse drug effects, such as nausea, abdominal discomfort and headaches, all statins harbour the risk of myopathy and fatal rhabdomyolysis. Usually, the frequency of myopathy is low but the incidence increases during concomitant drug therapy. Statins do not differ in their pharmacodynamic property. Therefore, the differences in their pharmacokinetic profiles, i.e. affinity for metabolising enzymes, constitute the rationale for choosing a specific statin especially for combination therapy. In order to point out harmful combinations of therapeutics, this review summarises the pharmacokinetic data of six clinically used statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin and simvastatin) with special regard to metabolism and drug interactions. In summary, statins that lack a significant hepatic metabolism, i.e. pravastatin, or that are metabolised by more than one cytochrome P450 isoenzyme, i.e. fluvastatin, or whose metabolism is taken over by other cytochrome P450 isoenzymes in case of blockage of the main metabolising enzyme, i.e. cerivastatin, are the least prone to drug interactions. Nevertheless, in case of a specific concomitant drug therapy known to be associated with a higher risk of adverse events, i.e. cyclosporin A and statin, clinical symptoms of myopathy and biochemical data, such as increasing serum creatine phosphokinase, should be monitored carefully.",2002.0,0,0 969,11600564,"Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol.",F J Chaves; J T Real; A B García-García; M Civera; M E Armengod; J F Ascaso; R Carmena,"The aims of this study were to examine the presence of mutations in the low-density lipoprotein receptor gene among subjects clinically diagnosed with familial hypercholesterolemia and to analyze whether the molecular diagnosis helps to predict the response to simvastatin treatment in our familial hypercholesterolemia population. Fifty-five probands and 128 related subjects with familial hypercholesterolemia were studied. Genetic diagnosis was carried out following a three-step protocol based on Southern blot and PCR-single strand conformational polymorphism analysis. A randomized clinical trial with simvastatin was conducted in 42 genetically diagnosed subjects with familial hypercholesterolemia classified as carriers of null mutations (n = 22) and of defective mutations (n = 20). A mutation-causing familial hypercholesterolemia was identified in 46 probands (84%). In 41 of them (89%), a total of 28 point mutations were detected, 13 of which have not been previously described. The remaining five probands (11%) were carriers of large rearrangements. Familial hypercholesterolemia with null mutations showed a poor response to simvastatin treatment. The mean percentage reduction of plasma total and low-density lipoprotein cholesterol levels in these subjects were significantly lower (24.8 +/- 10.3 vs. 34.8 +/- 10.9, P = 0.04 and 30.0 +/- 39.8 vs. 46.1 +/- 18.2, P = 0.02, respectively) than in subjects with defective mutations. Baseline and posttreatment high-density lipoprotein cholesterol plasma values were significantly lower in subjects with familial hypercholesterolemia with null mutations (P < 0.001). In an outbreed Caucasian population, a three-step protocol for genetic screening detected a mutation in the low-density lipoprotein receptor gene in a high percentage (84%) of subjects with familial hypercholesterolemia. Subjects with familial hypercholesterolemia with null mutations (class I) showed lower plasma high-density lipoprotein cholesterol values and a poor low-density lipoprotein cholesterol response to simvastatin treatment.",2001.0,0,0 970,11600819,Clinical perspectives on HIV-associated lipodystrophy syndrome: an update.,A Shevitz; C A Wanke; J Falutz; D P Kotler,,2002.0,0,0 971,11601667,Telithromycin: an oral ketolide for respiratory infections.,D T Bearden; M M Neuhauser; K W Garey,"The ketolides represent a new subclass of antibiotics among the macrolide-lincosamide-streptogramin group. Telithromycin, the first ketolide to be awarded approvable status for clinical use, demonstrates in vitro activity against community-acquired respiratory pathogens including penicillin- and erythromycin-resistant Streptococcus pneumoniae. An extended half-life permits once-daily oral administration. Telithromycin is a substrate for cytochrome P450 (CYP) 3A4 and also inhibits drugs metabolized by CYP3A4. A relatively high frequency of mild-to-moderate gastrointestinal adverse effects has been reported. Similar clinical and microbiologic efficacy has been demonstrated with oral dosing in comparative clinical trials for community-acquired pneumonia, acute sinusitis, acute exacerbations of chronic bronchitis, and pharyngitis. Although limited data on penicillin-resistant S. pneumoniae and erythromycin-resistant Streptococcus pyogenes are available from clinical trials, this drug appears promising for respiratory infections caused by these pathogens.",2002.0,0,0 972,11602062,Antioxidants blunt high-density lipoprotein response to statin plus niacin therapy.,P M Kris-Etherton,,2002.0,0,0 973,11604563,Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.,P J Medina; J M Sipols; J N George,"Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is an inclusive term describing diverse syndromes of multiple etiologies with the common features of thrombocytopenia and microangiopathic hemolytic anemia. Other organ involvement, including renal failure, neurologic abnormalities, and gastrointestinal symptoms, is common. Adverse reactions to drugs increasingly are reported as a potential cause of TTP-HUS. More than 50 drugs and other substances have been associated with the development of TTP-HUS, but many case reports are difficult to interpret because there is uncertainty regarding the diagnosis of TTP-HUS and because there is uncertainty regarding the relation of drug exposure to the onset of TTP-HUS. A systematic analysis of reports of drug-associated TTP-HUS will be required to better understand the strength of clinical evidence linking drugs to the etiology of TTP-HUS. In this review, five drugs that have been the subject of the most and the most recent reports of drug-associated TTP-HUS are discussed: mitomycin C, cyclosporine, quinine, ticlopidine, and clopidogrel. The clinical features of TTP-HUS associated with these drugs are different, suggesting two principal mechanisms by which drugs may cause TTP-HUS: dose-related toxicity (mitomycin C, cyclosporine), and immune-mediated reaction (quinine, ticlopidine, clopidogrel). The role of plasma exchange is uncertain, but this treatment is appropriate because of the high mortality and morbidity of drug-associated TTP-HUS. Recognition of a drug-associated etiology in a patient with TTP-HUS is critical to avoid re-exposure and recurrent illness.",2002.0,0,0 974,11605688,Low-density lipoprotein apheresis for the treatment of refractory hyperlipidemia.,A Vella; A A Pineda; T O'Brien,"The advent of treatment with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors has meant that, with a combination of diet and drug therapy, adequate control of serum cholesterol concentrations can be achieved in most patients with hypercholesterolemia. However, some patients, primarily those with familial hypercholesterolemia (FH), may require additional therapy to lower their cholesterol levels. In recent years, low-density lipoprotein (LDL) apheresis has emerged as an effective method of treatment in these patients. The criteria for commencement of LDL apheresis are LDL cholesterol levels of 500 mg/dL or higher for homozygous FH patients, 300 mg/dL or higher for heterozygous FH patients in whom medical therapy has failed, and 200 mg/dL or higher for heterozygous FH patients with documented coronary disease and in whom medical therapy has failed. In addition to cholesterol lowering in patients with FH, other indications for LDL apheresis are emerging. These include its use in the treatment of graft vascular disease in patients receiving cardiac transplants as well as in the treatment of certain glomerulonephritides. This review examines the role of LDL apheresis in the management of lipid disorders and the evidence available to support its use in clinical practice.",2002.0,0,0 975,11605698,Effectiveness of colesevelam hydrochloride in decreasing LDL cholesterol in patients with primary hypercholesterolemia: a 24-week randomized controlled trial.,W Insull; P Toth; W Mullican; D Hunninghake; S Burke; J M Donovan; M H Davidson,"To evaluate the efficacy, tolerability, and safety of colesevelam hydrochloride, a new nonsystemic lipid-lowering agent. In this double-blind, placebo-controlled trial performed in 1998, 494 patients with primary hypercholesterolemia (low-density lipoprotein [LDL] cholesterol level > or = 130 mg/dL and < or = 220 mg/dL) were randomized to receive placebo or colesevelam (2.3 g/d, 3.0 g/d, 3.8 g/d, or 4.5 g/d) for 24 weeks. Fasting serum lipid profiles were measured to assess efficacy. Adverse events were monitored, and discontinuation rates and compliance rates were analyzed. The primary outcome measure was the mean absolute change of LDL cholesterol from baseline to the end of the 24-week treatment period. Colesevelam lowered mean LDL cholesterol levels 9% to 18% in a dose-dependent manner (P<.001), with a median LDL cholesterol reduction of 20% at 4.5 g/d. The reduction in LDL cholesterol levels was maximal after 2 weeks and sustained throughout the study. Mean total cholesterol levels decreased 4% to 10% (P<.001), while median high-density lipoprotein cholesterol levels increased 3% to 4% (P<.001). Median triglyceride levels increased by 5% to 10% in placebo and colesevelam treatment groups relative to baseline (P<.05), but none of these differences were significantly different from placebo. Mean apolipoprotein B levels decreased 6% to 12% in an apparent dose-dependent manner (P<.001). No significant differences occurred in adverse events or discontinuation rates between groups, and compliance rates were between 88% and 92% for all groups. Colesevelam was efficacious, decreasing mean LDL cholesterol levels by up to 18%, and well tolerated without serious adverse events.",2002.0,0,0 976,11641483,"Alzheimer's disease. Bad for the heart, bad for the mind?",J Marx,,2002.0,0,0 977,11668222,,,,,0,0 978,11675082,Economics of drug treatment: for which patients is it costeffective to lower cholesterol?,B Jönsson,"Today's society places a great emphasis on value for money, so medical interventions must not only be shown to be effective but also be proved to be costeffective. Drug treatment is no exception. In health economics, costeffectiveness is calculated differently depending on the indication and the perspective. For cholesterol-lowering drugs (as an example) there is a difference between primary and secondary intervention. In primary prevention, the cut off value for absolute risk when treatment is costeffective varies with age and sex, but in secondary prevention, although treatment is costeffective for all groups of patients, costeffectiveness varies with age, sex, cholesterol concentration, and other risk factors. There are three complementary approaches to economic assessment of secondary prevention-analysis of the whole population, subgroup analysis, and modelling.",2001.0,0,0 979,11675517,Melanoma.,J E Gershenwald,"The presentations at the American Society of Clinical Oncology 2001 meeting reported or updated the results of phase I, II, and III randomized trials and also reported important meta-analyses and retrospective studies impacting on the management of patients with melanoma. In the treatment of early stage melanoma, the prognostic significance of pathologic status of sentinel lymph nodes was affirmed. With respect to regional nodal involvement (American Joint Committee on Cancer [AJCC] stage III), investigators presented the interim results of the United Kingdom randomized low-dose interferon (IFN) trial, and up-to-date meta-analyses of several IFN trials including a pooled analysis of the Eastern Cooperative Oncology Group trials evaluating interferon in the adjuvant setting. In the advanced disease setting (AJCC stage IV), several studies elucidated the pros and cons of biochemotherapy in patients with metastatic melanoma, with an emphasis on seeking to improve response in the central nervous system and durability of response in general. Thought provoking was new data regarding the potential for lovastatin to act as a chemopreventive agent for melanoma. Translational studies were presented, one supporting the importance of HLA-typing in developing targeted vaccine therapy. Finally, the results of a novel experimental melanoma vaccine were presented using autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96).",2002.0,0,0 980,11675906,Cerivastatin induces carotid artery plaque stabilization independently of cholesterol lowering in patients with hypercholesterolaemia.,T Kurata; M Kurata; T Okada,"To prevent cardiovascular events in hyperlipidaemic patients, plaque stabilization by inhibition of localized inflammatory reactions in the blood vessels is important in addition to cholesterol lowering. Cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin), has more potent enzyme-inhibitory effects than other statins and has also been reported in vitro to inhibit, at low concentrations, various inflammatory reactions due to plaque instability. Cerivastatin was therefore administered over 12 months to five patients with hypercholesterolaemia and atherosclerotic plaque diagnosed by ultrasonography of the carotid artery, and changes in the plaque composition were determined. The mean cholesterol level decreased over the study period, although not significantly. However, the mean percentage of fibrous matrix of the plaque increased significantly from a mean of 11.2 +/- 7.7% at study entry to 18.3 +/- 5.9% at the end of the study. Additionally, the mean maximum plaque height was significantly reduced from 3.7 +/- 0.9 mm to 3.0 +/- 0.7 mm. These results indicate that cerivastatin induces plaque stability independently of cholesterol lowering.",2002.0,0,0 981,11676300,Clinical-pharmacological strategies to assess drug interaction potential during drug development.,J Kuhlmann; W Mück,"Drug interactions in patients receiving multiple drug regimens are a constant concern for the clinician. With the increased availability of new drugs and their concomitant use with other drugs, there has been a rise in the potential for adverse drug interactions as demonstrated by the recent withdrawals of newly marketed drugs because of unacceptable interaction profiles. Therefore, the interaction potential of a new compound has to be assessed in detail, starting with preclinical in vitro and in vivo studies at candidate selection and continuously followed up through preclinical and clinical development. Since formal in vivo studies of all possible drug interactions are neither practicable nor suggestive, a careful selection of a limited number of drug combinations to be investigated in vivo during the development phase is indicated. Based on knowledge of pharmacokinetic and biopharmaceutical properties, a well balanced link between in vitro investigations and carefully selected in vivo interaction studies allows full assessment of the potential of a new drug to cause clinically relevant pharmacokinetic drug-drug interactions, prediction of a lack of interactions and derivation of the proper dose recommendations. Clinical pharmacology plays a number of key roles within the process of collecting information on drug interactions during preclinical and clinical development: addressing issues and/or favourable properties to be expected, thus contributing to the scientific assessment of development potential; setting up a rational in vivo drug-drug interaction programme; performing early mechanistic studies to link in vitro with in vivo information (employing 'cocktail' approaches if possible); reviewing co-medication sections for clinical trials; and conducting labelling-oriented interaction studies, after proof of concept. The fact that interactions can occur between various active substances should by itself be a conclusive argument against unnecessary polypharmacy. Prescribing fewer drugs on a rational basis can reduce the risk of adverse effects secondary to drug interactions and may help to improve the quality of drug treatment and to save costs.",2002.0,0,0 982,11676303,Calcineurin inhibitors and post-transplant hyperlipidaemias.,R Moore; D Hernandez; H Valantine,"Cardiovascular disease is now the leading cause of death in transplant recipients. This is due, in part, to the vulnerability of these patients to a complicated set of conditions including hypertension, diabetes mellitus, and post-transplant hyperlipidaemia (PTHL). PTHL is characterised by persistent elevations in total serum cholesterol, low density lipoprotein cholesterol and triglyceride levels. The causes of PTHL are complex and not fully understood, however several classes of immunosuppressants including the corticosteroids, rapamycins and calcineurin inhibitors, appear to play a role. PTHL has been observed in most studies in which patients received calcineurin inhibitor-based regimens, and has been observed with both tacrolimus and cyclosporin. Comparing these calcineurin inhibitors with regard to the relative incidence or severity of PTHL occurring during treatment is difficult because of the use of higher doses of corticosteroids in cyclosporin-based regimens, as compared with tacrolimus-based regimens. However, current expert opinion suggests that the discrepancies in the relative incidence and severity of PTHL are largely accounted for by this difference in corticosteroid dose. At this point in time, evidence for potential differences is scant and inconclusive. Further study is needed, not only to investigate differences in lipid profile, but also of the relative effects of these immunosuppressants on long term graft function as well as on cardiovascular morbidity and mortality. PTHL can be successfully managed with a combination of dietary management, reduction and, if appropriate, withdrawal of corticosteroids, and the administration of lipid-lowering drugs. With this combination of therapeutic options, the threats to long term health posed by PTHL may be effectively addressed.",2002.0,0,0 983,11676951,Emerging perspectives on lipid management: international approaches and global challenges.,A M Gotto,"The rapid growth in the understanding of the relation between cholesterol and coronary heart disease has introduced new challenges to the contemporary management of lipid disorders. The publication of the trials of the 3-hydroxy-3-methylglutaryl coenzyme-A inhibitors (statins) has invigorated support for the lipid hypothesis, and many advances have been made in understanding the mechanisms underlying atherosclerosis and the potential benefits of the statins. Several international groups have issued guidelines about desirable and undesirable lipid values to help clinical decision making. Despite the availability of such principles, there are many challenges to optimal management of lipid disorders.",2002.0,0,0 984,11676957,Preoperative lipid control with simvastatin protects coronary artery bypass grafts from obstructive graft disease.,J T Christenson,,2002.0,0,1 985,11678788,Statins for primary prevention: at what coronary risk is safety assured?,P R Jackson; E J Wallis; I U Haq; L E Ramsay,Increasingly HMG CoA reductase inhibitors (statins) are being used for primary prevention of vascular disease in patients with a raised cholesterol but at low absolute risk of coronary heart disease (CHD). This study uses clinical trial results to explore the limits of absolute safety for statin use in such patients. The major placebo controlled statin outcome trials were identified by automated and manual literature searches. Principal results including all cause mortality in placebo and intervention groups and baseline values of standard coronary risk factors were abstracted for each trial. For the trials identified the reduction in overall mortality with statin treatment for each study was regressed against the underlying CHD risk of the population recruited into that trial using a statistically robust method. The regression line describing the relationship between mortality benefit and risk suggests that statin use could be associated with an increase in mortality of 1% in 10 years. This would be sufficiently large to negate statin's beneficial effect on CHD mortality in patients with a CHD event risk less than 13% over 10 years. Absolute safety of statins has not been demonstrated for patients at low risk of CHD. Patients absolute risk of CHD should be calculated before starting statin treatment for primary prevention. Extensions of such treatment to low risk patients should await further evidence of safety.,2002.0,0,0 986,11679405,Novel clinical markers of vascular wall inflammation.,G J Blake; P M Ridker,"Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis and mediate many of the stages of atheroma development from initial leukocyte recruitment to eventual rupture of the unstable atherosclerotic plaque. Elevated plasma levels of several markers of the inflammatory cascade have been shown to predict future risk of plaque rupture. These markers include P-selectin, interleukin-6, tumor necrosis factor-alpha, soluble intercellular adhesion molecule-1, and C-reactive protein (CRP). Produced in the liver in response to interleukin-6, CRP has emerged as the most powerful inflammatory marker of future cardiovascular risk. Initially considered an innocent bystander in the atherosclerotic process, recent evidence suggests that CRP may have direct proinflammatory effects. Numerous large-scale, prospective studies have found that elevated baseline levels of CRP are a strong independent predictor of future vascular risk. Furthermore, aspirin and statin therapy appear to be particularly effective among individuals with high CRP levels. The addition of CRP screening to traditional lipid testing has the potential to identify individuals at high risk for future cardiovascular events who may benefit from targeted preventive interventions.",2002.0,0,0 987,11683781,Effects of pravastatin therapy on serum lipids and coronary reactivity are not associated with SREBP cleavage-activating protein polymorphism in healthy young men.,Y M Fan; R Laaksonen; T Janatuinen; R Vesalainen; P Nuutila; J Knuuti; T Lehtimäki,,2002.0,0,0 988,11684077,Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial--FAT).,J Malik; V Melenovsky; D Wichterle; T Haas; J Simek; R Ceska; J Hradec,"It has been repeatedly proven that statins improve endothelial function in isolated hypercholesterolaemia but there is far less evidence in the case of combined hyperlipidaemia. Studies assessing the effects of fibrates on endothelium have been neglected. Therefore, we conducted a trial in which the effects of fenofibrate and atorvastatin monotherapy on both endothelium-dependent vascular reactivity and biochemical parameters were compared in patients with combined hyperlipidaemia. 29 otherwise healthy males (aged 47.4+/-7.8 years) with combined hyperlipidaemia (total cholesterol 7.55+/-1.20 mmol/l, triglycerides 5.41+/-4.54 mmol/l) were included into the randomised, single-blind, cross-over study to receive either 200 mg of micronised fenofibrate or 10 mg of atorvastatin daily--each of the drugs for a period of 10 weeks. Analysed biochemical parameters were as follows: serum total-, LDL- and HDL-cholesterol, apolipoproteins A-I and B, triglycerides, fibrinogen, uric acid, C-reactive protein (CRP), insulin, and homocysteine. Endothelial function was investigated by duplex Doppler ultrasonography at the brachial artery. Two indices of endothelial-dependent postischaemic changes were used - the recently introduced index of peak blood flow (PBF) representing the level of reactive hyperaemia and traditional flow-mediated dilatation (FMD). We observed a small improvement in FMD after both fenofibrate and atorvastatin (from 2.26% to 2.98% and 2.87%, respectively; NS). PBF increased from 448 ml/min to 536 ml/min after fenofibrate (P=0.04) and to 570 ml/min after atorvastatin (P=0.03). The effects of both fenofibrate and atorvastatin on endothelial function did not differ significantly (P-values of 0.82 and 0.47 for FMD and PBF, respectively). Significant correlations (P<0.01) between the changes of vascular reactivity and biochemical indices were found between FMD and CRP (r=-0.60) and between both FMD and PBF, and insulinaemia (r=-0.48 and -0.56, respectively) only during treatment with fenofibrate. Both fenofibrate and atorvastatin significantly improved endothelium-dependent vascular reactivity without mutual difference. The PBF was superior to FMD for the detection of this improvement. The beneficial effect of both drugs did not correlate with the change of lipid profile during therapy. The improvement of vascular reactivity during treatment with fenofibrate (opposed to atorvastatin) was related to the reduction of indirect marker of chronic vessel wall inflammation and of insulin resistance. The PBF was more reproducible than FMD because of considerably lower intra-subject variability.",2002.0,0,0 989,11684078,Impaired endothelium-dependent vasodilation in type 2 diabetes mellitus and the lack of effect of simvastatin.,M A van de Ree; M V Huisman; F H de Man; J C van der Vijver; A E Meinders; G J Blauw,"Although type 2 diabetes is recognized as an independent risk factor for cardiovascular disease and cardiovascular disease is associated with endothelial dysfunction, the influence of type 2 diabetes per se on the endothelial function is controversial. HMG-CoA-reductase inhibitors have been shown to have short-term beneficial effects on endothelial dysfunction among patients with dyslipidemia or cardiovascular disease. The effect of HMG-CoA reductase inhibitors on the endothelial function in diabetes is largely unknown. Seventeen patients with type 2 diabetes, free of cardiovascular disease and no other cardiovascular risk factors, except for dyslipidemia, were studied together with ten healthy volunteers. The effect of 5-hydroxytryptamine, as an endothelium-dependent vasodilator, and sodium nitroprusside, as an endothelium-independent vasodilator, on the forearm blood flow was measured using venous occlusion plethysmography. 5-Hydroxytryptamine and sodium nitroprusside, infused in the brachial artery, caused a dose-dependent vasodilation. The vasodilator response to 5-hydroxytryptamine was significantly lower among the diabetic patients, 42 and 56%, than among the controls, 73 and 103%, at a dose of 0.3 and 0.9 ng/kg/min, respectively (P<0.05 and P<0.001). Vasodilator responses to sodium nitroprusside were comparable among the diabetic patients and controls. A 6-week treatment with simvastatin 40 mg once daily did not change the vasodilator responses to 5-hydroxytryptamine or sodium nitroprusside among the patients with diabetes. The results of this study indicate that the endothelial function is impaired in type 2 diabetes and is not restored after a 6-week treatment period with simvastatin 40 mg.",2002.0,0,0 990,11684632,Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis.,G M Novaro; I Y Tiong; G L Pearce; M S Lauer; D L Sprecher; B P Griffin,"Recent studies have supported the hypothesis that calcific aortic stenosis is the product of an active inflammatory process, with similarities to atherosclerosis. We sought to determine whether therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) might slow the progression of aortic stenosis. A retrospective study of 174 patients (mean age 68+/-12 years) with mild to moderate calcific aortic stenosis was conducted. Patients required normal left ventricular function, /=2 echocardiograms performed at least 12 months apart. Fifty-seven patients (33%) received treatment with a statin; the remaining 117 (67%) did not. The statin group was older and had a higher prevalence of hypertension, diabetes mellitus, and coronary disease. During a mean follow-up of 21 months, patients treated with statin had a smaller increase in peak and mean gradient and a smaller decrease in aortic valve area. When annualized, the decrease in aortic valve area for the nonstatin group was 0.11+/-0.18 cm(2) compared with 0.06+/-0.16 cm(2) for those treated with a statin (P=0.03). In multivariate analysis, statin usage was a significant independent predictor of a smaller decrease in valve area (P=0.01) and a lesser increase in peak gradient (P=0.02). Statin-treated patients, despite a higher risk profile for progression, had reduced aortic stenosis progression compared with those not treated with a statin. These data provide justification for a prospective randomized trial to substantiate whether statin therapy slows the progression of aortic stenosis.",2002.0,0,0 991,11689228,Statins do not affect platelet inhibition with clopidogrel during coronary stenting.,V L Serebruany; A I Malinin; K P Callahan; P A Gurbel; S R Steinhubl,,2002.0,0,0 992,11693468,Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia.,H S Malhotra; K L Goa,"Atorvastatin is a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In dosages of 10 to 80 mg/day, atorvastatin reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride and very low-density lipoprotein (VLDL)-cholesterol and increases high-density lipoprotein (HDL)-cholesterol in patients with a wide variety of dyslipidaemias. In large long-term trials in patients with primary hypercholesterolaemia. atorvastatin produced greater reductions in total cholesterol. LDL-cholesterol and triglyceride levels than other HMG-CoA reductase inhibitors. In patients with coronary heart disease (CHD), atorvastatin was more efficacious than lovastatin, pravastatin. fluvastatin and simvastatin in achieving target LDL-cholesterol levels and, in high doses, produced very low LDL-cholesterol levels. Aggressive reduction of serum LDL-cholesterol to 1.9 mmol/L with atorvastatin 80 mg/day for 16 weeks in patients with acute coronary syndromes significantly reduced the incidence of the combined primary end-point events and the secondary end-point of recurrent ischaemic events requiring rehospitalisation in the large. well-designed MIRACL trial. In the AVERT trial, aggressive lipid-lowering therapy with atorvastatin 80 mg/ day for 18 months was at least as effective as coronary angioplasty and usual care in reducing the incidence of ischaemic events in low-risk patients with stable CHD. Long-term studies are currently investigating the effects of atorvastatin on serious cardiac events and mortality in patients with CHD. Pharmacoeconomic studies have shown lipid-lowering with atorvastatin to be cost effective in patients with CHD, men with at least one risk factor for CHD and women with multiple risk factors for CHD. In available studies atorvastatin was more cost effective than most other HMG-CoA reductase inhibitors in achieving target LDL-cholesterol levels. Atorvastatin is well tolerated and adverse events are usually mild and transient. The tolerability profile of atorvastatin is similar to that of other available HMG-CoA reductase inhibitors and to placebo. Elevations of liver transaminases and creatine phosphokinase are infrequent. There have been rare case reports of rhabdomyolysis occurring with concomitant use of atorvastatin and other drugs. Atorvastatin is an appropriate first-line lipid-lowering therapy in numerous groups of patients at low to high risk of CHD. Additionally it has a definite role in treating patients requiring greater decreases in LDL-cholesterol levels. Long-term studies are under way to determine whether achieving very low LDL-cholesterol levels with atorvastatin is likely to show additional benefits on morbidity and mortality in patients with CHD.",2002.0,0,0 993,11696467,Clinical and angiographic factors associated with asymptomatic restenosis after percutaneous coronary intervention.,P N Ruygrok; M W Webster; V de Valk; G A van Es; J A Ormiston; M A Morel; P W Serruys,"Angiographic restenosis after percutaneous coronary interventional procedures is more common than recurrent angina. Clinical and angiographic factors associated with asymptomatic versus symptomatic restenosis after percutaneous coronary intervention were compared. All patients with angiographic restenosis from the BENESTENT I, BENESTENT II pilot, BENESTENT II, MUSIC, WEST 1, DUET, FINESS 2, FLARE, SOPHOS, and ROSE studies were analyzed. Multivariate analysis evaluated 46 clinical and angiographic variables, comparing those with and without angina. The 10 studies recruited 2690 patients who underwent percutaneous revascularization and 6-month follow-up angiography (86% of those eligible). Restenosis (>/=50% diameter stenosis) occurred in 607 patients and was clinically silent in 335 (55%). Male sex (P=0.008), absence of antianginal therapy with nitrates (P=0.0002) and calcium channel blockers (P=0.02) at 6 months, greater reference diameter after the procedure (P=0.04), greater reference diameter at follow-up (P=0.004), and lesser lesion severity (percent stenosis) at 6 months (P=0.0004) were univariate predictors of asymptomatic restenosis. By multivariate analysis, only male sex (P=0.04), greater reference diameter at follow-up (P=0.002), and lesser lesion severity at 6 months (P=0.0001) were associated with restenosis without angina. Approximately half of patients with angiographic restenosis have no symptoms. The only multivariate predictors of silent restenosis at 6 months were male sex, greater reference diameter at follow-up, and lesser lesion severity on follow-up angiography.",2002.0,0,0 994,11700538,An inflammatory drug prospect.,B De Strooper; G König,,2002.0,0,0 995,11703619,Effect of fluvastatin on acute renal allograft rejection: a randomized multicenter trial.,H Holdaas; A G Jardine; D C Wheeler; I B Brekke; P J Conlon; B Fellstrøm; A Hammad; I Holme; H Isoniemi; R Moore; P A Rowe; P Sweny; D A Talbot; J Wadstrøm; Ø Østraat,"Statin therapy has been reported to reduce the acute rejection rate following renal transplantation in a pilot study. The present study is the first randomized, double-blind and adequately powered study to examine the effect of statins on acute rejection of renal allografts. A total of 364 patients were randomly assigned to receive either fluvastatin 40 mg or placebo in combination with conventional cyclosporine-based immunosuppressive therapy. The primary end point was treated first acute rejection. Secondary end points included biopsy-proven rejection, histological severity of rejection, occurrence of steroid-resistant rejection, and serum creatinine at three months following transplantation. Fluvastatin was well tolerated; no patients developed myositis or rhabdomyolysis. There was no difference in the acute rejection rate [86 (47.3%) fluvastatin vs. 87 (47.8%) placebo] and no significant difference in the severity of rejection, steroid resistant rejection or mean serum creatinine at three months (160 micromol/L vs. 160 micromol/L). Total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglyceride levels increased following renal transplantation. With the exception of the increase in HDL-C, which was augmented, the increases in lipid parameters were significantly reduced by fluvastatin (total cholesterol +17.5% vs. 35.7%; LDL-C +6.3% vs. 46.7%; HDL-C +43.3% vs. 38.1%; triglyceride +52.2% vs 77.6%). Contrary to the reported effects of statins, fluvastatin had no effect on the incidence or severity of acute rejection following renal transplantation. There were no increases in adverse events. A significant and potentially beneficial alteration in the lipid profile was observed in the early post transplant period. We conclude that fluvastatin may be used safely to correct dyslipidemia in patients with end-stage renal failure through the peri-transplant period.",2002.0,0,0 996,11703953,Effect of pravastatin on myocardial protection during coronary angioplasty and the role of adenosine.,T M Lee; S F Su; T F Chou; C H Tsai,"Pravastatin has been shown, in an experimental model of ischemia reperfusion, to increase adenosine levels, which exert a potent and protective effect on the heart. The purpose of this study was to investigate whether pravastatin can provide cardioprotection by increased production of adenosine in patients undergoing coronary angioplasty, a clinical model of ischemia reperfusion. Thirty-five hyperlipidemic patients who underwent elective angioplasty for a major epicardial coronary artery were randomly allocated to either 3-month pravastatin or placebo before catheterization. In the placebo group, the mean ST-segment shift during the second balloon inflation was similar that observed during the first inflation, whereas in the preconditioned patients, the shift was significantly less, which is consistent with ischemic preconditioning. In the pravastatin-treated patients, the changes of ST-segment shift were similar between the first and second balloon inflations. In contrast, the patients who received aminophylline developed higher ST-segment shifts during the first and second inflations than those in the pravastatin-treated group alone. Measurements of chest pain score and myocardial lactate extraction ratios during inflation mirrored those of the ST-segment shift. The present study demonstrates that administration of pravastatin results in a significant gain in tolerance to ischemia during angioplasty. The effect of pravastatin was abolished by aminophylline, suggesting that the cardioprotective effect of pravastatin may result from activation of adenosine receptors.",2002.0,0,0 997,11703958,Cholesterol lowering with statins reduces exercise-induced myocardial ischemia in hypercholesterolemic patients with coronary artery disease.,J A Ramires; A C Sposito; A P Mansur; O R Coelho; M Maranhão; L A Cesar,"Coronary flow reserve is mainly influenced by the combination of luminal stenosis and vascular dilation capacity. Thus, after statin treatment, the reduction of ischemic threshold in patients submitted to exercise testing could be intensely influenced by angiographic severity. In this study, we verify the effect of statin treatment on exercise-induced myocardial ischemia in hypercholesterolemic patients with a broad range of coronary angiographic severities. Patients with 2 consecutive positive exercise tests, coronary stenosis > or =70%, total cholesterol > or =300 mg/dl, and triglycerides < or =200 mg/dl were randomly assigned to a 16-week treatment period with either diet alone (n = 39) or diet plus statins (simavastatin, n = 31 and pravastatin, n = 10). Statin-treated patients had a significant variation in total cholesterol (-46% vs -2.7%; p <0.01), low-density lipoprotein cholesterol (-58% vs 0.8%; p <0.01), and high-density cholesterol (+28% vs -6%; p <0.05) in comparison with the diet-only group. After 16 weeks of treatment, 36 patients (92%) in the diet group still had positive exercise tests, whereas only 7 patients (15%) of the statin group had a positive test (p <0.01). The proportion of positive tests was significantly reduced in subgroups of patients with 1-, 2-, or 3-vessel disease. Regarding the severity of coronary stenosis, the proportion of positive tests was significantly reduced in patients with stenosis between 70% and 90% and in patients with stenosis > or =90%. Moreover, the proportion of positive tests tended to decrease to a greater extent in patients with mild coronary disease. In conclusion, cholesterol-lowering treatment with statins reduces exercise-induced myocardial ischemia in hypercholesterolemic patients with mild or severe epicardial coronary stenosis.",2002.0,0,0 998,11704711,Acute statin treatment in reducing risk after acute coronary syndrome: the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) Trial.,C H Ahsan; A Shah; M Ezekowitz,Three-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) reduce coronary events and death in both primary and secondary prevention trials. In these trials benefit did not appear for years after randomization. It is noteworthy that these trials did not include patients with recent myocardial infarctions or unstable angina. It is well known that mortality and recurrent ischemic events rates are the highest in the early period after acute coronary syndromes. Favorable physiologic effects of statins have been described within a few weeks of exposure to the statin in a number of experimental studies. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study was designed to bridge the gap between primary and secondary prevention trials and specifically included patients with unstable angina or non-ST elevation myocardial infarction.,2002.0,0,0 999,11705478,Learning from the cerivastatin experience.,J A Farmer,,2002.0,0,0 1000,11705583,Acute coronary syndrome without ST elevation: implementation of new guidelines.,C W Hamm; M Bertrand; E Braunwald,"Unstable angina and non-ST-segment-elevation myocardial infarction have in recent years been recognised as frequent and important clinical manifestations of coronary-artery disease. The European (ESC) and American (ACC/AHA) professional societies last year released guidelines on diagnosis, risk stratification, and treatment of these disorders. These guidelines summarise similarly the current evidence and translate them to clinical practice. Most important changes relate to the inclusion of troponins into the risk stratification algorithm, the addition of low-molecular-weight heparin and glycoprotein IIb/IIIa antagonists to medical treatment, and the role of invasive management for improved long-term outcome. Guidelines are constantly challenged by newly emerging study results. Recently, early invasive management and clopidogrel have been found to exert further benefit to this high-risk group of patients. Accordingly, the societies on both sides of the Atlantic will work together closely to update and implement these guidelines.",2002.0,0,0 1001,11705814,Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia.,C D Garlichs; S John; A Schmeisser; S Eskafi; C Stumpf; M Karl; M Goppelt-Struebe; R Schmieder; W G Daniel,"Hypercholesterolemia, a risk factor for cardiovascular disease, is associated with inflammation and hypercoagulability. Both can be mediated by the CD40 system. This study investigated whether the CD40 system is upregulated in patients with moderate hypercholesterolemia and whether it is influenced by therapy with a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Fifteen patients with moderate hypercholesterolemia and 15 healthy control subjects were investigated. CD154 and P-selectin were analyzed on platelets and CD40 was analyzed on monocytes before and under therapy with the statin cerivastatin by double-label flow cytometry. Blood concentrations of soluble CD154 and monocyte chemoattractant protein-1 (MCP-1) were evaluated. Our main findings were as follows. Patients with moderate hypercholesterolemia showed a significant increase of CD154 and P-selectin on platelets and CD40 on monocytes compared with healthy subjects. Soluble CD154 showed a nonsignificant trend for higher plasma levels in patients. A positive correlation was found for total or LDL cholesterol and CD154, but not for CD40 on monocytes. The latter was upregulated in vitro by C-reactive protein, which was found to be significantly elevated in patients with moderate hypercholesterolemia. CD154 on platelets proved to be biologically active because it enhanced the release of MCP-1, which was markedly elevated in an in vitro platelet-endothelial cell coculture model and in the serum of patients. Short-term therapy with a HMG-CoA reductase inhibitor significantly downregulated CD40 on monocytes and serum levels of MCP-1. Patients with moderate hypercholesterolemia show upregulation of the CD40 system, which may contribute to the known proinflammatory, proatherogenic, and prothrombotic milieu found in these patients.",2002.0,0,0 1002,11707010,Four cases of tendinopathy in patients on statin therapy.,P Chazerain; G Hayem; S Hamza; C Best; J M Ziza,"During the last decade, statins have been widely prescribed as lipid-lowering drugs. Their overall safety profile is good. The main musculoskeletal side effects have consisted of muscle pain and weakness, peripheral neuropathy, and a few cases of drug-induced lupus. We report the first four cases of tendinopathy in patients receiving statin therapy. There were three men and one woman. The diagnoses were extensortenosynovitis at the hands (case 1), tenosynovitis of the tibialis anterior tendon (case 2), and Achilles tendinopathy (cases 3 and 4). Two patients were on simvastatin and two on atorvastatin. The tendinopathy developed 1 to 2 months after treatment initiation. The outcome was consistently favorable within 1 to 2 months after discontinuation of the drug. Similar cases have been reported to French pharmacovigilance centers. This report of four cases of tendinopathy draws attention to a possible and heretofore unrecognized side effect of a drug class that is becoming increasingly popular. Statins are effective in lowering high cholesterol levels in patients with type IIa or IIb hypercholesterolemia. They have been widely used for the last decade, particularly in the secondary and primary prevention of major coronary events. Statins act by inhibiting the enzyme hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Although most patients tolerate statins extremely well, a few experience side effects requiring treatment discontinuation. Reported musculoskeletal side effects include myalgia and a few cases of rhabdomyolysis and polymyositis. Induced lupus and peripheral neuropathy are exceedingly rare.",2002.0,0,0 1003,11707240,[Coronary artery bypass graft combined with transmyocardial laser revascularization. Survival and functional class at one-year follow-up].,I Díaz De Tuesta; R Martínez,"The use of Transmyocardial Laser Revascularization (TMLR) as a strategy to treat unstable angina has been reported in many studies. We analyze its safety and effectiveness in combined procedures (CABG + TMLR). A non-randomized, retrospective cohort study was performed from May 4, 1999 to May 25, 2000 in 21 TMLR patients (18 combined CABG + TMLR) and 118 CABG only procedures. Mortality and NYHA analyses were determined by telephone at follow-up. Three hospital deaths were observed: one isolated TMLR patient, one valvular + CABG + TMLR patient, and one CABG + TMLR patient. A significantly higher incidence of preoperative angina was found in the group of patients with TMLR + CABG, than in the group with only CABG (83 vs 25%; p < 0.001). There were no differences in age, gender, ejection fraction, Parsonnet and EuroSCORE risk estimation, or mortality (5.1% isolated CABG, 5.6% combined). No episode of angina was detected during follow-up in the CABG + TMLR group: 88% patients were NYHA I, and 21% NYHA II. Incomplete coronary revascularization may be complemented with TMLR in the areas in which CABG is not possible without increased mortality. This technique may avoid postoperative unstable angina due to residual ischemic areas.",2002.0,0,0 1004,11709192,"Gene expression microarray analysis in cancer biology, pharmacology, and drug development: progress and potential.",P A Clarke; R te Poele; R Wooster; P Workman,"With the imminent completion of the Human Genome Project, biomedical research is being revolutionised by the ability to carry out investigations on a genome wide scale. This is particularly important in cancer, a disease that is caused by accumulating abnormalities in the sequence and expression of a number of critical genes. Gene expression microarray technology is gaining increasingly widespread use as a means to determine the expression of potentially all human genes at the level of messenger RNA. In this commentary, we review developments in gene expression microarray technology and illustrate the progress and potential of the methodology in cancer biology, pharmacology, and drug development. Important applications include: (a) development of a more global understanding of the gene expression abnormalities that contribute to malignant progression; (b) discovery of new diagnostic and prognostic indicators and biomarkers of therapeutic response; (c) identification and validation of new molecular targets for drug development; (d) provision of an improved understanding of the molecular mode of action during lead identification and optimisation, including structure-activity relationships for on-target versus off-target effects; (e) prediction of potential side-effects during preclinical development and toxicology studies; (f) confirmation of a molecular mode of action during hypothesis-testing clinical trials; (g) identification of genes involved in conferring drug sensitivity and resistance; and (h) prediction of patients most likely to benefit from the drug and use in general pharmacogenomic studies. As a result of further technological improvements and decreasing costs, the use of microarrays will become an essential and potentially routine tool for cancer and biomedical research.",2002.0,0,0 1005,11711002,"In patients with heart disease, is the benefit of lipid-lowering therapy with statins similar in older patients to that in younger patients?",A Adelman,,2002.0,0,0 1006,11711005,Clinical inquiries. What laboratory monitoring is appropriate to detect adverse drug reactions in patients on cholesterol-lowering agents?,D Weismantel; P Danis,,2002.0,0,0 1007,11712826,Conditional risk factors in men with previous myocardial infarction: relevance of C3 and homocysteine.,A Muscari; M C Mele; L Bastagli; G Poggiopollini; V Tomassetti; G Drago; C Legnani; A Barini; O Cappelletti; P Boni; P Puddu,"To establish which traditional and conditional risk factors were effectively treated, and which remained active, in patients with previous myocardial infarction (PMI). In 47 PMI patients recently submitted to cardiological assessment and in 42 controls (50-70 years old men), traditional risk factors (total cholesterol, high-density lipoprotein cholesterol, blood glucose, blood pressure, cigarette smoking and body mass index) and the following variables were measured: fibrinogen, plasminogen activator inhibitor-1 (PAI-1), lipoprotein(a) [Lp(a)], total homocysteine, plasma folates, vitamin B12, high sensitivity C-reactive protein and C3 complement. Most patients were taking beta-blockers, ACE inhibitors and statins. Accordingly, patients had lower blood pressure and cholesterol values than controls. Moreover, they consumed less alcohol and coffee and did not differ from controls in cigarette smoking and body mass index. Conversely, patients had higher levels of homocysteine, fibrinogen, C3 complement and Lp(a), although of these factors only C3 and homocysteine remained significantly associated with PMI in multivariate analysis. C-reactive protein, PAI-1 and especially C3 often correlated with traditional risk factors in controls, but these correlations tended to disappear or reverse in PMI patients. Fibrinogen inversely correlated with alcohol consumption. Homocysteine correlated (inversely) with plasma folates only. Lp(a) did not correlate with any variable. Forty-seven patients with previous myocardial infarction displayed an excellent control of traditional risk factors, but they had higher mean C3 and homocysteine levels than the control group.",2002.0,0,0 1008,11712864,,,,,0,0 1009,11714084,Pharmacological management of high triglycerides and low high-density lipoprotein cholesterol.,P O Szapary; D J Rader,"Elevated serum triglycerides and low high-density lipoprotein (HDL) cholesterol are part of a metabolic syndrome that is increasingly being recognized as an important risk factor for cardiovascular disease. Several classes of pharmacological agents including fibrates, niacin and statins, can modify the triglyceride-HDL axis. Fibrates in particular have recently been shown in clinical trials not only to increase HDL, but also to reduce cardiovascular mortality in secondary prevention. More research is needed to further define the role of fibrates when used alone and in combination with statins in high-risk individuals.",2002.0,0,0 1010,11714208,Lopinavir-Ritonavir: a new protease inhibitor.,E M Mangum; K K Graham,"Lopinavir is a new protease inhibitor that is structurally related to ritonavir. It recently was approved by the Food and Drug Administration as a coformulation with ritonavir under the brand name Kaletra. Ritonavir substantially increases lopinavir drug exposure by inhibiting cytochrome P450 isoenzyme 3A4. Based on limited data, lopinavir-ritonavir demonstrates safety and efficacy in both antiretroviral-naive and protease inhibitor-experienced patients. It has the ability to durably suppress human immunodeficiency virus (HIV) RNA for up to 2 years in antiretroviral-naïve patients. Compared with nelfinavir, it had superior virologic control at 48 weeks in antiretroviral-naïve patients. Its side effects include diarrhea, abnormal stools, abdominal pain, nausea, vomiting, and asthenia. A number of patients experienced grade 3-4 laboratory abnormalities in liver function tests, cholesterol, and triglycerides while receiving this drug combination. The exact resistance patterns of lopinavir-ritonavir are unknown, but the Department of Health and Human Services strongly recommends it for the initial treatment of HIV-infected adults and adolescents.",2002.0,0,0 1011,11714215,Physician-prompting statin therapy intervention improves outcomes in patients with coronary heart disease.,D E Hilleman; M S Monaghan; C L Ashby; J E Mashni; K Woolley; C M Amato,"To evaluate the effectiveness of a posthospital discharge intervention that prompted physicians to increase the use and effectiveness of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) in patients with coronary heart disease (CHD). Participants were 612 patients with CHD who were admitted to a coronary care unit. The control group (303 patients admitted from October 1-December 31, 1998) received no follow-up intervention. The intervention group (309 patients admitted fromJanuary 1-March 31, 1999) had follow-up letters sent or phone calls made to their primary care physicians with patient-specific recommendations concerning assessment of lipid profiles and statin therapy. Over a 2-year follow-up period, assessment of lipid profiles, use of therapy, and adverse clinical outcomes were compared between the control and intervention groups. At hospital discharge, there was no significant difference in the use of statins between the groups. At each reported follow-up interval, the percentages of patients having lipid profiles measured, being treated with a statin, receiving titrated dosages of a statin, and achieving low-density lipid (LDL) cholesterol goals set by the National Cholesterol Education Program (NCEP) were significantly greater in the intervention group compared with the control group (all p<0.05). At the end of the 2-year follow-up period, nearly three-fourths (72%) of the intervention group were receiving a statin, compared with 43% of the control group. In addition, 55% of the intervention group achieved their NCEP LDL goal, compared with only 10% of the control group. Recurrent myocardial infarction, hospitalization for myocardial ischemia, coronary revascularization, and cardiovascular mortality were significantly reduced in the intervention group compared with the control group (all p<0.05). A relatively simple physician-prompting intervention significantly increased assessment of lipid status, frequency of statin use, achievement of LDL treatment goals, and titration of lipid drug dosages. In addition, the improved use of statins significantly reduced adverse cardiovascular outcomes. This intervention tool should be more broadly applied in patient populations eligible to receive these agents.",2002.0,0,0 1012,11716156,Medical care from childhood to adulthood in type 1 and type 2 diabetes.,G Costi; S Ten; N K Maclaren,"Diabetes mellitus comprises a heterogeneous group of diseases that have in common the development of macro- and microvascular complications. It is now possible to identify subjects at high risk of Type 1 or Type 2 diabetes, especially in the patient's family members. Preventive interventions are quickly becoming available, and can help delay the onset of the disease and thereby reduce complications in these subjects. Furthermore the correct etiological diagnosis of diabetes is fundamental in providing the best treatment for the patient. Maturity-onset diabetes of the young (MODY) syndrome should be suspected in cases of a subtle onset of diabetes and autosomal dominant inheritance. Mitochondrial DNA mutations should be considered when a diabetic patient also suffers from deafness or if there is a family history of this combination in the mother side of the family. Atypical diabetes has to be identified by the physician to avoid mistakes when the patient enters the non-insulin-dependent phase. In the case of Wolfram's syndrome a gene analysis for each family member should be performed to identify heterozygote subjects. Recently, many discoveries in genetics help us better understand the pathogenesis of the diseases and diagnose the monogenic form of diabetes more easily. If all family members are followed in the same center, clues from the family history are readily available for differential diagnosis and preventive interventions can be established more effectively.",2002.0,0,0 1013,11716837,"Effect of FR194738, a potent inhibitor of squalene epoxidase, on cholesterol metabolism in HepG2 cells.",M Sawada; M Matsuo; H Hagihara; N Tenda; A Nagayoshi; H Okumura; K Washizuka; J Seki; T Goto,"(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[2-methyl-2-(3-thienylmethoxy)propyloxy]benzylamine hydrochloride (FR194738) inhibited squalene epoxidase activity in HepG2 cell homogenates with an IC50 value of 9.8 nM. In the study using intact HepG2 cells, FR194738 inhibited cholesterol synthesis from [14C]acetate with an IC50 value of 4.9 nM, and induced intracellular [14C]squalene accumulation. On the other hand, the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor simvastatin reduced both cholesterol and squalene synthesis from [14C]acetate. Incubation with simvastatin for 18 h produced increases in HMG-CoA reductase activity in HepG2 cells, which was related to the degree of reduction in cholesterol synthesis. The HMG-CoA reductase activity increased by 13- and 19-fold at the concentrations of simvastatin that inhibited cholesterol synthesis by 65% and 82%, respectively. In contrast, FR194738 did not increase HMG-CoA reductase activity at the concentrations that inhibited cholesterol synthesis by 24% and 69%, and moderate increase (4.6-fold) was observed at the concentration that inhibited cholesterol synthesis by 90%. These results suggest that non-sterol metabolite(s) derived from mevalonate prior to the squalene epoxidation step in the cholesterol synthetic cascade have a regulatory role in the suppression of HMG-CoA reductase activity. We speculate that FR194738 inhibits cholesterol synthesis with a minimal change of the regulator(s) and would be highly effective in the treatment of hypercholesterolemia.",2002.0,0,0 1014,11717980,Certain progress of clinical research on Chinese integrative medicine.,K Chen; B Yu,,2002.0,0,0 1015,11718459,Prevention of coronary heart disease through treatment of infection with Chlamydia pneumoniae? Estimation of possible effectiveness and costs.,C Sanderson; M Kubin,"Evidence has been accumulating for a link between Chlamydia pneumoniae and coronary heart disease (CHD). A spreadsheet model was used to estimate the impact of different strategies for screening and treating C. pneumoniae on the incidence of myocardial infarction and cardiac mortality over a 1-year post-intervention period. It was found that screening would potentially be most cost-effective in men aged over 35 with a history of myocardial infarction (around ł2,000 per life-year saved). Cost-effectiveness would be inferior in those with established heart disease but no history of myocardial infarction (MI), and poor for people at elevated risk of CHD. If causality of the association were proven, the cost-effectiveness of treating C. pneumoniae in post-MI patients would compare favourably with, for example, statins for treating hypercholesterolaemia.",2002.0,0,0 1016,11720280,The role of risk factors in the development of atherosclerosis.,J Frohlich; M Dobiasova; S Lear; K W Lee,"Our understanding of risk factors for atherogenesis has changed significantly over the last decade. In addition to better grasp of the mechanism of action of the ""classic"" (causal) risk factors, a number of potentially important new factors has emerged. In this review we briefly summarize the evidence of the relation between atherosclerosis and the currently recognized causal risk factors, namely, age, smoking, LDL cholesterol, HDL cholesterol, hypertension, and diabetes. More emphasis has been put on description of the emerging entities such as atherogenic profile of plasma lipoproteins with discussion of LDL and HDL subclasses, Lp(a), homocysteine, and, last but not least, on the role of infection and inflammation in atherogenesis. Whenever possible, we tried to summarize the relevant lines of evidence such as epidemiological, pathological, genetic, and clinical trial data linking the specific factor with atherosclerosis.",2002.0,0,0 1017,11721672,Evaluation of the implementation of a local treatment guideline in secondary prevention post-myocardial infarction.,F Reid; B Fossland; A D Flapa; C C Duckelmann; S A Hudson,"To validate and implement an audit tool to assess quality and appropriateness of prescribing. To compare inpatient prescribing of secondary prevention in post myocardial infarction patients before and after introduction of a local treatment guideline. Descriptive, non-experimental retrospective case note review comparing patients treated before and after the implementation of a clinical guideline. Comparison of quality of prescribing in two patient groups. Analysis of Group 1 patients showed that 41% required treatment with an angiotensin converting enzyme inhibitor (ACE-I), and 23% of those did not receive treatment, 20% of patients on ACE-I received sub-therapeutic doses. Seventy-two per cent of patients required treatment with a statin and 22% of those did not receive a statin. Comparison of the treatment of Group 2 showed that, of 53 patients (50% of Group 2) requiring an ACE-I, 100% received it, although 15% received sub-therapeutic doses. Of 69 patients (64% of Group 2) requiring treatment with a statin 96% were prescribed a statin. Improvements in prescribing of beta-Blockers, ACE-I and statins were statistically significant. Prescribing improved significantly for beta-Blockers, ACE-I and statins after guideline introduction with anticipated benefits to patient outcomes.",2002.0,0,0 1018,11723009,Low-density-lipoprotein cholesterol goals for patients with coronary disease: treating between the lines.,D D Waters; P Y Hsue,,2002.0,0,0 1019,11723015,Effect of an aggressive lipid-lowering strategy on progression of atherosclerosis in the left main coronary artery from patients in the post coronary artery bypass graft trial.,C W White; F L Gobel; L Campeau; G L Knatterud; S A Forman; J S Forrester; N L Geller; J A Herd; A Hickey; B J Hoogwerf; D B Hunninghake; Y Rosenberg; M L Terrin; Post Coronary Artery Bypass Graft Trial Investigators,"The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of two lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol levels to a mean yearly cholesterol level from 93 to 97 mg/dL compared with a moderate reduction to a level of 132 to 136 mg/dL decreased the progression of atherosclerosis in saphenous vein grafts. Low-dose anticoagulation did not affect progression. This secondary analysis tested the hypothesis that a similar decrease in progression of atherosclerosis would also be present in native coronary arteries as measured in the left main coronary artery (LMCA). A sample of 402 patients was randomly selected from 1102 patients who had baseline and follow-up views of the LMCA suitable for analysis. Patients treated with the aggressive lipid-lowering strategy had less progression of atherosclerosis in the LMCA as measured by changes in minimum (P=0.0003) lumen diameter or the maximum percent stenosis (P=0.001), or the presence of substantial progression (P=0.008), or vascular occlusion (P=0.005) when compared with the moderate strategy. A strategy of aggressive lipid lowering results in significantly less atherosclerosis progression than a moderate approach in LMCAs.",2002.0,0,0 1020,11723099,Lipid lowering does not improve endothelial function in subjects with poorly controlled diabetes.,J Mansourati; L G Newman; S H Roman; A Travis; M Rafey; R A Phillips,,2002.0,0,0 1021,11724206,Treatment with atorvastatin improves small artery compliance in patients with severe hypercholesterolemia.,E Leibovitz; N Hazanov; R Zimlichman; M Shargorodsky; D Gavish,"We studied the effect of atorvastatin on arterial compliance in patients with severe hypercholesterolemia. Seventeen patients with low-density lipoprotein cholesterol levels above 170 mg/dL, were included in the study, none of whomever received hypolipidemic medication or had other risk factors. Patients were followed for five visits, every 4 weeks. After 20 weeks of treatment, lipid profile improved significantly. Large artery elasticity index did not change significantly, but small artery elasticity index increased by 21% (4.6+/-0.5 to 5.6+/-0.9, P < .01). Although none of our patients suffered from hypertension, both systolic and diastolic blood pressure (BP) decreased significantly (6 mm Hg and 3 mm Hg, respectively). We conclude that atorvastatin improves the elasticity of small arteries and reduces systolic and diastolic BP in patients with severe hypercholesterolemia.",2002.0,0,0 1022,11725812,Effect of prescription benefit changes on medical care utilization in a Medicare HMO population.,R Balkrishnan; W G Byerly; F T Camacho; A Shrestha; R T Anderson,"To examine the impact of 2 cost-containment efforts in prescription benefits in successive years that included changes in copayment and coverage levels, expanded generic coverage, and brand name prescription drug limit-of-coverage in a Medicare health maintenance organization (HMO). The benefit changes included moving to a drug benefit with increased total coverage and higher copayments in the first year (1998) and to one with brand name limit-of-coverage and unlimited generic availability in the second year (1999). A repeated-measures analytical design with enrollee follow-up before and after introduction of the 2 policies. A cohort of 2411 older adults continuously enrolled in a Medicare HMO since 1998 was followed up for 1 year pre-post for healthcare service utilization and costs; 259 patients enrolled since 1997 were available to test the effects of the first policy change. Bivariate and multivariate analyses found a significant decrease of 27% in prescription costs, a 4% decrease in physician visits, and a 6% decrease in total costs associated with the change in prescription benefit in the second year (1999). The policy change in the first year (1998) resulted in a 29% increase in prescription costs and 38% increased total costs for the HMO. Introduction of a prescription benefit that included substantial brand name limit-of-coverage and generic drug coverage expansion was associated with significantly reduced prescription costs. In addition, this change did not seem to increase nonprescription-related healthcare service use in the population.",2002.0,0,0 1023,11727350,Rational prescribing of statins.,H Purcell; C Daly; M Sheppard; J Morrell,,2002.0,0,0 1024,11727466,The evaluation of pharmacologic therapy in humans: a brief summary of the drug evaluation process and guidelines for clinical trials as they related to women.,J B Schwartz,"Significant progress has been made in including women in clinical and drug evaluation trials. Nonetheless, for most drugs currently on the market, analysis of benefits by sex is not available. At least some of the adverse effects of newer drugs in women could be due to the lack of inclusion in studies from which therapeutic regimens were derived. The data currently available on potential sex differences in pharmacokinetics and pharmacodynamics are also limited by having been obtained from healthy subjects receiving only one medication in studies designed only to detect moderate-to-large (> 30-50%) differences between the sexes. The clinical environment is different: patients consume multiple medications, including over-the-counter medications as well as nutraceuticals and dietary supplements; patients are, on average, older than healthy volunteers or even patients enrolled in investigational studies; and patients are more likely to have multiple diseases. In addition, adequate numbers of women still have not been enrolled in clinical trials for the therapy of many common disorders. The prudent clinician will remember that every time a therapy is initiated for an individual patient, especially a female patient, it is a clinical trial and the outcome is uncertain.",2002.0,0,0 1025,11728245,Cerivastatin.,A Cheng-Lai,"Cerivastatin is a synthetic and enantiomerically pure 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. It has been recognized for its high pharmacologic potency, uncomplicated pharmacokinetic profile, and low drug-interaction potential. The efficacy of cerivastatin has been demonstrated in a number of clinical trials involving patients with primary hypercholesterolemia and mixed dyslipidemia. Cerivastatin was found to have dose-dependent reduction in total cholesterol and low-density lipoprotein (LDL) cholesterol. At the 0.4 mg daily dose, cerivastatin was found to lower LDL cholesterol by approximately 35% (mean reductions of 33-39%). The triglyceride-lowering effect of cerivastatin is also dose dependent; however, there is a much stronger association between baseline triglyceride levels and the triglyceride-lowering effect of cerivastatin. A dosage of 0.4 mg daily has been shown to reduce triglycerides by a mean of 28% in patients with baseline triglyceride levels of > 300 mg/dL. At the time of its initial approval by the US Food and Drug Administration (FDA) in 1997, cerivastatin was available only in 0.2 mg and 0.3 mg strengths. The recent FDA approval of the 0.4-mg strength dose has made cerivastatin a more competitive drug in lipid-lowering efficacy among the HMG-CoA reductase inhibitors.",2002.0,0,0 1026,11728357,Effect of pravastatin on endothelial function in patients with coronary artery disease (cholesterol-independent effect of pravastatin).,A Masumoto; Y Hirooka; K Hironaga; K Eshima; S Setoguchi; K Egashira; A Takeshita,,2002.0,0,0 1027,11728362,"Rapid effects on vascular function after initiation and withdrawal of atorvastatin in healthy, normocholesterolemic men.",U Laufs; S Wassmann; S Hilgers; N Ribaudo; M Böhm; G Nickenig,,2002.0,0,0 1028,11728917,Statins and their potential for osteoporosis.,G R Mundy,,2002.0,0,0 1029,11730394,,,,,0,0 1030,11730833,Atorvastatin improves blood rheology in patients with familial hypercholesterolemia (FH) on long-term LDL apheresis treatment.,S Banyai; M Banyai; J Falger; M Jansen; E Alt; K Derfler; R Koppensteiner,"To determine the effect of atorvastatin on blood rheology in patients with familial hypercholesterolemia (FH) on regular LDL apheresis, we prospectively studied the rheological variables fibrinogen, plasma viscosity, red cell aggregation, whole blood viscosity, hematocrit and platelet aggregation in 12 patients (two homozygous, ten heterozygous) before and during treatment with atorvastatin. Baseline values of red cell aggregation and whole blood viscosity were increased in FH patients on regular LDL apheresis compared with healthy controls (P<0.05), whereas fibrinogen, plasma viscosity and hematocrit were similar in the two groups. Treatment with atorvastatin reduced red cell aggregation (P<0.01), whole blood viscosity (P<0.01), plasma viscosity (P<0.01) and platelet aggregation (P<0.05), but caused a slight increase in plasma fibrinogen (by 5%; P<0.01). Our findings suggest that atorvastatin improves blood rheology in patients with FH on regular LDL-apheresis. This improvement in blood flow properties may contribute to the well-known beneficial effects of atorvastatin on cardiovascular risk in patients with severe hyperlipidemia and atherosclerotic vascular disease.",2002.0,0,0 1031,11731186,Estrogen/progesterone replacement versus pravastatin and their sequential association in hypercholesterolemic postmenopausal women.,A Lemay; S Dodin; L Turcot; F Déchêne; J C Forest,"The objectives of this study were to assess serum lipid changes in response to an oral estrogen combined with progesterone (Group A) as compared with pravastatin (Group B) and to evaluate the additive effects of the sequential addition of statin to hormonal replacement therapy (HRT) and of HRT to statin. Thirty-seven of 63 hypercholesterolemic menopausal women initially submitted to a 4-month diet were randomised to oral conjugated estrogens (0.625 mg)/micronised progesterone (200 mg) or to pravastatin (40 mg). After 6 months, each group received both medications for another 6 months. Nineteen percent of women corrected their lipids below decision levels with diet alone. Low density lipoprotein-cholesterol (LDL-C) decreased by 8+/-5% with HRT and by 26+/-3% (P<0.001) with the statin. These single medications increased high density lipoprotein-cholesterol (HDL-C) by 13+/-5% (P<0.01) and 11+/-7%, respectively. Combined interventions produced cumulative LDL-C reductions of 40+/-2 and 42+/-3% (P<0.001) and additive HDL-C augmentations of 16+/-4 and 23+/-5% (P<0.01) with proportional changes in apolipoprotein (Apo)B-100 and ApoA-1. These combined effects brought the atherogenic index (C/HDL-C) for Groups A and B, respectively, from a moderate (5.18+/-0.25 and 5.87+/-0.18) to a reduced (3.35+/-0.20 and 3.52+/-0.19) risk category. Triglycerides (TG) which were increased by HRT and decreased by the statin returned to baseline during combined treatments. No changes in diet, physical activity or anthropomorphometric measurements explained the lipid modifications. In menopausal patients with elevated C not responding to diet, pravastatin was most effective to decrease LDL-C, and oral estrogen-micronised progesterone most effective to increase HDL-C. Marked reduction of the atherogenic index is achieved by sequential combinations of medications resulting from beneficial cumulative effects on both C-LDL and C-HDL.",2002.0,0,0 1032,11735317,Cholesterol: an important but relatively overemphasized risk factor for ischemic heart disease.,H R Hellstrom,"Educational messages directed at the public to prevent ischemic heart disease (IHD) are generally based on cholesterol-reduction. However, IHD has multiple risk factors, and a study was performed to help determine whether or not the allocation of educational messages among risk factors is appropriate: The severity of high cholesterol was compared with the severity of multiple other major risk factors for IHD, and the beneficial effects of cholesterol-reduction was compared with the benefits of multiple other major preventative factors for IHD. It was found that high cholesterol levels, and multiple other risk factors, generally give a risk of around 2.0 for developing IHD. Cholesterol-reduction by statins, and multiple other factors which prevent IHD, generally reduce the risk of IHD by about 30-40%. It was concluded that the allocation of educational messages to reduce the incidence of IHD should significantly increase discussions of non-cholesterol risk and preventative factors.",2002.0,0,0 1033,11735640,Orlistat: in the prevention and treatment of type 2 diabetes mellitus.,G M Keating; B Jarvis,"Orlistat is a nonsystemically acting gastric and pancreatic lipase inhibitor that limits the absorption of dietary fat. A retrospective pooled analysis of three 2-year, double-blind, randomised, placebo-controlled trials involving patients with obesity revealed that orlistat recipients were more likely to experience an improvement, and less likely to experience a deterioration, in glucose tolerance status than placebo recipients. In comparison with placebo, orlistat recipients had significantly greater reductions in glycosylated haemoglobin and fasting plasma glucose levels in large, double-blind, randomised, placebo-controlled studies of 24 to 52 weeks' duration involving patients with obesity and type 2 diabetes mellitus. In one such study, the dosage of concomitant sulphonylureas was able to be reduced in more orlistat than placebo recipients (43.2 vs 28.9%), with discontinuation of sulphonylurea therapy achieved in 11.7% of orlistat recipients. The most common adverse effects reported in orlistat recipients with type 2 diabetes mellitus relate to the gastrointestinal system and are similar to those reported in studies involving patients without type 2 diabetes mellitus.",2002.0,0,0 1034,11735645,Hepatotoxicity with thiazolidinediones: is it a class effect?,A J Scheen,"Decreased insulin sensitivity plays a major role in various human diseases. particularly type 2 diabetes mellitus, and is associated with a higher risk of atherosclerosis and cardiovascular complications. Thiazolidinediones, more commonly termed glitazones, are the first drugs to specifically target muscular insulin resistance. They have proven efficacy for reducing plasma glucose levels in patients with type 2 diabetes mellitus treated with diet alone, sulphonylureas, metformin or insulin. In addition, they are associated with some improvement of the cardiovascular risk profile. However, troglitazone, the first compound approved by the Food and Drug Administration in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozen deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to unique properties of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy with regard to blood glucose control in patients with type 2 diabetes mellitus as compared with troglitazone. In controlled clinical trials, the incidence of significant (> or =3 x upper limit of normal) increases in liver enzyme levels (ALT in particular) was similar with rosiglitazone or pioglitazone as compared with placebo, whereas troglitazone was associated with a 3-fold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only a few case reports of hepatotoxicity have been reported in patients treated with rosiglitazone until now, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. It should be mentioned that troglitazone, unlike pioglitazone and rosiglitazone, induces the cytochrome P450 isoform 3A4, which is partly responsible for its metabolism, and may be prone to drug interactions. Importantly enough, obesity, insulin resistance and type 2 diabetes mellitus are associated with liver abnormalities, especially non-alcoholic steatohepatitis, independent of any pharmacological treatment. This association obviously complicates the selection of patients who are good candidates for a treatment with glitazones as well as the monitoring of liver tests after initiation of therapy with any thiazolidinedione compound. While regular monitoring of liver enzymes is still recommended and more long term data are desirable, current evidence from clinical trials and postmarketing experience in the US supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone.",2002.0,0,0 1035,11735736,Cardiologists like statins-more than patients do.,M Mitka,,2002.0,0,0 1036,11737581,"Coronary artery disease in uremia: Etiology, diagnosis, and therapy.",D J Goldsmith; A Covic,"Cardiovascular disease is a major challenge to nephrologists, whether we deal with patients with pre-end-stage renal failure, on dialysis or after successful renal transplantation. It is the most common cause for death in patients with a functional allograft, and prevents many dialysis patients from being engrafted. Coronary artery disease is a diagnostic and therapeutic challenge, as it differs in some respects from that seen in non-uremic cohorts, and lacks much of the evidence-base on which therapeutic intervention rests. This review examines the experimental and clinical literature on cardiovascular disease in uremia, focusing on coronary artery disease. We focus on the incidence, presenting syndromes, screening tools, and interventions in the context of acute and chronic coronary syndromes. Recent evidence comparing coronary angioplasty, coronary artery stenting, and bypass surgery in subjects with renal failure is also reviewed. Coronary artery disease is more prevalent in uremia, more difficult to diagnose and less rewarding to treat compared to non-uremic subjects. Many more randomized trials are needed. In the absence of information from such trials, we advocate aggressive control of conventional and novel cardiovascular risk factors, and early intervention for symptomatic coronary disease.",2002.0,0,0 1037,11738123,Participant recruitment in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).,S Pressel; B R Davis; G T Louis; P Whelton; H Adrogue; D Egan; M Farber; G Payne; J Probstfield; H Ward; ALLHAT Research Group,"The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a practice-based, randomized, multicenter clinical trial in 42,419 high-risk hypertensive patients aged 55 years and older; 10,356 of these patients are also in a lipid-lowering trial component. The purpose of the antihypertensive component is to determine whether the occurrence of fatal coronary heart disease and/or nonfatal myocardial infarction differs between patients randomized to diuretic (chlorthalidone) and those randomized to either calcium antagonist (amlodipine), angiotensin-converting enzyme inhibitor (lisinopril), or alpha-adrenergic blocker (doxazosin) therapy. (The doxazosin arm has been discontinued.) The purpose of the lipid-lowering component is to determine whether lowering low-density lipoprotein cholesterol with a 3-hydroxymethyl-glutaryl coenzyme A reductase inhibitor (pravastatin) in moderately hypercholesterolemic patients will reduce all-cause mortality compared to a control group receiving ""usual care."" ALLHAT recruited patients from a variety of practice settings from February 1994 through January 1998. Sites were paid for randomizations and are paid for completed follow-up visits and documented study events. Communication and monitoring were facilitated by nine regional coordinator teams. It was recognized from the outset that patient recruitment would be a very large task because of the number of participants (> 40,000) needed, the ambitious nature of the goal for recruitment of African-Americans (> 55%), and the knowledge that many investigators had limited experience recruiting participants for clinical trials. Multiple adjustments in the initial ALLHAT overall recruitment plan facilitated achievement of sample size goals for both components of the trial. The experience obtained from this large trial should be valuable for the planning and implementation of successful recruitment in future trials.",2002.0,0,0 1038,11738278,The effects of lipid-lowering and antioxidant vitamin therapies on flow-mediated vasodilation of the brachial artery in older adults with hypercholesterolemia.,J H Stein; C M Carlsson; K Papcke-Benson; S E Aeschlimann; A Bodemer; M Carnes; P E McBride,"The goal of this study was to determine the long-term effects of statins and antioxidant vitamins on flow-mediated vasodilation of the brachial artery in older adults with hypercholesterolemia. Lipid-lowering therapy and antioxidant vitamins improve endothelium-dependent vasodilation in young and middle-aged adults with hypercholesterolemia, but their effects in older adults are not known. Two double-blind, placebo-controlled studies were performed in individuals > or =70 years old with low-density lipoprotein cholesterol (LDL-C) > or =140 mg/dl. In the first study, 37 subjects were randomized to receive (group 1) pravastatin for six months then pravastatin and vitamin E for six additional months or (group 2) vitamin E for six months, then pravastatin and vitamin E for six additional months. In the second study, additional 17 subjects sequentially received simvastatin for six months, then simvastatin and vitamins C and E for six additional months. Flow-mediated vasodilation of the brachial artery was measured by high-resolution ultrasound. At baseline, subjects in both studies were similar in age (mean +/- SD, 75.8 +/- 4.2 years), gender, systolic blood pressure, total cholesterol (261.6 +/- 37.4 mg/dl), LDL-C (180.3 +/- 28.1 mg/dl), high-density lipoprotein cholesterol and triglycerides levels. Flow-mediated vasodilation was severely impaired (2.2 +/- 3.9%). Both statins reduced total and LDL-C levels (p < 0.001); however, neither statin, antioxidant vitamin regimen nor the combination of statins and antioxidant vitamins improved flow-mediated vasodilation of the brachial artery. At baseline, nitroglycerin-mediated vasodilation also was impaired (10.7 +/- 5.6%) and did not change in either study. Older adults with hypercholesterolemia have impaired flow-mediated vasodilation of the brachial artery that does not improve after one year of therapy with statins and antioxidant vitamins, despite significant lipid-lowering.",2002.0,0,0 1039,11738308,"Statin therapy, inflammation and recurrent coronary events in patients following coronary stent implantation.",D H Walter; S Fichtlscherer; M B Britten; P Rosin; W Auch-Schwelk; V Schächinger; A M Zeiher,"We sought to investigate whether statin therapy affects the association between preprocedural C-reactive protein (CRP) levels and the risk for recurrent coronary events in patients undergoing coronary stent implantation. Low-grade inflammation as detected by elevated CRP levels predicts the risk of recurrent coronary events. The effect of inflammation on coronary risk may be attenuated by statin therapy. We investigated a potential interrelation among statin therapy, serum evidence of inflammation, and the risk for recurrent coronary events in 388 consecutive patients undergoing coronary stent implantation. Patients were grouped according to the median CRP level (0.6 mg/dl) and to the presence of statin therapy. A primary combined end point event occurred significantly more frequently in patients with elevated CRP levels without statin therapy (RR [relative risk] 2.37, 95% CI [confidence interval] [1.3 to 4.2]). Importantly, in the presence of statin therapy, the RR for recurrent events was significantly reduced in the patients with elevated CRP levels (RR 1.27 [0.7 to 2.1]) to about the same degree as in patients with CRP levels below 0.6 mg/dl and who did not receive statin therapy (RR 1.1 [0.8 to 1.3]). Statin therapy significantly attenuates the increased risk for major adverse cardiac events in patients with elevated CRP levels undergoing coronary stent implantation, suggesting that statin therapy interferes with the detrimental effects of inflammation on accelerated atherosclerotic disease progression following coronary stenting.",2002.0,0,0 1040,11738332,Heterogeneity of response to lipid-lowering therapy.,R G Bach,,2002.0,0,0 1041,11738334,"Vascular endothelial growth factor: angiogenesis, atherogenesis or both?",J Dulak; A Jozkowicz; M Frick; H F Alber; W Dichtl; S P Schwarzacher; O Pachinger; F Weidinger,,2002.0,0,0 1042,11739979,Pravastatin improves cerebral vasomotor reactivity in patients with subcortical small-vessel disease.,P Sterzer; F Meintzschel; A Rösler; H Lanfermann; H Steinmetz; M Sitzer,"Recent investigations have suggested an important role of statins in the prevention of stroke and dementia independent of their lipid-lowering properties. Using transcranial Doppler sonography (TCD), we examined acetazolamide reactivity as a marker of cerebral vasoreactivity in patients with subcortical small-vessel disease before and after pravastatin treatment. In 16 patients (mean age 68+/-10 years) with subcortical small-vessel disease, cerebral vasomotor reactivity was tested using TCD insonating the middle cerebral artery. Cerebral blood flow velocity (CBFV) increase after bolus injection of 1 g acetazolamide was determined before and after 2-month treatment with pravastatin sodium 20 mg daily. Relative CBFV increase was significantly greater after pravastatin treatment (41.9+/-23.7% versus 55.7+/-18.3%, P=0.004). Comparison of CBFV at rest before and after treatment with pravastatin did not show significant differences. There was a strong negative correlation between the pravastatin-induced enhancement of vasomotor reactivity and the pretreatment CBFV increase (beta=-0.64, P=0.019). No associations were found between the effect of pravastatin on vasomotor reactivity and pretreatment levels or changes of LDL cholesterol. This pilot study provides the first evidence for a significant improvement of cerebral vasomotor reactivity by statin therapy in patients with cerebral small-vessel disease. The results may help to elucidate the preventive effect of statins and provide insights into the pathophysiology of cerebral small-vessel disease.",2002.0,0,0 1043,11741564,Comparison of physician-managed lipid-lowering care in patients with coronary heart disease in two time periods (1994 and 1999).,D A Smith; D Harnick; R Kilaru,,2002.0,0,0 1044,11748098,,,,,0,0 1045,11748225,Transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and Multidrug resistance-associated protein 2 (MRP2/ABCC2).,Makoto Sasaki; Hiroshi Suzuki; Kousei Ito; Takaaki Abe; Yuichi Sugiyama,"Human organic anion transporting polypeptide 2 (OATP2/SLC21A6) and multidrug resistance-associated protein 2 (MRP2/ABCC2) play important roles in the vectorial transport of organic anions across hepatocytes. In the present study, we have established a double-transfected Madin-Darby canine kidney (MDCK II) cell monolayer, which expresses both OATP2 and MRP2 on basal and apical membranes, respectively. The basal-to-apical transport of 17 beta estradiol 17 beta-d-glucuronide (E(2)17 beta G), pravastatin, and leukotriene C(4) (LTC(4)), which are substrates of OATP2 and MRP2, was significantly higher than that in the opposite direction in the double-transfected cells. Such vectorial transport was also observed for taurolithocholate sulfate, which is transported by rat oatp1 and Mrp2. The K(m) values of E(2)17 beta G and pravastatin for the basal-to-apical flux were 27.9 and 24.3 microm, respectively, which were comparable with those reported for OATP2. Moreover, the MRP2-mediated export of E(2)17 beta G across the apical membrane was not saturated. In contrast, basal-to-apical transport of estrone-3-sulfate and dehydroepiandrosterone sulfate, which are significantly transported by OATP2, but not by MRP2, was not stimulated by MRP2 expression. The double-transfected MDCK II monolayer expressing both OATP2 and MRP2 may be used to analyze the hepatic vectorial transport of organic anions and to screen the transport profiles of new drug candidates.",2002.0,0,0 1046,11749112,Visual fields and tiagabine: a quandary.,K R Kaufman; F E Lepore; B J Keyser,"This case report describes the development of asymptomatic visual field defects (VFDs) in a psychiatric patient with bipolar disorder receiving adjunctive tiagabine treatment. These defects were apparently reversible upon the discontinuation of tiagabine. Controlled clinical trials are indicated to determine if this finding is indicative of a class effect for all GABAergic antiepileptic drugs (AEDs), as already noted with vigabatrin, or if this case represents an incidental finding with tiagabine (41 references).",2002.0,0,0 1047,11750563,Control of risk factors for cardiovascular disease in long-term renal transplant recipients.,M R First; V R Peddi; P Weiskittel; E S Woodle,,2002.0,0,0 1048,11751664,Hypercholesterolaemia and lipid lowering treatment do not affect the acute endogenous fibrinolytic capacity in vivo.,D E Newby; F N Witherow; R A Wright; P Bloomfield; C A Ludlam; N A Boon; K A A Fox; D J Webb,"To assess acute tissue plasminogen activator (t-PA) release in vivo in patients with hypercholesterolaemia in the presence and absence of lipid lowering treatment and in matched normocholesterolaemic controls. Parallel group comparison and double blind randomised crossover. University hospital. Eight patients with hypercholesterolaemia (> 7.8 mmol/l) and eight matched normocholesterolaemic controls (< 5.5 mmol/l). Blood flow and plasma fibrinolytic factors were measured in both forearms during unilateral brachial artery infusions of the endothelium dependent vasodilator substance P (2-8 pmol/min) and the endothelium independent vasodilator sodium nitroprusside (1-4 microg/min). In patients, measurements were made on three occasions: at baseline and after six weeks of placebo or pravastatin 40 mg daily administered in a double blind randomised crossover design. Acute release of t-PA. Compared with patients, in normocholesterolaemic control subjects substance P caused greater dose dependent increases in forearm blood flow (p < 0.05) but similar increases in plasma t-PA antigen and activity concentrations. During pravastatin treatment in patients, total serum cholesterol fell by 22% from a mean (SEM) of 8.1 (0.3) to 6.4 (0.4) mmol/l (p = 0.002) and substance P induced vasodilatation was no longer significantly impaired in comparison with controls. However, despite reproducible responses, pravastatin treatment was not associated with significant changes in basal or substance P induced t-PA release. Hypercholesterolaemia and lipid lowering treatment cause no demonstrable effects on acute substance P induced t-PA release in vivo. This suggests that the preventative benefits of lipid lowering treatment are unlikely to be mediated by improvements in endogenous fibrinolysis.",2002.0,0,0 1049,11753902,Can the potential benefits of statins in general medical practice be extrapolated to liver transplantation?,D A Neal; G J Alexander,"Hypercholesterolemia is a common complication of liver transplantation and is a risk factor for cardiovascular disease after renal and heart transplant. The effect of hyperlipidemia after liver transplantation is less certain, but a less favorable outcome is to be expected. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins have proven efficacy in reducing serum cholesterol and mortality from cardiovascular disease in the general population. Early evidence shows that statins are safe and effective in treating hypercholesterolemia after liver transplantation. Studies in cardiovascular disease have shown that statins exhibit beneficial properties independent of lipid-lowering. These include anti-inflammatory effects and improvement in endothelial function. Recently, statins were shown to repress induction of major histocompatibility complex class II complexes by interferon-gamma, which in turn suppresses activation of T lymphocytes. Such effects may assume significance when using statins after solid-organ transplants. Pravastatin has been shown to reduce acute rejection after cardiac and renal transplantation and to also reduce natural killer cell cytotoxicity in these populations. It remains to be seen whether statins will demonstrate similar benefits after liver transplantation.",2002.0,0,0 1050,11755921,Effects of pravastatin treatment on lipoprotein subclass profiles and particle size in the PLAC-I trial.,James D Otvos; Irina Shalaurova; David S Freedman; Robert S Rosenson,"Lipoprotein subclass analyses may facilitate coronary heart disease (CHD) risk stratification and provide insight into the cardioprotective benefits of statins (3-hydroxymethylglutaryl-coenzyme A reductase inhibitors). This study evaluated the influence of pravastatin on lipoprotein subclass profiles to determine whether subjects with predominantly large LDL (LDL size >20.5 nm) or small LDL (LDL size < or =20.5 nm) at baseline differ in responsiveness to drug treatment. Frozen plasma specimens were analyzed from a subset of participants in the Pravastatin Limitation of Atherosclerosis in the Coronaries (PLAC-I) trial at baseline and after treatment for 6 months with pravastatin (n=154) or placebo (n=138). Lipids were measured by standard chemical methods and lipoprotein subclasses by nuclear magnetic resonance (NMR) spectroscopy. Pravastatin-induced changes in lipid levels were similar in subjects with large or small LDL at baseline. Levels of the most abundant LDL subclass were preferentially lowered by pravastatin, resulting in an increase in average LDL size for those with a predominance of small LDL. High-risk CHD subjects with small LDL particles gain at least as much pharmacological benefit from pravastatin as those with large LDL, as evidenced by reductions in the numbers of total and small LDL particles, and increases in average LDL and HDL particle size.",2002.0,0,0 1051,11755933,A pharmacoepidemiological assessment of the effect of statins and fibrates on fibrinogen concentration.,Patrick Maison; Louise Mennen; David Sapinho; Beverley Balkau; Jacques Sigalas; Marie-Christine Chesnier; Evelyne Eschwège; D.E.S.I.R. Study Group,"Plasma fibrinogen is strongly associated with cardiovascular morbi-mortality. We investigated in the large cohort of the D.E.S.I.R. (data from an epidemiological study on the insulin resistance syndrome) study, the relationship between change in fibrinogen concentration over a 3-year follow-up and fibrate and statin use. Fibrinogen concentrations were higher at baseline among individuals treated with statins (n=130) compared to those treated with fibrates (n=251), even after adjustment for confounding factors (including total cholesterol, HDL cholesterol and triglycerides) (mean (S.D.): 2.8 (0.6) vs. 3.1 (0.6), P<0.001). We compared change in fibrinogen concentrations at 3 years of follow-up, between individuals who started fibrate (n=126) or statin (n=127) treatment during the follow-up and individuals (n=3906) who stayed without treatment during this period. After adjustment for baseline fibrinogen level, age, sex and changes in total cholesterol, triglycerides and alcohol intake, fibrinogen concentration decreased after fibrate treatment, while it increased after statin treatment and in those not using lipid lowering drugs (-0.07 (0.54) vs. 0.10 (0.54) vs. 0.08 (0.52) g/l respectively, P=0.01). No differences were observed between different statins or different fibrates. In conclusion, fibrates in contrast with statins may combine lipid-lowering with a beneficial effect on fibrinogen. This effect is independent of changes in cholesterol and triglyceride concentrations.",2002.0,0,0 1052,11755936,Effect of pravastatin on responsiveness to N-monomethyl-L-arginine in patients with hypercholesterolaemia.,Michaela Bayerle-Eder; Gabriele Fuchsjäger-Mayrl; Anna Sieder; Elzbieta Polska; Michael Roden; Thomas Stulnig; Martin G Bischof; Werner Waldhäusl; Leopold Schmetterer; Michael Wolzt,"Improvement of endothelial function in hypercholesterolaemia is attributed to lipid lowering and to pleiotropic effects of statin therapy. We investigated whether responsiveness to inhibition of constitutive NO formation with N-monomethyl-L-arginine (L-NMMA) is improved after 7 and 28 days of pravastatin. Twelve female and four male subjects with mild or moderate primary hypercholesterolaemia were randomized to pravastatin (20 mg per oral (p.o.) n=8) or placebo (n=8) in a double blind parallel group design. Vascular responsiveness was studied by intravenous bolus infusions of L-NMMA (cumulative doses of 3 and 6 mg/kg). Mean arterial blood pressure (MAP) and pulse rate (PR) were measured noninvasively, pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation amplitudes (FPA) and renal plasma flow (RPF) was measured by the PAH clearance method. Pravastatin lowered plasma cholesterol levels by 16 and 24% after 7 and 28 days of treatment, respectively (P<0.01). L-NMMA caused comparable changes in MAP, PR and RPF between groups. L-NMMA reduced FPA to a similar extent in both groups before and after 7 days of treatment, but the response to L-NMMA was significantly enhanced after 28 days of pravastatin (21%; P<0.001 vs baseline) and greater than after placebo (15%; P<0.01 vs pravastatin). Pravastatin enhances responsiveness to L-NMMA in the ocular microvasculature. Improved responsiveness is associated with changes in total cholesterol levels.",2002.0,0,0 1053,11755944,"Remarkably high prevalence of small dense low-density lipoprotein in Japanese men with coronary artery disease, irrespective of the presence of diabetes.",Shinji Koba; Tsutomu Hirano; Gen Yoshino; Keiko Sakai; Taro Sakaue; Mitsuru Adachi; Takashi Katagiri,"To examine how prevalence of the small dense LDL phenotype (LDL particle diameter < or =25.5 nm) is associated with coronary artery disease (CAD) in type 2 diabetic and non-diabetic Japanese men, an ethnic group with a low incidence of CAD, 85 non-diabetic men and 45 type 2 diabetic men with angiographically documented CAD, and 142 control men and 76 type 2 diabetic men without CAD were studied. Mean LDL particle diameter was determined using 2-16% polyacrylamide gel electrophoresis. LDL particle diameters in CAD patients were much smaller than those in controls (25.2+/-0.7 vs. 26.0+/-0.4 nm, mean+/-S.D., P<0.0001). LDL size was smaller in diabetic subjects (25.6+/-0.6 nm) and became even smaller in diabetics with CAD (25.0+/-1.0 nm). Prevalence of small dense LDL was markedly higher in both non-diabetic and diabetic CAD patients than that in non-diabetic and diabetic patients without CAD (71, 76, 23 and 42%, respectively). CAD patients had lower HDL-cholesterol and apo A1 levels, and higher triglyceride levels than those in diabetic and non-diabetic CAD-free patients, while total- and LDL-cholesterol levels were even lower in CAD group, and remnant-like particle-cholesterol, lipoprotein (a) and insulin levels were comparable among four groups. LDL size was significantly associated with triglyceride, HDL-cholesterol and glycemic control. Logistic regression analysis revealed that the small dense LDL phenotype was significantly associated with the incidence of CAD independent of low levels of HDL-cholesterol or high levels of triglyceride in both non-diabetic and diabetic cases. These results suggest that high prevalence of small dense LDL is a leading cause of CAD in both diabetic and non-diabetic Japanese men. Type 2 diabetes shows a greater capacity to reduce LDL size, which may contribute to the high incidence of CAD in the diabetic population.",2002.0,0,0 1054,11756992,Roles of interleukin-6 and macrophage inflammatory protein-2 in pneumolysin-induced lung inflammation in mice.,Anita W Rijneveld; Germie P van den Dobbelsteen; Sandrine Florquin; Theodore J Standiford; Peter Speelman; Loek van Alphen; Tom van der Poll,"Pneumolysin (PLY), a toxin synthesized by Streptococcus pneumoniae, is an important virulence factor in pneumococcal disease. This study evaluated the effects of PLY in lungs of mice. Intranasal inoculation with PLY was associated with a dose-dependent influx of polymorphonuclear leukocytes (PMNL) in bronchoalveolar lavage fluid (BALF) and increased concentrations of interleukin (IL)-6, macrophage inflammatory protein (MIP)-2, and KC in BALF. PLY mutants with either reduced cytolytic activity or reduced cytolytic and complement-activating activities were less potent in inducing PMNL recruitment to the lung (P<.05), which suggests that PLY cytolytic activity is very important for the inflammatory response. IL-6 and MIP-2 also played a role in PLY-induced PMNL recruitment; this response was partially diminished in IL-6 gene-deficient mice and in mice treated with anti-MIP-2 antiserum. PLY may play an important role in the induction of an inflammatory response in the pulmonary compartment in the early phase of pneumococcal pneumonia.",2002.0,0,0 1055,11757504,"Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.",B G Brown; X Q Zhao; A Chait; L D Fisher; M C Cheung; J S Morse; A A Dowdy; E K Marino; E L Bolson; P Alaupovic; J Frohlich; J J Albers,"Both lipid-modifying therapy and antioxidant vitamins are thought to have benefit in patients with coronary disease. We studied simvastatin-niacin and antioxidant-vitamin therapy, alone and together, for cardiovascular protection in patients with coronary disease and low plasma levels of HDL. In a three-year, double-blind trial, 160 patients with coronary disease, low HDL cholesterol levels and normal LDL cholesterol levels were randomly assigned to receive one of four regimens: simvastatin plus niacin, vitamins, simvastatin-niacin plus antioxidants; or placebos. The end points were arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, myocardial infarction, stroke, or revascularization). The mean levels of LDL and HDL cholesterol were unaltered in the antioxidant group and the placebo group; these levels changed substantially (by -42 percent and +26 percent, respectively) in the simvastatin-niacin group. The protective increase in HDL2 with simvastatin plus niacin was attenuated by concurrent therapy with antioxidants. The average stenosis progressed by 3.9 percent with placebos, 1.8 percent with antioxidants (P=0.16 for the comparison with the placebo group), and 0.7 percent with simvastatin-niacin plus antioxidants (P=0.004) and regressed by 0.4 percent with simvastatin-niacin alone (P<0.001). The frequency of the clinical end point was 24 percent with placebos; 3 percent with simvastatin-niacin alone; 21 percent in the antioxidant-therapy group; and 14 percent in the simvastatin-niacin-plus-antioxidants group. Simvastatin plus niacin provides marked clinical and angiographically measurable benefits in patients with coronary disease and low HDL levels. The use of antioxidant vitamins in this setting must be questioned.",2002.0,0,0 1056,11758073,Cost-effectiveness of prescribing statins according to pharmaceutical benefits scheme criteria.,S S Lim; T Vos; A Peeters; D Liew; J J McNeil,"(i) To analyse how well Pharmaceutical Benefits Scheme (PBS) criteria for prescribing lipid-lowering therapy identify people most at risk of coronary heart disease (CHD); and (ii) to determine the cost-effectiveness of primary prevention therapy with pravastatin according to these criteria in Australia. (i) Analysis of targeting of CHD risk according to PBS criteria; (ii) cost-effectiveness analysis for pravastatin as primary preventive therapy (40 mg/day), with a 20-year projection from 1999. (i) Men and women aged 25-69 years from the 1989 National Heart Foundation Risk Factor Prevalence Survey; (ii) Australian men and women, aged 25-85 years, excluding those with diabetes and existing CHD. (i) Proportion eligible for lipid lowering treatment according to PBS criteria within 15-year risk of CHD mortality groups; (ii) average net cost in Australian dollars ($) per year of life saved (YOLS), with 80% uncertainty ranges (UR). (i) PBS criteria do not adequately identify those most at risk of CHD, as only 61% of Australians (aged 25-69 years) with a greater than 10% 15-year risk of CHD mortality were eligible for treatment; and 11% of those at low risk of CHD mortality (< 2.5% over 15 years) were eligible for treatment. (ii) Cost-effectiveness of treatment according to PBS criteria was estimated at $110,000 (80% UR, $96,000-$150,000) per YOLS for men and $87,000 (80% UR, $80,000-$130,000) per YOLS for women. As an indicator of the likely recurrent annual costs, total first-year treatment costs (excluding the costs of non-compliers) were estimated at $940 million. Assuming compliance of 50%, cost-effectiveness of treatment was markedly improved using 32.5% 15-year risk of CHD mortality as a cut-off, with ratios of $31,000 (80% UR, $27,000-$40,000) per YOLS for men and $39,000 (80% UR, $33,000-$53,000) per YOLS for women. First-year treatment costs of $940 million were the same as treating according to PBS criteria, but absolute health impact in terms of deaths averted and years of life saved was more than doubled. While PBS criteria do target patients at risk of CHD, there is room for improvement in identifying those most at risk of CHD, and treatment according to PBS criteria is not likely to be the most cost-effective. For optimal cost-effectiveness, targeting of therapy for primary CHD prevention needs to be based on population-specific, multivariable risk.",2002.0,0,0 1057,11758079,Statin-associated myopathy.,I Hamilton-Craig,"Myopathy occurs in 0.1%-0.2% of patients receiving statins in clinical trials. This adverse effect is shared by all statins, but is more common with cerivastatin, especially in combination with gemfibrozil. The risk of myopathy is increased by: the use of high doses of statins, concurrent use of fibrates, concurrent use of hepatic cytochrome P450 inhibitors, acute viral infections, major trauma, surgery, hypothyroidism and other conditions. Statin-associated myopathy should be suspected when a statin-treated patient complains of unexplained muscle pain, tenderness or weakness. Statin therapy should be stopped in cases of suspected myopathy, and serum creatine kinase levels should be checked and monitored. No specific therapies other than statin withdrawal and supportive measures for rhabdomyolysis are currently available.",2002.0,0,0 1058,11758081,Is aggressive lipid-lowering therapy preferable to angioplasty in stable coronary artery disease?,P M Ellis,,2002.0,0,1 1059,11759948,Interactions between the renin-angiotensin system and dyslipidemia: relevance in atherogenesis and therapy of coronary heart disease.,B K Singh; J L Mehta,"Hypertension and hypercholesterolemia, two major risk factors for atherosclerotic disease, frequently coexist in patients with hypertension and CAD. Data from clinical studies suggest the existence of lipoprotein-neurohormonal interactions that may adversely affect vascular structure and reactivity. Data from preclinical studies suggest that RAS may be upregulated by abnormal lipids, most likely via production of ox-LDL. On the other hand, activation of RAS leads to release of ROS and transcriptional upregulation of LDL and ox-LDL uptake in macrophages, smooth muscle cells and endothelial cells. These findings extend our understanding of the interplay among risk factors to synergistically increase cardiovascular risk, and of the anti-atherosclerotic effects of local ACE inhibition to reduce cardiovascular risk. Trials aimed at modifying RAS along with drugs lowering total- and LDL-cholesterol levels and inhibitors of oxidative modification of LDL-cholesterol will address the clinical relevance of this biological interaction.",2002.0,0,0 1060,11760542,[Examination and treatment of dyslipemia after myocardial infarction--are the goals achieved?].,H Kanstrup; J F Lassen; L Heickendorff; M L Larsen,"According to guidelines, medical treatment of dyslipidaemia in post-AMI patients should await assessment of underlying lipid disorders and the outcome of dietary treatment. The risk of patients not being treated with lipid-lowering therapy because of lack of follow-up has led to more aggressive guidelines recommending statin treatment even before discharge from hospital. In a study comprising 730 patients, we have shown that, although most patients were discharged from the coronary care unit without statin treatment, a traditional rehabilitation programme succeeded in assessing more than 95% of the patients for underlying lipid disorders, and more than 75% of patients with plasma cholesterol > or = 5.5 mmol/l received lipid-lowering therapy within the first year. Most patients were treated with statins. Statins, however, were given in smaller doses than those used in the clinical trials, and only 52% of the treated patients reached the recommended goal of plasma cholesterol lower than 5 mmol/l.",2002.0,0,0 1061,11763158,Mechanism of action of thiazolidinediones.,M Flemmer; J Scott,"Type 2 diabetes is associated with multiple metabolic abnormalities including insulin resistance and the procoagulant state. Thiazolidenediones are an emerging class of insulin sensitizers which have the potential to mitigate many of the complications of diabetes. Mechanisms of action of the thiazolidenediones are discussed together with their possible pitfalls. Presently, evidence to clearly define the role of thiazolidenedionesfor the treatment of type 2 diabetes is lacking.",2002.0,0,0 1062,11763159,Current and future treatment strategies for type 2 diabetes: the beta-cell as a therapeutic target.,B Tyrberg; F Levine,"Diabetes affects millions of people worldwide. The most common variants are type 1 diabetes with autoimmune destruction of the pancreatic beta-cells and type 2 diabetes with peripheral insulin resistance and beta-cell dysfunction. In spite of tremendous research, current pharmacological regimens are still sub-optimal for adequate blood glucose control. As a consequence, patients with diabetes are at significant risk for development of serious long-term complications, such as blindness and kidney disease. This review will discuss present and future strategies for the treatment of type 2 diabetes with a focus on the more recently recognized problems of beta-cell dysfunction and loss. The treatment strategies presented include promotion of beta-cell proliferation and differentiation by glucagon-like peptide 1 receptor agonists.",2002.0,0,0 1063,11764864,Quinupristin-dalfopristin: a new antibiotic for severe gram-positive infections.,J P Manzella,"The steady increase in resistant organisms is related to the widespread use of antibiotics in community and hospital settings. New therapeutic options are needed, including treatments for infections caused by antibiotic-resistant gram-positive organisms. Quinupristin-dalfopristin, the first formulation of a distinct class of antibiotics known as the streptogramins, has activity against a range of gram-positive bacteria that are usually resistant to other agents, including vancomycin-resistant Enterococcus faecium. The pharmacodynamic (postantibiotic effect) and pharmacokinetic characteristics of quinupristin-dalfopristin allow dosing at eight- to 12-hour intervals. The safety profile of the formulation is generally favorable, with no demonstrable ototoxicity, nephrotoxicity, bone marrow suppression, or cardiovascular adverse effects. Reversible arthralgias, myalgias, and peripheral venous irritation are the formulation's major side effects. A potential for drug interactions exists because quinupristin-dalfopristin significantly inhibits the cytochrome P450-3A4 enzyme system. Quinupristin-dalfopristin has been shown to be effective in the management of documented severe infections caused by vancomycin-resistant E. faecium, nosocomial pneumonia, and infections related to the use of intravascular catheters.",2002.0,0,0 1064,11765297,Impact of the cost of prescription drugs on clinical outcomes in indigent patients with heart disease.,M D Schoen; R J DiDomenico; S E Connor; J E Dischler; J L Bauman,"To measure the impact that economic relief for prescription drugs to indigent patients with cardiovascular disease has on indicators of disease control. Prospective cohort study. University inner-city outpatient clinic. One hundred sixty-three indigent patients with heart disease who were uninsured or whose insurance plan did not provide prescription drug coverage and who had baseline data. Patients were assisted in obtaining prescription drugs, free of charge, in an attempt to improve adherence to their drug regimens. The primary end point was to determine if cardiovascular outcome measures (i.e., international normalized ratio [INR], blood pressure, low-density lipoprotein [LDL] cholesterol, and hospitalizations) and drug adherence improved in all patients after 6 months of prescription assistance compared with a 6-month baseline period. In patients receiving warfarin, mean INR increased from 2.44 +/- 0.64 at baseline to 2.61 +/- 0.53 at 6 months (p<0.05). In patients with hypertension, mean blood pressure decreased from 138 +/- 20/80 +/- 11 mm Hg at baseline to 138 +/- 19/78 +/- 12 mm Hg at 6 months (p<0.05 for diastolic blood pressure only). The mean LDL level for patients on lipid-lowering drugs significantly decreased from 126 +/- 39 mg/dl at baseline to 108 +/- 38 mg/dl at 6 months (p<0.001). For each disease measure, the improved disease control seen at 6 months persisted throughout 24 months of follow-up. Hospitalizations for the entire cohort decreased from 85 at baseline to 49 at 6 months. Patient drug adherence improved from 48.5% at baseline to 72.7% at 6 months (p<0.001). Drug adherence and clinical outcomes improved, and the number of hospitalizations declined when cardiovascular drugs were obtained for patients who could not afford to pay for them. Health care insurance plans that do not provide coverage for cardiovascular prescription drugs may be more costly secondary to poor disease control and increased hospitalizations.",2002.0,0,0 1065,11765310,Do hypolipidemic drugs lower medical expenses?,J M Kauffman,,2002.0,0,0 1066,11770860,Inflammatory mechanisms in atherosclerosis: from laboratory evidence to clinical application.,G J Blake; P M Ridker,"From the initial stages of leukocyte recruitment to diseased endothelium, to eventual rupture of unstable atheromatous plaque, pro-inflammatory mechanisms mediate key steps in atherogenesis and its complications. Lipid lowering, both with diet and statin therapy, has been shown to have favorable effects on inflammatory processes in atheromatous plaque. Several plasma markers of inflammation have been found to predict future cardiovascular risk, both among patients with acute coronary syndromes and myocardial infarction, and among healthy men and women. C-reactive protein (CRP), a pattern recognition molecule linked to the innate immune system, is a sensitive marker of low-grade vascular inflammation, which may also have direct pro-inflammatory actions. Recent studies have shown that statin therapy may lower CRP levels independent of lipid-lowering effects. Statin therapy may also be highly effective for the prevention of cardiovascular events among individuals with elevated CRP levels. The role of statin therapy for plaque stabilization in acute coronary syndromes, and for prevention of future plaque rupture among healthy individuals with evidence of vascular inflammation, is an area of active research.",2002.0,0,0 1067,11770871,The use over time of statins in coronary patients in an Italian tertiary referral center.,A Gaspardone; I Proietti; L Altamura; F Tomai; F Versaci; F Crea; L Chiariello; P A Gioffrè,"In the last decade, large-scale clinical trials have consistently shown that therapy with statins is of great benefit to patients with and at risk of developing coronary artery disease. We assessed, in a sample of patients with coronary artery disease in whom coronary angiography was indicated and hospitalized in the last 10 years, the use of statins at admission. One hundred patients with stable coronary artery disease were randomly selected per year from 1991 to 2000. The final study population consisted of 1000 patients. The prescription of statins for > or = 6 months before hospital admission was determined from a hospital-wide clinical database. From 1995, the prevalence of patients treated with statins at hospital admission progressively increased. In 1991, only 2% of patients were treated with statins before hospital admission while in the year 2000, 38% of patients were receiving this treatment. The mean prevalence of patients treated with statins before and after 1995 was 3 vs 22% (p < 0.0001) respectively. The distribution of the demographic and clinical parameters and the prevalence of conventional cardiovascular risk factors were similar in patients treated or not treated with statins. After 1994, in coincidence with the publication of the results of clinical trials showing the benefit of statins in patients with coronary artery disease, the use of these drugs increased significantly. This finding suggests that the widespread diffusion of the results of the major clinical trials and of guidelines drawn up by medical associations have had a significant impact on statin prescription in patients with coronary artery disease. Nevertheless our data also indicate that, despite overwhelming evidence on the benefits of statin therapy, in current clinical practice cardiologists are not optimally utilizing lipid management and that statins are frequently prescribed without an appropriate analysis of risk factors.",2002.0,0,0 1068,11772284,Statins in the 21st century: end of the simple story?,S A Doggrell,"The development of the HMG-CoA reductase inhibitors (the statins) has lead to important advances in the management of cardiovascular disease. There have several landmark mortality and morbidity clinical trials with the statins. The 4S (Scandinavian Simvastatin Survival Study) was the first large-scale randomised cholesterol-lowering trial to show a decrease in mortality. In patients with coronary heart disease and relatively high cholesterol, simvastatin decreased mortality, hospital stays, the risk of undergoing myocardial re-vascularisation, stroke and transient ischaemic attack. The CARE (Cholesterol and Recurrent Events) trial showed that lowering average cholesterol levels after myocardial infarction with pravastatin reduced a composite primary end point of coronary mortality and myocardial infarction, coronary bypass surgery, angioplasty and strokes. The LIPID (Long-term Intervention with Pravastatin in Ischaaemic Disease) study showed that lowering average cholesterol levels after previous myocardial infarction or unstable angina reduced mortality. WOSCOPS (The West of Scotland Coronary Prevention Study) was the first trial to demonstrate the benefit of pravastatin, as primary prevention for cardiovascular disease, in men with high cholesterol levels. AFCAPS/Tex CAPS (The Air Force/Texas Coronary Atherosclerosis Prevention Study) showed that the benefits of lowering cholesterol levels were also evident in healthy men and women who initially had average cholesterol levels. Rather surprisingly the reductions in mortality and morbidity with statins are only associated with small improvements in coronary angiographic findings. A preliminary study indicated than lovastatin prevented restenosis, but larger and better-controlled studies indicate that the statins do not have beneficial effects in restenosis. Effects other than lipid-lowering or as a consequence of their lipid-lowering may contribute to the beneficial effects of statins. These effects include improvement in vascular endothelial function, cardiac remodelling, changes in blood rheology, anti-oxidant, anti-inflammatory and anti-hypertensive actions.",2002.0,0,0 1069,11772290,Statins and neuroprotection.,N Delanty; C J Vaughan; N Sheehy,"The beneficial effect of beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in primary prevention of coronary artery disease in those with hypercholesterolaemia and in secondary prevention in those with established coronary vascular disease are now well known. A growing body of evidence suggests that statins also possess important additional clinical benefits, such as stroke risk reduction. In this article we review the evidence that statins may be neuroprotective, especially in the brain parenchyma during stroke. We also review the observational data that statins may prevent the onset of dementia.",2002.0,0,0 1070,11772294,Novel agents for managing dyslipidaemia.,J D Best; A J Jenkins,"An elevated low-density lipoprotein (LDL) cholesterol level is a strong predictor of coronary heart disease (CHD) risk. Over the past seven years, equally strong evidence has accumulated that lowering LDL cholesterol with HMG-CoA reductase inhibitors or statins reduces CHD risk and there is now widespread use of these agents for the primary and secondary prevention of CHD. Treatment issues remain regarding the appropriate degree of LDL cholesterol reduction and whether, in people with very high levels, it would be preferable to achieve the LDL cholesterol goal with a powerful statin alone or combined with an agent that lowers LDL cholesterol by a different mechanism. The main focus in the development of novel agents is the patient with low high-density lipoprotein (HDL) cholesterol, usually associated with hypertriglyceridaemia. Already prevalent as a risk factor for CHD, this abnormality has been linked with insulin resistance, which is likely to increase greatly over the next decade, along with increasing obesity and diabetes. Agents that have potent HDL cholesterol raising capacity include cholesteryl ester transfer protein (CETP) inhibitors, retinoid X receptor (RXR) selective agonists, specific peroxisome proliferator-activated receptor (PPAR) agonists and oestrogen-like compounds. Another area of development involves agents that will lower both cholesterol and triglyceride levels, such as partial inhibitors of microsomal triglyceride transfer protein (MTP) and perhaps squalene synthase inhibitors and agonists of AMP kinase. Future emphasis will be on correcting all lipid abnormalities for the prevention of CHD, not just lowering LDL cholesterol.",2002.0,0,0 1071,11772295,Cardiac protection by pharmacological modulation of inflammation.,R Latini; S Masson; R Bertini; A P Maggioni; P Ghezzi; L Calvillo,"Inflammation is a reaction to primary injury of various kinds, such as infection and trauma, which has both beneficial and detrimental effects. Inflammation has been associated with major diseases of the heart and vessels. Research has focused not only on ischaemia but also on post-ischaemic reperfusion, which is known to activate and amplify the inflammatory response. Although reperfusion should always be attempted in the clinical environment, it has been shown experimentally that it can cause some cardiac damage, in addition to that caused by ischaemia. Therefore, it is reasonable to attempt to increase the benefit obtainable with reperfusion by modulating inflammatory processes triggered by reperfusion itself. In this field, different potential therapeutic targets have been identified and interventions have been tested over the last 30 years. With the exception of adenosine, which probably does not act merely through inhibition of the inflammatory response, no other compounds have yet proven successful in clinical trials. Active research is ongoing. Broadening the approach from the heart to the cardiovascular system, promising data is emerging on cardiovascular protection conferred by statins in patients with coronary heart disease (CHD) and high levels of C-reactive protein (CRP), a systemic marker of inflammation. Similarly, results of trials aimed at preventing cardiovascular events by eradicating chronic infections will be among the first to directly test whether such therapies will decrease risks of cardiovascular disease.",2002.0,0,0 1072,11772305,Ongoing clinical trials in systemic hypertension.,J Mann; P Oddou,"Hypertension was identified as a cardiovascular risk factor in the late fifties and still remains a public health issue. The number of patients treated reaches only half of those diagnosed and, of those treated, half fail to reach target blood pressure. Furthermore, the number of antihypertensive drugs reaching the market has increased exponentially in the last few years, however, the impact on treatment and on attaining target blood pressure levels remains to be seen. The high percentage of treated patients who do not reach target blood pressure, combined with the high number of patients requiring more than one antihypertensive drug, have triggered a series of long-term morbidity and mortality trials comparing different therapeutic approaches ('new' pharmacological classes vs. 'old' pharmacological classes). These are described in this paper.",2002.0,0,0 1073,11772316,Peginterferon alfa-2a (40 kDa) monotherapy: a novel agent for chronic hepatitis C therapy.,S Zeuzem; J E Heathcote; N Martin; K Nieforth; M Modi,"Current therapy for hepatitis C remains far from optimal. The modification of IFN by the attachment of a polyethylene glycol (PEG) moiety has produced long-lasting IFNs. A 40 kDa branched peginterferon alfa-2a (40 kDa) (PEG-IFN alfa-2a) has unique pharmacokinetic and pharmacodynamic properties. PEG-IFN alfa-2a is absorbed in a sustained manner and its clearance is reduced substantially compared with IFN alfa-2a, resulting in sustained serum drug concentrations. These constant serum drug levels stay above the EC(50) values (effective concentration 50%) needed for antiviral, antiproliferative and immunomodulatory actions. Sustained virological responses were significantly greater in patients who received PEG-IFN alfa-2a versus IFN alfa-2a, with a similar side effect profile. Histological improvements were seen in patients who achieved sustained virological responses and were frequently observed among patients who did not achieve a virological response. The advantages of PEG-IFN alfa-2a were also seen in patients with cirrhosis or hepatitis C virus (HCV) genotype 1.",2002.0,0,0 1074,11772420,A general assessment of the safety of HMG CoA reductase inhibitors (statins).,Donald M Black,"Few principles in medicine today are as well accepted as the benefits of using statins to reduce cardiovascular risk factors and to prevent cardiovascular disease. The recent withdrawal of a statin (cerivastatin) has lead to a re-examination of all statins, and an attempt to better assess the risk-benefit ratio of this class of drugs. Although the benefits of statin treatment are well known from a myriad of clinical trials, the safety of these compounds has not been an issue since lovastatin was first introduced in 1987. This report provides a brief review of statin safety, and reiterates the excellent profile of this class of drugs.",2003.0,0,0 1075,11772421,Statins and inflammatory markers.,Christopher C Case; Christie M Ballantyne,"Inflammation is involved in the initiation and progression of atherosclerosis and the development of atherosclerotic events. Understanding of the molecular basis of inflammation has led to the identification of markers that may be important new targets in atherothrombotic disease. Inflammatory markers, such as cell adhesion molecules, cytokines, and high-sensitivity C-reactive protein, have been shown to predict future cardiovascular events in individuals with and without established disease. 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, or statins, inhibit the synthesis of cholesterol and have been demonstrated to reduce cardiovascular morbidity and mortality. Recently, statins have been shown to modulate several of the mechanisms of inflammation in atherosclerosis in vitro and in vivo, including reduction of inflammatory markers in clinical trials. In this article, we briefly review the biology, epidemiology, and clinical trial data on the effects of statins on some of the more promising inflammatory markers.",2003.0,0,0 1076,11773670,Cost-effectiveness analysis of applying the Cholesterol and Recurrent Events (CARE) study protocol in Hong Kong.,J Chau; B M Cheung; S M McGhee; I J Lauder; C P Lau; C R Kumana,"To determine the cost-effectiveness of secondary prevention with pravastatin in Hong Kong patients with coronary heart disease and average cholesterol levels. Cost-effectiveness analysis based on published results of the CARE study. Men and women post-myocardial infarction with average cholesterol levels. Cost-effectiveness analysis: cost per life saved, cost per fatal or non-fatal coronary event prevented, cost per procedure prevented, and cost per fatal or non-fatal stroke prevented. Cost-utility analysis: gross cost and net cost per quality-adjusted life year gained calculated using two alternative models. Cost per life saved or death prevented was HK$4,442,350 (non-discounted); cost per fatal or non-fatal cardiac event prevented HK$1,146,413; cost per procedure prevented HK$732,759; and cost per fatal or non-fatal stroke prevented HK$2,961,566. Net cost per quality adjusted life year gained was HK$73,218 and HK$65,280 non-discounted, respectively using the two alternative models. The results of this study can assist in prioritising the use of health care resources in Hong Kong but should be considered alongside the benefits and costs of alternative interventions for coronary heart disease.",2002.0,0,0 1077,11773716,Rhabdomyolysis and statin therapy: relevance to the elderly.,Domenic A Sica; Todd W B Gehr,"A recent debate has emerged as to the risk-benefit ratio of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). This debate has centered on the withdrawal of the HMG-CoA reductase inhibitor cerivastatin (Baycol). Its withdrawal was prompted by an unacceptably high rate of rhabdomyolysis associated with its use. The development of rhabdomyolysis in cerivastatin-treated patients surprised few, since myotoxicity is a class effect with HMG-CoA reductase inhibitors. What has sprung from the cerivastatin experience, though, is the concept of ""guilt by association""; thus, other members of this class are now viewed in a similarly negative light. Such misgivings are understandable, but to a degree may be ill-advised, since differences exist in the risk and therefore the rate of rhabdomyolysis occurrence among the various HMG-CoA reductase inhibitors. In this regard, pravastatin and fluvastatin are least likely to provoke muscle cell damage, which, at least in part, relates to their not being metabolized by the cytochrome P-450 (CYP) 3A4 pathway. When muscle damage does occur with HMG-CoA reductase inhibitors, it is commonly the result of drug-drug interactions rather than a specific adverse response to HMG-CoA reductase inhibitor monotherapy. Such drug-drug interactions inevitably result in higher plasma concentrations of an HMG-CoA reductase inhibitor and thereby an increased risk of myotoxicity. A growing consensus supports an expanded use of HMG-CoA reductase inhibitors in elderly patients. Polypharmacy and altered drug metabolism both put the elderly patient at increased risk of myotoxicity when drugs in the HMG-CoA reductase inhibitor class are administered. Physicians must take many factors into account when selecting a member of the HMG-CoA reductase inhibitor class, particularly as relates to their use in the multiply medicated elderly patient.",2002.0,0,0 1078,11773719,Hyperlipidemia in the elderly: two new observations.,Dennis L DeSilvey,,2002.0,0,0 1079,11774104,Fluvastatin improves lipid abnormalities in patients with moderate to advanced chronic renal insufficiency.,Ola Samuelsson; Per-Ola Attman; Carolyn Knight-Gibson; Henrik Mulec; Lars Weiss; Petar Alaupovic,"Chronic renal insufficiency is characterized by specific abnormalities in lipoprotein metabolism, affecting both apolipoprotein A (apo A)- and apo B-containing lipoproteins. To evaluate the effects of fluvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on renal dyslipoproteinemia, we performed a randomized, double-blind, placebo-controlled, two-way, period cross-over study. Study patients were administered fluvastatin, 40 mg/d, or placebo during 8 weeks in randomized order. Forty-five nonnephrotic patients (28 men, 17 women) without diabetes with moderate to advanced chronic renal insufficiency participated in the study. Their mean age was 56.4 +/- 11.0 years. Glomerular filtration rate ranged from 12 to 44 mL/min/1.73 m2 of body surface area (mean, 27.5 +/- 10.5 mL/min/1.73 m2). Fluvastatin treatment resulted in significant reductions in the primary outcome variables low-density lipoprotein cholesterol (LDL-C; -26%; P < 0.001), apo B (-21%; P < 0.001), and lipoprotein B complex (Lp-Bc) (-14%; P < 0.01). There were statistically significant differences between fluvastatin and placebo treatment for the secondary outcome variables total cholesterol (-19%), triglycerides (TGs; -13%), VLDL-C (-13%), apo E (-13%), and Lp-B (-22%). There was no treatment effect on high-density lipoprotein cholesterol or lipoprotein(a). Fluvastatin treatment was well tolerated, with no serious adverse events during the study. In conclusion, fluvastatin treatment was well tolerated in patients with moderately advanced renal insufficiency and led to a significant reduction in cholesterol-rich, but to a lesser extent in TG-rich, apo B-containing lipoproteins. It remains to be clarified whether these positive changes in lipoprotein profile also will result in attenuation of the atherosclerotic process in these patients, as well as beneficially affect the progression of chronic renal failure.",2002.0,0,0 1080,11777291,Comparison of therapy with simvastatin 80 mg and 120 mg in patients with familial hypercholesterolaemia.,A S Wierzbicki; P J Lumb; G Chik,"High-dose preparations of simvastatin and atorvastatin have recently become available to treat resistant hypercholesterolaemia aggressively, but few studies have compared these two agents. This study compared the efficacy of simvastatin 80 mg and 120 mg in 22 patients with severe familial hypercholesterolaemia over a three-month period using an open label format. Simvastatin 120 mg was reasonably well tolerated and delivered a further 8% reduction in LDL over 80 mg, giving a total reduction of 55 +/- 13%, while further decreasing triglycerides (18%) and continuing to raise HDL (13%) further than the 80 mg dose. However, transient adverse changes were noted in both lipoprotein (a) and fibrinogen and 20% of patients were unable to tolerate the higher dose. One late case of rhabdomyolysis was observed, suggesting patients on the 120 mg dose require continued regular review.",2002.0,0,0 1081,11779513,Benefits of immediate initiation of statin therapy following successful coronary stent implantation in patients with stable and unstable angina pectoris and Q-wave acute myocardial infarction.,Dirk H Walter; Stephan Fichtlscherer; Martina B Britten; Wolfgang Auch-Schwelk; Volker Schächinger; Andreas M Zeiher,"Statin therapy reduces clinical events in patients with stable coronary artery disease. Recent data indicate that the beneficial effects of statin therapy may also extend to patients experiencing an acute ischemic coronary event. However, the potential role of statins to further modify clinical outcome in patients undergoing coronary stent implantation has not been addressed. Therefore, we investigated whether the initiation of statin therapy immediately after successful coronary stent implantation improves short-term clinical outcome in 704 patients (335 patients with stable angina pectoris [AP], 224 patients with unstable AP, and 145 patients with Q-wave acute myocardial infarction [AMI]). Compared with the lowest risk group (patients with stable AP receiving statin therapy), patients with unstable AP (RR 6.9, 95% confidence interval [CI] 1.5 to 31, p = 0.004) and patients with Q-wave AMI (RR 7.6, 95% CI 1.5 to 37, p = 0.004) experienced an increased risk for the occurrence of the primary combined end point of cardiac death and AMI. Importantly, initiation of statin therapy abrogated the increased risk in patients with unstable AP to the level of patients with stable AP receiving statin therapy (RR 1.5, 95% CI 0.2 to 11, p = 0.7). In contrast, statin therapy did not affect the RR in patients with Q-wave AMI during 6-month follow-up (RR 7.9, 95% CI 1.6 to 39 vs RR 7.6, 95% CI 1.5 to 37, p = NS). The beneficial effects of statin therapy after successful coronary stent implantation in unstable AP were most prominent during the first 4 weeks after the ischemic episode. Statins appear to contribute to the rapid transformation of unstable coronary artery disease into a stable condition with a very low event rate over the forthcoming 6 months in patients with unstable AP undergoing successful coronary stent implantation.",2002.0,0,0 1082,11779522,,,,,0,0 1083,11779527,Incidence of new coronary events in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol > or = 125 mg/dl treated with statins versus no lipid-lowering drug.,Wilbert S Aronow; Chul Ahn,,2002.0,0,0 1084,11781127,Utilization of lipid-lowering drugs in men and women. a reflection of the research evidence?,Isabelle Savoie; Arminée Kazanjian,"This study analyzes the utilization of statin lipid-lowering drugs in a Canadian province using a population-wide drug prescription database. The utilization pattern is compared to the results of a systematic review of randomized controlled trials on their effectiveness. The study found that 74.7% of individuals prescribed a statin had no reported history of coronary heart disease (CHD). Women without CHD formed 23.1% of statins recipients; 32.9% of individuals filling a statin prescription were age 70 and over. Only 15.3% of men with CHD had been prescribed a statin. Based on the systematic review, 88.7% of the utilization of statins in this Canadian province was not supported by the results of the systematic review. Considering baseline lipid-levels does not substantially alter these findings. This study concludes that statins prescribing practices need to be realigned with research evidence. This implies refocusing utilization away from women and the elderly, towards men with CHD.",2002.0,0,0 1085,11783599,Clinical course and treatment of IgA nephropathy.,J Mustonen; J Syrjänen; I Rantala; A Pasternack,"Impairment of renal function, severe proteinuria and arterial hypertension are the strongest clinical predictors of an unfavorable outcome in IgA nephropathy (IgAN). Glomerulosclerosis and interstitial fibrosis are the most reliable histologic prognostic markers. Metabolic syndrome and insulin resistance probably affect the clinical course of the disease. Among the known gene polymorphism it seems that there is a link between the ACE gene D allele and the progression of IgAN. Elevated blood pressure should be actively treated. The target blood pressure is 130/80 mmHg or less and the goal should also be to reduce proteinuria. Several large-scale trials are currently testing corticosteroids and other drugs in the treatment of IgAN.",2002.0,0,0 1086,11786112,HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients.,Stephen L Seliger; Noel S Weiss; Daniel L Gillen; Bryan Kestenbaum; Adrianne Ball; Donald J Sherrard; Catherine O Stehman-Breen,"BACKGROUND.: Patients with end-stage renal disease (ESRD) suffer from markedly higher rates of cardiovascular disease than the general population. Although therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (""statins"") has been demonstrated to reduce the mortality from cardiovascular disease in patients without ESRD, only 10% of patients on dialysis are treated with these medications by day 60 of ESRD. We determined whether the use of statins is associated with a reduction in cardiovascular-specific death and total mortality in ESRD patients. Data were analyzed from the U.S. Renal Data System Dialysis Morbidity and Mortality Wave-2 study, a cohort of randomly selected patients who were initiating dialysis in 1996. Information about the use of statins as well as other baseline characteristics was abstracted from the patients' dialysis records by dialysis personnel. Cox proportional hazards models were developed to determine the association between use of statins at baseline and subsequent risk of mortality, with adjustment for known mortality risk factors. Follow-up data were available for 3716 patients through July 1998. At baseline, 362 (9.7%) of patients were using statins. These patients had a mortality rate of 143/1000 person-years, compared with a rate of 202/1000 person-years for patients not using statins. Statin use was independently associated with a reduced risk of total mortality [relative risk (RR)=0.68, 95% confidence interval (CI)=0.54, 0.87] as well as cardiovascular-specific mortality (RR=0.64, 95% CI=0.45, 0.91). In contrast, the use of fibrates was not associated with reduced mortality (RR=1.29). Statin use was associated with a reduction in cardiovascular-specific death and total mortality in patients on dialysis.",2002.0,0,0 1087,11786154,"Influence of HMG-CoA reductase inhibitors on markers of coagulation, systemic inflammation and soluble cell adhesion.",Christoph Bickel; Hans J Rupprecht; Stefan Blankenberg; Christine Espinola-Klein; Gerd Rippin; Gerd Hafner; Johannes Lotz; Winfried Prellwitz; Jürgen Meyer; AtheroGene Group,"Beneath its lipid-lowering properties additional non-lipid effects of statin therapy are discussed. We therefore examined the impact of statins on laboratory markers of coagulation, inflammation and soluble cell adhesion to further explore these effects in 950 hospitalised patients with angiographically proven CAD. Although no significant differences were found in total cholesterol, LDL and HDL and triglyceride levels a statistically lower value in 277 statin-treated patients was found for von Willebrand factor [162(130/224) vs. 208(154/283)%, P=0.0001], leukocyte count [6.9(5.8/8.4) vs. 7.3(6.1/9.4)/nl, P=0.0005], high sensitive CRP [4.3(1.8/10.8) vs. 7.6(2.8/20.0) mg/dl, P=0.0001], interleukin-6 [9.5(5.1/18.7) vs. 14.4(7.2/28.1) mg/dl, P=0.0001] and soluble p-selectin [112.6(82.0/146.0) vs. 127.8(93.8/162.4) mg/dl, P=0.001] compared to 673 patients without statin therapy. This result was confirmed in a subgroup of 510 patients matched for age, gender and percentage of acute coronary syndromes. In statin treated patients significantly lower levels of coagulation, systemic inflammation and soluble cell adhesion markers were found. Therefore the effect of statin therapy may also be mediated by additional non-lipid-lowering effects.",2002.0,0,0 1088,11786451,"Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.",Antithrombotic Trialists' Collaboration,"To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events. Collaborative meta-analyses (systematic overviews). Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen. 287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens. ""Serious vascular event"": non-fatal myocardial infarction, non-fatal stroke, or vascular death. Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000. Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.",2002.0,0,0 1089,11786505,HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: a comparative study using different statins.,Franz Wiesbauer; Christoph Kaun; Gerlinde Zorn; Gerald Maurer; Kurt Huber; Johann Wojta,"1. The results of several clinical studies investigating the effect of statin therapy on the fibrinolytic system in vivo are inconclusive. We compared the effect of six different statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, simvastatin) on components of the fibrinolytic system expressed by human vascular endothelial cells and smooth muscle cells and by the human hepatoma cell line HepG2. 2. All statins used except pravastatin significantly decreased PAI-1 production in human endothelial and smooth muscle cells. This effect was also seen in the presence of IL-1 alpha and TNF-alpha. All statins except pravastatin increased t-PA production in human smooth muscle cells. On a molar basis cerivastatin was the most effective HMG CoA reductase inhibitor used. Only simvastatin and lovastatin increased t-PA production in endothelial cells. The effects on the fibrinolytic system were reversed by mevalonate. Statins decreased mRNA levels for PAI-1 in endothelial and smooth muscle cells and increased mRNA levels for t-PA in smooth muscle cells. Statins did not affect PAI-1 expression in HepG2 cells. Cell viability was not influenced by statins in endothelial cells and HepG2 cells whereas in smooth muscle cells a cytotoxic effect was seen at high concentrations. 3. If the effects on the fibrinolytic system of vascular cells in vitro shown in this study are also operative in vivo one could speculate that by increasing t-PA and decreasing PAI-1 at sites of vascular lesions statins might reduce fibrin formation and thrombus development. Such an effect might contribute to the clinically proven benefits of statin therapy.",2002.0,0,0 1090,11786509,Vascular dysfunction in hyperglycemia: is protein kinase C the culprit?,David D Gutterman,,2002.0,0,0 1091,11788002,Lipid-lowering agents and fibrinolysis: lack of effect in vitro.,S M Elzaher; C J Pallister; C D Dunn,,2002.0,0,0 1092,11790688,Eligibility for lipid-lowering drug therapy in primary prevention: how do the Adult Treatment Panel II and Adult Treatment Panel III Guidelines compare?,Antonio M Gotto; Lewis H Kuller,,2002.0,0,0 1093,11790969,Hyperlipidaemia and cardiovascular disease: C-reactive protein and atherosclerosis--new dimensions.,Fahmy W F Hanna; Basil G Issa,,2002.0,0,0 1094,11790971,Therapy and clinical trials.,Julia Platts,,2002.0,0,0 1095,11792128,Statins and mortality.,J Muntwyler; F Gutzwiller,,2002.0,0,0 1096,11792134,Why some patients respond poorly to statins and how this might be remedied.,G R Thompson; F O'Neill; M Seed,,2002.0,0,0 1097,11792135,,,,,0,0 1098,11792349,"Dose response, safety, and efficacy of an extended-release formulation of lovastatin in adults with hypercholesterolemia.",John R Crouse; Peter Lukacsko; Robert Niecestro; Lawrence Friedhoff,,2002.0,0,0 1099,11792351,Frequency of creatine kinase elevation during treatment with fluvastatin.,Renee Benghozi; Michele Bortolini; Yan Jia; Jonathan L Isaacsohn; August J Troendle; Leonard Gonasun,,2002.0,0,0 1100,11793629,A comparison of clinical outcome studies among cholesterol-lowering agents.,T R Lousberg; A M Denham; J R Rasmussen,"To review and compare clinical trials of cholesterol-lowering agents that evaluated clinical end points as the primary outcome measure; specifically, to determine whether all agents that decrease cholesterol impact clinical outcomes similarly. Primary articles were identified through a MEDLINE search (1966-February 2001) and through secondary sources. All of the articles identified from the data sources were evaluated. Articles that included clinical end points as the primary outcome measure were included in this review. Clinical trials were assessed according to study population (primary vs. secondary prevention of coronary artery disease), baseline and follow-up lipid profiles, and clinical outcome data. Both cardiac and noncardiac morbidity and mortality were evaluated. The differences in study populations, study methods, and changes in lipid values were compared and contrasted between trials to evaluate their effect on outcomes. Niacin and bile acid sequestrants should be considered as add-on therapy when therapeutic goals cannot be attained with a hydroxymethyl glutaryl-coenzyme A reductase inhibitor (stain). Estrogen therapy cannot be recommended solely for cardioprotection. Fibrates are most effective in patients with high baseline triglycerides, low baseline high-density lipoprotein cholesterol, and low to average low-density lipoprotein cholesterol (LDL). Statins are considered first line for the treatment of elevated LDL in both the primary and secondary prevention of coronary heart disease. They are well tolerated, have the strongest data to support their use, and have been shown to decrease total mortality.",2002.0,0,0 1101,11794427,Maintenance of low-density lipoprotein goal with step-down pravastatin therapy.,Maqual R Graham; Cameron C Lindsey; James A Kennedy,"To determine whether patients who had achieved their National Cholesterol Education Program (NCEP)-derived goals for low-density lipoprotein (LDL) cholesterol with pravastatin would benefit from step-down therapy. Prospective, randomized, open-label study Kansas City Veterans Affairs Medical Center. One hundred four men who were taking pravastatin once/day and had maintained their NCEP-defined LDL goal for at least 3 months. Fifty-three patients were randomized to group 1, for which the dosing frequency was changed from daily to every other day, and 51 patients were randomized to group 2, for which the daily dose was halved. Fasting lipid profiles and hepatic transaminase levels were analyzed at baseline, 2 months, and 4 months. Lifestyle, concomitant drug therapy, adverse events, weight, and compliance were noted at baseline and month 4. Thirty-one patients (58%) from group 1 and 22 patients (43%) from group 2 did not remain at their LDL goal after step-down pravastatin therapy Mean LDL at study end was 113 mg/dl for group 1 and 104 mg/dl for group 2 (p=0.04). More than half (51%) of the patients enrolled did not remain at their LDL goal with step-down pravastatin therapy Therefore, we do not recommend a step-down approach for patients who have achieved their LDL goals. If a clinician decides, however, to attempt dosage reduction, the preferred regimen appears to be to halve the current dose once/day (vs administering the current dose every other day). A fasting lipid profile should be evaluated at 2 months and 4 months after step-down therapy begins to ensure that desired outcomes are achieved.",2002.0,0,0 1102,11794460,Coronary revascularization on balance: Robert L. Frye lecture.,Katherine M Detre; Richard Holubkov,"The first generation of multicenter randomized controlled trials of coronary artery bypass surgery vs medical treatment in the 1970s found survival advantage only in patients with left main coronary artery disease or with multiple risk factors. Over time, these results have remained reproducible and biologically plausible and continue to be the basis for contemporary guidelines for bypass surgery. Percutaneous coronary intervention (PCI), which became available some 10 years after surgery, was compared with medical treatment in various clinical settings. Patients with stable angina receiving aggressive medical therapy had survival rates comparable to those undergoing PCI in several trials. In the presence of unstable angina, evidence suggests benefit from intervention after stabilization. In the setting of acute myocardial infarction or cardiogenic shock, PCI showed results superior to lytic therapy in centers with large PCI volume. A comparison of the 2 revascularization methods in the 1990s resulted in no overall 7-year survival difference except in patients with treated diabetes in whom bypass surgery prolonged life compared with angioplasty. None of the revascularizations had an effect on the incidence of myocardial infarctions, but importantly, the presence of bypass grafts reduced their fatal impact compared with both medical treatment and PCI. All revascularization trials reported improvement in quality of life, including symptoms, compared with less aggressive therapy. In the pursuit to explain 3 decades of steady decline of cardiovascular mortality in the United States, health economists attempted to model the decline due to availability of intervention by estimates obtained from contemporary randomized prevention and intervention trials. They concluded that, thus far, treatments have made a greater contribution to the decline than has primary prevention. Randomized trials not only contribute to evidence-based clinical practice, but also can reveal underlying biological mechanisms and provide quantitative data to model population trends. Thus, they should be regarded as the basic science of medical therapeutics and population health.",2002.0,0,0 1103,11795072,A risk factor for atherosclerosis: triglyceride-rich lipoproteins.,M J Malloy; J P Kane,"Compelling evidence from meta-analysis of a number of clinical studies on a large aggregate of patients has established an increased level of triglycerides as an independent risk factor for atherosclerotic heart disease. The finding of triglyceride-rich lipoproteins in human atheromata has provided substantial pathophysiologic evidence for a direct role in atherogenesis. Hypertriglyceridemia is commonly embedded in the context of a metabolic syndrome that includes central obesity, insulin resistance, low levels of HDL cholesterol, and often hypertension. Hypertriglyceridemia also appears to underlie the phenomenon of small dense LDL in most instances. Therapeutic interventions must be directed at underlying obesity, insulin resistance, and diabetes when present, as well as addressing metabolic determinants of dyslipidemia per se. Diet, exercise, weight loss, and avoidance of alcohol are the cornerstones of treatment. The choice of medication should be based on the lipoprotein phenotype. Niacin, fibric acid derivatives, and omega-3 fatty acids are most useful in treating severe hypertriglyceridemia. HMG-CoA reductase inhibitors are useful in some phenotypes with moderately increased triglyceride levels. Evidence from a number of clinical trials indicates that mitigation of risk of coronary heart disease, and possibly stroke, can be effected by reducing levels of plasma triglycerides.",2002.0,0,0 1104,11799261,Effect of cerivastatin on urinary albumin excretion and plasma endothelin-1 concentrations in type 2 diabetes patients with microalbuminuria and dyslipidemia.,T Nakamura; C Ushiyama; K Hirokawa; S Osada; N Shimada; H Koide,"To determine whether cerivastatin, a newly developed novel synthetic potent statin, exerts a renoprotective effect, we assessed urinary albumin excretion (UAE) and plasma and urinary endothelin (ET)-1 concentrations in normotensive microalbuminuric type 2 diabetes patients with dyslipidemia. Sixty normotensive type 2 diabetic patients (38 men and 22 women; mean age 56.5 years) with microalbuminuria (20-200 microg/min) and dyslipidemia (total cholesterol >200 mg/dl, LDL cholesterol >160 mg/dl, HDL cholesterol <35 mg/dl, and triglyceride >150 mg/dl) were enrolled in a double-blind study for 6 months, receiving either cerivastatin (0.15 mg/day) or placebo. Plasma and urinary ET-1 concentrations were measured by radioimmunoassay. Cerivastatin did not affect serum creatinine and HbA(1c) levels, and reduced systolic blood pressure slightly, but not significantly. Plasma levels of total cholesterol and LDL cholesterol were significantly reduced (p < 0.01), and plasma triglyceride levels were also reduced significantly (p < 0.05) after 6 months of cerivastatin treatment. A concomitant significant decrease in UAE (p < 0.01), and urinary and plasma ET-1 concentrations (p < 0.01) were found during this period. The use of cerivastatin is associated with decreased microalbuminuria and plasma and urinary ET-1 levels in microalbuminuric patients with type 2 diabetic mellitus and speculate that this may represent an amelioration of renal injury.",2002.0,0,0 1105,11801860,The use of fibrates and of statins in preventing atherosclerosis in diabetes.,G Steiner,"Atherosclerotic cardiovascular disease is the most common complication of diabetes. Recent guidelines in the USA have underlined the importance of treating lipid abnormalities in people with diabetes in order to reduce the risk of this complication. Should lifestyle approaches not be sufficient drugs will need to be added. The two most common classes of drugs to correct lipoprotein abnormalities are the statins and the fibrates. Each has a role to play and their use depends on the nature of the lipid abnormality that is present. Thus, rather than considering their use as an 'either/or' situation, this review will consider the uses of each class. In addition, as correcting the lipoprotein abnormalities may not account for all of the benefit produced by these agents, their non-lipid, pleotropic effects that may be antiatherogenic will also be reviewed.",2002.0,0,0 1106,11801863,Value or desirability of hemorheological-hemostatic parameter changes as endpoints in blood lipid-regulating trials.,R Corti; J J Badimon,"High levels of plasma lipids have been recognized as a major risk factor in the development and progression of atherosclerosis, and to influence hemorheological factors that may predispose to thrombotic complications. Lipid-lowering interventions have been associated with a significant reduction of morbidity and mortality. Several mechanisms have been postulated for the observed clinical effect. Serum lipid-regulating therapies may reduce cardiovascular risk not only by altering the arterial wall, improving disturbed endothelial function, atherogenesis and plaque stability, but also through their antithrombogenic effects and influence on blood flow properties associated with hyperlipidemia. In this article, we will review the recent literature and discuss the value of hemorheological-hemostatic findings as surrogate endpoints for clinical trials in dyslipidemic patients.",2002.0,0,0 1107,11807300,Amplification of low-frequency antiviral CD8 T cell responses using autologous dendritic cells.,Marie Larsson; David T Wilkens; Jean-François Fonteneau; Thomas J Beadle; Melissa J Merritt; Rhonda G Kost; Patrick A J Haslett; Susan Cu-Uvin; Nina Bhardwaj; Douglas F Nixon; Barbara L Shacklett,"To utilize the potent antigen-presenting capacity of mature dendritic cells (MDC) in order to develop a rapid, sensitive method for quantifying antigen-specific CD8 T cells present at low frequency in peripheral blood. Peripheral blood mononuclear cells (PBMC) were obtained from seven HIV-1-positive individuals with low to moderate CD8 T cell responses, including five on highly active antiretroviral therapy (HAART). IFN-gamma ELISPOT assays were performed using either monocytes or MDC to present antigens expressed by recombinant vaccinia viruses (r-VV). Peripheral blood-derived monocytes were cultured for 5-6 days in the presence of IL-4 and granulocyte macrophage colony-stimulating factor, then matured in monocyte-conditioned medium. MDC were infected with r-VV and co-cultured in an ELISPOT assay with autologous monocyte-depleted PBMC. Relative to autologous monocytes, MDC amplified detection of antigen-specific CD8 T cells by 2-30-fold in response to antigens from HIV-1, Epstein-Barr virus and cytomegalovirus. Furthermore, antigenic specificities were revealed that had not been detected using standard ELISPOT of PBMC. This assay will prove useful for the detection of memory T cells present at low frequency, and may be of interest for identifying subdominant cytotoxic T lymphocyte epitopes. This method may have broad applications for the detection of antiviral CD8 T cell responses in patient populations in whom such responses have been difficult to detect, including HIV-1-seropositive individuals with advanced disease or undergoing HAART.",2002.0,0,0 1108,11808936,Chemoprevention of colorectal cancer.,Karin Gwyn; Frank A Sinicrope,"Colorectal cancer is the third most incident cancer in the United States and is second only to lung cancer as a cause of cancer-related mortality. Colorectal cancer develops through a multistep process characterized by histopathological precursor lesions and molecular genetic alterations. This sequential process of tumorigenesis provides opportunities for the development and testing of both primary and secondary prevention strategies. This review focuses on chemoprevention, which is defined as the use of natural or synthetic agents to reverse the process of carcinogenesis. Epidemiological studies have consistently shown that chronic intake of nonsteroidal anti-inflammatory drugs (NSAIDs), principally aspirin, can reduce the incidence of colorectal adenomas and carcinomas. Evaluation of NSAIDs, including newer selective cyclo-oxygenase-2 inhibitors, in carcinogen-induced and genetically manipulated animal models of colorectal cancer demonstrates that these drugs are effective chemopreventive agents. In humans, the NSAID sulindac has been studied in familial adenomatous polyposis patients and was found to regress colorectal adenomas in a placebo-controlled trial. More recently, the selective cyclo-oxygenase-2 inhibitor Celebrex was also shown to be effective in familial adenomatous polyposis and was approved by the Food and Drug Administration as a adjuct to usual care in these patients. NSAIDs, as well as other chemopreventive agents, are currently being studied in patients at increased risk of colorectal cancer, including those with sporadic adenomas. The outcome of these studies has the potential to impact patient management practices. However, chemopreventive agents cannot be recommeded at present for average-risk individuals or for those with sporadic colorectal neoplasia. In addition to demonstrating efficacy, chemopreventive agents must be safe and well tolerated for chronic administration and should be relatively cost-effective. Although still in its infancy, the field of chemoprevention is an exciting and rapidly advancing area of investigation. Chemopreventive strategies, if effective, offer the promise of producing a paradigm shift in our current approach to colorectal cancer.",2002.0,0,0 1109,11809001,Anabolic agents for treating postmenopausal osteoporosis.,P J Meunier,"The main efficacy criterion for drugs against osteoporosis is protection against fractures. Many resorption-inhibiting agents meet this criterion, including estrogens, alendronate, risedronate, raloxifene, calcitonin, and calcium-vitamin D supplements). Conversely, among anabolic agents, only parathyroid hormone (PTH) is known to reduce the fracture risk, the mechanism being increased bone matrix production by osteoblasts with no alterations in the mechanical properties of bone. Although fluoride salts induce a marked increase in bone mineral density (BMD), there is no evidence that this protects against vertebral or peripheral fractures. Growth hormone, IGF-I, statins, and strontium ranelate are under investigation. A recent controlled clinical trial in 1,637 women with osteoporosis showed that daily subcutaneous injections of PTH (1-34) (20 or 40 microg) for 21 months reduced the fracture risk. With 20 microg/day, the reductions were 65% for vertebral fractures and 57% for extravertebral fractures, 11% of patients had moderate postinjection hypercalcemia, and BMD increased by 9% at both the lumbar spine and the femoral neck. These findings open up the exciting possibility that PTH used alone or in combination with resorption-inhibiting agents may be helpful. To date, PTH is the only anabolic agent that has proved capable of reducing the risk of vertebral and extravertebral fractures in women with established postmenopausal osteoporosis.",2002.0,0,0 1110,11809427,Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia.,Michael Davidson; Patrick Ma; Evan A Stein; Antonio M Gotto; Ali Raza; Rohini Chitra; Howard Hutchinson,"This randomized, double-blind, placebo-controlled trial was conducted in 52 centers in North America to compare the effects of the new, highly effective statin, rosuvastatin, with atorvastatin and placebo in hypercholesterolemic patients. After a 6-week dietary run-in, 516 patients with low-density lipoprotein (LDL) cholesterol > or =4.14 mmol/L (160 mg/dl) and < 6.47 mmol/L (250 mg/dl) and triglycerides < or =4.52 mmol/L (400 mg/dl) were randomized to 12 weeks of once-daily placebo (n = 132), rosuvastatin 5 mg (n = 128), rosuvastatin 10 mg (n = 129), or atorvastatin 10 mg (n = 127). The primary efficacy end point was percent change in LDL cholesterol. Secondary efficacy variables were achievement of National Cholesterol Education Program (NCEP) Adult Treatment Panel II (ATP II), ATP III, and European Atherosclerosis Society LDL cholesterol goals and percent change from baseline in high-density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, non-HDL cholesterol, apolipoprotein B, and apolipoprotein A-I. Rosuvastatin 5 and 10 mg compared with atorvastatin 10 mg were associated with greater LDL cholesterol reductions (-40% and -43% vs 35%; p <0.01 and p <0.001, respectively) and HDL cholesterol increases (13% and 12% vs 8%, p <0.01 and p <0.05, respectively). Total cholesterol and apolipoprotein B reductions and apolipoprotein A-I increases were also greater with rosuvastatin; triglyceride reductions were similar. Rosuvastatin 5 and 10 mg were associated with improved achievement in ATP II (84% in both rosuvastatin groups vs 73%) and ATP III (84% and 82% vs 72%) LDL cholesterol goals, and rosuvastatin 10 mg was more effective than atorvastatin in achieving European Atherosclerosis Society LDL cholesterol goals. Both treatments were well tolerated.",2002.0,1,1 1111,11811718,Statins in acute coronary syndromes: start them in the hospital.,Monica Acevedo; Dennis L Sprecher,"Most patients with an acute coronary syndrome should start taking a statin drug while still in the hospital if they are not already taking a statin, according to recent studies. In this situation, a statin drug should be started if the low-density lipoprotein (LDL) value is 130 mg/dL or higher, or perhaps even 100 mg/dL or higher.",2002.0,0,0 1112,11812397,Inhalation anthrax revisited.,Lee Goldman,,2002.0,0,0 1113,11812402,Associations between Fc gamma receptor IIA polymorphisms and the risk and prognosis of meningococcal disease.,Pere Domingo; Eduardo Muñiz-Diaz; Maria A Baraldès; Marina Arilla; Nicolau Barquet; Roser Pericas; Cándido Juárez; Pedro Madoz; Guillermo Vázquez,"In vitro studies have shown that the neutrophil Fc gamma receptor IIA (FcgammaRIIA) polymorphism influences the phagocytic capacity of neutrophils and the removal of encapsulated bacteria from the bloodstream. In particular, the R/R131 allotype is associated with less phagocytic activity. We performed a case-control study to determine the influence of the FcgammaRIIA polymorphism (R/R131, R/H131, H/H131) on the risk and outcome of meningococcal disease. The polymorphisms were measured in 130 patients with microbiologically proven meningococcal disease diagnosed from 1987 to 1998 (cases) and 260 asymptomatic sex-matched blood donors (controls). Clinical manifestations and complications of meningococcal disease were recorded, and a prognostic score (based on age, hemorrhagic diathesis, neurologic signs, and the absence of preadmission antibiotic) therapy was calculated. The distributions of FcgammaRIIA allotypes were similar in cases and controls. However, among patients with meningococcal infection, fulminant meningococcal disease (odds ratio [OR] = 3.9; 95% confidence interval [CI]: 1.0 to 16; P = 0.04) and meningococcemia without meningitis (OR = 3.0; 95% CI: 1.4 to 7.8; P = 0.004) were more common in those with the FcgammaRIIA-R/R131 allotype. Complications were also significantly more frequent in these patients. Of the 42 patients with the R/R131 allotype, 31 (74%) had an adverse prognostic score, compared with 7% (4 of 59) of those with the R/H131 allotype and 3% (1 of 29) of those with the H/H131 allotype (P <0.0001). The FcgammaRIIA-R/R131 allotype is associated with more severe forms of meningococcal disease.",2002.0,0,0 1114,11812672,"Clinical trials update: The Heart Protection Study, IONA, CARISA, ENRICHD, ACUTE, ALIVE, MADIT II and REMATCH. Impact Of Nicorandil on Angina. Combination Assessment of Ranolazine In Stable Angina. ENhancing Recovery In Coronary Heart Disease patients. Assessment of Cardioversion Using Transoesophageal Echocardiography. AzimiLide post-Infarct surVival Evaluation. Randomised Evaluation of Mechanical Assistance for Treatment of Chronic Heart failure.",Amala A Louis; I Renata Manousos; Alison P Coletta; Andrew L Clark; John G F Cleland,,2002.0,0,0 1115,11814176,"Postmenopausal hormone replacement therapy and major clinical outcomes: a focus on cardiovascular disease, osteoporosis, dementia, and breast and endometrial neoplasia.",Sarah E Dick; Dawn E DeWitt; Bradley D Anawalt,"Current data suggest that hormone replacement therapy (HRT) might have a beneficial role in the prevention of cardiovascular disease (CVD), osteoporosis, and dementia in postmenopausal women, but other therapies should be considered for the treatment of these conditions. In this review we evaluated the potential benefits of HRT for CVD, osteoporosis, and dementia, and compared HRT with proven, effective therapies. In addition, we identified the potential risks of breast and endometrial neoplasia, and an early risk of CVD and thromboembolic disease associated with HRT use.",2002.0,0,0 1116,11816268,Rosuvastatin for the treatment of patients with hypercholesterolemia.,Pang H Chong; Barbara T Yim,"To review the currently available information on rosuvastatin in the treatment of primary hypercholesterolemia. MEDLEY (2000-January 2001), MEDLIT, MEDLINE, EMBASE, SciSearch, Current Contents, Derwent, Drug, BIOSIS, Adis LMS Drug Alerts, and International Pharmaceutical Abstracts (1994-July 2001) were searched; unpublished data obtained from the manufacturer were also included. Studies evaluating rosuvastatin including abstracts, proceedings, and data on file from the manufacturer were considered for inclusion. English-language literature was evaluated for pharmacology, pharmacodynamics, pharmacokinetics, therapeutic use, and adverse effects of rosuvastatin. Additional relevant citations were used in the introductory material and discussion section. English-language study abstracts selected for inclusion were limited to those on human subjects. Animal data were included only if human data were not available. Resuvastatin, a new synthetic hydroxymethylglutaryl coenzyme A reductase inhibitor (HMG-CoA RI), recently completed Phase III clinical trials. At a dosage of 1-80 mg/d, the drug significantly reduced total cholesterol and low-density-lipoprotein cholesterol (LDL-C) and produced beneficial effects on other lipid parameters as well. Overall, resuvastatin was well tolerated. In hypercholesterolemic patients, rosuvastatin reduced LDL-C and other lipid parameters to a greater degree than currently available agents. One advantage of rosuvastatin is that it achieves target LDL-C goals in a greater proportion of treated patients with similar adverse events compared with those treated with other HMG-CoA RIs. The potential to reduce risk of coronary heart disease events and decrease mortality as well as cost comparisons with currently used HMG-CoA RIs remains a subject of further investigation.",2002.0,0,0 1117,11816337,[Heart Protection Study].,Mogens Lytken Larsen; Per Rossen Hildebrandt,,2002.0,0,0 1118,11818357,Do lipid-lowering drugs cause erectile dysfunction? A systematic review.,Kash Rizvi; John P Hampson; John N Harvey,"Erectile dysfunction (ED) is common although under-reported by patients. Along with the better known causes of ED, drug-induced impotence needs to be considered as a cause of this symptom. Lipid-lowering drugs have been prescribed increasingly. Their relationship to ED is controversial. Our aim was to clarify the relationship between lipid-lowering therapy and ED. A secondary aim was to assess the value of the systematic review procedure in the area of adverse drug reactions. A systematic review was carried out using computerized biomedical databases and Internet sources. Terms denoting ED were linked with terms referring to lipid-lowering drugs. Information was also sought from regulatory agencies. A significant literature was identified, much from obscure sources, which included case reports, review articles, and information from clinical trials and from regulatory agencies. Information from all of these sources identified fibrates as a source of ED. A substantial number of cases of ED associated with statin usage have been reported to regulatory agencies. Case reports and clinical trial evidence supported the suggestion that statins can also cause ED. Some information on possible mechanisms was obtained, but the mechanism remains uncertain. The systematic review procedure was applied successfully to collect evidence suggesting that both statins and fibrates may cause ED. More numerous reports to regulatory agencies complemented more detailed information from case reports to provide a new perspective on a common area of prescribing.",2002.0,0,0 1119,11818488,Breast cancer risk reduction: strategies for women at increased risk.,Rowan T Chlebowski,"Breast cancer risk reduction now represents an achievable medical objective. Current interventions include selective estrogen receptor modulators (SERMs), prophylactic surgery, and lifestyle change. For SERMs, current evidence supports tamoxifen use for breast cancer risk reduction whereas raloxifene requires further study. Prophylactic mastectomy and prophylactic oophorectomy, effective in retrospective clinical experiences, should be considered only for women at substantial risk willing to accept the irreversible consequences of these procedures. Although dietary fat intake is under clinical trial evaluation, lifestyle change, including weight loss, dietary change, and increased physical activity, can be recommended based on other health considerations. Use of any intervention requires careful breast cancer risk assessment, risk-benefit calculations, and informed decision making with full patient participation. Future breast cancer risk assessment may incorporate additional biologic measures of estrogen exposure and/or analyses of collected breast cells. Under active evaluation are novel SERMs, aromatase inhibitors/inactivators, gonadotrophin-releasing hormone agonists, retinoids, statins, and tyrosine kinase and cyclooxygenase-2 inhibitors.",2002.0,0,0 1120,11819151,"Cholesterol, essential fatty acids, and suicide.",Jürgen Brunner; K G Parhofer; P Schwandt; T Bronisch,"Epidemiological and clinical studies have described an association between lower serum cholesterol concentrations and increased suicide risk that is not entirely attributable to depression-related malnutrition and weight loss. Recent epidemiological studies with greater samples and longer follow-up periods, however, have even shown a positive correlation between cholesterol concentrations and suicide risk after controlling for potential confounding variables. A meta-analysis of earlier intervention trials suggested that cholesterol lowering could cause or worsen depressive symptoms and increase the risk of suicide. Large trials of statins (simvastatin, lovastatin, and pravastatin) did not show an increase of suicide mortality. The aim of this selective review is to critically discuss the current evidence for a potential link between cholesterol, essential fatty acids, depression, suicide, impulsivity, and aggression. Preclinical data support the hypothesis that cholesterol reduction may contribute to the serotonergic abnormalities that have been postulated in suicidal subjects. Recently, it was hypothesised that a decreased consumption of polyunsaturated fatty acids, especially omega-3 fatty acids, may be a risk factor for depression and suicide. Currently, we do not have sufficient evidence that cholesterol-lowering therapies increase the risk of depression and suicide. Increasing the dietary intake of omega-3 fatty acids may increase central serotonergic activity and reduce impulsive and aggressive behaviours.",2002.0,0,0 1121,11821324,Commentary: Can health outputs of routine practice approach those of clinical trials?,J T Hart,,2002.0,0,0 1122,11821696,Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk.,Alain Simon; Jérôme Gariepy; Gilles Chironi; Jean-Louis Megnien; Jaime Levenson,"Increased intima-media thickness (IMT) is a non-invasive marker of early arterial wall alteration, which is easily assessed in the carotid artery by B-mode ultrasound, and more and more widely used in clinical research. Methods of IMT measurement can be categorized by two approaches: (i) measurement at multiple extracranial carotid sites in near and far walls and (ii) computerized measurement restricted to the far wall of the distal common carotid artery. Because IMT reflects global cardiovascular risk, its normal value might be better defined in terms of increased risk rather than in terms of statistical distribution within a healthy population. The available epidemiological data indicate that increased IMT (at or above 1 mm) represents a risk of myocardial infarction and/or cerebrovascular disease. Close relationships have been shown between: (i) most traditional cardiovascular risk factors; (ii) certain emerging risk factors such as lipoproteins, psychosocial status, plasma viscosity, or hyperhomocysteinemia; and (iii) various cardiovascular or organ damages such as white matter lesion of the brain, left ventricular hypertrophy, microalbuminuria or decreased ankle to brachial systolic pressure index. Thus, IMT gives a comprehensive picture of the alterations caused by multiple risk factors over time on arterial walls. Prospective primary and secondary prevention studies have also shown that increased IMT is a powerful predictor of coronary and cerebrovascular complications (risk ratio from 2 to 6) with a higher predictive value when IMT is measured at multiple extracranial carotid sites than solely in the distal common carotid artery. Therapeutic double-blind trials have shown that lipid-lowering drugs, such as resin and overall statines, and to a lesser extent antihypertensive drugs, such as calcium antagonists, may have a beneficial effect on IMT progression in asymptomatic or in coronary patients. However, methodological standardization of IMT measurement still needs to be implemented before routine measurement of IMT can be proposed in clinical practice as a diagnostic tool for stratifying cardiovascular risk in primary prevention and for aggressive treatment decision. It can be anticipated however, that the presence of increased carotid IMT in one individual with intermediate cardiovascular risk would lead to his classification into the high-risk category and thus influence the aggressiveness of risk factor modifications.",2002.0,0,0 1123,11821701,Antagonists of the angiotensin II type 1 receptor: an approach to control vascular disease beyond blood pressure lowering?,Paolo Pauletto,,2002.0,0,0 1124,11822972,Statin therapy after acute myocardial infarction: are we adequately treating high-risk patients?,Gregg C Fonarow,"After acute myocardial infarction, patients remain at high risk for recurrent cardiovascular events and mortality. Despite the compelling scientific and clinical trial evidence that lipid-lowering medications reduce mortality in patients after acute myocardial infarction, this life-saving therapy continues to be underutilized. A number of studies in a variety of clinical settings have documented that a significant proportion of patients after myocardial infarction are not receiving treatment with lipid-lowering medications when guided by conventional care. It has recently been demonstrated that implementation of a hospital-based system for initiation of statins prior to hospital discharge results in a marked increase in treatment rates, improved long-term patient compliance, more patients reaching low-density lipoprotein levels of less than 100 mg/dL, and improved clinical outcomes. Adopting in-hospital initiation of lipid-lowering medications as the standard of care for patients hospitalized with acute myocardial infarction could dramatically improve treatment rates and thus substantially reduce the risk of future coronary events and prolong life in the large number of patients hospitalized each year.",2003.0,0,0 1125,11823672,Effect of controlled release/extended release metoprolol on carotid intima-media thickness in patients with hypercholesterolemia: a 3-year randomized study.,Olov Wiklund; Johannes Hulthe; John Wikstrand; Caroline Schmidt; Sven-Olof Olofsson; Göran Bondjers,"Beta-adrenergic blockade has in several studies been shown to improve survival after myocardial infarction. In animal experiments beta-blockers have also shown an antiatherosclerotic effect. The aim of this study was to test the hypothesis that the beta-blocker metoprolol succinate controlled release/extended release (CR/XL), when given to patients with hypercholesterolemia on concomitant lipid-lowering therapy, provides an additional antiatherosclerotic effect to that provided by the statins, measured as carotid intima-media thickness (IMT). We conducted a randomized, double-blind, placebo-controlled, single center trial to compare the effect of metoprolol CR/XL (100 mg once daily) and placebo on the progression of carotid IMT during 36 months of treatment in patients with hypercholesterolemia and signs of early atherosclerosis in the carotid artery. Most patients were prescribed lipid-lowering treatment with statins. A highly significant difference in the progression rate of the composite variable of carotid bulb IMT+common carotid IMT was observed between the metoprolol CR/XL and placebo groups after 1 year of treatment (-0.08 versus -0.01 mm; P=0.004), an effect that was sustained after 3 years of follow-up (-0.06 versus +0.03 mm; P=0.011). The patients had high levels of total cholesterol at randomization: 9.4 mmol/L in the metoprolol CR/XL group and 8.6 mmol/L in the placebo group. During the study the 2 randomization groups were treated with lipid-lowering drugs, mainly statins, to a similar extent, and total cholesterol was reduced to 6.4 mmol/L at end of follow-up in both groups. The results from the present study in patients with hypercholesterolemia under concomitant lipid-lowering therapy are the first clinical data to show an antiatherosclerotic effect of beta-blockade as additional therapy to statins. The data indicate that statin treatment and treatment with beta-blockers affect different mechanisms in the atherosclerotic process and have additive beneficial effects.",2002.0,0,0 1126,11824669,Can statins reduce the inflammatory response to cardiopulmonary bypass? A clinical study.,E Florens; S Salvi; J Peynet; C Elbim; Z Mallat; A Bel; A Nguyen; A Tedgui; C Pasquier; P Menasché,"In addition to lowering lipid levels, statins might reduce leukocyte-endothelial cell interactions. Therefore, we assessed whether this effect could limit the inflammatory response to cardiopulmonary bypass (CPB) in cardiac surgical patients. Twenty patients undergoing valve or coronary operations with tepid (34 degrees C) CPB were randomized to receive an oral dose of atorvastatin (40 mg the evening before and 40 mg the morning of surgery) or to serve as controls. Pre- and post-CPB blood samples were assayed for neutrophil CD11b surface adhesion molecule and oxidative burst. Plasma levels of interleukins 6 and 8, P-selectin, soluble intercellular adhesion molecule-1, and lactoferrin were measured by enzyme-linked immunosorbent assay (ELISA). In addition, right atrial biopsies were taken before and at the end of CPB, and processed for the expression of the transcription nuclear factor-kappa B (NF-kappaB). The two groups did not differ with regard to pre- and intraoperative data. Except for P-selectin, postbypass values of all markers significantly increased over baseline values, but atorvastatin therapy failed to attenuate the magnitude of this increase. In the two groups, the expression of NF-kappaB significantly (p = 0.004) increased over baseline without group effect. Postoperative clinical outcomes did not differ either between the two groups. These data show that acute preoperative statin therapy fails to limit the inflammatory response to CPB; however, the data also document a major upregulation of NF-kappaB during cardiac operations, thereby providing a sound rationale for interventions targeted at inactivating this key component of the inflammatory cascade.",2002.0,0,0 1127,11825315,Pharmacological approaches to preserving and restoring coronary endothelial function.,O L Woodman,"There is compelling evidence that the endothelium is critical to normal coronary vascular function and that endothelial dysfunction, generally indicated by an impairment of endothelium-dependent vasodilatation, is an important component of coronary artery disease (CAD). Endothelial cells synthesise and release a number of factors, including prostacyclin, nitric oxide (NO), endothelium-derived hyperpolarising factor (EDHF) and endothelin, which are important in the regulation of vascular tone and the control of platelet and leukocyte adhesion, aggregation and migration. NO appears to be the critical factor in the preservation of normal coronary vascular function and there is a well-established correlation between CAD and an impairment of NO activity. Thus, to preserve endothelial function, drugs have been used to either increase the synthesis of NO, or to decrease its breakdown. Fortuitously, compounds such as the HMG-CoA reductase inhibitors, angiotensin (AT) converting enzyme inhibitors (ACEIs), AT receptor antagonists and oestrogen, which have been introduced into clinical practice because of other beneficial effects, have also been shown to improve coronary endothelial function through a variety of mechanisms. In addition, L -arginine, the substrate for NO synthesis, and the anti-oxidants ascorbate and alpha-tocopherol, are able to increase NO synthesis and bioavailability respectively. Studies in experimental animals strongly support the ability of these agents to enhance the activity of endothelium-derived NO but clinical trials have failed to demonstrate reversal of established CAD. Whether these agents preserve endothelial function and prevent the development of CAD remains to be established.",2002.0,0,0 1128,11825316,Current practice in the treatment of hyperlipidaemias.,P Duriez,"Primary and secondary prevention trials for coronary heart disease (CHD) in hyperlipidaemic or so-called 'normolipidaemic' patients with drugs affecting lipid metabolism have clearly confirmed that even slight alterations in lipoprotein metabolism are major risk factors for CHD. The global cardiovascular risk must be determined before deciding to treat patients with drugs affecting lipid metabolism. Screening for dyslipidaemia consists of determining cholesterol (C), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and triglyceride (TG) plasma levels and the decision to treat depends mainly on LDL-C plasma levels. Furthermore, secondary dyslipidaemia must be diagnosed and primary disease must be adequately treated. There are four classes of available lipid-regulating drugs: HMG-CoA reductase inhibitors (statins), bile acid sequestrants (resins), peroxisome proliferator-activated receptor-alpha (PPAR- alpha) activators (fibrates) and nicotinic acid. All four will be discussed in this review. Clinical trials have shown that drugs improving lipid metabolism reduce CHD relative risk from 24% (secondary prevention) to 37% (primary prevention) and the absolute risk from 2% (primary prevention) to 8.5% (secondary prevention). These studies indicate that the number of patients needed to be treated to economise one clinical event ranges from 12 (secondary prevention) to 50 (primary prevention). Clinical trials are currently testing the hypothesis that 'lower LDL-C is better'.",2002.0,0,0 1129,11825336,A critical evaluation of the NICE guidelines for post-myocardial infarction prophylaxis. National Institute for Clinical Excellence.,K F Fox; UK National Institute for Clinical Excellence,"The UK National Institute for Clinical Excellence (NICE) has recently published guidelines on prophylaxis for patients who have experienced a myocardial infarction (MI). Based on a previously commissioned extensive review of the literature, the recommendations are antiplatelet therapy, beta-blockers and angiotensin converting enzyme inhibitors (ACEIs) for all patients; statins for those with hypercholesterolaemia; spironolactone for those with moderate-to-severe heart failure (HF); and insulin for those with diabetes. While there may be concerns about some of the details (eg., the possible adverse interaction between aspirin and ACEIs), comments on the use of statins for those with HF, the lack of advice on the choice of lipid-lowering therapy for those intolerent of statins, the dangers of spironolactone therapy and the practicality of intensive insulin treatment, the guidelines are firmly based on sound evidence of efficacy and cost effectiveness. The NICE guidelines should therefore stimulate the provision of resources to address the gap between current practice and these recommendations.",2002.0,0,0 1130,11829081,Therapies to improve bone mineral density and reduce the risk of fracture: clinical trial results.,Nelson B Watts,"Osteoporosis is a skeletal disorder that is associated with lowered bone mineral density and increased risk of fracture. Numerous clinical trials have been conducted to study drugs and lifestyle changes that can either prevent bone loss in perimenopausal women or prevent fractures in women with established osteoporosis. The role of estrogen alone or in combination with androgen as hormone replacement therapy is discussed for its potential value in osteoporosis prevention and treatment. Additional therapies that are examined for prevention and treatment of osteoporosis include tibolone, bisphosphonates (alendronate and risedronate), selective estrogen-receptor modulators, calcitonin and parathyroid hormone. Experimental therapies that are in different phases of evaluation in osteoporosis management include statins as well as tumor necrosis factor-receptor antagonists. Other strategies include nonpharmacologic interventions, such as calcium supplements, vitamin D and exercise.",2002.0,0,0 1131,11829698,"Effects of diet and simvastatin on serum lipids, insulin, and antioxidants in hypercholesterolemic men: a randomized controlled trial.",Antti Jula; Jukka Marniemi; Risto Huupponen; Arja Virtanen; Merja Rastas; Tapani Rönnemaa,"Limited information exists on the interaction between diet and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and the interaction's effect on serum lipid and lipoprotein levels, insulin sensitivity, and circulating antioxidant vitamin and provitamin levels. To evaluate the separate and combined effects of diet and simvastatin therapy on serum levels of lipids, lipoproteins, antioxidants, and insulin. Randomized, controlled crossover trial conducted from August 1997 to June 1998 in 120 previously untreated hypercholesterolemic men aged 35 to 64 years who were recruited from the community in Turku, southwestern Finland. After a 4- to 6-week placebo run-in period, participants were randomly allocated to a habitual diet (n = 60) or dietary treatment group (n = 60), and each of these groups was further randomized in a double-blind crossover fashion to receive simvastatin (20 mg/d) or placebo, each for 12 weeks (n = 30 in each group). The main goals of the dietary treatment were to reduce energy intake from saturated plus trans-unsaturated fats to no more than 10% by replacing them partly with monounsaturated and polyunsaturated fats rich in omega-3 fatty acids and to increase intake of fruits, vegetables, and dietary fiber. Changes in levels of total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol; triglycerides; apolipoprotein B; insulin; glucose; and antioxidants at week 12 of each treatment period, compared among the 4 groups. Dietary treatment decreased levels of total cholesterol by 7.6% (P<.001), LDL cholesterol by 10.8% (P<.001), HDL cholesterol by 4.9% (P =.01), apolipoprotein B by 5.7% (P =.003), serum insulin by 14.0% (P =.02), and alpha-tocopherol by 3.5% (P =.04). Simvastatin decreased levels of total cholesterol by 20.8%, LDL cholesterol by 29.7%, triglycerides by 13.6%, apolipoprotein B by 22.4%, alpha-tocopherol by 16.2%, beta-carotene by 19.5%, and ubiquinol-10 by 22.0% (P<.001 for all) and increased levels of HDL cholesterol by 7.0% (P<.001) and serum insulin by 13.2% (P =.005). Glucose levels remained unchanged in all groups. The effects of dietary treatment and simvastatin were independent and additive. A modified Mediterranean-type diet rich in omega-3 fatty acids efficiently potentiated the cholesterol-lowering effect of simvastatin, counteracted the fasting insulin-elevating effect of simvastatin, and, unlike simvastatin, did not decrease serum levels of beta-carotene and ubiquinol-10.",2002.0,0,0 1132,11830753,Cilostazol (pletal): a dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine uptake.,Y Liu; Y Shakur; M Yoshitake; J Kambayashi Ji,"Cilostazol (Pletal), a quinolinone derivative, has been approved in the U.S. for the treatment of symptoms of intermittent claudication (IC) since 1999 and for related indications since 1988 in Japan and other Asian countries. The vasodilatory and antiplatelet actions of cilostazol are due mainly to the inhibition of phosphodiesterase 3 (PDE3) and subsequent elevation of intracellular cAMP levels. Recent preclinical studies have demonstrated that cilostazol also possesses the ability to inhibit adenosine uptake, a property that may distinguish it from other PDE3 inhibitors, such as milrinone. Elevation of interstitial and circulating adenosine levels by cilostazol has been found to potentiate the cAMP-elevating effect of PDE3 inhibition in platelets and smooth muscle, thereby augmenting antiplatelet and vasodilatory effects of the drug. In contrast, elevation of interstitial adenosine by cilostazol in the heart has been shown to reduce increases in cAMP caused by the PDE3-inhibitory action of cilostazol, thus attenuating the cardiotonic effects. Cilostazol has also been reported to inhibit smooth muscle cell proliferation in vitro and has been demonstrated in a clinical study to favorably alter plasma lipids: to decrease triglyceride and to increase HDL-cholesterol levels. One, or a combination of several of these effects may contribute to the clinical benefits and safety of this drug in IC and other disease conditions secondary to atherosclerosis. In eight double-blind randomized placebo-controlled trials, cilostazol significantly increased maximal walking distance, or absolute claudication distance on a treadmill. In addition, cilostazol improved quality of life indices as assessed by patient questionnaire. One large randomized, double-blinded, placebo-controlled, multicenter competitor trial demonstrated the superiority of cilostazol over pentoxifylline, the only other drug approved for IC. Cilostazol has been generally well-tolerated, with the most common adverse events being headache, diarrhea, abnormal stools and dizziness. Studies involving off-label use of cilostazol for prevention of coronary thrombosis/restenosis and stroke recurrence have also recently been reported.",2002.0,0,0 1133,11831543,Comparative pharmacokinetics of lovastatin extended-release tablets and lovastatin immediate-release tablets in humans.,Jim X Sun; Robert Niecestro; Gale Phillips; Jason Shen; Peter Lukacsko; Lawrence Friedhoff,"The pharmacokinetics of lovastatin and its active metabolite lovastatin acid was evaluated in 9 healthy subjects in a three-period crossover study following a single oral dose of lovastatin extended-release (ER) tablets and lovastatin immediate-release (IR) tablets. Participants were dosed with lovastatin IR 40 mg tablets following a standard breakfast, lovastatin ER 40 mg tablets following a standard breakfast, and lovastatin ER 40 mg tablets underfasting conditions. Serial plasma samples were collected for up to 48 hours postdose and assayed for lovastatin and lovastatin acid using a liquid chromatography/mass spectroscopy/mass spectroscopy method. Lovastatin ER tablets, unlike lovastatin IR tablets, exhibited delayed- and extended-release characteristics. The relative bioavailability, in terms of area under the curve values, of lovastatin (156%) and lovastatin acid (124%) was greater from lovastatin ER tablets as compared with lovastatin IR tablets when given with breakfast. An even greater increase in the bioavailability of lovastatin (261%) and lovastatin acid (231%) was observed when the lovastatin ER tablets were administered under fasting conditions. Thus, greater gastrointestinal tract drug absorption of lovastatin from lovastatin ER tablets was demonstrated. Ingestion of a standard breakfast prior to administration of lovastatin ER tablets decreased absorption of lovastatin by approximately 40%, relative to lovastatin ER tablets under fasting conditions.",2002.0,0,0 1134,11831546,Pharmacokinetic and pharmacodynamic assessments of HMG-CoA reductase inhibitors when coadministered with everolimus.,John M Kovarik; Stefan Hartmann; Martine Hubert; Stephane Berthier; Werner Schneider; Bernd Rosenkranz; Christiane Rordorf,"The authors assessed the mutual influence of the immunosuppressant everolimus (Certican) and the HMG-CoA reductase inhibitors atorvastatin and pravastatin when coadministered based on pharmacokinetic and pharmacodynamic measures. In this randomized, open-label, three-way crossover study, 24 healthy men received three single-dose oral treatments: 2 mg everolimus, 20 mg atorvastatin (n = 12) or 20 mg pravastatin (n = 12), and the respective statin coadministered with everolimus. Consecutive treatments were separated by a 14-day washout. The pharmacokinetics of all three drugs and total HMG-CoA reductase inhibitors were measured. Everolimus Cmax was reduced by 9% and 10% with atorvastatin and pravastatin coadministration; the corresponding decreases in everolimus AUC were 5% and 6%, respectively. Everolimus coadministration increased the Cmax of atorvastatin by 11% but had no influence on atorvastatin AUC. Coadministration of everolimus with pravastatin was associated with a 10% decrease in pravastatin Cmax and a 5% decrease in the AUC. The elimination half-lives of the two statins were unaffected by everolimus. Changes in total HMG-CoA reductase inhibitors in plasma exhibited generally similar patterns as for the parent statin exposures. Single-dose administrations of everolimus with either atorvastatin or pravastatin did not influence the pharmacokinetics of everolimus, atorvastatin, pravastatin, or total HMG-CoA reductase inhibitors in plasma to a clinically relevant extent.",2002.0,0,0 1135,11831837,The MRC/BHF Heart Protection Study: preliminary results.,Rory Collins; Richard Peto; Jane Armitage,"The Heart Protection Study (HPS), with over 20,500 subjects, is the largest trial of statin therapy ever conducted. It provides important and definitive new information on women, the elderly, diabetics, and people with low baseline cholesterol pre-treatment and those with prior occlusive non-coronary vascular disease. It is a prospective double blind randomised controlled trial with a 2 x 2 factorial design investigating prolonged use (>5 years) of simvastatin 40 mg and a cocktail of antioxidant vitamins (650 mg vitamin E, 250 mg vitamin C and 20 mg beta-carotene). The HPS specifically included patients with high risk for coronary heart disease (CHD) but characteristics that excluded them from participation in previous statin trials. Simvastatin 40 mg treatment showed benefit across all patient groups regardless of age, gender or baseline cholesterol value and proved safe and well tolerated. Results show a 12% reduction in total mortality, a 17% reduction in vascular mortality, a 24% reduction in CHD events, a 27% reduction in all strokes and a 16% reduction in non-coronary revascularisations. Among high-risk patients in this western population (with a minimum total cholesterol [TC] > or = 3.5 mmol/l at entry) there appears to be no threshold cholesterol value below which statin therapy is not associated with benefit; even among those with pre-treatment cholesterol levels below current national recommended targets. Over the 5.5 year study period patients and their doctors were encouraged to add an active non-study statin to the study regimen if they wished to do so. Thus the trial eventually had only two-thirds complying with the original intention-to-treat design. Nevertheless, results were highly significant for the study statin--simvastatin 40 mg once daily. Preliminary results of the HPS are negative for the antioxidant vitamin cocktail but provide reassurance that vitamins do no harm.",2002.0,0,0 1136,11833826,"A multiple-dose pharmacodynamic, safety, and pharmacokinetic comparison of extended- and immediate-release formulations of lovastatin.",Michael H Davidson; Peter Lukacsko; Jim X Sun; Gale Phillips; Edward Walters; Arnold Sterman; Robert Niecestro; Lawrence Friedhoff,"Because lovastatin is efficiently extracted by the liver and because its administration in divided doses is associated with increased efficacy, an extended-release (ER) formulation may have the potential for a dose-sparing advantage relative to the immediate-release (IR) formulation in the treatment of hypercholesterolemia. This study compared the short-term pharmacodynamics, safety, and pharmacokinetics of multiple doses of lovastatin ER with those of lovastatin IR in patients with fasting low-density lipoprotein cholesterol (LDL-C) levels between 130 and 250 mg/dL and fasting triglyceride levels < 350 mg/dL. The study had a randomized, single-blind, positive-controlled, 2-way crossover design, with a 4-week diet/placebo run-in period and two 4-week active-treatment periods. During period 1, patients received either lovastatin ER or lovastatin IR (both 40 mg OD). After 4 weeks of the initial study treatment and a 2-week washout period, patients were switched to the alternate treatment (period 2). Pharmacodynamic parameters (LDL-C, high-density lipoprotein cholesterol, total cholesterol, and triglyceride levels) were evaluated by combining data from weeks 3 and 4 of treatment. In a pharmacokinetic substudy, maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve from zero to 24 hours (AUC(024)) were determined for lovastatin, lovastatin acid, and total and active inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on days 1 and 28 of active treatment. The geometric mean ratio of AUC(0-24) (lovastatin ER/lovastatin IR) was also calculated for each of these substances. Of 76 patients who entered the run-in period, 26 (12 men, 14 women; mean age, 56.2 years) were randomized to receive active treatment and 24 were included in the efficacy analysis; 13 patients were included in the pharmacokinetic substudy, 12 of whom had complete pharmacokinetic data. Compared with lovastatin IR, lovastatin ER produced a 3.9% greater reduction in LDL-C (P = 0.044). Changes in other lipid parameters were not statistically significant. In the pharmacokinetic substudy, C(max) values for lovastatin, lovastatin acid, and in hibitors of HMG-CoA reductase were lower at day 28 with lovastatin ER than with lovastatin IR. The AUC(0-24) ratio for lovastatin was 1.91 (90% CI, 1.77 - 3.35), reflecting higher bioavailability of the prodrug with lovastatin ER; in contrast, the ratios for lovastatin acid and active and total inhibitors of HMG-CoA reductase were < 1. In this short-term study in a small number of patients, lovastatin ER 40 mg produced significantly greater LDL-C lowering than did an equal dose of lovastatin IR, with a relatively low C(max) and comparable systemic exposure to lovastatin acid and active and total inhibitors of HMG-CoA reductase. Lovastatin ER was well tolerated, with no discontinuations due to adverse events.",2002.0,0,0 1137,11834769,Costs of aspirin and statins in general practice.,A Drummond; S Kwok; J Morgan; P N Durrington,"Aspirin and statins are the two drugs most commonly indicated for secondary prevention of atherosclerotic disease in the UK. Statin treatment, which is more expensive, is under-prescribed. To assess the expenditure in Greater Manchester general practices on aspirin and statins. Survey of general practice records. Practice registers were searched for patients receiving regular prescriptions for aspirin. For each patient, the next patient of the same sex, aged within +/- 5 years, not on aspirin, acted as a control. Details of all medications were recorded. In a sub-study, records of 100 patients on aspirin were studied to determine indications for aspirin prescription. There were 1003 (511 men, 492 women) in each group; mean age was 70 years in both groups. In the sub-study, 79% of patients received aspirin for established vascular disease, 9% for hypertension, 5% for diabetes mellitus, 5% for unknown reasons and 2% for arthritis. Of the patients on aspirin, 67% received dispersible aspirin 75 mg/day. The rest were on higher doses (10%) or on more expensive preparations (22%), costing up to 22.4 p/day. The mean daily cost of aspirin was 1.7p. Dyspepsia treatment was received by 266 patients and 194 controls (p<0.001). There was a wide range of dyspepsia medications (10-306p/day), averaging in the groups as a whole 15.5p/day in patients and 12.5p/day in controls. Of the patients on aspirin, 28% received statins, compared to 4% of controls. Mean daily expenditure on statins in patients was 23.4p. Assuming the difference in the use of medication for dyspepsia between patients and controls was due to aspirin, the full cost of aspirin treatment was 4.7p/day. Statins were probably under-prescribed in aspirin-takers, many of whom would have been at high CHD risk.",2002.0,0,0 1138,11834772,Diabetic nephropathy: how effective is treatment in clinical practice?,N Joss; K R Paterson; C J Deighan; K Simpson; J M Boulton-Jones,"Diabetic nephropathy is the most common cause of end-stage renal failure in patients starting dialysis in the developed world. In clinical trials, interventions, particularly blood pressure control, have achieved major reductions in the rate of decline in renal function. To investigate whether results from clinical trials can be achieved in routine clinical practice. Observational study of 170 consecutive patients referred to a combined diabetic-renal clinic over a 10 year period. We collected demographic and laboratory data from the electronic patient record. Median serum creatinine at referral was 170 micromol/l and was >350 micromol/l in 26% of patients. Mean blood pressure (BP) was 159/85. The publication of guidelines by the Scottish Intercollegiate Guidelines Network in 1997, recommending more active intervention and earlier referral, had no impact on referral BP and creatinine. In the 125 patients with at least 1 year follow-up, significant improvements in BP, albuminuria, HbA(1c) and serum cholesterol were seen. In the 63 patients followed up for 3 years (median creatinine 120 micromol/l), the median rate of decline in renal function slowed from 0.52 ml/min/month (first year) to 0.27 ml/min/month (third year) (p=0.003), nearly doubling the time to end-stage renal failure. Patients referred early to a combined diabetic-renal clinic benefited by slowing in the rate of decline of renal function. A challenging but achievable standard for audit would be to reduce the rate of progression to <0.25 ml/min/month in 70% of patients with diabetic nephropathy presenting with a serum creatinine <150 micromol/l.",2002.0,0,0 1139,11835043,Policosanol: clinical pharmacology and therapeutic significance of a new lipid-lowering agent.,Ioanna Gouni-Berthold; Heiner K Berthold,"Policosanol is a mixture of higher primary aliphatic alcohols isolated from sugar cane wax, whose main component is octacosanol. The mixture has been shown to lower cholesterol in animal models, healthy volunteers, and patients with type II hypercholesterolemia. We reviewed the literature on placebo-controlled lipid-lowering studies using policosanol published in peer-reviewed journals as well as studies investigating its mechanism of action and its clinical pharmacology. At doses of 10 to 20 mg per day, policosanol lowers total cholesterol by 17% to 21% and low-density lipoprotein (LDL) cholesterol by 21% to 29% and raises high-density lipoprotein cholesterol by 8% to 15%. Because higher doses have not been tested up to now, it cannot be excluded that effectiveness may be even greater. Daily doses of 10 mg of policosanol have been shown to be equally effective in lowering total or LDL cholesterol as the same dose of simvastatin or pravastatin. Triglyceride levels are not influenced by policosanol. At dosages of up to 20 mg per day, policosanol is safe and well tolerated, as studies of >3 years of therapy indicate. There is evidence from in vitro studies that policosanol may inhibit hepatic cholesterol synthesis at a step before mevalonate generation, but direct inhibition of the hydroxy-methylglutaryl-coenzyme A reductase is unlikely. Animal studies suggest that LDL catabolism may be enhanced, possibly through receptor-mediated mechanisms, but the precise mechanism of action is not understood yet. Policosanol has additional beneficial properties such as effects on smooth muscle cell proliferation, platelet aggregation, and LDL peroxidation. Data on efficacy determined by clinical end points such as rates of cardiac events or cardiac mortality are lacking. Policosanol seems to be a very promising phytochemical alternative to classic lipid-lowering agents such as the statins and deserves further evaluation.",2002.0,0,0 1140,11835933,Effects of simvastatin (40 and 80 mg) on highly sensitive C-reactive protein in patients with combined hyperlipidemia.,Michael Miller; Ishwarlal Jialal,,2002.0,0,0 1141,11835951,Potential indications for angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease.,Amir Halkin; Gad Keren,"Angiotensin-converting enzyme (ACE) inhibitors are well established as first-line therapy for patients with left ventricular dysfunction, diabetic patients with hypertension or renal disease, and patients recovering from myocardial infarction. Angiotensin II and bradykinin regulate cellular proliferation, inflammation, and endothelial function, thus playing an important role in the pathogenesis of atherosclerosis. A large body of experimental evidence reporting that ACE inhibitors limit these effects has formed the rationale for major clinical trials of these drugs in the management of atherosclerotic vascular disease. The first trial to be completed demonstrated that ACE inhibition improves the prognosis of patients who have, or are at risk of, atherosclerotic vascular disease, independent of its effects on left ventricular function and hypertension. Expanding the indications for ACE inhibitors is now evidence driven, although the choice of agent for these new indications remains to be determined by further research.",2002.0,0,0 1142,11835959,Limitations of a meta-analysis investigating the association between cancer and statin use.,Hiroshi Iwata; Tomonori Aoyama; Eiji Kusumi; Tamae Hamaki; Masahiro Kami,,2002.0,0,0 1143,11836262,Clinical review 141: lipids and atherosclerosis: lessons learned from randomized controlled trials of lipid lowering and other relevant studies.,Robert A Kreisberg; Albert Oberman,,2002.0,0,0 1144,11836286,Atorvastatin lowers C-reactive protein and improves endothelium-dependent vasodilation in type 2 diabetes mellitus.,K C B Tan; W S Chow; S C F Tam; V H G Ai; C H L Lam; K S L Lam,"Endothelial dysfunction is frequently found in diabetic subjects. This study was performed to investigate whether atorvastatin therapy was able to reverse endothelial dysfunction in type 2 diabetes and, if so, whether the effect was due to its antiinflammatory action. Eighty patients (baseline low density lipoprotein, 4.37 +/- 0.71 mmol/liter) were randomized to atorvastatin (10 mg daily for 3 months, followed by 20 mg daily for 3 months) or placebo in a double blind study. Endothelial function was assessed by high resolution vascular ultrasound, and high sensitivity C-reactive protein (CRP) was assessed by immunoturbidimetric assay. Diabetic patients had higher CRP (P < 0.01) than matched nondiabetic controls, and both endothelium-dependent and independent vasodilation were impaired (P < 0.01). Atorvastatin (10 and 20 mg) lowered plasma cholesterol by 32.9% and 38.0%, triglyceride by 15.4% and 23.1%, and low density lipoprotein by 43.4% and 50.1%, respectively. At 6 months, plasma CRP decreased in the atorvastatin group compared with baseline (P < 0.05). Endothelium-dependent vasodilation improved in the atorvastatin group compared with the placebo group (P < 0.05). The percent change in endothelium-dependent vasodilation at 6 months correlated with the percent change in CRP (r = -0.44; P < 0.05), but not with changes in plasma lipids. In conclusion, treatment with atorvastatin in type 2 diabetes led to a significant improvement in endothelium-dependent vasodilation, which might be partly related to its anti-inflammatory effect.",2002.0,0,0 1145,11839623,Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention.,Albert W Chan; Deepak L Bhatt; Derek P Chew; Martin J Quinn; David J Moliterno; Eric J Topol; Stephen G Ellis,"Long-term administration of statin therapy has been shown to reduce major coronary events and cardiac mortality within randomized clinical trials. In addition to lowering lipids, statins favorably affect platelet adhesion, thrombosis, endothelial function, inflammation, and plaque stability, which may potentially improve outcome after percutaneous coronary intervention (PCI). Therefore, we hypothesized that statin therapy has an early beneficial effect among patients undergoing PCI. Each year from 1993 to 1999, we prospectively collected data among the first 1000 patients undergoing PCI. Patients who presented with acute or recent myocardial infarction or cardiogenic shock were excluded from the analysis. Baseline, procedural, and 6-month data of statin-treated and non-statin-treated patients were compared. Propensity score and multivariate survival analysis were used to adjust for heterogeneity between the two groups. Of 5052 patients who completed follow-up, 26.5% were treated with statin at the time of the procedure. Statin therapy was associated with a mortality reduction at 30 days (0.8% versus 1.5%; hazard ratio, 0.53; P=0.048) and at 6 months (2.4% versus 3.6%; hazard ratio, 0.67; P=0.046). After adjusting for the propensity to receive statin therapy before the procedure and other confounders, statin therapy remained an independent predictor for survival at 6 months after coronary intervention (hazard ratio, 0.65; 95% CI, 0.42 to 0.99; P=0.045). In this large study cohort, statin therapy among PCI patients seems to be associated with a significant mortality advantage at early and intermediate-term follow-up.",2002.0,0,0 1146,11840884,Lipid lowering agents. How important are they in secondary prevention of coronary heart disease?,David M Colquhoun,"Coronary heart disease (CHD) is still the single major cause of death in our community despite the dramatic decline in prevalence over the past 20 years or so. The first presentation of CHD in up to 50% of patients is one of the acute coronary syndromes, either acute myocardial infarction or unstable angina. Ninety percent of patients survive the acute episode and remain at high risk of further coronary events. To review recent evidence regarding the importance of lipid lowering in preventing further coronary events--secondary prevention. The statins ushered in a new era of CHD prevention. Their discovery facilitated an enormous amount of basic research regarding pathogenesis of atherosclerosis and huge clinical trials that demonstrated dramatic reduction of vascular events and improved survival. Lipid lowering is central to secondary prevention in CHD and almost all patients who have had an acute coronary event benefit from statin therapy.",2002.0,0,0 1147,11840912,Endocrinology.,John R Burgess,,2002.0,0,0 1148,11843691,Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain.,Sandra Locatelli; Dieter Lütjohann; Hartmut H J Schmidt; Carsten Otto; Ulrike Beisiegel; Klaus von Bergmann,"Previous studies have shown that patients with early onset of Alzheimer disease and vascular dementia have higher levels of circulating brain-derived 24S-hydroxycholesterol (cerebrosterol). Two recent epidemiological studies indicated that treatment with inhibitors of cholesterol synthesis (statins) reduces the incidence of Alzheimer disease. To test the hypothesis that treatment with high-dosage simvastatin reduces circulating levels of 24S-hydroxycholesterol. Prospective, 24-week treatment trial for lowering of cholesterol levels. We conducted assessments at baseline, week 6, and week 24. An academic outpatient clinical study. Eighteen patients who met the criteria for hypercholesterolemia. Treatment with 80 mg/d of simvastatin at night. Plasma lipoprotein levels were measured enzymatically; lathosterol, by means of gas chromatography; and 24S-hydroxycholesterol, by means of gas chromatography-mass spectrometry. Simvastatin reduced total plasma cholesterol levels by 36% and 35% after 6 and 24 weeks, respectively (P<.001). Lathosterol levels were reduced by 74% and 72%, respectively, and the ratio of lathosterol to cholesterol, an indicator of whole-body cholesterol synthesis, was reduced by 60% and 61%, respectively (P<.001). Plasma 24S-hydroxycholesterol levels were lowered by 45% and 53%, respectively (P<.001). The ratio of 24S-hydroxycholesterol to cholesterol also decreased significantly (-12% [P=.01] and -23% [P<.002], respectively). The further reduction of 24S-hydroxycholesterol levels and its ratio to cholesterol from weeks 6 to 24 was also significant (P=.02 for both). The greater reduction of plasma concentrations of 24S-hydroxycholesterol compared with cholesterol indicates that simvastatin in a dosage of 80 mg/d reduces cholesterol turnover in the brain. The present results might describe a possible mechanism of how long-term treatment with statins could reduce the incidence of Alzheimer disease.",2002.0,0,0 1149,11843693,,,,,0,0 1150,11844650,"Estrogen, statins, and polyunsaturated fatty acids: similarities in their actions and benefits-is there a common link?",U N Das,"To investigate whether there is any common link between estrogen, statins, and polyunsaturated fatty acids (PUFAs), which have similar actions and benefits. To critically review the literature pertaining to the actions of estrogen, statins, and various PUFAs. Estrogen, statins, and PUFAs enhance nitric oxide synthesis, suppress the production of proinflammatory cytokines such as tumor necrosis factor(alpha), interleukin-1, interleukin-2, and interleukin-6, show antioxidant-like and antiatherosclerotic properties, have neuroprotective actions, and by themselves or their products inhibit tumor cell proliferation and improve osteoporosis. Estrogen, statins, and PUFAs not only have similar actions but also appear to interact with each other. For instance, the binding of estrogen to its receptor on the cell membrane may be determined by its lipid content, statins and PUFAs inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, statins influence the metabolism of PUFAs, and PUFA deficiency enhances 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Statins and PUFAs inhibit tumor cell proliferation, suppress ras activity, and may prevent neurodegeneration and improve cognitive functions such as learning and memory. This suggests that PUFAs might be mediators of the actions of statins. Estrogen boosts cognitive performance in women after menopause and may protect against Alzheimer's disease. The common link between estrogen, statins, and PUFAs may be nitric oxide. Hence, a combination(s) of estrogen or its derivatives, statins, and various PUFAs may form a novel approach in the management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, osteoporosis, cancer, neurodegenerative conditions, and to improve memory.",2002.0,0,0 1151,11845103,[Cost of cardiovascular risk factor prevention in middle-aged French men. The PRIME study].,P Marques-Vidal; D Arveiler; P Amouyel; P Ducimetière; J Ferrières,"Little is known regarding the cost of cardiovascular risk factor prevention in France. In this study, we assessed the cost of antihypertensive and hypolipidaemic drug treatment in middle-aged French men without history of coronary heart disease. A cross-sectional study was conducted between 1991 and 1993 in 1606 subjects treated for hypertension or dyslipidaemia from the three French centres participating in the PRIME study. The daily cost of treatment (in Euros) was assessed using data from the Agence Nationale du Médicament. Mean daily cost of hypertension was 0.65 euro per patient; after multivariate adjustment, obese subjects had a mean daily cost of 0.74+/-0.03 euro (adjusted mean +/- standard error) versus 0.66+/-0.03 euro for non-obese (p<0.001). Only 58% of hypertensive subjects were adequately controlled, and this percentage was higher in the Toulouse centre (80.1%) than in Lille (44.4%) or Strasbourg (50.2%), p<0.001. Fibrates were the most frequently prescribed hypolipidemic drug; nevertheless, prescription of statins was higher than fibrates in the Toulouse centre, which led to a higher mean daily cost for dyslipidaemia, which was further confirmed by multivariate adjustment: 0.59+/-0.05 euro (adjusted mean +/- standard error) in Toulouse versus 0.44+/-0.04 euro in Lille and 0.44+/-0.04 euro in Strasbourg. Only 54% of treated dyslipidemic subjects had their lipid levels within normal values, and this percentage was significantly lower (44%) in Strasbourg than in Lille (58%) or Toulouse (59%) (p<0.001). The prescription of anti-hypertensive or hypolipidemic drugs differs according to centre, leading to significant differences in mean daily cost of treatment. A considerable percentage of treated subjects is not adequately controlled, with possible consequences at the economical level.",2002.0,0,0 1152,11845111,Use of alternatives to estrogen for treatment of menopause.,J V Pinkerton; R Santen,"Women frequently chose alternatives to hormone replacement therapy (HRT) for treatment of menopause even though medical indications for estrogens may be present. Prior breast cancer or fear of breast cancer is a major consideration. This review of alternatives to estrogen discusses the evidence linking breast cancer to HRTs and compares potential risks and benefits of HRT to nonHRT alternatives for relief of vasomotor symptoms, vaginal atrophy, neurocognitive changes and prevention of heart disease and osteoporosis. Practical guidelines are suggested for use of alternatives for each problem.",2002.0,0,0 1153,11847951,FDA adverse event reports on statin-associated rhabdomyolysis.,Mohamed A Omar; James P Wilson,"To determine the number of cases of statin-associated rhabdomyolysis reported to the Food and Drug Administration for 6 statins and to profile the cases. A retrospective analysis of all domestic and foreign reports of statin-associated rhabdomyolysis between November 1997 and March 2000 was conducted. Outcome measures included the total number of reports (initial plus follow-up), the number of unique cases, age, gender, percentages of report codes and role codes, and frequencies of concomitant interacting drugs that may have precipitated rhabdomyolysis, outcomes codes, and report source codes. There were 871 reports of statin-associated rhabdomyolysis in the 29-month time frame examined, representing 601 cases. The following number of cases were associated with each of the individual statins: simvastatin, 215 (35.8%); cerivastatin, 192 (31.9%); atorvastatin, 73 (12.2%); pravastatin, 71 (11.8%); lovastatin, 40 (6.7%); and fluvastatin, 10 (1.7%). Drugs that may have interacted with the statins were present in the following number of cases: mibefradil (n = 99), fibrates (n = 80), cyclosporine (n = 51), macrolide antibiotics (n = 42), warfarin (n = 33), digoxin (n = 26), and azole antifungals (n = 12). The reports of 62.1% of cases were classified as expedited. Statins were designated as the primary suspect in 72.0% of the cases. Death was listed as the outcome in 38 cases. The majority of reports (n = 556) were from health professionals. Compared with the other statins, simvastatin and cerivastatin were implicated in a relatively higher number of reports. Because of the various limitations of a spontaneous reporting-system database, caution is urged when interpreting the relative number of cases reported.",2002.0,1,1 1154,11849201,Statins and the risk of idiopathic venous thromboembolism.,Chen-Chang Yang; Susan S Jick; Hershel Jick,"To evaluate the association between current statin use and the risk of idiopathic venous thromboembolism (VTE). A population-based retrospective follow-up with a nested case-control analysis using the General Practice Research Database. There were 72 cases of idiopathic VTE. Using normolipidaemic nonuse as the reference group, the adjusted relative risks for idiopathic VTE for current/recent statin use, past statin use, past other lipid-lowering drug use, and hyperlipidaemic nonuse were 0.8 (0.3, 2.7), 2.4 (0.6, 10.0), 1.8 (0.4, 7.4), and 0.9 (0.4, 2.0) in the follow-up analysis, and were 1.1 (0.3, 4.3), 3.7 (0.6, 24.1), 2.0 (0.3, 11.6), and 0.4 (0.2, 1.2) in the case-control analysis. Current statin use was not associated with a reduced risk of idiopathic VTE.",2002.0,0,0 1155,11849647,Treating atherosclerosis: local drug delivery from laboratory studies to clinical trials.,A H Gershlick,"Treating only the specific section of the vascular bed that is diseased appears to make sense. Giving drugs systematically to treat perhaps only a few centimetres of affected artery carries with it the risk of systemic side effects and reduced efficacy consequent on low concentrations of agent at the site of the problem. There has thus been great interest since the early 1990s in local drug delivery. Initial targets were the thrombotic response to plaque disruption but the problems arising from the incidental damage inflicted by devices used in interventional cardiology and the pathological consequences of this, namely smooth muscle cell initiated intimal hyperplasia, soon became the focus of pre-clinical studies. Problems to be overcome were the low efficiency of delivery of drugs and the low retention rates. Solutions to these problems included the development of strategies to target drugs, through the use of antibodies directed at antigens newly released at the site of damage. As it became clear that stents were becoming central to the attainment of a better clinical response to intervention by their inherent physical properties, it also became obvious that stents could be used to deliver agents. Issues such as which stent, how to load the drug onto the stent and what drug to use to inhibit the unwanted pathobiological response are ongoing issues.",2002.0,0,0 1156,11849659,Influence of LDL receptor gene mutation and apo E polymorphism on lipoprotein response to simvastatin treatment among adolescents with heterozygous familial hypercholesterolemia.,Marie Claude Vohl; Francois Szots; Michel Lelièvre; Paul J Lupien; Jean Bergeron; Claude Gagné; Patrick Couture,"The efficacy of the inhibitors of HMG CoA reductase shows considerable interindividual variation and intense research has focused in the recent years to identify the genetic loci and environmental factors responsible for this variability. A randomized, double-blind, placebo-controlled clinical trial with simvastatin, an HMG CoA reductase inhibitor, was conducted in 63 adolescents (47 treated versus 17 controls) with heterozygous FH. The patients were grouped according to known low-density lipoprotein (LDL) receptor gene mutation class. After 6 weeks of treatment with 20 mg/d of simvastatin, the mean reduction in plasma LDL-cholesterol in patients with a receptor-negative mutation (n=33) was 39% whereas, in the receptor-defective mutation group (n=14), it was 31% (P=0.01). Multiple regression analyses showed that there was a significant association between the apo E polymorphism and LDL-cholesterol response to simvastatin only among heterozygotes for a receptor-negative mutation. In subjects carrying a receptor-defective mutation, however, we observed that 51% of the variability in LDL-cholesterol response was explained by variations in the dosage of simvastatin expressed in mg/kg/day (P=0.0028). There was no significant association between LDL-cholesterol response and the dosage of simvastatin among heterozygotes for a receptor-negative mutation. The results of the present study have shown that the contribution of apo E polymorphism and the dosage of simvastatin to the LDL-cholesterol responsiveness is influenced by the nature of the LDL receptor gene mutation.",2002.0,0,0 1157,11849660,Lipid-lowering therapy with fluvastatin inhibits oxidative modification of low density lipoprotein and improves vascular endothelial function in hypercholesterolemic patients.,Teruo Inoue; Masatoshi Hayashi; Kan Takayanagi; Shigenori Morooka,"This prospective randomized trial was designed to elucidate clinically the effect of fluvastatin on inhibiting oxidation of the low density lipoprotein (LDL) and improving the vascular endothelial function as well as its lipid-lowering effects, in comparison with pravastatin. Of 64 consecutive dyslipidemic patients, 40 patients, whose level of total cholesterol or LDL-cholesterol maintained the criteria of the hypercholesterolemia in spite of 12-week dietary therapy, were randomly assigned to receive either fluvastatin (n=20) or pravastatin (n=20). We assessed the titer of antibody against oxidized LDL (anti-Ox-LDL) as a biomarker for LDL-oxidation, and the forearm blood flow response during reactive hyperemia by venous occlusion plethysmography, which indicates the endothelium-dependent vasodilator capacity. After the 16-week lipid-lowering therapy, the anti-Ox-LDL titer significantly decreased in the fluvastatin group (P<0.01) but did not change in the pravastatin group. The percent increase in the forearm blood flow at the peak reactive hyperemia from the baseline value (%RH) significantly increased in the fluvastatin group (P<0.001) but did not change in the pravastatin group. The ratio of the %RH after the therapy over the baseline value negatively correlated with that of the anti-Ox-LDL titer (R=0.73, P<0.001) in all patients. Fluvastatin may serve as an ideal drug for reducing the risk of atherosclerosis, not only by its cholesterol-lowering effect but also by its unique effects of inhibiting LDL oxidation and improving the vascular endothelial function.",2002.0,0,0 1158,11849859,Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia. Fukuoka Atherosclerosis Trial (FAST).,Yasunori Sawayama; Chie Shimizu; Naoyasu Maeda; Masafumi Tatsukawa; Naoko Kinukawa; Samon Koyanagi; Seizaburo Kashiwagi; Jun Hayashi,"This study investigated the effect of reducing serum lipids on carotid artery intima-media thickness (IMT) in asymptomatic patients with hypercholesterolemia from Fukuoka, Japan. Carotid atherosclerosis is a strong, independent predictor of morbidity and mortality in patients with coronary heart disease (CHD). A total of 246 asymptomatic hypercholesterolemic patients (mean age 66 years) were randomized to receive either probucol (500 mg/day, n = 82) or pravastatin (10 mg/day, n = 83) or to enter a control group (diet alone, n = 81); they were followed for two years. The change in IMT in the common carotid artery was the primary end point measure, and the incidence of major cardiovascular events was the secondary measure. Over the two-year period, serum low-density lipoprotein (LDL) cholesterol was significantly reduced in the pravastatin group (36%), the probucol group (29%) and the control group (12%) (p < 0.0001, p < 0.0001 and p < 0.05, respectively). After two years, the probucol and pravastatin groups showed a significant reduction in IMT (-13.9% and -13.9% and p < 0.01 and p < 0.01, respectively), but there was significant IMT thickening (23.2%; p < 0.05) in the control group. Probucol reduced the rate of IMT increase, independently of its reduction of LDL or high-density lipoprotein cholesterol. Moreover, there was a significantly lower incidence of cardiac events in the probucol group (2.4%) than in the control group (13.6%) (p = 0.0136). Probucol reduced cholesterol levels and stabilized plaque, leading to a lower incidence of cardiac events in these hypercholesterolemic patients.",2002.0,0,0 1159,11851538,Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial.,Adelaide M Arruda-Olson; Douglas W Mahoney; Ajay Nehra; Marilyn Leckel; Patricia A Pellikka,"The relationship between sildenafil citrate use and reported adverse cardiovascular events in men with coronary artery disease (CAD) is unclear. To evaluate the cardiovascular effects of sildenafil during exercise in men with CAD. Randomized, double-blind, placebo-controlled crossover trial conducted March to October 2000 at a US ambulatory-care referral center among 105 men with a mean (SD) age of 66 (9) years who had erectile dysfunction and known or highly suspected CAD. All patients underwent 2 symptom-limited supine bicycle echocardiograms separated by an interval of 1 to 3 days after receiving a single dose of sildenafil (50 or 100 mg) or placebo 1 hour before each exercise test. Hemodynamic effects of sildenafil during exercise (onset, extent, and severity of ischemia) assessed by exercise echocardiography. Mean (SD) resting ejection fraction was 56% (7%) (range, 39%-68%). After sildenafil use, resting systolic blood pressure was reduced from 135 (19) mm Hg to 128 (17) mm Hg, for a mean change of -7 mm Hg (95% confidence interval [CI], -9 to -4 mm Hg; P<.001). After placebo use, the mean (SD) change was from 135 (20) mm Hg to 133 (19) mm Hg, a difference of -2 mm Hg (95% CI, -6 to 0.3 mm Hg; P =.08). The difference between mean change after sildenafil and placebo use was 4.3 (95% CI, 0.9-7.7; P =.01). Resting heart rate, diastolic blood pressure, and wall motion score index (a measure of the extent and severity of wall motion abnormalities) did not change significantly in either group. Exercise capacity was similar with sildenafil use (mean [SD], 4.5 [1.0] metabolic equivalents) and placebo use (mean [SD], 4.6 [1.0] metabolic equivalents; mean difference, 0.07; 95% CI, -.06 to 0.19; P =.29). Exercise blood pressure and heart rate increments were similar. Dyspnea or angina developed in 69 patients who took sildenafil and 70 patients who took placebo (P =.89); exercise electrocardiography was positive in 12 patients (11%) who took sildenafil and 17 patients (16%) who took placebo (P =.09). Exercise-induced wall motion abnormalities developed in similar numbers of patients after sildenafil and placebo use (84 and 86 patients, respectively; P =.53). Wall motion score index at peak exercise was similar after sildenafil and placebo use (mean [SD], 1.4 [0.4] vs 1.4 [0.4]; mean difference, 0.01; 95% CI, -0.01 to 0.03; P =.40). In men with stable CAD, sildenafil had no effect on symptoms, exercise duration, or presence or extent of exercise-induced ischemia, as assessed by exercise echocardiography.",2002.0,0,0 1160,11851868,Both cerivastatin and fenofibrate improve arterial vasoreactivity in patients with combined hyperlipidaemia.,M Sebestjen; B Zegura; I Keber,"The aim of this study was to compare the effects of cerivastatin and fenofibrate on endothelium dependent and independent arterial dilation. In a prospective, double blind study, 38 overweight, nonsmoking, males aged between 40 and 60 years with combined hyperlipidaemia were randomized and, after 6 weeks run-in phase with American Heart Association step I diet treatment, submitted to 12 weeks' treatment either with fenofibrate (250 mg daily) or cerivastatin. Cerivastatin was given in a daily dose of 0.2 mg for 6 weeks and was increased to 0.4 mg daily, if the LDL-C did not decrease below 3.0 mmol x L(-1). Flow-mediated (endothelium-dependent) dilation (FMD) and nitroglycerin-induced (endothelium-independent) [gliceryltrinitrate (GTN)] dilation of brachial artery were measured using high resolution ultrasound. The FMD increased from 3.4 +/- 3.3 to 9.3 +/- 2.4% (P < 0.001) in the cerivastatin group, and from 3.3 +/- 2.8 to 6.5 +/- 3.1% (P < 0.001) in the fenofibrate group, the improvement being significantly better after cerivastatin (P=0.006). GTN increased from 11.5 +/- 4.1 to 16.2 +/- 3.5% (P < 0.01) and from 11.1 +/- 2.5 to 16.0 +/- 2.9% (P < 0.01), respectively, with no difference between the groups. Cerivastatin reduced total cholesterol by 24%, LDL-cholesterol by 31%, triglycerides by 24%, ox-LDL by 29% and increased HDL-cholesterol by 5%, whilst, after fenofibrate, these changes were -15, -13, -41, -17 and 18%, respectively. Only the decrease of LDL-C turned out to be an independent predictor the FMD improvement. The improvement in GTN-induced dilation did not correlate with the changes in blood lipids. Both cerivastatin and fenofibrate lead to an improvement of endothelium-dependent and endothelium-independent dilation of brachial artery in overweight patients with combined hyperlipidaemia and no other atherosclerotic risk factors. The effects on FMD were greater in subjects receiving cerivastatin than in subjects receiving fenofibrate, but the effects on GTN were equal in both groups.",2002.0,0,0 1161,11852667,Inhibition of platelet aggregation and expression of alpha granule membrane protein 140 and thromboxane B2 with pravastatin therapy for hypercholesterolemia.,Li-Ping Ma; Da-Nian Nie; Sherry X Hsu; Song-Mei Yin; Li-Zhou Xu; Joao V Nunes,"The drugs in the group of the ""statins"" lower blood lipids, especially cholesterol, thereby reducing a risk factor for, and diminishing the incidence of, clinically important cerebrocardiovascular events. Cardiovascular events and stroke are significant causes of morbidity and mortality in China and the United States. Statins reduce platelet-mediated thrombus formation and atherosclerotic progression through mechanisms not completely elucidated. While important, the lipid-lowering action of statins does not completely explain their multifaceted benefits. Nonlipid related mechanisms are essential to such effects. The authors explore these nonlipid related mechanisms of action of pravastatin that may translate into clinically relevant benefits. This study was conducted in Guangzhou, China. Twenty-one hypercholesterolemic patients were treated with pravastatin--10-20 mg/day for 12 weeks. Blood for tests was obtained at baseline and after 8 and 12 weeks of pravastatin therapy. After 8- and 12-weeks of therapy, significant decreases were observed in the following: (1) total blood cholesterol and low density lipoprotein-C (P < 0.01), (2) ADP-induced maximum platelet aggregation (P < 0.01), (3) TXB2 or thromboxane B2 in platelets (P < 0.01), and (4) expression of GMP-140 or granule membrane protein-140 (P < 0.01). The therapeutic effects of the drug did not vary significantly with length of therapy. Pravastatin induces inhibition of platelet aggregation and expression of TXB2 and GMP-140, the likely causes of thrombus formation, atherosclerotic progression, and subsequently cardiovascular events. These potential beneficial events occur within 8 weeks of pravastatin therapy.",2002.0,0,0 1162,11854133,,,,,0,0 1163,11856903,3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and rhabdomyolysis: considerations in the renal failure patient.,Domenic A Sica; Todd W B Gehr,"An intense debate has developed as to the risk-benefit ratio of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) following the withdrawal of cerivastatin. The development of rhabdomyolysis in cerivastatin-treated patients should have surprised few since myotoxicity is an accepted class effect of statins. What has sprung from the cerivastatin experience though is a concern for other members of this class. Such misgivings, although understandable, are ill advised. Without question, differences exist in the risk of rhabdomyolysis occurrence amongst the various statins. In this regard, pravastatin and fluvastatin are least likely to produce rhabdomyolysis, which, in part, relates to the fact they are not metabolized by the cytochrome P450 3A4 pathway. When muscle damage occurs with statins it is most often the result of a drug-drug interaction rather than a specific adverse response to statin monotherapy. Such drug-drug interactions increase plasma concentrations of a statin and thereby increase the risk of myotoxicity. A growing consensus exists which supports an expanded use of statins in a range of patient groups including the renal failure patient. Polypharmacy and altered drug metabolism increase the risk of myotoxicity, albeit to an ill-defined degree, in this population. Many factors should enter into the choice of a statin in the multiply medicated renal failure patient.",2002.0,0,0 1164,11856905,"Accelerated atherosclerosis, dyslipidemia, and oxidative stress in end-stage renal disease.",Surekha Mathur; Sridevi Devaraj; Ishwarlal Jialal,"Premature atherosclerosis is a major cause of morbidity and mortality in end-stage renal disease patients. Dyslipidemia and increased oxidative stress contribute to premature atherogenesis in these patients. The dyslipidemia of end-stage renal disease consists of both quantitative and qualitative abnormalities in serum lipoproteins. Qualitative changes include hypertriglyceridemia (increased remnant lipoproteins), low high-density lipoprotein-cholesterol, and increased lipoprotein (a). In addition to quantitative changes, lipoproteins in end-stage renal disease undergo compositional and qualitative changes that make them pro-atherogenic, such as various modifications of apolipoprotein B, including oxidation, and modification by advanced glycation end-products. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and low-dose fibrates could be effective therapies for lipid disorders. The best evidence for increased oxidative stress in end-stage renal disease is the demonstration of increased plasma F2-isoprostanes. Confirmation of the positive findings with high-dose alpha-tocopherol in the Secondary Prevention with Antioxidants of Cardiovascular Disease in End-stage Renal Disease Study is urgently needed. Clinical trials with statins and other drugs that improve dyslipidemia also need to be undertaken. These therapies could clearly lead to a reduction in cardiovascular morbidity and mortality in these patients.",2002.0,0,0 1165,11860367,Chemotherapy of Chagas disease.,Julio A Urbina,"In this article we review the current status of chemotherapeutic approaches for the specific treatment of Chagas disease or American Trypanosomiasis, as well as new rational approaches being developed as a consequence on the increased understanding of the biochemistry and physiology of its causative agent, the protozoan parasite Trypanosoma cruzi. Currently available drugs (nitrofurans and nitroimidazoles), developed empirically over three decades ago, are unsatisfactory due to frequent toxic side effects and limited efficacy, particularly in the prevalent chronic form of the disease. Furthermore, studies of their mechanism of action have shown that their antiparasitic activity is inextricably linked to mammalian host toxicity. Recent advances in this field include the demonstration that new triazole derivatives, with selective inhibitory activity on the parasite's de novo sterol biosynthesis and special pharmacokinetic properties, can induce radical parasitological cure of both acute and chronic Chagas experimental disease. These compounds are active against nitrofuran- and nitroimidazole-resistant T.cruzi strains and maintain their activity even if the hosts are immunosuppressed and are thus logical candidates for clinical trials with Chagas disease patients. Inhibitors of cruzipain, a cathepsin L-like protease responsible for the major proteolytic activity in all stages of the life cycle of the parasite, can selectively block the proliferation of T.cruzi, both in vitro and in vivo and have curative activity in murine models of acute Chagas disease; a significant effort is being devoted to their development as antiparasitic drugs. Alkyl-lysophospholipids, which selectively block phosphatidyl-choline biosynthesis in T.cruzi, are promising antiparasitic agents with good oral activity and low toxicity. Other biochemical pathways have been identified as potential chemotherapeutic targets, including hypoxanthine-guanine phosphoribosyl transferase and the enzymes involved in the synthesis and metabolism of trypanothione and inorganic pyrophosphate.",2002.0,0,0 1166,11861438,Can measurement of serum apolipoprotein B replace the lipid profile monitoring of patients with lipoprotein disorders?,Saman Miremadi; Allan Sniderman; Jiri Frohlich,"Current clinical guidelines require that five indices (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and the total/HDL cholesterol ratio) be measured or calculated to assess the lipid-related risk of vascular disease. All five are also targets of therapy and therefore all must be measured initially and at follow-up. Considerable evidence indicates that apolipoprotein B (apo B) is a better index of reaching or not reaching treatment targets than total or LDL cholesterol. The objective of this study was to examine whether measurement of a single marker (apo B) led to the same categorization of risk as the traditional five indices (lipid profile). If both apo B and lipid profile indicated that the patient was either within or outside their respective treatment targets, the indices were considered concordant. If not, the indices were considered discordant. Concordance/discordance was examined in 215 patients at their first and last clinic visit. Concordance was high in both higher (88% at the first and 92% at the last clinic visit) and lower (76% at the first and 78% at the last clinic visit) risk groups at both the initial and final visits. Discordance was virtually restricted to the group with hypertriglyceridemia with normal concentrations of apo B, a group in which little independent evidence points to any substantially increased risk of vascular disease. These data raise the possibility that at least for high risk patients treated with statins, follow-up could be simplified and expenses reduced if only apo B were measured. They also raise the possibility that outcome might be improved if the therapeutic algorithm were simplified.",2002.0,0,0 1167,11863310,Long-term effect of lipid-lowering therapy on atherosclerosis of abdominal aorta in patients with hypercholesterolemia: noninvasive evaluation by a new image analysis program.,Yasumichi Arai; Nobuyoshi Hirose; Ken Yamamura; Mitsuru Kimura; Akira Murayama; Isamu Fujii; Motoo Tsushima,"Recent clinical studies have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are effective in the prevention of cardiovascular events and regression of atherosclerotic lesions evaluated by angiography. In this study, the authors investigated how lipid-lowering therapy effects on the progression of aortic atherosclerosis by using plain and enhanced computed tomography (CT) of the lower abdominal aorta. Twenty-nine hyperlipidemic patients (mean age 61.4 +/- 7.2 yr) were enrolled in a prospective open-labeled study. All patients underwent baseline CT scanning of abdominal aorta, screening for serum lipid profile and coagulation-fibrinolysis measurement, then treatment with simvastatin was begun. After 2 years, a follow-up CT scan was done and atherosclerotic lesions were compared between baseline and on-treatment scan. In spite of significant improvement of lipid and fibrinolytic profiles by simvastatin administration, mean aortic wall thickening volume (AWV) was increased during observation period. When patients were divided into subgroups by the levels of on-treatment LDL cholesterol (LDL-C), development rate of AWV was more potently suppressed in patients whose on-treatment LDL-C were below 125 mg/dL (median LDL-C). We could not find any associations of coagulation-fibrinolysis measurements with atherosclerotic lesions. In regard to aortic calcification volume (ACV), low levels of total and HDL cholesterol and higher age were associated with aortic calcification at baseline. These results suggest that aggressive treatment with LDL-C below 125 mg/dL may suppress the progression of wall thickening and factors that promote arterial calcifications and those for wall thickening may be different.",2002.0,0,0 1168,11865968,Pharmacokinetics of fluvastatin in subjects with renal impairment and nephrotic syndrome.,S Appel-Dingemanse; T Smith; M Merz,"The pharmacokinetics (PK) and safety of fluvastatin, a hydroxymethylglutaryl-coenzyme A reductase inhibitor, were assessed in subjects with renal impairment and nephrotic syndrome. In a single-center, open-label, parallel-group study, a single dose of fluvastatin 40 mg was administered to subjects (8 per group, n = 48) with nephrotic syndrome (group II), healthy subjects (group I), and subjects with various degrees of renal impairment (groups III to VI). Subjects undergoing hemodialysis received two doses, one 2 days before and one just prior to hemodialysis. Blood samples to determine the PK parameters of fluvastatin were collected from 0 to 12 hours after drug intake. Noncompartmental PK evaluation and statistical analysis (descriptive and ANOVA) were performed. Safety was evaluated and vital signs were monitored. There was no difference in the PK parameters AUC0-infinity and Cmax of fluvastatin between healthy subjects and subjects with renal impairment. Fluvastatin was not removed from plasma by hemodialysis. In patients with nephrotic syndrome, the values for AUC0-infinity and Cmax were less than half of those obtained in the other groups; terminal half-life values, however, were comparable. Fluvastatin was well tolerated in all study participants. Only few adverse events of mild to moderate intensity were reported. There were no clinically relevant changes in laboratory parameters in the subjects with renal impairment. Renal impairment did not affect the PK of fluvastatin after a single oral dose. Exposure to fluvastatin was lower in subjects with nephrotic syndrome. Fluvastatin also was well tolerated in subjects with nephrotic syndrome.",2002.0,0,0 1169,11866679,Ketolides in the treatment of respiratory infections.,George G Zhanel; Daryl J Hoban,"The ketolides are a new class of macrolides specifically designed to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides are semi-synthetic derivatives of the 14-membered macrolide erythromycin A. There are currently two ketolides in the late stages of clinical development in the US (telithromycin [HMR-364, Kelek; Aventis] and ABT-773 [Abbot Laboratories]), as well as newer compounds in earlier stages of testing. Ketolides have a mechanism of action very similar to that of erythromycin A. They potently inhibit protein synthesis by interacting close to the peptidyl transferase site of the bacterial 50S ribosomal subunit. Ketolides bind to ribosomes with higher affinity than macrolides. The ketolides exhibit good activity against Gram-positive and some Gram-negative aerobes and have are active against macrolide-resistant Streptococcus species, including most mef A and erm B strains of Streptococcus pneumoniae. Ketolides have pharmacokinetics which allow once-daily dosing and extensive tissue distribution with very high uptake into respiratory tissues and fluids relative to serum. Evidence suggests the ketolides are primarily metabolised by the cytochrome P450 (CYP) enzyme system in the liver and that elimination is a combination of biliary, hepatic and urinary excretion. Clinical trial data are only available for telithromycin and have focused on respiratory tract infections (RTIs) including community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), sinusitis and streptococcal pharyngitis. Bacteriological and clinical cure rates have been similar to comparators. Ketolides have similar safety profiles to the newer macrolides. In summary, early clinical trials support the clinical efficacy of the ketolides in common RTIs, including activity against macrolide-resistant pathogens.",2002.0,0,0 1170,11867043,Need for a moratorium on percutaneous transluminal coronary angioplasty in stable coronary artery disease.,David T Nash,,2002.0,0,0 1171,11867924,Risk/benefit evaluation of drugs: the role of the pharmaceutical industry in Germany.,R Schosser,"Drugs that are efficacious have usually also undesired side effects. When applying for marketing authorization of a drug, demonstration of a positive risk/benefit ratio is a prerequisite for approval by the competent authorities. Once on the market, risk/benefit evaluation has to be continued in order to determine whether the risk/benefit ratio is still positive or not. The German Drug Law, by means of article 5, poses this responsibility on the pharmaceutical entrepreneur. Specific instructions on how to perform the risk/benefit evaluation can be derived from article 5, and a decision matrix was developed to support taking action if the risk/benefit ratio has changed. Historical and current examples are presented to illustrate changes of the risk/benefit ratio, problems associated with detecting risk signals, and the resulting regulatory actions.",2002.0,0,0 1172,11868059,Effect of very-low-dose niacin on high-density lipoprotein in patients undergoing long-term statin therapy.,Jennifer Wink; George Giacoppe; James King,"A low level of high-density lipoprotein (HDLC) is a proven risk factor for coronary artery disease. Niacin raises HDLC levels, but it is infrequently used because of its side effect profile. Niacin's side effects are dose related. This study tests the hypothesis that very low-dose niacin, in conjunction with long-term statin therapy, will improve the lipid profile by significantly raising the level of HDLC, with fewer side effects than traditional doses of niacin. Fifty patients undergoing stable statin therapy for 3 months were blindly randomized to receive either placebo or niacin 50 mg administered by mouth 2 times daily for 3 months. Patients with diabetes and active smokers were excluded. Each patient completed a questionnaire regarding current medical problems, medications, and lifestyle before and after the therapy. Patients were questioned about any possible side effects that occurred during the medication trial. The primary end points were change in HDLC level and patient-reported side effects. Thirty-nine patients completed the study. Very low-dose niacin added to statin therapy increased the mean HDLC, 2.1 mg/dL in niacin group (standard error of the mean, 0.767) versus -0.56 mg/dL for placebo group (standard error of the mean-.816, P =.0246 by analysis of variance). Five patients receiving niacin, versus 2 patients receiving placebo, had episodes of flushing. No major side effects were noted. No patients stopped the study medication as a result of side effects. The addition of very low-dose niacin to statin therapy increased HDLC cholesterol significantly, while avoiding the side effects that are associated with traditional doses of niacin therapy.",2002.0,0,0 1173,11868800,Effect of roxithromycin on the pharmacokinetics of lovastatin in volunteers.,M Bucher; G Mair; F Kees,"To investigate the influence of concomitant administration of roxithromycin on the plasma pharmacokinetics of lovastatin. In an open, randomized, crossover study, 12 healthy volunteers received 80 mg lovastatin orally either alone or concomitantly with 300 mg roxithromycin after 5-day pretreatment with roxithromycin 300 mg daily. Plasma concentrations of lovastatin (lactone and acid) were determined using high-performance liquid chromatography, and the pharmacokinetic parameters were estimated. The mean (+/- SD) pharmacokinetic parameters of lovastatin lactone with and without roxithromycin were maximum concentration (Cmax) 8.49+/-6.80/16.3+/-9.4 ng ml(-1), time to Cmax (tmax) 1.8+/-0.4/1.7+/-0.6 h, terminal plasma half-life (t1/2) 4.3+/-2.0/3.7+/-2.5 h, area under the plasma concentration-time curve from zero to infinity (AUC0-infinity) 53+/-60/85+/-67 ng ml(-1) h. The respective parameters of lovastatin acid were Cmax 24.6+/-13.4/17.8+/-11.0 ng ml(-1), tmax 3.7+/-1.1/4.1+/-0.7 h, t1/2 3.2+/-2.5/4.3+/-2.8 h, AUC0-infinity 149+/-123/105+/-58 ng ml(-1) h. Mean bioavailability of lovastatin lactone was lower and that of lovastatin acid was higher with concomitant treatment. However, the differences were significant only with respect to lovastatin lactone (AUC and Cmax) and Cmax of lovastatin acid. Roxithromycin does not influence the pharmacokinetics of lovastatin in such a way that dosage adjustment of lovastatin seems to be necessary during co-administration.",2002.0,0,0 1174,11871921,"Statin use, bone mineral density, and fracture risk: Geelong Osteoporosis Study.",Julie A Pasco; Mark A Kotowicz; Margaret J Henry; Kerrie M Sanders; Geoffrey C Nicholson; Geelong Osteoporosis Study,"Recent data suggest that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decrease fracture risk and increase bone mineral density (BMD). This cross-sectional study is set in southeastern Australia. We evaluated the association between statin use, fracture risk, and BMD in 1375 women (573 with incident fractures and 802 without incident fracture, all drawn from the same community). Fractures were identified radiologically. Medication use and lifestyle factors were documented by questionnaire. Unadjusted odds ratio for fracture associated with statin use was 0.40 (95% confidence interval [CI], 0.23-0.71). Adjusting for BMD at the femoral neck, spine, and whole body increased the odds ratio to 0.45 (95% CI, 0.25-0.80), 0.42 (95% CI, 0.24-0.75), and 0.43 (95% CI, 0.24-0.78), respectively. Adjusting for age, weight, concurrent medications, and lifestyle factors had no substantial effect on the odds ratio for fracture. Statin use was associated with a 3% greater adjusted BMD at the femoral neck (P =.08), and BMD tended to be greater at the spine and whole body but did not achieve statistical significance. The substantial 60% reduction in fracture risk associated with statin use is greater than would be expected from increases in BMD alone.",2002.0,0,0 1175,11872916,Stroke prevention therapy beyond antithrombotics: unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: an invited review.,Philip B Gorelick,"It is estimated that about half of cardiovascular disease risk is explained by conventional risk factors. The realization that atherosclerosis is an inflammatory disease has led to a search for new stroke and cardiovascular disease risk factors and treatments. As such, the vulnerable atherosclerotic plaque has become the main focus for new medical strategies for plaque stabilization and stroke prevention. In this invited review, I discuss inflammation as a possible risk factor for stroke, unifying mechanisms in ischemic stroke pathogenesis, and new avenues for stroke prevention---statin agents, angiotensin-converting enzyme inhibitors, and vitamins. These new stroke prevention therapies may help to reduce inflammation, serve to stabilize the atherosclerotic plaque, or act by other protective mechanisms. Beyond the traditional antithrombotic agents, statin agents, angiotensin-converting enzyme inhibitors, and vitamins may prove to be important additions to our armamentarium for stroke prevention.",2002.0,0,0 1176,11872991,"C-reactive protein, statins, and the primary prevention of atherosclerotic cardiovascular disease.",Edmund A Bermudez; Paul M Ridker,"Emerging data implicate inflammation as integral to atherosclerosis and its complications. From a clinical perspective, the inflammatory biomarker C-reactive protein has demonstrated consistent predictive value in the detection of individuals at high risk for cardiovascular disease. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduces C-reactive protein as well as low-density lipoprotein cholesterol, thus providing a potential additional mechanism for the reduction in cardiovascular events associated with the use of these agents. Evidence from the Air Force/Texas Coronary Atherosclerosis Prevention Study suggests that statin therapy may be effective in reducing incident coronary events among those with elevated levels of C-reactive protein but normal levels of low-density lipoprotein cholesterol. These data, along with accumulating laboratory data, support a potential anti-inflammatory benefit of statins. Large-scale, randomized trials in the primary prevention of acute coronary events among individuals without overt hyperlipidemia but with evidence of elevated C-reactive protein are now needed to directly test this hypothesis.",2002.0,0,0 1177,11873000,Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047.,Carl J Fichtenbaum; John G Gerber; Susan L Rosenkranz; Yoninah Segal; Judith A Aberg; Terrence Blaschke; Beverly Alston; Fang Fang; Bradley Kosel; Francesca Aweeka; NIAID AIDS Clinical Trials Group,"Lipid lowering therapy is used increasingly in persons with HIV infection in the absence of safety data or information on drug interactions with antiretroviral agents. The primary objectives of this study were to examine the effects of ritonavir (RTV) plus saquinavir soft-gel (SQVsgc) capsules on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin, and the effect of pravastatin on the pharmacokinetics of nelfinavir (NFV) in order to determine clinically important drug-drug interactions. Randomized, open-label study in healthy, HIV seronegative adults at AIDS Clinical Trials Units across the USA. Three groups of subjects (arms 1, 2, and 3) received pravastatin, simvastatin or atorvastatin (40 mg daily each) from days 1-4 and 15-18. In these groups, RTV 400 mg and SQVsgc 400 mg twice daily were given from days 4-18. A fourth group (arm 4) received NFV 1250 mg twice daily from days 1-14 with pravastatin 40 mg daily added from days 15-18. Statin and NFV levels were measured by liquid chromatography/tandem mass spectrometry. Fifty-six subjects completed both pharmacokinetic study days. In arms 1-3, the median estimated area under the curves (AUC)(0-24) for the statins were: pravastatin (arm 1, n = 13), 151 and 75 ng.h/ml on days 4 and 18 (decline of 50% in presence of RTV/SQVsgc), respectively (P = 0.005); simvastatin (arm 2, n = 14), 17 and 548 ng.h/ml on days 4 and 18 (increase of 3059% in the presence of RTV/SQVsgc), respectively (P < 0.001); and total active atorvastatin (arm 3, n = 14), 167 and 289 ng.h/ml on days 4 and 18 (increase of 79% in the presence of RTV/SQVsgc), respectively (P < 0.001). In arm 4, the median estimated AUC(0-8) for NFV (24 319 versus 26 760 ng.h/ml; P = 0.58) and its active M8 metabolite (15 565 versus 14 571 ng.h/m; P = 0.63) were not statistically different from day 14 to day 18 (without or with pravastatin). Simvastatin should be avoided and atorvastatin may be used with caution in persons taking RTV and SQVsgc. Dose adjustment of pravastatin may be necessary with concomitant use of RTV and SQVsgc. Pravastatin does not alter the NFV pharmacokinetics, and thus appears to be safe for concomitant use.",2002.0,1,1 1178,11873095,"Rosuvastatin demonstrates greater reduction of low-density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: a randomized, double-blind study.",R Paoletti; M Fahmy; G Mahla; J Mizan; H Southworth,"Rosuvastatin (Crestor), a new, highly efficacious statin, has demonstrated dose-dependent low-density lipoprotein cholesterol (LDL-C) reductions of up to 65% in a dose-ranging programme with doses of 1 to 80 mg. A randomized, double-blind multicentre trial compared rosuvastatin with commonly used starting doses of pravastatin and simvastatin to determine relative efficacy in LDL-C reduction and impact on other lipid parameters in primary hypercholesterolaemia. A total of 502 patients (greater-than-or-equal 18 years; LDL-C greater-than-or-equal 4.14 mmol/l [160 mg/dl] and < 6.50 mmol/l [250 mg/dl] and triglycerides less-than-or-equal 4.52 mmol/l [400 mg/dl]) were randomized to 12 weeks of rosuvastatin 5 mg (n = 120) or 10 mg (n = 115), pravastatin 20 mg (n=]137) or simvastatin 20 mg (n = 130). Rosuvastatin 5 and 10 mg reduced LDL-C by 42 and 49%, respectively, compared with 28% for pravastatin (P < 0.001 versus both rosuvastatin doses) and 37% for simvastatin (P < 0.01 versus rosuvastatin 5 mg; P < 0.001 versus 10[?]mg). National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP II) goals were achieved by 87% of rosuvastatin 10[?]mg patients, 71% of rosuvastatin 5[?]mg patients, 53% of pravastatin patients, and 64% of simvastatin patients; similar proportions of patients achieved NCEP ATP III goals. European Atherosclerosis Society (EAS) goals were achieved by 83, 63, 20 and 50% of patients, respectively. All study treatments were well tolerated. Both doses of rosuvastatin were more effective than pravastatin and simvastatin in meeting NCEP ATP II and EAS LDL-C targets. Rosuvastatin 10 mg was more effective than pravastatin and simvastatin in meeting NCEP ATP III targets.",2002.0,1,1 1179,11874384,Maximizing the value of medicines by including pharmacogenetic research in drug development and surveillance.,C Brazell; A Freeman; M Mosteller,"Genetics provides significant opportunities to maximize the safety and efficacy of medicines. Over the next 3--5 years, it may be possible to develop tools that use selective information from patients' DNA to enable healthcare professionals to predict more accurately those patients at risk of serious adverse events to some medicines currently available. This is likely to be followed, over the next 5--10 years, by the application of the technology to predict more accurately if individual patients will obtain a therapeutic benefit from a particular medicine. The ability to accurately predict patient response will inevitably change the way medicines are developed, evaluated, and prescribed. Advances in single nucleotide polymorphism (SNP) map technology are likely to drive this innovation. Abbreviated SNP profiles will provide the means to define medicine response tests, thereby allowing clinicians to select the medicine to which the patient is likely to gain the greatest benefit and least risk. This will help to maximize efficacy and reduce the incidence of drug-related adverse events. It may be possible to identify SNP profiles during larger Phase II clinical trials which predict efficacy, and use these to form the basis of Phase III entry criteria. As a result, Phase III trials may be streamlined for many medicines making them smaller, more efficient, and more focused. In addition it may be possible to incorporate pharmacogenetics into postmarketing surveillance strategies to provide a means to identify SNPs which predict uncommon serious adverse drug reactions, and so refine the initial medicine response test. The ability to develop drugs with a predictable response will allow clinicians to provide targeted treatment for patients, with greater confidence of safety and efficacy. Patients therefore will receive more efficacious, timely, and well-tolerated medicines. The challenge for those involved in drug development is to model and evaluate the application of pharmacogenetics so that steps can be taken to realize this potential.",2002.0,0,0 1180,11875296,Statins and vascular protection: a 'radical' view.,Albert Ferro,,2002.0,0,0 1181,11875327,Management of postmenopausal osteoporosis: position statement of the North American Menopause Society.,North American Menopause Society.,"The North American Menopause Society (NAMS) established a goal to create an evidence-based position statement regarding the management of postmenopausal osteoporosis. NAMS followed the general principles established for evidence-based guidelines to create this document. A MEDLINE search was conducted. Clinicians and researchers acknowledged to be experts in the field of osteoporosis were enlisted to review the evidence. The NAMS Board of Trustees reviewed and approved the final document. Osteoporosis, which has its highest rate of occurrence in postmenopausal women, increases the risk for fractures, including hip and spine fractures. These injuries are often associated with particularly high morbidity and mortality. Given the health implications of osteoporotic fractures, the primary goal of osteoporosis therapy is to prevent fractures by slowing or preventing bone loss, maintaining bone strength, and minimizing or eliminating factors that may contribute to falls. The evaluation of postmenopausal women for osteoporosis risk requires the recording of a medical history, a physical examination, and diagnostic tests. Major risk factors for osteoporosis are age, genetics, lifestyle (especially nutrition), and menopausal status. Management focuses first on nonpharmacologic measures, such as a balanced diet including adequate calcium and vitamin D intakes, appropriate exercise, smoking cessation, avoidance of excessive alcohol intake, and fall prevention. If pharmacologic therapy is indicated, FDA-approved options are estrogens (prevention only), bisphosphonates and selective estrogen-receptor modulators (prevention and treatment), and calcitonin (treatment only). Management of postmenopausal osteoporosis involves identifying the potential risk for osteoporosis and osteoporotic fracture, followed by measures that focus on reducing modifiable risk factors through lifestyle changes and, if indicated, pharmacologic therapy.",2002.0,0,0 1182,11875588,Detection of coronary microvascular disease by means of cardiac scintigraphy.,Shinro Matsuo; Yasuyuki Nakamura; Tetsuya Matsumoto; Masayuki Takahashi; Masahiko Kinoshita,"A 76-year-old woman strictly defined as having cardiac syndrome X underwent cardiac scintigraphies. A reversible perfusion abnormality was identified by (201)thallium in the inferior segment of the left ventricle. (123)iodine meta-iodo-benzyl-guanigine uptake showed extremely diminished uptake in the inferior segment of the myocardium. (123)iodine labelled beta-methyl-iodophenyl pentadecanoic acid myocardial single photon emission computed tomography showed decreased uptake of the inferior segment in the early image, whereas the delayed images revealed significant fill-in of the tracer in the inferior segment of the myocardium. These findings suggest that coronary microvascular dysfunction causes regional myocardial ischemia, resulting in metabolic and sympathetic abnormality.",2002.0,0,0 1183,11879274,New advances in the management of cutaneous T-cell lymphoma.,S K Young,,2002.0,0,0 1184,11879671,Microcirculation down under.,Tailoi Chan-Ling; Mary E Gerritsen; Caryl E Hill; Paul Kubes; Michael Perry,"The Seventh World Congress for Microcirculation, organized by the Australian and New Zealand Microcirculation Society, was held on 19-22 August 2001 in Sydney, New South Wales, Australia.",2002.0,0,0 1185,11885403,Efficacy of HMG-CoA reductase inhibitors in treating osteoporosis.,April A Richard; Tina M Harrison,"The Therapy Consultation section provides brief advice, in question-and-answer format, on how to handle specific drug-therapy problems. Readers are invited to submit questions, which will be referred to a consultant for an answer. The problems should not be highly specialized or unusual, nor should they be mundane. Questions are answered briefly, largely on the basis of judgment and personal experience of the consultant, although selected references may be cited to substantiate the consultant's advice.",2002.0,0,0 1186,11886300,,,,,0,0 1187,11887555,[Which patients with acute coronary syndrome without ST segment elevation should be handled invasively/interventionally when?].,C Kaiser; N Balmelli; M Pfisterer,"Until recently the therapeutic approach in patients with acute coronary syndrome without ST-segment elevation focused on medical stabilization. Usually cardiac catheterization and revascularisation were performed later only if the stabilized patient had provoked ischemia. Since angioplasty became safer with the introduction of coronary stents, and since new potent antithrombotic agents (i.e. tienopyridines or glycoprotein-receptorIIb/IIIa-antagonists) have been developed, early angioplasty has become much more effective. Moreover major progress has been made in risk-stratification, which allow an individual therapeutic strategy for each patient according to his risk-status. We discuss the most important randomised clinical trials comparing a conservative versus an invasive strategy and introduce a new algorithm for risk-stratification und therapy in acute coronary syndromes without ST-elevation.",2002.0,0,0 1188,11887556,[Secondary prevention after acute coronary syndrome--role of modern drug therapy].,W Angehrn,"Treatment of acute coronary syndrome is under rapid progress. Nevertheless, the early complication rate remains high. Standard antithrombotic treatment is Aspirin 100 mg/d. Patients with elevated risk should be treated with Aspirin and Clopidogrel if primary invasive strategy ist not intended. Independent of the cholesterol level, statins should be given in the early phase of acute coronary syndrome. Dose adaptation is recommended after three months corresponding to the national guidelines. Mainly in diabetes mellitus, additional treatment with an ACE inhibitor lowers the overall cardiovascular risk also in patients without arterial hypertension or congestive heart failure. Six months after the acute event, risk stratification should be adapted.",2002.0,0,0 1189,11888350,Improving safety reporting from randomised trials.,John P A Ioannidis; Joseph Lau,"Randomised clinical trials offer a unique opportunity for capturing safety information under a controlled setting that minimises biases in the comparison of different therapeutic options. Nevertheless, empirical evidence across diverse medical fields suggests that the reporting of safety information in clinical trials is largely neglected and receives less attention compared with efficacy outcomes. An analysis of 192 randomised trials has shown that reasons for withdrawals due to toxicity were specified per study arm in only 46% of the trial reports. Adequate reporting of clinical adverse effects and laboratory-determined toxicity occurred in only 39 and 29% of the trials, respectively, even with lenient definitions of what constitutes adequate reporting. The use of standardised scales for adverse effects is a prerequisite for improved reporting on safety in randomised trials. Safety data need to be collected and analysed in a systematic fashion and active surveillance for toxicity during the conduct of a randomised trial is preferable to passive surveillance. Standardised reporting of safety data does not necessarily require extensive space to accomplish. It is essential to provide numerical data per study arm on each type of adverse effect along with a categorisation of the severity of the adverse effects with an emphasis on severe and life-threatening reactions. The severity grading must be referred to well-known standardised scales and new scales need to be carefully defined. Information on withdrawals due to toxicity is also important to report, along with the specific reasons leading to discontinuation. Tabulation of information may be helpful and rare or not previously reported adverse effects should be described in detail. The availability of newer options such as electronic publication, publication of raw databases, large database research, meta-analytic approaches, and prospective registration of clinical trials and of their databases may further improve the safety insights we can gain from randomised clinical trials.",2002.0,0,0 1190,11888360,"Design, analysis and presentation of multinational economic studies: the need for guidance.",Francis Pang,"Over the last decade, there has been a proliferation in the number of economic evaluations of pharmaceuticals to meet the growing demand for information about the economic benefits of healthcare technologies. The majority of these studies have been commissioned by pharmaceutical companies for the purposes of drawing attention to the resource and quality-of-life aspects of new or existing products. Such information has become important in overcoming a new obstacle, namely the demonstration of cost effectiveness (the so-called 'fourth hurdle'), in addition to the three well-established criteria of quality, tolerability and efficacy. To ensure the maintenance of standards, guidance for economic evaluations has emerged lately in the form of guidelines, regulations, principles, policies and positions. Drummond outlined three purposes of these guidelines, as follows: as a requirement prior to reimbursement, as statements of methodological standards, and as a statement of ethical standards. Such guidelines are designed to assist both the economic analyst and the decision-maker. In laying out the state of the art regarding the methodology of economic evaluation, guidelines assist the analyst in performing high-quality, scientifically valid studies, and assist the decision-maker in properly interpreting and assessing their quality. In response to these growing requirements for cost-effectiveness data globally, it has become increasingly common for economic evaluations to be conducted on an international scale. However, the recommendations in pharmacoeconomics guidelines regarding the manner in which these multinational economic evaluations should be designed, analysed and presented are too limited to be of any real value. This article examines the various issues that must be taken into consideration when conducting multinational studies, and provides a review of the techniques and approaches that have been suggested to date. It concludes with recommendations for potential inclusion in future sets of pharmacoeconomic guidelines.",2002.0,0,0 1191,11888512,The effects of hydroxy-methyl-glutaryl co-enzyme A reductase inhibitors on platelet thrombus formation.,Paul D Thompson; Niall M Moyna; C Michael White; Kelly M Weber; Satyendra Giri; David D Waters,"Hydroxy-methyl-glutaryl co-enzyme A reductase inhibitors (HMG CoA RIs) markedly improve the lipid profile of patients with hypercholesterolemia, but the magnitude and time course of the effect of these drugs on other risk factors for atherosclerosis are not well defined. We employed a random assignment, double-blind design to compare the effect of 8 weeks of HMG CoA RI therapy with either pravastatin (40 mg QD; n=12) or simvastatin (20 mg QD; n=12) with placebo (n=13) on serum lipids, platelet thrombus formation (PTF), and markers of inflammation and thrombosis in patients with coronary artery disease. PTF was measured using a validated ex vivo perfusion chamber system. Total and LDL cholesterol decreased 20.3 +/- 12.7% and 31.4 +/- 16.5% in the HMG CoA RI group and were unchanged with placebo (P<0.01). Triglycerides also decreased 15.3 +/- 22.5% with HMG CoA RI therapy, but increased 8.4 +/- 30.0% with placebo (P=0.01). PTF increased 54.1 +/- 89.0% with placebo and decreased 8.0 +/- 46.82% with HMG CoA RI treatment (P<0.01). HMG CoA RI therapy with pravastatin or simvastatin reduces PTF after only 8 weeks of therapy. Such lipid effects may contribute to the prompt reduction in cardiovascular events noted in some clinical trials.",2002.0,0,0 1192,11888983,Renovascular hypertension: problems in evaluation and management.,Robert A Kloner; Stephen C Textor; Morton E Tavel,,2002.0,0,0 1193,11889008,Relationship between lipid levels and clinical outcomes in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Trial: to what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels?,R John Simes; Ian C Marschner; David Hunt; David Colquhoun; David Sullivan; Ralph A H Stewart; Wendy Hague; Anthony Keech; Peter Thompson; Harvey White; John Shaw; Andrew Tonkin; LIPID Study Investigators,"The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial showed that pravastatin significantly reduced mortality and coronary heart disease (CHD) events in 9014 patients with known CHD and total cholesterol 4.0 to 7.0 mmol/L at baseline. Secondary objectives included assessment of CHD event reduction according to lipid levels. We investigated the relationships of baseline and on-study lipids with subsequent CHD events in separate Cox models. Treatment effect on CHD event reduction was examined by baseline lipids and after adjustment for on-study lipid levels. Baseline lipids were significant predictors of CHD events. The adjusted relative risk per mmol/L (on placebo) was 1.24 (P=0.004) for total cholesterol, 1.28 (P=0.002) for low-density lipoprotein cholesterol, and 0.52 (P=0.004) for high-density lipoprotein cholesterol. Apolipoproteins A1 and B were strong predictors (each P=0.001). Pravastatin reduced the risk of the composite outcome of fatal CHD or nonfatal myocardial infarction by 24% (95% confidence interval [CI], 15% to 32%) and the expanded end point of fatal CHD, nonfatal myocardial infarction, unstable angina, or coronary revascularization by 17% (95% CI, 10% to 24%). Similar relative effects were observed for different categories of baseline lipids. The proportion of treatment effect explained by on-study lipid levels was 67% (95% CI, 27% to 106%) for the composite and 97% (95% CI, 49% to 145%) for the expanded end point. The most important lipids associated with event reduction were apolipoprotein B, low-density lipoprotein cholesterol, and the combination of total and high-density lipoprotein cholesterol. Changes in lipid levels can explain all or most of the observed benefit of pravastatin. Some treatment effect may also be mediated through nonlipid changes.",2002.0,0,0 1194,11890163,Minor long-term changes in weight have beneficial effects on insulin sensitivity and beta-cell function in obese subjects.,A M Rosenfalck; H Hendel; M H Rasmussen; T Almdal; T Anderson; J Hilsted; S Madsbad,"To evaluate the long-term effect of changes in body composition induced by weight loss on insulin sensitivity (SI), non-insulin mediated glucose disposal, glucose effectiveness (SG)and beta-cell function. Glucose metabolism was evaluated before and after participation in a two-year weight loss trial of Orlistat vs. placebo, combined with an energy and fat restricted diet. Twelve obese patients (11 women, 1 man), age 45.8 +/- 10.5 years, body weight (BW) 99.7 +/- 13.3 kg, BMI 35.3 +/- 2.8 kg/m(2). At inclusion and 2 years later an oral glucose tolerance test (OGTT) and a frequently sampled intravenous glucose tolerance test (FSIGT) were performed. Body composition was estimated by a dual-energy X-ray absorptiometry (DXA) whole body scanning. The patients obtained varying changes in BW ranging from a weight loss of 17.8 kg to a weight gain of 6.0 kg. Corresponding changes in fat mass (FM) varied from a 40% reduction to a19% increase. A significant decrease in both fasting (p = 0.038) and 2 h (p = 0.047) blood glucose at OGTT was found. The improvement in insulin sensitivity (SI) estimated by means of Bergmans Minimal Model, was significantly and linearly correlated to change in total FM (r = - 0.83,p = 0.0026). A multiple regression analysis showed that changes in truncal FM was the strongest predictor of change in S(I) explaining 67% of the variation. First phase insulin response (AIRg)remained unchanged whereas insulin disposition index increased significantly (p = 0.044). At inclusion five patients had impaired glucose tolerance of which four, who lost weight, were normalized at the retest 2 years later. In obese subjects long-term minimal or moderate changes in weight were found to be linearly associated with changes in insulin sensitivity. In obese subjects with impaired glucose tolerance even a minor weight loss was able to normalize glucose tolerance.",2002.0,0,0 1195,11890840,"Serum lipoprotein levels, statin use, and cognitive function in older women.",Kristine Yaffe; Elizabeth Barrett-Connor; Feng Lin; Deborah Grady,"Few strategies are available for the prevention of cognitive impairment in elderly persons. Serum lipoprotein levels may be important predictors of cognitive function, and drugs that lower cholesterol may be effective for the prevention of cognitive impairment. To determine whether serum lipoprotein levels, the 4-year change in serum lipoprotein levels, and the use of statin drugs are associated with cognition in older women without dementia. An observational study of 1037 postmenopausal women with coronary heart disease enrolled in the Heart and Estrogen/progestin Replacement Study (participants at 10 of 20 centers). The Modified Mini-Mental State Examination was administered at the end of the study after 4 years of follow-up. Women whose score was less than 84 points (>1.5 SDs below the mean) were classified as having cognitive impairment. Lipoprotein levels (total, high-density lipoprotein, and low-density lipoprotein [LDL] cholesterol and triglycerides) were measured at baseline and at the end of the study; statin use was documented at each visit. Compared with women in the lower quartiles, women in the highest LDL cholesterol quartile at cognitive testing had worse mean plus minus SD Modified Mini-Mental State Examination scores (93.7 plus minus 6.0 vs 91.9 plus minus 7.6; P =.002) and an increased likelihood of cognitive impairment (adjusted odds ratio, 1.76; 95% confidence interval, 1.04-2.97). A reduction in the LDL cholesterol level during the 4 years tended to be associated with a lower odds of impairment (adjusted odds ratio, 0.61; 95% confidence interval, 0.36-1.03) compared with women whose levels increased. Higher total and LDL cholesterol levels, corrected for lipoprotein(a) levels, were also associated with a worse Modified Mini-Mental State Examination score and a higher likelihood of impairment, whereas high-density lipoprotein cholesterol and triglyceride levels were not associated with cognition. Compared with nonusers, statin users had higher mean plus minus SD Modified Mini-Mental State Examination scores (92.7 plus minus 7.1 vs 93.7 plus minus 6.1; P =.02) and a trend for a lower likelihood of cognitive impairment (odds ratio, 0.67; 95% confidence interval, 0.42-1.05), findings that seemed to be independent of lipid levels. High LDL and total cholesterol levels are associated with cognitive impairment, and lowering these lipoprotein levels may be a strategy for preventing impairment. The association between statin use and better cognitive function in women without dementia requires further study.",2002.0,0,0 1196,11892686,Measuring treatment effects of cilostazol on clinical trial endpoints in patients with intermittent claudication.,James A M Smith,"Intermittent claudication (IC) comprises the most common presenting symptoms of peripheral arterial disease (PAD), which itself is a manifestation of systemic atherosclerosis. Typical symptoms of IC are aching pain, numbness, and fatigue in the lower extremities. Symptoms are induced by walking or exercise and usually resolve with rest. The cornerstone of treating IC is risk-factor reduction and a supervised exercise regimen. Pharmacotherapy specifically indicated for the treatment of IC includes a new drug, cilostazol, and the traditional drug, pentoxifylline. Cilostazol also has antiplatelet, antithrombotic, and vasodilatory activity, as well as a positive effect on serum lipids. Eight multicenter clinical trials, seven in the U.S. and one in the U.K., used objective and subjective clinical endpoints to assess the treatment efficacy of cilostazol. Objective endpoints included maximal and pain-free walking distance (MWD and PFWD, respectively), the ankle-brachial index, peripheral hemodynamic measurements, and serum lipid levels. Subjective endpoints, assessed by patient questionnaires, included perceived functional status and health-related quality of life. Cilostazol treatment showed statistically significant increases in MWD and PFWD within 4 weeks, as well as improvements in physical functional status at 24 weeks, compared with placebo and pentoxifylline. Increases in high-density lipoprotein cholesterol and decreases in plasma triglycerides were also noted. Subjective assessments appeared to match objective parameters.",2002.0,0,0 1197,11892913,Angiogenesis: a therapeutic target in arthritis.,D A Walsh; L Haywood,"A variety of pharmacological strategies are being subjected to clinical trial to inhibit neovascularization of solid tumors. Increased angiogenesis is also a key component of synovitis and bone modeling in arthritis. Molecular mechanisms and pathological consequences of blood vessel growth in arthritis are now being elucidated. Preclinical studies of angiogenesis inhibitors in animal models of inflammatory arthritis support the hypothesis that inhibition of neovascularization may reduce inflammation and joint damage. Clinical data are consistent with these models being predictive of efficacy in rheumatoid arthritis. However, controlled studies of specific anti-angiogenic agents in human arthritis remain limited. Further studies are required to demonstrate that pharmacological agents can effectively inhibit articular angiogenesis, and ameliorate inflammation and subsequent joint damage. Potential toxicity of angiogenesis inhibitors in reproduction, growth and development and wound repair may be circumvented by short-term or local application, or by targeting molecular mechanisms that are specific to pathological rather than physiological angiogenesis.",2002.0,0,0 1198,11893827,Angiotensin-converting enzyme insertion/deletion polymorphism does not influence the restenosis rate after coronary stent implantation.,Markus Ferrari; Harald Mudra; Lars Grip; Vassilis Voudris; Volker Schächinger; Peter de Jaegere; Johannes Rieber; Dirk Hausmann; Martin Rothman; Dietmar H Koschyk; Hans R Figulla; OPTICUS ACE Substudy,"Experimental studies have shown an activation of the angiotensin-converting enzyme (ACE) system as a response to endothelial injury. Recent publications have elucidated the hypothesis that the ACE gene polymorphism may influence the level of late luminal loss after coronary stent implantation. It is still unclear whether the polymorphism of the angiotensin gene is a major predictor of the extent of neointimal hyperplasia. In this multicenter study, we therefore tested the relationship between the ACE gene polymorphism and the restenosis rate after coronary stent implantation. As a substudy of the optimization with intracoronary ultrasound (ICUS) to reduce stent restenosis (OPTICUS) study, we analyzed ACE serum levels and the ACE gene polymorphism in 154 patients at 9 different centers. All patients underwent elective coronary stent implantation in a stenosis of a major coronary vessel. Balloon inflations were repeated until a satisfactory result was achieved in on-line quantitative coronary angiography or ICUS fulfilling the OPTICUS study criteria. After follow-up of 6 months, all patients underwent reangiography under identical projections as the baseline procedure. A blinded quantitative analysis of the initial procedure as well as the follow-up examinations were performed by an independent core laboratory. ACE gene polymorphism and ACE serum activity were measured at the 6-month follow-up in a double-blinded setting. With respect to the ACE gene polymorphism, there were three subgroups: DD genotype (48 patients), ID (83 patients) and II (23 patients). The subgroups did not differ in regard to age, gender, extent of coronary artery disease, stenosis length, initial degree of stenosis or degree of stenosis after stent implantation. In all, 39 patients (25.3%) had significant restenosis: 12 DD patients (25.0%), 18 ID patients (21.7%) and 9 II patients (39.1%) (odds ratio 2.164, 95% confidence interval 0.853-5.493). We obtained the following results for ACE serum levels: 0.53 micromol/l/s in the DD subgroup, 0.29 micromol/l/s in the ID subgroup and 0.09 micromol/l/s in the II subgroup (p < 0.001). Multivariate logistic regression analysis of the influence of ACE gene polymorphism on the restenosis rate after coronary stent implantation adjusted for lesion length (>12 mm), ACE inhibitor or hydroxymethylglutaryl coenzyme A reductase (CSE) inhibitor treatment, age, male gender, diabetes mellitus, hypertension, high cholesterol, family history, smoking and three-vessel disease did not uncover any statistic significance. In contrast to other study groups, we were unable to disclose that the DD polymorphism of the ACE gene was associated with a higher rate of restenosis after coronary stent implantation in this multicenter study. In addition, patients with higher ACE serum levels did not show a higher restenosis rate in this trial. We conclude that the pathogenesis of restenosis is a multifactorial process involving various genetic and nongenetic factors.",2002.0,0,0 1199,11894724,Cholesterol reduction in patients with lower limb atherosclerotic disease.,Jean Bismuth; Steen Christian Kofoed; Henrik H Sillesen,"Patients with peripheral arterial disease (PAD) have a 2-3 times increased risk of death and in the most severe stage, critical peripheral ischaemia, the mortality rate is around 50% within 4-5. This poor survival rate is due to concomitant coronary and cerebrovascular atherosclerotic disease. Among the major risk factors for atherosclerosis are dyslipidaemia, smoking, hypertension and diabetes. Large randomised trials have shown that dyslipidaemia is easily modifiable in both patients with and without established coronary artery disease, with significant reductions in cardiovascular morbidity and mortality. Although none of these trials directly measured peripheral vascular status, there is every indication that conclusions submitted for patients with ischaemic heart disease can be translated to patients with peripheral vascular disease. The object of this review was therefore to divulge current evidence available supporting active treatment of dyslipidaemia in patients with peripheral vascular disease.",2002.0,0,0 1200,11895049,Effect of colesevelam on lovastatin pharmacokinetics.,Joanne M Donovan; James C Kisicki; Mark R Stiles; William G Tracewell; Steven K Burke,"To assess potential interactions of colesevelam hydrochloride and lovastatin in healthy volunteers when lovastatin alone was administered with dinner, both lovastatin and colesevelam were administered with dinner, and colesevelam was administered with dinner and lovastatin was administered 4 hours later with a snack. A single-center, open-label, 3-period, crossover drug interaction study was performed with 22 healthy volunteers. Blood samples were collected at specified intervals before and after dosing, and plasma concentrations of lovastatin and lovastatin hydroxyacid were measured using a liquid chromatography/mass spectroscopy/mass spectroscopy method. Maximal concentration (Cmax), AUC from time 0 to the last time point measured (AUC0-t), and AUC0-infinity values for lovastatin were 102%, 94%, and 104%, and for lovastatin hydroxyacid were 102%, 91%, and 92%, respectively, of control values when colesevelam and lovastatin were coadministered with dinner. Administration of colesevelam with dinner and lovastatin 4 hours later with a snack resulted in a decreased Cmax and AUC0-t for lovastatin (63% and 37%, respectively; p < 0.05) and an increased Cmax and AUC0-t for lovastatin hydroxyacid (61% and 50%, respectively; p < 0.05), both compared with lovastatin alone administered with dinner. Colesevelam had no significant effect on lovastatin pharmacokinetics when coadministered with lovastatin at dinner. A split-dosing regimen resulted in alterations in pharmacokinetic parameters for lovastatin and lovastatin hydroxyacid that are likely due to known differences in the pharmacokinetics of lovastatin when administered to patients with meals or in a fasting state.",2002.0,0,0 1201,11895060,Telithromycin: the first of the ketolides.,Christopher S Shain; Guy W Amsden,"To review the chemistry, spectrum of activity, pharmacology, clinical efficacy, and safety of telithromycin. A MEDLINE search from 1966 to December 2000 was performed via OVID and PubMed using the following search terms: HMR 3647, HMR3647, Ketek, RU 66647, and telithromycin. An extensive review of retrieved literature, abstracts from international scientific conferences, and minutes from regulatory authority meetings was also performed. Medicinal chemistry, in vitro, animal, and human trials were reviewed for information on the antimicrobial activity, clinical efficacy, pharmacology, and safety of telithromycin. Several chemical modifications to the macrolide structure have led to the development of telithromycin, the first ketolide antimicrobial that demonstrates improved activity against penicillin- and macrolide/azalide-resistant Streptococcus pneumoniae due to its unique binding to the ribosomal target site. Although telithromycin may be useful in the treatment of community-acquired respiratory tract infections due to its activity against common typical and atypical pathogens, questions concerning its reliable activity against Haemophilus influenzae need to be addressed. Telithromycin's pharmacokinetics permit once-daily dosing for abbreviated periods and good distribution into lung tissue and phagocytic cells. Clinical and bacteriologic cure rates have been similar to those of comparator agents in human efficacy trials; however, the incidence of adverse gastrointestinal events were generally higher with telithromycin patients. Like other macrolides and many newer fluoroquinolones, telithromycin's ability to prolong the QTc interval is a potential safety issue, especially in elderly patients with predisposing conditions or those who are concurrently receiving drugs that are substrates for CYP2D6 and 3A4. Liver function test elevations demonstrated during clinical trials, although not overtly severe, may warrant monitoring in some patients taking multiple hepatically metabolized/cleared agents. Telithromycin offers potential advantages over traditional macrolides/azalides for community-acquired respiratory tract infections caused by macrolide-resistant pathogens. Further studies are needed to elucidate its clinical efficacy against H. influenzae, potential drug interactions, and safety in various subpopulations.",2002.0,0,0 1202,11895826,Recent developments in neurology.,Samuel Wiebe; Michael W Nicolle,,2002.0,0,0 1203,11897207,Comparison of efficacy and safety of atorvastatin and simvastatin in patients with dyslipidemia with and without coronary heart disease.,Dean G Karalis; Andrew M Ross; Ralph M Vacari; Harvey Zarren; Robert Scott,"The efficacy and safety of atorvastatin 10 mg versus simvastatin 20 mg and atorvastatin 80 mg versus simvastatin 80 mg was determined in a 6-week, prospective, randomized, open-label, blinded end-point trial of dyslipidemic patients with and without coronary heart disease. A total of 1,732 patients with hypercholesterolemia and triglycerides < or =600 mg/dl (6.8 mmol/L) were randomized to receive either atorvastatin 10 mg (n = 650), simvastatin 20 mg (n = 650), atorvastatin 80 mg (n = 216), or simvastatin 80 mg (n = 216). The primary efficacy parameter was the change in low-density lipoprotein (LDL) cholesterol from baseline to week 6. Secondary efficacy parameters included the percent change from baseline to week 6 in total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, very-low-density lipoprotein cholesterol, apolipoprotein B, and the percent of patients achieving their National Cholesterol Education Program (NCEP) LDL cholesterol goal at study end. Atorvastatin had significantly greater reductions from baseline in LDL cholesterol than simvastatin in both comparator groups: atorvastatin 10 mg (37.1%) versus simvastatin 20 mg (35.4%) (p = 0.0097), and atorvastatin 80 mg (53.4%) versus simvastatin 80 mg (46.7%) (p <0.0001). Atorvastatin 10 and 80 mg also provided significantly greater reductions in total cholesterol, triglycerides, very-low-density lipoprotein cholesterol, and apolipoprotein B than simvastatin 20 and 80 mg, respectively (all p <0.05). All treatment groups had a significantly decreased LDL cholesterol/HDL cholesterol ratio from baseline (all p <0.0001). In both comparator groups a higher proportion of atorvastatin-treated patients reached their NCEP LDL cholesterol goal compared with simvastatin. All 4 study treatments were well tolerated.",2002.0,1,1 1204,11897208,Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia.,Moti L Kashyap; Mark E McGovern; Kathleen Berra; John R Guyton; Peter O Kwiterovich; Wayne L Harper; Phillip D Toth; Laurence K Favrot; Boris Kerzner; Stephen D Nash; Harold E Bays; Phillip D Simmons,"Combination therapy is increasingly recommended for patients with multiple lipid disorders, especially those at high risk for coronary events. We investigated the long-term safety and effectiveness of a new drug formulation containing once-daily extended-release niacin and lovastatin. A total of 814 men and women (mean age 59 years) with dyslipidemia were enrolled in a 52-week multicenter, open-label study. We used 4 escalating doses (niacin/lovastatin in milligrams): 500/10 for the first month, 1,000/20 for the second, 1,500/30 for the third, and 2,000/40 for the fourth month through week 52. Dose-dependent effects were observed for all major lipid parameters. At week 16, mean low-density lipoprotein (LDL) cholesterol and triglycerides were reduced by 47% and 41%, respectively; mean high-density lipoprotein (HDL) cholesterol was increased by 30% (all p <0.001). LDL/HDL cholesterol and total/HDL cholesterol ratios were also decreased by 58% and 48%, respectively. These effects persisted through week 52, except for the mean increase in HDL cholesterol, which had increased to 41% at 1 year. Lipoprotein (a) and C-reactive protein also decreased in a dose-related manner (by 25% and 24%, respectively, on 2,000/40 mg; p <0.01 vs baseline). Treatment was generally well tolerated. The most common adverse event was flushing, which caused 10% of patients to withdraw. Other adverse events included gastrointestinal upset, pruritus, rash, and headache. Drug-induced myopathy did not occur in any patient. The incidence of elevated liver enzymes to >3 times the upper limit of normal was 0.5%. Once-daily niacin/lovastatin exhibits substantial effects on multiple lipid risk factors and represents a significant new treatment option in the management of dyslipidemia.",2002.0,0,0 1205,11897431,Refractory angina pectoris: mechanism and therapeutic options.,Michael C Kim; Annapoorna Kini; Samin K Sharma,"As the survival of patients with primary coronary events continues to increase, the number of patients presenting with coronary artery disease unsuitable to further revascularization techniques and symptoms refractory to medical therapy also continues to rise. The aims of this review were to define the population of patients with refractory angina pectoris and to present the therapeutic options currently available for this condition. Refractory angina pectoris is defined, and traditional medical therapies are discussed. Then, current therapeutic options for patients with refractory angina are extensively reviewed. A multitude of therapeutic options exist for patients with refractory angina pectoris. Small, uncontrolled studies have shown a potential benefit for additional antiplatelet and antithrombotic therapy. In randomized trials, neurostimulation has been shown to be effective in reducing angina symptoms. Enhanced external counterpulsation is a viable treatment option for select patients with refractory angina. In many randomized trials, laser revascularization has been shown to diminish angina symptoms, although no placebo-controlled studies exist to date. Gene therapy is a promising area of research in this field. Percutaneous in situ coronary venous arterialization is in its infancy, but may be able to treat many patients if proved successful. No data support the role of chelation therapy in this population. Heart transplantation remains a final option for these patients. Further research of the techniques mentioned in this review is warranted. The importance of randomized, double-blinded, placebo-controlled trials cannot be overemphasized, as the placebo effect of these therapies is probably marked.",2002.0,0,0 1206,11897445,Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension.,Kathryn E Ferrier; Michael H Muhlmann; Jean Philippe Baguet; James D Cameron; Garry L Jennings; Anthony M Dart; Bronwyn A Kingwell,"We sought to investigate the effects of intensive cholesterol reduction on large artery stiffness and blood pressure in normolipidemic patients with isolated systolic hypertension (ISH). Isolated systolic hypertension is associated with elevated cardiovascular morbidity and mortality and is primarily due to large artery stiffening, which has been independently related to cardiovascular mortality. Cholesterol-lowering therapy has been efficacious in reducing arterial stiffness in patients with hypercholesterolemia, and thus may be beneficial in ISH. In a randomized, double-blinded, cross-over study design, 22 patients with stage I ISH received three months of atorvastatin therapy (80 mg/day) and three months of placebo treatment. Systemic arterial compliance was measured noninvasively using carotid applanation tonometry and Doppler velocimetry of the ascending aorta. Atorvastatin treatment reduced total and low-density lipoprotein cholesterol and triglyceride levels by 36 +/- 2% (p < 0.001), 48 +/- 3% (p < 0.001) and 23 +/- 5% (p = 0.003), respectively, and increased high density lipoprotein cholesterol by 7 +/- 3% (p = 0.03). Systemic arterial compliance was higher after treatment (placebo vs. atorvastatin: 0.36 +/- 0.03 vs. 0.43 +/- 0.05 ml/mm Hg, p = 0.03). Brachial systolic blood pressure was lower after atorvastatin treatment (154 +/- 3 vs. 148 +/- 2 mm Hg, p = 0.03), as were mean (111 +/- 2 vs. 107 +/- 2 mm Hg, p = 0.04) and diastolic blood pressures (83 +/- 1 vs. 81 +/- 2 mm Hg, p = 0.04). There was a trend toward a reduction in pulse pressure (71 +/- 3 vs. 67 +/- 2 mm Hg, p = 0.08). Intensive cholesterol reduction may be beneficial in the treatment of patients with ISH and normal lipid levels, through a reduction in large artery stiffness.",2002.0,0,0 1207,11899129,Acute generalized exanthematous pustulosis induced by icodextrin.,I A Al-Hoqail; R I Crawford,,2002.0,0,0 1208,11902822,Adrenocorticotrophic hormone exerts marked lipid-lowering effects in simvastatin-treated patients.,A Hardarson; G Sigurdsson; E Olafsdottir; J Dallongeville; A L Berg; M Arnadottir,"Recently, it was reported that treatment with adrenocorticotrophic hormone (ACTH) has a strong lipid-lowering effect in healthy individuals. The mechanism behind this has not been established. The aim of the present investigation was to study the effect of ACTH on the plasma lipoprotein pattern in patients treated with a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor. The ACTH treatment was given to 10 patients who were on long-term treatment with simvastatin 40 mg daily. ACTHI-24 was administered at the dose of 1 mg daily for four consecutive days. Blood samples for analyses of lipids, lipoproteins and apolipoproteins were collected before and after treatment. Second baseline was obtained 2 weeks after the end of treatment. The serum concentrations of cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein(a) fell significantly by 16, 23, 23, 10 and 38%, respectively. The serum apolipoprotein E concentration increased significantly by 39%; the fraction that was not associated with apolipoprotein B increased by 47% whereas the fraction that was did not change significantly. There were no changes in the serum concentrations of high density lipoprotein (HDL) cholesterol and apolipoprotein AI. At the second baseline, the lipid variables had generally returned to previous levels. In patients on long-term simvastatin treatment, ACTH had marked lowering effects on the lipoproteins that contain apolipoprotein B. Moreover, the serum apolipoprotein E concentration increased significantly in response to ACTH treatment.",2002.0,0,0 1209,11907366,Long-term follow-up of patients with acute hypertriglyceridemia-induced pancreatitis.,Vassilios G Athyros; Olga I Giouleme; Nikolaos L Nikolaidis; Themistoklis V Vasiliadis; Vassilios I Bouloukos; Athanasios G Kontopoulos; Nikolaos P Eugenidis,"An acute and potentially life-threatening complication of hypertriglyceridemia (HTG) is acute pancreatitis (AP). Hypertriglyceridemia, usually severe, may be primary in origin or secondary to alcohol abuse, diabetes mellitus, pregnancy, and use of drugs. The efficacy of treatment to prevent relapses in 17 patients with AP attributed to HTG was investigated in the current prospective study. The mean follow-up period of patients was 42 months. Hypertriglyceridemia-induced AP comprised 6.9% of all patients with AP (n = 246) hospitalized in our clinic during the study (6 years). Causative conditions of HTG-induced AP were familial HTG in eight patients, HTG caused by uncontrolled diabetes mellitus in five, HTG aggravated by drugs in two (one by tamoxifen and one by fluvastatin), familial hyperchylomicronemia (HCM) in one, and lipemia of pregnancy in one. During the acute phase of pancreatitis, patients underwent standard treatment. Thereafter, HTG was efficiently controlled with high dosages of fibrates or a fibrate plus acipimox, except for the patient with HCM, who was on a specific diet (the only source of fat was a special oil consisting of medium chain triglyceride) and taking a high dosage of acipimox. One of the patients died during the acute phase of pancreatitis with acute respiratory distress syndrome. During follow-up, maintenance treatment was successful and only one patient relapsed, because he discontinued diet and drug treatment. Appropriate diet and drug treatment, including dose titration, of severe HTG is very effective in preventing relapses of HTG-induced AP.",2002.0,0,0 1210,11908249,Lipid-lowering therapy at hospital discharge after coronary artery bypass grafting.,Ujjaini Khanderia; Tracy V Faulkner; Kevin A Townsend; Daniel S Streetman,,2002.0,0,0 1211,11909575,Comparison of low-density lipoprotein cholesterol lowering by pravastatin to <100 mg/dl versus >100 mg/dl on brachial artery vasoreactivity in patients with severe hypercholesterolemia and previous atherosclerotic events or diabetes mellitus.,John P Lekakis; Christos M Papamichael; Paraskevi Barbaki; Theodoros G Papaioannou; Kimon S Stamatelopoulos; Anna G Dagre; Stamatios F Stamatelopoulos,,2002.0,0,0 1212,11909576,Design of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 trial.,Christopher P Cannon; Carolyn H McCabe; Rene Belder; Jeanne Breen; Eugene Braunwald,,2002.0,0,0 1213,11910595,Concurrent use of simvastatin and estrogen--progestin therapy compared with each therapy alone for hypercholesterolemia in postmenopausal women.,G M Darling; J A Johns; P I McCloud; S R Davis,"Substantial improvements in lipoprotein-lipid profiles have previously been shown with both simvastatin and combined estrogen-progestin therapy in postmenopausal hypercholesterolemic women. Since little is known about the impact of the concomitant use of these therapies, the effects of concurrent hormone therapy and simvastatin in hypercholesterolemic postmenopausal women have been evaluated. Twenty-three postmenopausal women with fasting serum total cholesterol levels greater than 250 mg/dl received, in a randomized cross-over design, simvastatin (10 mg daily) for 8 weeks or postmenopausal hormone therapy (up to 1.25 mg of conjugated equine estrogens plus 5 mg of medroxyprogesterone acetate daily) for 8 weeks, with an 8-week wash-out interval between the two treatment periods. In a third, non-randomized treatment period after a second wash-out interval, each woman received a combination of simvastatin and postmenopausal hormone therapy in the same dosage regimens as above. Fasting blood was sampled monthly from baseline to measure total cholesterol, high- and low-density lipoprotein (HDL and LDL) cholesterol, triglycerides and lipoprotein(a). For total cholesterol, the mean decreases with hormone therapy, simvastatin and combination therapy were 12% (95% confidence interval 6-17%), 26% (20-31%) and 28% (24-31%), respectively, and for LDL cholesterol 21% (14-27%), 37% (30-44%) and 46% (41-51%), respectively. Simvastatin was more effective than hormone therapy (p < 0.001), while the effect of the combined therapy was even greater (total cholesterol, p = 0.012; LDL cholesterol, p < 0.001). The level of HDL cholesterol increased similarly with each treatment: 4% (-3-11%), 6% (2-10%) and 7% (2-13%), respectively. Triglyceride levels increased with hormone therapy and decreased with simvastatin (p < 0.001), while there was little change with the combination (effect of combined therapy vs. simvastatin, p = 0.002; vs. hormone therapy, p < 0.001). Both hormone therapy and combined therapy reduced lipoprotein(a) similarly (-23% and -14%, respectively, p = 0.078). Simvastatin had no effect on lipoprotein(a) levels. For postmenopausal women with hypercholesterolemia, use of a statin in combination with continuous combined oral estrogen and progestin therapy can result in a more cardioprotective lipoprotein-lipid profile than that achieved with either therapy used alone.",2002.0,0,0 1214,11910873,[Primary prevention of cardiovascular diseases by nonpharmacological means].,Wolfgang Lengfelder,"Primary prevention with drugs such as ACE inhibitors, statins and betablockers is highly effective, but due to expensiveness not cost-effective. The aim of this review article was to demonstrate whether nonpharmacological therapy with life-style factors (nonsmoking, healthy eating pattern, increased physical activity) can reduce the incidence of classic risk factors and the cardiovascular morbidity and mortality. The effect of several important life-style factors such as different diets, nonsmoking and physical activity was analyzed by means of an inquiry of the literature. Randomized actual studies demonstrate that a healthy diet can influence the beginning and progression of hypertension and diabetes mellitus. Epidemiologic studies show with high consistency that nonsmoking, regular physical activity and an diet rich in fruit and vegetables, low-fat products, fish and lean meat is associated with a lower incidence of cardiovascular events and mortality. A further decrease of the cardiovascular morbidity can be reached by combining several of these life-style variables. Life-style factors such as a healthy eating pattern, nonsmoking and regular physical activity can contribute to an enormous health benefit in the general population and save money for the public social systems. Therefore the promotion of this healthy life-style should be a major aim of the health policy.",2002.0,0,0 1215,11911562,Effectiveness of low doses of simvastatin versus atorvastatin: resolving conflicting evidence.,Camilla Chong; Steven Kelly; Matthew Bradley,,2002.0,0,0 1216,11911755,Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial.,Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF),"Decompensated congestive heart failure (CHF) is the leading hospital discharge diagnosis in patients older than 65 years. To compare the efficacy and safety of intravenous nesiritide, intravenous nitroglycerin, and placebo. Randomized, double-blind trial of 489 inpatients with dyspnea at rest from decompensated CHF, including 246 who received pulmonary artery catheterization, that was conducted at 55 community and academic hospitals between October 1999 and July 2000. Intravenous nesiritide (n = 204), intravenous nitroglycerin (n = 143), or placebo (n = 142) added to standard medications for 3 hours, followed by nesiritide (n = 278) or nitroglycerin (n = 216) added to standard medication for 24 hours. Change in pulmonary capillary wedge pressure (PCWP) among catheterized patients and patient self-evaluation of dyspnea at 3 hours after initiation of study drug among all patients. Secondary outcomes included comparisons of hemodynamic and clinical effects between nesiritide and nitroglycerin at 24 hours. At 3 hours, the mean (SD) decrease in PCWP from baseline was -5.8 (6.5) mm Hg for nesiritide (vs placebo, P<.001; vs nitroglycerin, P =.03), -3.8 (5.3) mm Hg for nitroglycerin (vs placebo, P =.09), and -2 (4.2) mm Hg for placebo. At 3 hours, nesiritide resulted in improvement in dyspnea compared with placebo (P =.03), but there was no significant difference in dyspnea or global clinical status with nesiritide compared with nitroglycerin. At 24 hours, the reduction in PCWP was greater in the nesiritide group (-8.2 mm Hg) than the nitroglycerin group (-6.3 mm Hg), but patients reported no significant differences in dyspnea and only modest improvement in global clinical status. When added to standard care in patients hospitalized with acutely decompensated CHF, nesiritide improves hemodynamic function and some self-reported symptoms more effectively than intravenous nitroglycerin or placebo.",2002.0,0,0 1217,11911905,Are high-density lipoprotein and triglyceride levels important in secondary prevention: impressions from the BIP and VA-HIT trials.,E Rizos; D P Mikhailidis,"Two major trials, the Bezafibrate Infarction Prevention Trial (BIP) and the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) were conducted to clarify the contribution of correcting diminished high density lipoprotein (HDL) (and lowering triglyceride, TG) levels to the risk of cardiovascular events in patients with coronary heart disease (CHD). In BIP, bezafibrate did not significantly reduce the risk of CHD. In contrast, in VA-HIT, gemfibrozil significantly reduced the risk of CHD (22% reduction in primary end point, P=0.006). These trials differ in several respects making direct comparisons difficult. For example, the placebo arm in VA-HIT had a greater prevalence of primary events than that in BIP (22 vs. 15%). The baseline mean LDL value in BIP was also higher compared to that in VA-HIT (148 vs. 112 mg/dl; 3.82 vs. 2.89 mmol/l). Other trials (e.g., AFCAPS and LIPID) showed that patients with LDL values similar to those in BIP benefited significantly from treatment with statins. Therefore, the BIP population may have been more effectively treated with a statin. In contrast, in VA-HIT the LDL level was close to those recommended in the USA and the UK for secondary prevention (100 and 115 mg/dl; 2.6 and 3.0 mmol/l, respectively). Guidelines emphasise that the LDL level is the main treatment target. However, BIP and VA-HIT suggest that correcting HDL and TG levels may be beneficial especially when the LDL level has reached the target value. We may have become too focused on LDL levels and the use of statins.",2002.0,0,0 1218,11913471,Should statin therapy be considered for patients with elevated C-reactive protein? The need for a definitive clinical trial.,P M Ridker,,2002.0,0,0 1219,11914249,Coronary heart disease in patients with low LDL-cholesterol: benefit of pravastatin in diabetics and enhanced role for HDL-cholesterol and triglycerides as risk factors.,Frank M Sacks; Andrew M Tonkin; Timothy Craven; Marc A Pfeffer; James Shepherd; Anthony Keech; Curt D Furberg; Eugene Braunwald,"In two large secondary prevention trials of pravastatin, risk reduction was not significant in participants who had low baseline LDL-C concentrations (that is, <125 mg/dL). We conducted exploratory analyses of participant characteristics, lipid risk factors, and risk reduction in this group. Among 13 173 participants with coronary heart disease (CHD), 2607 had baseline LDL-C <125 mg/dL. Those with LDL-C <125 compared with > or =125 mg/dL were more likely to be diabetic (15% versus 9%), hypertensive (46 versus 41%), and male (89% versus 83%); they had higher triglycerides (169 versus 154 mg/dL), lower HDL-C (36.5 versus 38 mg/dL), and similar body mass index (27 kg/m2); and pravastatin lowered their LDL-C by 36 mg/dL (32%) versus 45 mg/dL (29%). During 5.8-year (mean) follow-up, HDL-C and triglycerides were both significantly stronger predictors of recurrent CHD events in participants with LDL-C <125 than > or =125 mg/dL. In diabetic participants with low LDL-C, pravastatin decreased CHD events from 34% to 22% (relative risk, 0.56; 95% CI, 0.37 to 0.83; P=0.004), significantly different from the effect in nondiabetic participants with low LDL-C (P interaction, 0.005) (event rate, 21%; relative risk, 1.06 [95% CI, 0.89 to 1.27]). There were trends toward risk reduction in smokers and in those with low HDL-C, <40 mg/dL. Among patients with CHD who have low LDL-C, diabetics have much higher subsequent CHD event rates than do nondiabetics. Pravastatin reduced the event rate in diabetics to that of nondiabetic participants. The results also suggest enhanced therapeutic potential for improving HDL-C and triglycerides in patients with CHD who have low LDL-C concentrations.",2002.0,0,0 1220,11914253,Withdrawal of statins increases event rates in patients with acute coronary syndromes.,Christopher Heeschen; Christian W Hamm; Ulrich Laufs; Steven Snapinn; Michael Böhm; Harvey D White; Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators,"HMG-CoA Reductase Inhibitors (statins) reduce cardiac event rates in patients with stable coronary heart disease. Withdrawal of chronic statin treatment during acute coronary syndromes may impair vascular function independent of lipid-lowering effects and thus increase cardiac event rate. We investigated the effects of statins on the cardiac event rate in 1616 patients of the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study who had coronary artery disease and chest pain in the previous 24 hours. We recorded death and nonfatal myocardial infarction during the 30-day follow-up. Baseline clinical characteristics did not differ among 1249 patients without statin therapy, 379 patients with continued statin therapy, and 86 patients with discontinued statin therapy after hospitalization. Statin therapy was associated with a reduced event rate at 30-day follow-up compared with patients without statins (adjusted hazard ratio, 0.49 [95% CI, 0.21 to 0.86]; P=0.004). If the statin therapy was withdrawn after admission, cardiac risk increased compared with patients who continued to receive statins (2.93 [95% CI, 1.64 to 6.27]; P=0.005) and tended to be higher compared with patients who never received statins (1.69 [95% CI, 0.92 to 3.56]; P=0.15). This was related to an increased event rate during the first week after onset of symptoms and was independent of cholesterol levels. In a multivariate model, troponin T elevation (P=0.005), ST changes (P=0.02), and continuation of statin therapy (P=0.008) were the only independent predictors of patient outcome. Statin pretreatment in patients with acute coronary syndromes is associated with improved clinical outcome. However, discontinuation of statins after onset of symptoms completely abrogates this beneficial effect.",2002.0,0,0 1221,11916536,Overview of therapies for prevention of restenosis after coronary interventions.,S M Garas; P Huber; N A Scott,"Coronary artery disease is a leading cause of morbidity and mortality in the United States and across the world. The economic impact of coronary artery disease is staggering and on the rise. Percutaneous transluminal coronary angioplasty is widely used to treat severe, symptomatic coronary stenosis. The Achilles heel of angioplasty is restenosis of those treated arteries. As a result, numerous therapies, including mechanical and pharmacological approaches, to prevent restenosis have been studied. A greater understanding of the pathophysiology of restenosis has enhanced the success of these therapeutic approaches. To date, the most important and successful approach to limit restenosis has been the use of coronary stents. Stents have reduced the rate of restenosis from approximately 50% down to 20-30%. However, in-stent restenosis presents a new and an even more challenging dilemma. The success of adjunctive drug therapy has been promising, but, as of yet, very limited. Antithrombotic agents have reduced acute thrombosis and many of the acute complications of angioplasty. New approaches and therapies are very encouraging, and provide great hope in the treatment of restenosis. Brachytherapy has shown success in the treatment of in-stent restenosis, and recently has been approved by the United States Food and Drug Administration for this indication. Drug-eluting stents using antiproliferative drugs are the most exciting new advance in preventing restenosis, currently in Phase III trials. Gene therapy, targeted drug delivery, and newer antithrombotic agents are also under investigation. We will review the pathophysiology of restenosis, animal models, pharmacological therapies, and mechanical approaches for the treatment of restenosis.",2002.0,0,0 1222,11918519,Potential use of HMG-CoA reductase inhibitors for osteoporosis.,Lolita M Cushenberry; Magaly Rodriguez de Bittner,"To review the current clinical data describing the effects of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in bone formation and reduction of fracture incidence and their potential use for osteoporosis. English-language articles and abstracts were identified from a MEDLINE database search (1966-May 2001) that used the key words osteoporosis, HMG-CoA reductase inhibitors, and treatment. All the articles identified from the data sources were evaluated, and all information deemed relevant was included in this review. In the past, there has been considerable emphasis placed in the detection, prevention, and treatment of osteoporosis. New drug therapies have been introduced in the market aimed at decreasing bone loss and increasing bone formation, with the ultimate goal of decreasing fractures. Currently, there are a variety of agents available for the treatment of osteoporosis. A limited number of case-control studies have suggested that HMG-CoA reductase inhibitors (statins) may have the potential to reduce the risk of fractures by increasing bone formation, although other studies have failed to show a benefit in fracture reduction. The potential benefit of this therapy is still undetermined because of a lack of randomized, controlled, clinical trials and conflicting data. At this time, there are limited data on the role of statins in the treatment of osteoporosis. Practitioners must be cautious when using these agents over other proven conventional therapies. Randomized, controlled, clinical trials are needed to accurately determine the role of these agents in the treatment of osteoporosis.",2002.0,0,0 1223,11918622,Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes.,H M Colhoun; M J Thomason; M I Mackness; S M Maton; D J Betteridge; P N Durrington; G A Hitman; H A W Neil; J H Fuller; Collaborative AtoRvastatin Diabetes Study (CARDS),"There are few data on the role of lipid lowering in the primary prevention of coronary heart disease (CHD) in diabetic patients. This paper describes the design of a collaborative clinical trial between Diabetes UK, the NHS Research and Development Directorate and Pfizer UK, that addresses this question. The Collaborative AtoRvastatin Diabetes Study (CARDS) is a multicentre, randomized, placebo-controlled, double-blind clinical trial of primary prevention of cardiovascular disease in patients with Type 2 diabetes. The primary objective is to investigate whether treatment with the hydroxymethylglutaryl coenzyme A reductase inhibitor, atorvastatin, reduces the incidence of major cardiovascular events. At entry patients have at least one other risk factor for CHD in addition to diabetes, namely current smoking, hypertension, retinopathy, or micro- or macroalbuminuria. At randomization patients have been selected for a serum low-density lipoprotein (LDL) cholesterol concentration < or = 4.14 mmol/l (160 mg/dl) and triglycerides < or = 6.78 mmol/l (600 mg/dl). Randomization was completed in June 2001. Patients will be followed until 304 primary endpoints have accrued (expected date early 2005). The trial includes 2838 men and women aged 40-75 years. This report describes the design and administration of the study and reviews the evidence to date of the effectiveness of lipid-lowering therapy in Type 2 diabetes. The case for lipid-lowering therapy for the primary prevention of CHD in diabetes has not been demonstrated. CARDS will provide essential information on the extent of any benefits and adverse effects of lipid-lowering therapy in diabetic patients without prior CHD.",2002.0,0,0 1224,11918754,A placebo-controlled trial examining atorvastatin in dyslipidemic patients undergoing CAPD.,Kevin P G Harris; David C Wheeler; Camilla C Chong; Atorvastatin in CAPD Study Investigators. Continuous ambulatory peritoneal dialysis,"Individuals with chronic renal disease are at high risk of cardiovascular morbidity and mortality, and therefore the management of dyslipidemia is particularly important in this patient population. This double-blind randomized study investigated the efficacy and safety of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, atorvastatin, in continuous ambulatory peritoneal dialysis (CAPD) patients with dyslipidemia. Following a two- to four-week baseline period, patients with low-density lipoprotein (LDL)-cholesterol > or =3.5 mmol/L (135 mg/dL) were randomized to receive either atorvastatin 10 mg (N = 82) or placebo (N = 95) for 16 weeks. If LDL-cholesterol remained > or =3.5 mmol/L, the dose of atorvastatin was titrated to 20 mg and 40 mg after four and eight weeks, respectively. After four weeks a significantly greater proportion of patients receiving atorvastatin 10 mg had achieved the LDL-cholesterol goal < or =3.5 mmol/L compared with patients receiving placebo (85.4% vs. 16.0%; P < or = 0.001). The statistically significant difference between the two groups was maintained at week 8 and week 16 (P < or = 0.001 at both time points). At week 16, patients receiving atorvastatin had significantly greater reductions from baseline in LDL-cholesterol, total cholesterol, triglycerides and total cholesterol:HDL-cholesterol ratio (all P = 0.0001), and a significantly greater increase from baseline in HDL-cholesterol (P = 0.001) than patients receiving placebo. The overall adverse event profile for atorvastatin was similar to that observed with placebo. Atorvastatin was effective in achieving target LDL-cholesterol levels in a high proportion of the dyslipidemic CAPD patients studied at doses that are well tolerated.",2002.0,0,0 1225,11919129,"A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone.",Mehmood A Khan; John V St Peter; Jay L Xue,"To characterize potential differences in glycemic control, plasma lipid level, and weight in a cohort of patients previously treated with troglitazone (TROG) who were switched to either pioglitazone or rosiglitazone. After a 2-week washout from TROG, 186 patients were randomly assigned to receive either pioglitazone (PIO) or rosiglitazone (ROSI). Weight, HbA(1c), and fasting lipid profile were documented before discontinuing TROG and at 4 months after starting either pioglitazone or rosiglitazone. Secondarily, the effect of concurrent medications on study outcomes was assessed. A total of 127 patients completed follow-up: 67 individuals in the PIO group (32 women, 35 men) and 60 individuals in the ROSI group (33 women, 27 men). There were no significant differences in gender mix, age, weight, fasting lipid profile, or HbA(1c) between the ROSI and PIO groups. After 4 months of randomized treatment, no change in HbA(1c) from baseline between or within groups was noted. Both groups experienced an equal and significant increase in weight from baseline of approximately 2.0 kg. Thiazolidinedione and HMG-CoA reductase inhibitor therapy had significant and independent effects on lipid profile (P < 0.005). Significant improvements in lipid profile were noted in the PIO group (P < 0.01), whereas none were detected with conversion to ROSI. Specifically, the PIO group experienced an average decrease in total cholesterol of approximately 20 mg/dl. Differing effects on lipid profile were apparent after random conversion from TROG to either PIO or ROSI, despite similar weight increase and glycemic control. The clinical significance of these differences remains to be determined, and further comparative research is warranted.",2002.0,0,0 1226,11926698,Selective cholesterol absorption inhibition: a novel strategy in lipid-lowering management.,E Leitersdorf,"Many individuals throughout Europe have risk factors for coronary heart disease (CHD) and are non-compliant with recommended treatments, despite guidelines for the reduction of low-density lipoprotein cholesterol (LDL-C) and the prevention of CHD. Significant numbers who should receive pharmacotherapy for hypercholesterolaemia do not, and one-third of treated patients do not achieve recommended target LDL-C levels. Optimum doses of statins, which have demonstrated undisputed efficacy in the treatment of hypercholesterolaemia in clinical trials, are seldom used; the inconvenience of dosage adjustments and safety concerns, particularly myalgia, may constitute obstacles to their optimal use for LDL-C reduction in clinical practice. Ezetimibe is the first selective cholesterol absorption inhibitor that has demonstrated clinical benefits when used as either monotherapy or in combination with other lipid-modifying agents.",2002.0,0,0 1227,11926875,Clinical evidence for critical cardiac care.,Janet M Torpy,,2002.0,0,0 1228,11926876,From the Food and Drug Administration.,Lester M Crawford,,2002.0,0,0 1229,11927515,Statin attenuates increase in C-reactive protein during estrogen replacement therapy in postmenopausal women.,Kwang Kon Koh; William H Schenke; Myron A Waclawiw; Gyorgy Csako; Richard O Cannon,"HMG-CoA reductase inhibitor (statin) therapy reduces cardiovascular risk, mechanisms of which may include diminished arterial inflammation, as suggested by reduction in levels of C-reactive protein (CRP). Because oral estrogens increase CRP in postmenopausal women, with potential inflammatory and thrombotic consequences that could compromise any benefit to cardiovascular risk, we determined whether the coadministration of a statin might modify the estrogenic effect on CRP. In a double-blind, 3-period crossover study, 28 postmenopausal women (average LDL cholesterol 163+/-36 mg/dL) were randomly assigned to daily conjugated equine estrogens (CEEs) 0.625 mg, simvastatin 10 mg, or their combination for 6 weeks, with each treatment period separated by 6 weeks. CEEs increased median CRP levels from 0.27 to 0.46 mg/dL, simvastatin decreased CRP from 0.29 to 0.28 mg/dL, and the therapies combined increased CRP from 0.28 to 0.36 mg/dL (all P< or =0.02 versus respective baseline values). Post hoc testing showed that the 29% increase in CRP on the combination of CEEs with simvastatin was significantly less than the 70% increase in CRP on CEEs alone (P<0.05). The effect of combination therapy on CRP levels did not correlate with baseline CRP or with baseline or treatment-induced changes in levels of interleukin-6, lipoproteins, or flow-mediated dilation of the brachial artery as a measure of nitric oxide bioactivity. The combination of statin with estrogen may attenuate the potential harmful effects of estrogen therapy in postmenopausal women and maximize any benefit to cardiovascular risk.",2002.0,0,0 1230,11927522,Effect of 3 months of antimicrobial treatment with clarithromycin in acute non-q-wave coronary syndrome.,Juha Sinisalo; Kimmo Mattila; Ville Valtonen; Olli Anttonen; Jukka Juvonen; John Melin; Helena Vuorinen-Markkola; Markku S Nieminen; Clarithromycin in Acute Coronary Syndrome Patients in Finland (CLARIFY) Study Group,"Coronary artery disease, an inflammatory disease, may be caused by infection. We investigated whether the antibiotic clarithromycin would reduce morbidity and mortality in patients with acute non-Q-wave coronary syndrome. Altogether, 148 patients with acute non-Q-wave infarction or unstable angina were randomly assigned to receive double-blind treatment with either clarithromycin or placebo for 3 months. The primary end point was a composite of death, myocardial infarction, or unstable angina during treatment; the secondary end point was occurrence of any cardiovascular event during the entire follow-up period (average 555 days, range 138 to 924 days). There was a trend toward fewer patients meeting primary end-point criteria in the clarithromycin group than in the placebo group (11 versus 19 patients, respectively; risk ratio 0.54, 95% CI 0.25 to 1.14; P=0.10). By the end of the entire follow-up, 16 patients in the clarithromycin group and 27 in the placebo group had experienced a cardiovascular event (risk ratio 0.49, 95% CI 0.26 to 0.92; P=0.03). Clarithromycin appears to reduce the risk of ischemic cardiovascular events in patients presenting with acute non-Q-wave infarction or unstable angina. No signs of this effect diminishing were observed during follow-up.",2002.0,0,0 1231,11927795,ACE inhibitors and stroke: new considerations.,Domenic A Sica,,2002.0,0,0 1232,11932263,Clinical review 145: Pleiotropic effects of statins: lipid reduction and beyond.,S I McFarlane; R Muniyappa; R Francisco; J R Sowers,"There is accumulating evidence that statins have beneficial effects that are independent of their classical actions on lipoproteins. These effects include reductions in inflammation in the vasculature, kidney, and bone. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. These agents appear to reduce bone fractures and may improve insulin sensitivity and reduce the likelihood of persons progressing from impaired glucose tolerance to type II diabetes. Potential beneficial pleiotropic effects of statins are covered in this review.",2002.0,0,0 1233,11932481,Antioxidant vitamins and coronary disease.,Giuseppe G L Biondi-Zoccai; Antonio Abbate; Pierfrancesco Agostoni,,2002.0,0,0 1234,11933922,"A randomized, double-blind, placebo-controlled, 8-week study to evaluate the efficacy and safety of once daily atorvastatin (10 mg) in patients with elevated LDL-cholesterol.",K Y Wang; C T Ting,"Lowering of serum cholesterol levels by pharmacologic intervention with statins reduces the incidence of cardiovascular events in subjects with and without atherosclerotic manifestations. In an 8-week, randomized, double-blind study we compared the efficacy and safety of the new compound atorvastatin for reducing LDL-cholesterol (LDL-C) with placebo in an Asian patient cohort. Patients with LDL-C between 160 mg/dl and 250 mg/dl were randomly assigned to treatment with 10 mg atorvastatin or placebo once daily for 8 weeks. At the end of weeks 4 and 8 of the randomized phase, the serum concentrations of lipid parameters as well as safety parameters were determined. Fifty-four patients (32 males and 22 females) were enrolled. Twenty-six patients were assigned to the treatment group. The primary end-point, LDL-C, was reduced by 40% and 42% after 4 and 8 weeks of treatment in the atorvastatin treated patients (p<0.001). The reductions in total cholesterol and triglycerides were up to 31% and 23%, respectively. The HDL-C levels increased up to 11% (p=0.043). There were no significant adverse events. Transient increases in CPK levels (10 times) without myalgia were identified in 1 patient. Atorvastatin, 10 mg/day produced significant reductions in LDL-C, total cholesterol and triglycerides and an elevation of HDL-C levels when used as an adjunct to diet in hyperlipidemic patients. The majority of the clinical effects could be attained by week 4. The overall safety profile of atorvastatin was similar to that of placebo. Atorvastatin was considered to be well tolerated in this patient cohort.",2002.0,0,0 1235,11934339,Is pharmacological prevention of Alzheimer's a realistic goal?,Peter P Zandi; John C S Breitner; James C Anthony,"A growing body of evidence suggests that several classes of drugs marketed for other indications may be effective in the prevention of Alzheimer's disease. Among the most promising of these are nonsteroidal anti-inflammatory agents, oestrogens (oestrogen replacement therapy) and antioxidant vitamins. Other less well-established candidates include histamine H(2) receptor antagonists (H(2) blockers) and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). For each of these, we discuss possible mechanisms for their postulated neuroprotective effects and review the studies suggesting their benefits in Alzheimer's disease. We conclude that nonsteroidal anti-inflammatory drugs and oestrogen replacement therapies may be effective in preventing Alzheimer's disease only if taken during the latent phase of the disease several years prior to the appearance of disturbances. Antioxidants may also prevent Alzheimer's disease, but unlike nonsteroidal anti-inflammatory drugs and oestrogen replacement therapies, they may continue to have beneficial effects even after the clinical onset of the disease. The only way to demonstrate the efficacy of these agents will be through randomised, controlled prevention trials. Such trials are currently underway but conclusive results may not be available for several years. Although intriguing, more studies on the neuroprotective effects of statins and H(2) blockers are needed before trials of these agents are initiated. Finally, there are other classes of pharmacological compounds emerging on the horizon, including folic acid, anti-beta-sheet conformational agents, secretase inhibitors and vaccines, that may soon prove to be effective for the prevention of Alzheimer's disease.",2003.0,0,0 1236,11935713,Analysis of serious adverse events. Lipid-lowering therapy revisited.,Jim M Wright; Lorri Puil; Carol Lee Ken Bassett,,2002.0,0,0 1237,11936540,Statin-induced fibrotic nonspecific interstitial pneumonia.,S Lantuejoul; E Brambilla; C Brambilla; G Devouassoux,"Statins inhibit the 3-hydroxy-3-methylglutaryl coenzyme A reductase, reduce the serum level of low-density lipoprotein cholesterol, and are extensively prescribed to prevent cardiovascular mortality and morbidity. Few systemic adverse effects, such as pseudopolymyositis, lupus-like syndromes, and anecdotal hypersensitivity pneumonitis, have been reported. A simvastatin-induced diffuse interstitial pneumonia associated with a nonspecific interstitial pneumonia pattern at histological analysis is repoted here. Ultrastructural analysis showed a diffuse cytoplasmic accumulation of intralysosomial lamellar inclusions in type II pneumonocytes, histiocytes and endothelial cells, suggesting a shared pathogenesis with amphiphilic drug-induced toxic lung injury. Because statins are increasingly prescribed, statin-induced interstitial lung disorders may be more frequently observed and early recognition will be required.",2002.0,0,0 1238,11936570,A study of the interaction potential of azithromycin and clarithromycin with atorvastatin in healthy volunteers.,Guy W Amsden; Olatunde Kuye; Greg C G Wei,"Atorvastatin is a common option among the HMG-CoA reductase inhibitors for the treatment of lipid disorders because of its excellent lipid-lowering efficacy and overall safety profile. Although these agents can rarely cause rhabdomyolysis by themselves, macrolides, among other agents, have been demonstrated to increase the likelihood of this via inhibition of CYP metabolism of the lipid agent. This study investigated the potential for azithromycin and clarithromycin to inhibit the metabolism of atorvastatin. Although there was no interaction between azithromycin and atorvastatin, clarithromycin did have a significant effect on atorvastatin pharmacokinetic parameters. When coadministered, clarithromycin raised subject exposure (AUC24) by 82% and peak plasma concentrations by 56%. These data suggest that while azithromycin appears to be safe to coadminister with atorvastatin, clarithromycin should be avoided in patients taking this and similarly metabolized HMG-CoA inhibitors.",2002.0,0,0 1239,11937434,Complementary therapies for reducing the risk of osteoporosis in patients receiving luteinizing hormone-releasing hormone treatment/orchiectomy for prostate cancer: a review and assessment of the need for more research.,Mark A Moyad,"Osteoporosis in women has received a substantial amount of attention, but its impact in men is also significant and noteworthy. Those men who benefit from treatment for prostate cancer with androgen deprivation therapy (ADT) may also be at a higher risk for osteoporosis. Pharmacologic approaches to reduce this risk have received some attention. For example, agents such as bisphosphonates, estrogen receptor-binding drugs (diethylstilbestrol, tamoxifen, and raloxifene), calcitonin, and fluoride are some of the more promising interventions that have been previously outlined. In addition, statin drugs, or hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have recently been hypothesized to lower osteoporosis risk. However, complementary therapies, which may also have an impact on reducing osteoporosis risk, have not received attention. Dietary and supplemental calcium and vitamin D have been shown, in some preliminary investigations, to maintain bone density in women and men. Numerous healthy and affordable dietary sources of this mineral and vitamin exist, and large intakes can be realistically achieved through proper education. Similarly, the supplemental dosages required to impact risk have been moderate, appear to be safe, are of low cost, and thus may provide an additional route for reducing risk, especially if these interventions are initiated at the start of medical treatment. More studies in men receiving ADT are needed because the existing work has mostly focused on men without castrate levels of male hormone. Additionally, many studies with conventional and nonconventional agents have only focused on individuals with baseline osteoporosis, rather than normal bone mineral densities or osteopenia. Other promising complementary therapies, such as weight-bearing exercise and abstaining from smoking, may also be of benefit. Newer estrogenic-type supplements (eg, ipriflavone) appear interesting and have some preliminary data, but more research is desperately required to determine their actual impact and potential for adverse effects (such as lymphocytopenia from a recent trial). Simple, inexpensive, and potentially effective dietary and supplemental approaches to reduce the risk of osteoporosis in men exist, and they should be discussed with patients. Whether these approaches effectively reduce the risk of osteoporosis in men receiving androgen ablation remains to be determined. The possibility is intriguing, and future research is needed. In the meantime, it is important to keep in mind that these complementary approaches are, at the very least, an integral part of the conventional options used today to the reduce the risk of osteoporosis in men and women.",2002.0,0,0 1240,11937774,A rational approach to the selection of useful drugs for clinical practice.,Reynold Spector; Elliot S Vesell,"Confusion exists concerning optimal selection of drugs for clinical practice. Many reasons contribute to this confusion which derives from various sources including industry, the FDA and often less than ideal education of physicians in clinical pharmacology during medical school and thereafter. This presentation does not focus on allocating blame for the current unsatisfactory situation, but rather offers a solution to improve drug therapy. Our educational solution consists of a paradigm for rational drug therapy, specifically a checklist of eight criteria for physicians to review before prescribing drugs. Such a review would facilitate better estimation by physicians of risk/benefit ratios involving new, often expensive and, in some cases, questionably effective and safe drugs.",2002.0,0,0 1241,11939134,,,,,0,0 1242,11942772,"Fenofibrate of gemfibrozil for treatment of types IIa and IIb primary hyperlipoproteinemia: a randomized, double-blind, crossover study.",Alvaro Insua; Fabio Massari; Juan José Rodríguez Moncalvo; José Rubén Zanchetta; Ana María Insua,"To compare the hypolipidemic effects of gemfibrozil and micronized fenofibrate in patients with primary hyperlipoproteinemia, phenotypes IIa and IIb, with emphasis on their cholesterol-lowering effectiveness. A randomized, double-blind, double-dummy, crossover study was performed to assess the effects of gemfibrozil (900 mg) and micronized fenofibrate (200 mg), administered once daily, to 21 patients (45 to 70 years old)-16 with type IIa and 5 with type IIb primary hyperlipidemia. The two treatment periods lasted 6 weeks each; the run-in and washout periods were 4 weeks. Both drugs significantly reduced total cholesterol, calculated low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein B, and fibrinogen (P<0.01 for all calculations, except P<0.05 for fibrinogen with gemfibrozil therapy) and increased high-density lipoprotein (HDL) cholesterol (P<0.01). Neither drug affected Lp(a) lipoprotein, whereas uric acid was reduced only by fenofibrate (P<0.01). The percentage decrease in total cholesterol and LDL cholesterol was greater with fenofibrate than with gemfibrozil (-22% versus -15%, P<0.02; and -27% versus -16%, P<0.02, respectively). In contrast, reductions in levels of triglycerides (-54% versus -46.5%), apolipoprotein B, and fibrinogen, as well as the increase in HDL (+9% for both drugs), showed no significant difference between treatments. Separate analysis of patients with type IIb hyperlipoproteinemia showed essentially the same plasma lipid changes as for the overall group, but with greater modifications in triglyceride and HDL concentrations. Fenofibrate and gemfibrozil induced similar variations from baseline values in triglycerides, HDL cholesterol, apolipoprotein B, and fibrinogen, but the decreases in total and LDL cholesterol levels were greater with fenofibrate, in this group of patients with primary hyperlipidemia.",2002.0,0,0 1243,11942773,Effect of thiazolidinediones on high-density lipoprotein subfractions.,Fernando Ovalle; David S H Bell,"To evaluate the effects of thiazolidinediones (TZDs) on specific high-density lipoprotein (HDL) subfractions (HDL2 and HDL3) in patients with type 2 diabetes. We conducted a case-control study in a university diabetes clinic. The study included 45 patients with type 2 diabetes mellitus and dyslipidemia; 31 of these patients received a TZD (troglitazone), and 14 patients received metformin. At the time of the study, the mean duration of therapy was 7 and 11 months, respectively. In the TZD group, a significant increase of 12.6% occurred in the total HDL levels (from 34.9 +/- 2.2 mg/dL to 39.3 +/- 2.2 mg/dL; P = 0.0008), whereas no significant change was noted in the metformin group (from 40.9 +/- 3.5 mg/dL to 40.1 +/- 3.2 mg/dL; P = 0.14). All the increase in total HDL levels in the TZD group was due to an increase in the HDL3 subfraction, which rose by 16.7% (from 26.9 +/- 0.9 mg/dL to 31.4 +/- 1.2 mg/dL; P = 0.008). The HDL2 subfraction remained essentially unchanged (from 8.1 +/- 1.7 mg/dL to 7.9 +/- 1.4 mg/dL; P = 0.80). In the metformin group, no significant changes were found in either the HDL3 or the HDL2 subfractions. The TZD-induced increase in total HDL levels in our patients was entirely attributable to an increase in the HDL3 subfraction.",2002.0,0,0 1244,11947910,Effects of atorvastatin on postprandial plasma lipoproteins in postinfarction patients with combined hyperlipidaemia.,Susanna Boquist; Fredrik Karpe; Karin Danell-Toverud; Anders Hamsten,"Enhanced and prolonged postprandial lipaemia is implicated in coronary and carotid artery disease. This study assessed the effects of atorvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, on postprandial plasma concentrations of triglyceride-rich lipoproteins (TRLs). Sixteen middle-aged men with combined hyperlipidaemia (baseline low density lipoprotein (LDL) cholesterol and plasma triglyceride concentrations (median (interquartile range) of 4.54 (4.17-5.26)) and 2.66 (2.04-3.20) mmol/l, respectively) and previous myocardial infarction were randomised to atorvastatin 40 mg or placebo once daily for 8 weeks in a double-blind, cross-over design. The apolipoprotein (apo) B-48 and B-100 contents were determined in subfractions of TRLs as a measure of chylomicron remnant and very low density lipoprotein (VLDL) particle concentrations (expressed as mg apo B-48 or apo B-100 per litre of plasma), in the fasting state and after intake of a mixed meal. Atorvastatin treatment reduced significantly the fasting plasma concentrations of VLDL cholesterol, LDL cholesterol and VLDL triglycerides (median% change) by 29, 44 and 27%, respectively, and increased high density lipoprotein (HDL) cholesterol by 19%, compared with baseline. The postprandial plasma concentrations of large (Svedberg flotation rate (Sf) 60-400) and small (Sf 20-60) VLDLs and chylomicron remnants were almost halved compared with baseline (mean 0-6 h plasma concentrations were reduced by 48% for Sf 60-400 apo B-100, by 46% for Sf 60-400 apo B-48, by 46% for Sf 20-60 apo B-100 and by 27% for Sf 20-60 apo B-48), and the postprandial triglyceridaemia was reduced by 23% during active treatment. In conclusion, atorvastatin 40 mg once daily causes profound reductions of postprandial plasma concentrations of all TRLs in combined hyperlipidaemic patients with premature coronary artery disease.",2002.0,0,0 1245,11947912,Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease.,Ingebjørg Seljeflot; Serena Tonstad; Ingvar Hjermann; Harald Arnesen,"The study was aimed at investigating the effects, after treatment for 1 year, of two different statins on the levels of circulating biochemical markers of endothelial function in patients with established coronary heart disease, with the hypothesis that statins might reduce these levels. Twenty-eight patients were randomized to treatment with atorvastatin and 30 to simvastatin for 1 year. The starting dose in both groups was 20 mg/day. Soluble forms of P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were determined to assess inflammatory activity of the endothelium, and tissue plasminogen activator antigen (tPAag), von Willebrand factor and thrombomodulin for evaluation of the haemostatic function. In the total study population there were significantly reduced levels after 1 year treatment in ICAM-1 (P<0.001), E-selectin (P=0.022) and P-selectin (P<0.001), whereas a significant increase was observed in VCAM-1 (P=0.003). Almost the same pattern was seen within both groups although the increase in VCAM-1 was only seen in the simvastatin group (P=0.017). An overall reduction in tPAag was further observed (P=0.048). The reduction in proinflammatory and to some extent haemostatic markers of endothelial function after 1 year treatment with either simvastatin or atorvastatin may be indicative of a less activated state of the endothelium which possibly may contribute to modulation of the progression of atherosclerosis.",2002.0,0,0 1246,11947915,A comparison of pravastatin and gemfibrozil in the treatment of dyslipoproteinemia in patients with non-insulin-dependent diabetes mellitus.,Morris Schweitzer; Daniel Tessier; William D Vlahos; Lawrence Leiter; Jean Paul Collet; Matthew J McQueen; Laurent Harvey; Petar Alaupovic,"The effects of pravastatin (pravachol) compared with gemfibrozil on cholesterol-rich and trigylceride-rich lipoproteins were evaluated in this multi-centered trial. Following an 8-12 week prerandomization phase, 136 patients with NIDDM and hypercholesterolemia were randomized to receive either pravastatin 40 mg or gemfibrozil 1200 mg daily for 16 weeks. The reduction of total cholesterol (TC), betaquant LDL and LDL cholesterol (LDL-C) was significantly greater in patients treated with pravastatin than with gemfibrozil. However, gemofibrozil treatment resulted in a significantly greater reduction of triglyceride (TG) levels than did treatment with pravastatin. Pravastatin reduced the concentration of apoB (-19.3%, P<0.001) and cholesterol-rich Lp-B (Lp-B+Lp-B; E) particles (-19%, P<0.001) to a significantly greater extent (P<-0.001) than gemfibrozil (-4.1 and -1%, respectively). Both gemfibrozil and pravastatin reduced the concentrations of trigylceride-rich Lp-Bc (-12.2 and -13.3%, respectively) and Lp-A-II;B;C;D;E (-19 and -12.7%, respectively) particles and their characteristic apoC-III constituent (-10.0 and -7.0%, respectively). In contrast, gemfibozil has a greater lowering effect compared with pravastatin on TG levels (-29.6 vs. -6.3%, respectively). Both pravastatin and gemfibrozil significantly increased the levels of apoA-I and, with both drugs, the elevated concentrations of apoA-I were due to significantly increased levels of Lp-A-I;A-II particles. By decreasing both cholesterol-rich Lp-B and triglyceride-rich Lp-Bc particles and increasing HDL-C and Lp-A-I;A-II particles in addition to proven efficacy in decreasing coronary events in NIDDM patients, pravastatin appears to be an appropriate choice for monotherapy in a broad range of diabetic patients with Type IIA and Type IIB hyperlipoproteinemias. These results also showed that direct measurement of lipoprotein family of particles provides important information not only about the composition but also the type and number of apoA- and apoB-containing lipoprotein particles.",2002.0,0,0 1247,11948705,"The effects of three different LDL-apheresis methods on the plasma concentrations of E-selectin, VCAM-1, and ICAM-1.",Klaus Empen; Carsten Otto; Uli C Brödl; Klaus G Parhofer,"Plasma concentrations of cellular adhesion molecules are associated with atherosclerotic diseases and major cardiovascular risk factors. It was shown that LDL-apheresis with dextran sulfate lowers the levels of E-selectin and ICAM-1 in patients with familial hypercholesterolemia. The effects of different LDL-apheresis methods have not been studied yet. Cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, fibrinogen, and the adhesion molecules E-selectin, VCAM-1, and ICAM-1 were measured in 20 patients with coronary heart disease and severe hyperlipoproteinemia immediately before and after regular LDL-apheresis. Treatment was performed by different apheresis methods (direct absorption, DA, n = 6; dextran sulfate adsorption, DS, n = 7; heparin precipitation, HP, n = 7). Rebound data of adhesion molecule levels were obtained from 2 patients of each group. Lipids were reduced similarly in all groups. The concentrations of all adhesion molecules were lowered during apheresis. The reduction of E-selectin (-31 +/- 7 vs. -6 +/- 5 and -6 +/- 5%, respectively, P < 0.001) was most prominent in the patients treated by heparin precipitation. Depending on the method of LDL-apheresis, the concentrations of VCAM-1 and E-selectin in the outlets of the LDL-apheresis columns were significantly lower compared to the concentration in the inlets. Plasma concentrations of adhesion molecules increased to their pre-apheresis values within 2 to 4 days following LDL-apheresis. The reductions of adhesion molecule levels observed during LDL-apheresis are at least partly due to adsorption to the LDL-apheresis column. The extent of absorption depends on the principle of extracorporeal LDL elimination.",2002.0,0,0 1248,11950378,Tamsulosin: a review of its pharmacology and therapeutic efficacy in the management of lower urinary tract symptoms.,Christopher J Dunn; Anna Matheson; Diana M Faulds,"Tamsulosin is a subtype-selective alpha(1A)- and alpha(1D )-adrenoceptor antagonist. alpha(1)-Receptors predominate in the prostate gland, prostatic capsule, prostatic urethra and bladder, and the relaxation of prostate and bladder smooth muscles is associated with improved maximal urine flow (Q(max)) and alleviation of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH). Tamsulosin 0.4 mg once daily in a modified-release formulation increased Q(max) and improved symptom scores relative to baseline to a greater extent than placebo in 12- and 13-week double-blind, randomised, multicentre, clinical trials in patients with LUTS, with statistical significance between treatments for Q(max) values in two of three published US and European studies. Tamsulosin is effective in patients with mild to severe LUTS associated with BPH, in patients with diabetes mellitus and in the elderly, and does not interfere with concomitant antihypertensive therapy. Pooled data based on patients receiving tamsulosin 0.4 or 0. 8mg once daily indicate maintenance of efficacy for up to 6 years. Tamsulosin 0.4 mg once daily was of similar efficacy to alfuzosin 2.5 mg three times daily, with less tendency to cause hypotensive effects, in a double-blind, randomised 12-week trial. Benefit of the drug has also been shown in patients with acute urinary retention or chronic abacterial prostatitis, those receiving high energy transurethral microwave thermotherapy, and in patients with prostate cancer with radiation-induced urethritis. Dizziness and abnormal ejaculation are stated to be the most common adverse events, with asthenia, postural hypotension and palpitations being seen less frequently (1 to 2% incidence), in patients receiving tamsulosin 0.4 mg once daily. Tamsulosin has not been associated with clinically significant changes in blood pressure in clinical trials. The alpha(1A)- and alpha(1D)-adrenoceptor antagonist tamsulosin, given at a dosage of 0.4 mg once daily in a modified-release formulation, is effective and well tolerated in the treatment of LUTS associated with BPH. Although the drug has been directly compared to date with one other agent only, data show overall that tamsulosin clearly offers advantages over other alpha(1)-adrenoceptor antagonists in terms of the need for a single daily dose only, and its low potential for hypotensive effects or interference with concomitant antihypertensive therapy. Dosage titration at the start of treatment is not necessary. Tamsulosin has a rapid onset of action and is effective in patients with moderate or severe symptoms. The drug is therefore a valuable therapeutic option, with both demonstrated and potential advantages over older nonselective agents, in the management of patients with LUTS associated with BPH.",2002.0,0,0 1249,11950425,"Relation of markers of inflammation (C-reactive protein, fibrinogen, von Willebrand factor, and leukocyte count) and statin therapy to long-term mortality in patients with angiographically proven coronary artery disease.",Christoph Bickel; Hans J Rupprecht; Stefan Blankenberg; Christine Espiniola-Klein; Axel Schlitt; Gerd Rippin; Gerd Hafner; Rainer Treude; Hisham Othman; Klaus-Peter Hofmann; Jürgen Meyer; AtheroGene Investigators,"We evaluated a possible interaction between statins and inflammation in 1,246 patients with angiographically diagnosed coronary artery disease. Four different inflammatory markers were determined: high, sensitive C-reactive protein (hs-CRP) (p = 0.001), fibrinogen (p = 0.006), von Willebrand factor (p = 0.006), and leukocyte count (p = 0.03); these levels were significantly higher among the 88 patients who died of cardiac causes during follow-up (median 2.9 years) than among survivors. In a multivariate backward stepwise Cox regression mode, only hs-CRP was evaluated to be a significant predictor of death from coronary artery disease. This prediction was lost in statin-treated patients. Compared with patients receiving statin medication, patients without statins did not have increased cardiac mortality (even when low-density lipoprotein [LDL] levels were >125 mg/dl) when hs-CRP levels were not elevated. In contrast, patients without statins and elevated hs-CRP (top quartile) had a 2.3-fold increase in risk for fatal coronary events, independent of LDL levels. In conclusion, only elevated hs-CRP was selected as an independent predictor of death. Statin therapy is associated with elevated hs-CRP, with a risk reduction for fatal coronary events, independent of LDL levels; this, in part, may be explained by the anti-inflammatory effects on atherosclerosis.",2002.0,0,0 1250,11952022,Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records.,Patrick J Boyle; Allen Bennett King; Leann Olansky; Albert Marchetti; Helen Lau; Raf Magar; John Martin,"The antihyperglycemic effects of pioglitazone hydrochloride and rosiglitazone maleate are well documented. The results of clinical trials and observational studies have suggested, however, that there are individual differences in the effects of these drugs on blood lipid levels. The present study evaluated the effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus. This was a retrospective review of randomly selected medical records from 605 primary care practices in the United States in which adults with type 2 diabetes received pioglitazone or rosiglitazone between August 1, 1999, and August 31, 2000. The outcome measures were mean changes in serum concentrations of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glycosylated hemoglobin (HbA1c) values. Treatment with pioglitazone was associated with a reduction in mean TG of 55.17 mg/dL, a reduction in TC of 8.45 mg/dL, an increase in HDL-C of 2.65 mg/dL, and a reduction in LDL-C of 5.05 mg/dL. Treatment with rosiglitazone was associated with a reduction in mean TG of 13.34 mg/dL, an increase in TC of 4.81 mg/dL, a reduction in HDL-C of 0.12 mg/dL, and an increase in LDL-C of 3.56 mg/dL. With the exception of HDL-C, the differences in mean changes in lipid parameters between treatment groups were statistically significant (P < 0.001, pioglitazone vs rosiglitazone). Reductions in HbA1c were statistically equivalent between treatments (1.04% pioglitazone, 1.18% rosiglitazone). Treatment with pioglitazone was associated with greater beneficial effects on blood lipid levels than treatment with rosiglitazone, whereas glycemic control was equivalent between the 2 treatments.",2002.0,0,0 1251,11952885,Effects of simvastatin and atorvastatin on inflammation markers in plasma.,O Wiklund; L Mattsson-Hultén; E Hurt-Camejo; J Oscarsson,"To study the effect of statins on plasma markers for inflammation. Patients with hypercholesterolemia were randomized in one of the following treatments: Simvastatin (S) + placebo: S 40 mg for 6 weeks - S 80 mg for 6 weeks - S 80 mg for 24 weeks and Atorvastatin (A) + placebo: A 20 mg for 6 weeks - A 40 mg for 6 weeks - A 80 mg for 24 weeks. Forty-seven patients with hypercholesterolemia were recruited in four different outpatient clinics. Samples were obtained at randomization after 6, 12 and 36 weeks. Plasma or serum was analysed for lipids and for inflammation markers: C-reactive protein (CRP), serum amyloid A (SAA), soluble phospholipase A2 (SPLA2), intercellular adhesion molecule-1 (ICAM-1) and interleukin-6 (IL-6). The reduction in LDL was similar for the two statins, except at the highest dose of atorvastatin (41 vs. 47%). The increase in HDL tended to be more pronounced in the simvastatin group, significantly so on the highest dose of atorvastatin (P < 0.05). CRP and SAA was significantly reduced by atorvastatin, whilst no reduction was seen for simvastatin. There was a significant difference in treatment effects between the two statins. Both statins caused a reduction in SPLA2. For IL-6 and ICAM-1 only small and inconsistent reductions were observed for both statins. Atorvastatin reduced the liver-derived acute-phase reactants, CRP and SAA, whilst the effect of simvastatin was small or absent. Small and inconsistent effects were seen for both statins on plasma levels of IL-6 and ICAM-1.",2002.0,0,0 1252,11957568,Statins and bone morphogenetic proteins: new pathways in bone formation.,C J Edwards,"Osteoporosis is a major public health problem leading to morbidity and mortality in many individuals. Treatment for osteoporosis has generally relied on mechanisms that decrease osteoclastic bone resorption. This review outlines new evidence that the cholesterol synthetic pathway may be important in bone metabolism and that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins may increase bone formation. An experimental observation reported that statins increase bone formation in rodents and that statins have an important role for the cholesterol synthetic pathway in bone formation. This may be via potent bone-forming growth factors, the bone morphogenetic proteins (BMPs). Subsequent epidemiological studies (including a meta-analysis of 8 studies) have suggested that statin use may be associated with increased bone mineral density (BMD) and decreased fracture risk in humans. However, more recently published studies have challenged the effect on fracture risk. The effect of statins on bone mineral density and fracture risk in retrospective studies suggests an exciting new direction for research in bone formation that may lead to advances in the therapy of osteoporosis.",2002.0,0,0 1253,11958392,Vascular complications in diabetes and their prevention.,E Kassab; S I McFarlane; J R Sower,"Diabetes mellitus is increasing throughout the world. Cardiovascular disease (CVD) accounts for up to 80% of excess mortality in this high-risk population. Patients with diabetes have the same CVD risk factors as those people without diabetes. However, these risk factors are much more powerful in diabetic patients. CVD risk is especially high for diabetic women, and premenopausal diabetic women lose all the protection normally afforded to them by female sex hormones. Controlled clinical trials have clearly demonstrated that rigorous treatment of blood pressure, dyslipidemia and platelet hyperaggrebility strikingly reduces CVD risk in diabetic patients. Strategies directed at interrupting the renin-angiotensin system (both tissue and systemic systems) and the use of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors have proven to be especially beneficial for this high-risk population.",2002.0,0,0 1254,11959219,Dyslipemia and long-term immunosuppression.,R Charco,,2002.0,0,0 1255,11959239,Lipid-lowering effect of atorvastatin in heart transplantation.,L Almenar Bonet; L Martínez-Dolz; M A Arnau Vives; J Rueda Soriano; A Osa Sáez; F Dicenta Gisbert; M Palencia Pérez,,2002.0,0,0 1256,11959338,Effect of pravastatin treatment on the evolution of extracoronary atherosclerosis in renal transplant patients.,F Cofan; R Gilabert; D Zambon; I Nunez; E Ros; M Cofan; J M Campistol; C Bru; F Oppenheimer,,2002.0,0,0 1257,11959339,Pravastatin improves low-density lipoprotein oxidation in renal transplantation.,F Cofan; D Zambon; J C Laguna; E Casals; E Ros; M Cofan; J M Campistol; F Oppenheimer,,2002.0,0,0 1258,11959343,Lipid-lowering long-term effects of six different statins in hypercholesterolemic renal transplant patients under cyclosporine immunosuppression.,A Martínez-Castelao; J M Grinyó; S Gil-Vernet; D Serón; M J Castiñeiras; R Ramos; J Alsina,,2002.0,0,0 1259,11959344,Effects of cerivastatin in dyslipemia and other cardiovascular risk factors after renal transplantation.,I Garcia; P Errasti; F J Lavilla; B Ballester; J Manrique; E Rossich; A Purroy,,2002.0,0,0 1260,11960327,HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis.,W W L Wong; J Dimitroulakos; M D Minden; L Z Penn,"The statin family of drugs target HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolemia for the past 15 years. Experimental evidence suggests this key biochemical pathway holds an important role in the carcinogenic process. Moreover, statin administration in vivo can provide an oncoprotective effect. Indeed, in vitro studies have shown the statins can trigger cells of certain tumor types, such as acute myelogenous leukemia, to undergo apoptosis in a sensitive and specific manner. Mechanistic studies show bcl-2 expression is down-regulated in transformed cells undergoing apoptosis in response to statin exposure. In addition, the apoptotic response is in part due to the depletion of the downstream product geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or other products of the mevalonate pathway including cholesterol. Clinically, preliminary phase I clinical trials have shown the achievable plasma concentration corresponds to the dose range that can trigger apoptosis of tumor types in vitro. Moreover, little toxicity was evident in vivo even at high concentrations. Clearly, additional clinical trials are warranted to further assess the safety and efficacy of statins as novel and immediately available anti-cancer agents. In this article, the experimental evidence supporting a role for the statin family of drugs to this new application will be reviewed.",2002.0,0,0 1261,11964921,"Recent advances in the epidemiology, prevention, diagnosis, and treatment of fungal pneumonia.",Melanie W Pound; Richard H Drew; John R Perfect,"Although pneumonia caused by fungi is not a common occurrence in the general population, disease in an enlarging immunocompromised population is encountered with increasing frequency. Fungal pneumonias are most frequently caused by Aspergillus spp., dimorphic fungi and Cryptococcus neoformans. Recent studies have identified risk factors of thrombocytopenia, environmental events (such as construction or renovation) and immunosuppressive drug therapies as being specific risk factors for invasive fungal disease in select patient populations. Diagnostic strategies to detect circulating antigens and polymerase chain reaction based detection systems have been explored to improve identification prior to the progressive advanced disease. Advances in prophylactic strategies include increased use of aerosolized formulations of amphotericin B, usually in conjunction with new and old systemic antifungal agents. Despite recent published guidelines for treatment of fungal pneumonia based on etiology, mortality remains high in some infections with advanced disease. Caspofungin, a new echinocandin antifungal, has recently been approved by the US Food and Drug Administration for the treatment of invasive Aspergillus infections in patients unresponsive to or unable to receive amphotericin B. A triazole antifungal, voriconazole, has shown promise in phase III clinical trials in patients with refractory fungal infections and is expected to be available in early 2002. Other echinocandin and triazole antifungals are under development in attempts to provide improved effective therapy for fungal pneumonia.",2002.0,0,0 1262,11965265,The IONA study: preparing the myocardium for ischaemia?,Edward J Lesnefsky,,2002.0,0,0 1263,11966402,Candidate gene approach for pharmacogenetic studies.,Huijun Z Ring; Deanna L Kroetz,"Genetic diversity in the form of single nucleotide DNA polymorphisms (SNPs) contributes to variable disease susceptibility and drug response. The candidate gene approach has been widely used to identify the genetic basis for pharmacogenetic traits and becomes increasingly more powerful with the recent advances in genomic technologies. High-throughput sequencing and SNP genotyping technologies allow the study of thousands of candidate genes and the identification of those involved in drug efficacy and toxicity. Expression-based genomic technologies such as DNA microarrays and proteomics also facilitate the understanding of important biological and pharmacological pathways, thus identifying more candidate genes for SNP studies. Candidate gene-based pharmacogenetic studies will lead to improved drug development, improved clinical trial design and therapeutics tailored to individual genotypes.",2002.0,0,0 1264,11966668,High persistence of statin use in a Danish population: compliance study 1993-1998.,John Larsen; Morten Andersen; Jakob Kragstrup; Lars F Gram,"Several studies have found that compliance with lipid-lowering drug (LLD) treatment is low. However, the results of these studies were based on crude measures of compliance. The aim of this study was to describe compliance with statin treatment by analysing prescription patterns on an individual level in a population-based prescription database over a 6 year period. For incident statin users, all prescriptions for statins and drugs indicating cardiovascular disease or diabetes were retrieved from the OPED prescription database covering a population of about 470,000 inhabitants. Treatment was considered discontinued if the interval between two prescriptions exceeded number of tablets prescribed, plus 30 days. Compliance was assessed in terms of persistence and continuity. Persistence was defined as the period from the first prescription date to the date of discontinuation. Continuity was defined as the number of days with treatment (=number of tablets) divided by the total number of days in the period of persistence. 11% of the study cohort only received a single statin prescription. Survival analyses revealed a median persistence of 41 months. Less than 15% of the patients had more than 20% days without therapy within the period of persistence. Patients under 45 years without drug indicators of cardiovascular disease or diabetes presented the lowest compliance. The study showed good compliance with statin treatment in terms of persistence and continuity. A high percentage of the youngest patients, however, seemed to discontinue treatment before obtaining the full benefit in terms of decreased risk of coronary heart morbidity and mortality.",2002.0,0,0 1265,11971940,Density distribution of electronegative LDL in normolipemic and hyperlipemic subjects.,José Luis Sánchez-Quesada; Sonia Benítez; Carles Otal; Miquel Franco; Francisco Blanco-Vaca; Jordi Ordóñez-Llanos,"The density distribution of electronegative LDL [LDL(-)], a cytotoxic and inflammatory fraction of LDL present in plasma, was studied in 10 normolipemic (NL), 6 FH, and 11 hypertriglyceridemic (HTG) subjects. Six LDL subclasses of increased density (LDL1 to LDL6) were isolated by density-gradient ultracentrifugation (DGU). NL and FH subjects showed prevalence of light LDL, whereas HTG subjects showed prevalence of dense LDL. LDL(-) proportion was determined from total LDL or LDL-density subclasses by anion-exchange chromatography. LDL from FH patients had increased LDL(-) (35.1 +/- 9.9%) compared with LDL from NL and HTG subjects (9.4 +/- 2.3% and 12.3 +/- 4.3%, respectively). Most LDL(-) was contained in dense subclasses in NL (LDL4-6, 67.7 +/- 3.1%) whereas most of LDL(-) from FH patients were contained in light LDL subclasses (LDL1-3) (86.2 +/- 1.6%). In these subjects, simvastatin therapy decreased LDL(-) to 28.2 +/- 6.7% and 21.2 +/- 5.6% at 3 and 6 months of treatment, respectively, due mainly to decreases in light LDL subclasses. In HTG subjects, half LDL(-) was contained in dense LDL subclasses (LDL4-6, 46.1 +/- 2.0%). Non-denaturing acrylamide gradient gel electrophoresis concurred with DGU data, as LDL(-) from NL showed a single band of lower size than non-electronegative LDL [LDL(+)], whereas LDL(-) from FH and HTG presented bands of greater size than its respective LDL(+). These results reveal the existence of light and dense LDL(-), indicate that hyperlipemia could promote the formation of light LDL(-) and suggest that LDL(-) could have different origins.",2002.0,0,0 1266,11971941,Effect of atorvastatin on chylomicron remnant metabolism in visceral obesity: a study employing a new stable isotope breath test.,Dick C Chan; Gerald F Watts; P Hugh R Barrett; Ian J Martins; Anthony P James; John C L Mamo; Trevor A Mori; Trevor G Redgrave,"Elevated plasma concentration of chylomicron remnants may be causally related to atherosclerosis in obesity. We examined the effect of atorvastatin on chylomicron remnant metabolism in 25 obese men with dyslipidaemia. A remnant-like emulsion labeled with cholesteryl [(13)C]oleate was injected intravenously into patients; the fractional catabolic rate (FCR) of the remnant-like emulsion was determined by measurement of (13)CO(2) in the breath and analyzed using compartmental modelling. Compared with placebo, atorvastatin significantly decreased the plasma concentrations of total cholesterol, triglycerides, LDL cholesterol, apolipoprotein B (apoB), and lathosterol (P < 0.001). ApoB-48 and remnant-like particle-cholesterol (RLP-C) both decreased significantly by 23% (P = 0.002) and 33% (P = 0.045), respectively. The FCR of the remnant-like emulsion increased significantly from 0.054 +/- 0.008 to 0.090 +/- 0.010 pools/h (P = 0.002). The decrease in RLP-C was associated with the decrease in plasma triglycerides (r = 0.750, P = 0.003). Furthermore, the change in FCR of remnant-like emulsions was inversely associated with the change in LDL-C (r = -0.575, P = 0.040), suggesting removal of LDL and chylomicron remnants by similar hepatic receptor pathways. We conclude that in obese subjects, inhibition of cholesterol synthesis with atorvastatin decreases the plasma concentrations of both LDL-C and triglyceride-rich remnants and that this may be partially due to an enhancement in hepatic clearance of these lipoproteins.",2002.0,0,0 1267,11972540,Management of intermittent claudication.,C P Shearman,,2002.0,0,0 1268,11975764,If LDL-C is the answer...what was the question? What do the data really show?,R E Katholi; C L Deitrick; K J Hardiek,"The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are frequently utilized in the treatment of hypercholesterolemia. With recently completed statin clinical cardiovascular outcomes data available, the purpose of this review is to analyze the relative benefits of each molecule and to determine whether ""lower is better"" is a correct hypothesis for secondary prevention. Twenty-one clinical studies, each with a duration of statin therapy of 6 months or longer, were reviewed, and the pharmacologic effects of these agents on cardiovascular outcomes was examined. As evaluated by study drug, statistical event reduction was achieved in seven of nine pravastatin studies, one of three simvastatin studies, one of six lovastatin studies, zero of two fluvastatin studies, and zero of one atorvastatin study. Pravastatin was the only statin proven statistically to reduce events in both primary and secondary prevention. Thus, all of the statins do not appear to be the same in terms of their ability to reduce cardiovascular events. Until head-to-head trials have been completed, these clinical outcomes data suggest that in patients with severe hypercholesterolemia who require high-dose statin therapy, simvastatin 80 mg each evening would appear to be the agent of choice. However, pravastatin 40 mg daily at bedtime appears to be a unique molecule, with the strongest evidence for event reduction in the majority of patients with moderate hypercholesterolemia with, or who are at risk for, coronary heart disease.",2002.0,0,0 1269,11975844,Lovastatin and extended-release niacin combination product: the first drug combination for the management of hyperlipidemia.,Eric K Gupta; Matthew K Ito,"Advicor (lovastatin and extended-release niacin) is the first cholesterol-lowering combination product to become available for the management of hyperlipidemia. Lovastatin significantly lowers low-density lipoprotein cholesterol, whereas niacin significantly lowers triglycerides and lipoprotein (a) and markedly increases high-density lipoprotein cholesterol. These effects are ideal for managing a variety of lipid disorders, including metabolic syndrome. Lovastatin and niacin reduce coronary heart disease mortality in primary and secondary prevention patients, respectively. The extended-release niacin component uses a unique technology to minimize adverse effects (e.g., flushing and hepatotoxicity) while retaining the same lipid-altering effects as immediate-release niacin. The combination product appears to be well tolerated, with discontinuation due to adverse effects other than flushing occurring in a similar percent of patients as for lovastatin in clinical trials. Approximately 9% of patients discontinued the combination product due to flush. No confined cases of myopathy or hepatotoxicity have been reported with this product. Once-daily dosing provides ease of administration that should improve compliance and result in a greater proportion of patients meeting their low-density lipoprotein cholesterol goals. The nomenclature surrounding niacin products used to treat dyslipidemias is confusing. While only two types of niacin formulations exist (immediate-release formulations and formulations which dissolve more slowly than immediate-release formulations), government regulations allow for slowly dissolved niacin formulations to be divided into two types of niacin products; those that are available over-the-counter (OTC) and those that are available by prescription only. Over-the-counter slowly dissolved niacin preparations are not classified as OTC per se, but are considered ""nutritional supplements"". For this reason, they fall under the jurisdiction of the Federal Trade Commission and do not fall under the umbrella of the FDA branch that controls dyslipidemic products (Endocrine and Metabolic Division of the Center for Drug Evaluation and Research). The slowly dissolved niacin nutritional supplements have not been reviewed by the FDA for safety nor efficacy in the treatment of dyslipidemia nor are they required to meet generic drug rules (even though various brands are available). These brands are described on their labels as ""sustained-release"", ""timed-release"", and ""slow-release"" for example. Only two slowly absorbed niacin products have been approved by the FDA for the treatment of dyslipidemia; they are Niaspan (Kos Pharmaceuticals, Inc., Miami, FL) and Advicor (Kos Pharmaceuticals, Inc., Miami, FL). The term ""extended-release"" has been given to these two products to simplify the terminology and differentiate the products from immediate-release niacin. In this review, we will use ""extended-release"" to refer to the FDA approved slowly dissolving niacin preparation and ""sustained-release"" to refer to the nutritional supplements (not FDA approved).",2002.0,0,0 1270,11976073,The lower the better? Reviewing the evidence for more aggressive cholesterol reduction and goal attainment.,Evan Stein,"There is considerable evidence that more aggressive lowering of low-density lipoprotein (LDL) cholesterol is associated with increased benefits in reducing atherosclerotic disease burden, supporting the notion of 'the lower, the better.' However, achievement of currently recommended goals has proven difficult with lipid-lowering agents at the commonly used doses. Current options for achieving greater LDL cholesterol reductions include use of high doses of the most effective of the available statins and use of high or moderate statin doses in combination with agents that work in a complementary manner (e.g. bile acid sequestrants or niacin). Near-term options may include statins with increased LDL cholesterol-lowering effectiveness and better-tolerated secondary agents that can be combined with statin therapy. Rosuvastatin (Crestor, AstraZeneca) is a new statin that may prove to be of considerable utility in achieving greater LDL cholesterol reductions than are currently possible with existing statins. Recent phase III clinical trials have shown that this agent produces significantly greater LDL cholesterol reductions than atorvastatin, simvastatin, or pravastatin in patients with primary hypercholesterolemia and significantly greater reductions than the maximal dose of atorvastatin in patients with familial hypercholesterolemia.",2002.0,0,0 1271,11976074,High risk/high priority: familial hypercholesterolemia--a paradigm for molecular medicine.,Herbert Schuster,"Familial hypercholesterolemia provides an excellent model for demonstrating how disease prevention can be facilitated by molecular characterization of a genetic disease. To achieve the most efficient yield in terms of patient identification and coronary heart disease prevention, family information should be obtained in the primary care setting. In the majority of cases, measurement of cholesterol levels in a patient's relatives is sufficient to determine presence or absence of familial hypercholesterolemia, and DNA testing may be used in those cases in which cholesterol level is not diagnostic. DNA testing has enabled a more refined assessment of the absolute cardiovascular risks associated with familial hypercholesterolemia, which is currently estimated to have a 50% mortality rate by age 60. Recent investigations using DNA testing have suggested that familial hypercholesterolemia is implicated in one of 12 cases of cardiovascular disease in individuals aged <65 years. Only the most potent lipid-modifying therapies should be used in those found to be affected by this disorder. In this regard, it is noteworthy that the new statin rosuvastatin (Crestor; AstraZeneca) was recently shown to produce significantly greater low-density lipoprotein (LDL) cholesterol reductions and high-density lipoprotein (HDL) cholesterol increases than atorvastatin in a large study in patients with familial hypercholesterolemia, while bringing more of these patients to LDL cholesterol goals. Familial hypercholesterolemia should serve as a paradigm of molecular medicine: we understand the genetic defect, we have the tools to identify the individuals who are at high risk of disease because they have the defect, and we have therapies that can prevent clinical disease. It nevertheless requires effort on the part of clinicians to ensure that optimal risk assessment is performed and optimal treatment provided.",2002.0,0,0 1272,11976075,Optimizing the pharmacology of statins: characteristics of rosuvastatin.,M John Chapman; Fergus McTaggart,"Rosuvastatin (Crestor, AstraZeneca) is a new synthetic statin that exhibits a number of highly desirable pharmacologic characteristics. The drug has a high affinity for the active site of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and exhibits greater potency in inhibiting enzyme activity and cholesterol synthesis in vitro than other statins. The effects of rosuvastatin are selective for hepatic cells, and there is minimal uptake of the drug by nonhepatic tissues. The vast majority of biologic activity of the drug is associated with the parent compound, which does not appear to undergo extensive metabolism. Hepatic metabolism appears to be minimal, and there is little evidence of metabolic interaction with cytochrome P450 3A4. In an early-phase study, rosuvastatin produced large and dose-related decreases in low-density lipoprotein (LDL) cholesterol of up to 65% in hypercholesterolemic patients. Rosuvastatin should constitute an important addition to current lipid-lowering interventions.",2002.0,0,0 1273,11978140,Treatment of cutaneous T cell lymphoma: current status and future directions.,Narin Apisarnthanarax; Rakshandra Talpur; Madeleine Duvic,"The treatment of cutaneous T cell lymphoma (CTCL), which includes mycosis fungoides and Sezary syndrome, has been in a state of continual change over recent decades, as new therapies are constantly emerging in the search for more effective treatments for the disease. However, prognosis and survival of patients with CTCL remains dependent upon overall clinical stage (stage IA-IVB) at presentation, as well as response to therapy. Past therapies have been limited by toxicity or the lack of consistently durable responses, and few treatments have been shown to actually alter survival, especially in the late stages of disease. Even aggressive chemotherapy has not been shown to improve overall survival compared to conservative sequential therapy in advanced disease, and adds the risk of immunosuppressive complications. Over the last decade, extracorporeal photopheresis has been the only single treatment that has been shown to improve survival in patients with Sezary syndrome, although its true efficacy and place in combination therapy remain unclear. Much of the focus of current research has been on combinations of skin-directed therapies and biological response modifiers, which improve response rates. The results of various trials over the years have also brought into favor the use of post-remission maintenance therapy with topical corticosteroids, topical mechlorethamine (nitrogen mustard), interferon-alpha, or phototherapy to prevent disease relapse. Recent novel developments in CTCL therapy include oral bexarotene, a retinoid X receptor-selective retinoid that has activity in all stages of CTCL, and the topical gel formulation of bexarotene, which plays a role in treating localized lesions. US Food and Drug Administration (FDA)-approved, oral systemic bexarotene has the advantage of a 48% overall response rate at a dosage of 300 mg/m(2)/day, and avoids immunosuppression and risk of central line and catheter-related infectious complications that are associated with other systemic therapies. Monitoring of triglycerides and use of concomitant lipid-lowering agents and thyroid replacement is required in most patients. Also recently FDA-approved, denileukin diftitox is the first of a novel class of fusion toxin proteins and is selective for interleukin-2R (CD25+) T cells, targeting the malignant T cell clones in CTCL. Denileukin diftitox is associated with capillary leak syndrome in 20 to 30% of patients, which may be ameliorated by hydration and corticosteroids. Higher response rates are possible by combining bexarotene with ""statin"" drugs and active CTCL therapies. Studies are being conducted on combining bexarotene and denileukin diftitox with other modalities. Biological response modifier therapies that are in current or future investigational trials include topical tazarotene, pegylated interferon, interleukin-2, and interleukin-12. At the forefront of systemic chemotherapy development, pegylated liposomal doxorubicin, gemcitabine, and pentostatin appear to have the greatest potential for success in CTCL therapy. Bone marrow transplantation, which is currently limited by the risk of graft-versus-host disease, offers the greatest potential for disease cure. Further developments for CTCL may include more selective immunomodulatory agents, vaccines, and monoclonal antibodies.",2002.0,0,0 1274,11978147,Lipid-lowering drug use and cardiovascular events after myocardial infarction.,Olaf H Klungel; Susan R Heckbert; Anthonius de Boer; Hubert G M Leufkens; Sean D Sullivan; Paul A Fishman; David L Veenstra; Bruce M Psaty,"The benefits of lipid-lowering drug treatment for the secondary prevention of coronary heart disease have been well established by randomized, controlled trials. Nonetheless, the risk of events has not been compared directly for inhibitors of hydroxymethylglutaryl coenzyme A reductase (statins) and non-statin lipid-lowering drugs. Further, it remains uncertain whether patients in usual practice who are treated with lipid-lowering drugs after myocardial infarction (MI) gain a similar benefit with regard to the risk of cardiovascular events compared with patients in randomized, controlled trials. To assess the association between lipid-lowering drug therapies in usual clinical practice and the risk of cardiovascular events in patients with a first MI who were discharged alive from the hospital. An inception-cohort study was performed among 1956 enrollees of Group Health Cooperative who sustained an incident MI between July 1986 and December 1996 and survived for at least 6 months after hospitalization. Subjects with untreated low-density-lipoprotein cholesterol concentrations > 130 mg/dL or untreated total cholesterol concentrations >200 mg/dL were included. The median duration of follow-up after the first MI was 3.3 years. Medical record review was used to collect information on cardiovascular risk factors. Computerized pharmacy records were used to assess antihyperlipidemic drug use during the first 6 months after hospitalization. Compared with 1263 subjects who did not receive lipid-lowering drug treatment, 373 subjects who received statins had a lower risk of recurrent coronary events (relative risk [RR] 0.59; 95% CI 0.39 to 0.89), stroke (RR 0.82; 95% CI 0.35 to 1.95), atherosclerotic cardiovascular mortality (RR 0.49; 95% CI 0.21 to 1.13), and any atherosclerotic cardiovascular event (RR 0.63; 95% CI 0.40 to 0.98). Among 320 subjects who used non-statin drug therapies, the RRs were 0.66 (95% CI 0.45 to 0.97) for recurrent coronary events, 0.95 (95% CI 0.46 to 1.95) for stroke, 0.68 (95% CI 0.35 to 1.32) for cardiovascular mortality, and 0.77 (95% CI 0.53 to 1.11) for any atherosclerotic cardiovascular event, compared with untreated hyperlipidemic patients. In this study of MI survivors, the use of lipid-lowering drug therapies after hospitalization was associated with a reduced risk of cardiovascular events. These results emphasize the importance of lipid-lowering drug treatment in patients with hyperlipidemia who survive a first MI.",2002.0,0,0 1275,11978227,Should antioxidants be added to simvastatin and niacin for patients with coronary disease?,Woodward Burgert; Warren P Newton,,2002.0,0,0 1276,11978260,Weekly versus daily dosing of atorvastatin.,R Douglas Iliff,"Twenty-four consecutive patients of a single family physician who had achieved NCEP-II goal levels of low-density lipoprotein cholesterol (LDL-C) on a daily atorvastatin dose of 10 mg for at least 6 months were invited to switch to 20 mg weekly. Mean LDL levels for the 22 patients who completed the trial had been reduced by 43% from baseline on 10 mg daily (P <.05) and were reduced by 22% from baseline on the seventh day following the last weekly dose of 20 mg (P <.05). Total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratios were reduced by 31% and 17%, respectively (both P <.05) and triglycerides by 20% and 10% (both P <.05).",2002.0,0,0 1277,11978263,Treatment of hyperlipidemia.,Eric Henley; Linda Chang; Sue Hollander,"In 1995 and 1996, US adults made more than 18 million office visits for the evaluation and treatment of hyperlipidemia, including 3.4% of all visits to family physicians. Among visits to family physicians, 4.1% included measurement of cholesterol levels.(1) Overall, mean cholesterol levels decreased from 220 in 1960-1962 to 203 in 1988-1994. During the same time period, the proportion of adults with elevated total cholesterol levels (> 240) decreased from 32% to 19%.(2) Despite this progress, the availability of more effective drugs, guidelines advocating increasingly aggressive treatment, and population-wide goals established in Healthy People 2010 will continue to increase the number of patients seen by family physicians for screening, diagnosis, and treatment of hyperlipidemia.",2002.0,0,0 1278,11978950,New advances in lipid-modifying therapies for reducing cardiovascular risk.,Eric Bruckert,"Over the last 30 years, several epidemiological and prospective studies have identified a number of risk factors for the development of cardiovascular disease. Lipid abnormalities are central among these risk factors, and their correction has been a major target for the medical community. The 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors (statins) are the most widely prescribed and best tolerated of the currently available lipid-modifying therapies. Newer agents in this class (e.g. rosuvastatin) have been developed that have proven to be more effective at lowering levels of low-density lipoprotein cholesterol (LDL-C). New formulations of drugs such as nicotinic acid can improve treatment regimens and reduce unpleasant side-effects, thereby improving patient compliance with this therapy. In terms of developing novel drugs, the introduction of cholesterol absorption inhibitors (e.g. ezetimibe) and ACAT inhibitors (e.g. avasimibe) will provide clinicians with therapies that exploit different therapeutic pathways to those currently being utilised. Combining these agents with statins could produce greater improvements in lipid profile than those seen to date. In addition, advances in our understanding of the pathophysiology of dyslipidaemia have led to the identification of other novel therapeutic targets, including cholesteryl ester transfer protein. Studies with experimental drugs have already demonstrated the potential of these approaches.",2002.0,0,0 1279,11981263,Hyperlipidemia in kidney disease: causes and consequences.,Meena Sahadevan; Bertram L Kasiske,"Dyslipidemias are common in patients with chronic kidney disease. The causes vary with the stage of kidney disease, the degree of proteinuria, and the modality of end-stage renal disease treatment. Dyslipidemias have been associated with kidney disease progression, and a number of small, randomized, controlled trials of lipid-lowering agents have been conducted. Unfortunately, the results of these trials, although encouraging, have been inconclusive because of the small numbers of patients enrolled. Dyslipidemias may also contribute to the high incidence of cardiovascular disease in patients with chronic kidney disease. This is most likely for patients with chronic renal insufficiency and for kidney transplant recipients. Less certain is the role of dyslipidemias in the pathogenesis of cardiovascular disease among dialysis patients.",2003.0,0,0 1280,11982746,Statins and the assessment of endothelial function.,Kaeng W Lee; Dirk C Felmeden; Gregory Y H Lip,,2002.0,0,0 1281,11982954,Comparison of different treatment regimens in a case of homozygous familial hypercholesterolemia.,Jean-Bernard Palcoux; Martine Meyer; Pierre Jouanel; Philippe Vanlieferinghen; Georges Malpuech,"The laboratory results of five periods of different treatment regimens were compared in a 19-year-old girl with homozygous familial hypercholesterolemia (FH): weekly low-density lipoprotein (LDL) apheresis sessions with dextran sulfate columns (LA 15, Kaneka Corporation, Osaka, Japan) without statin administration; weekly LDL apheresis with polyacrylate columns (DALI, Fresenius Adsorber Technology, Bad Homburg, Germany) without statin; LDL apheresis as in Period 2 with 40 mg atorvastatin daily; LDL apheresis as in Period 2 with 80 mg atorvastatin daily; and fortnightly LDL apheresis sessions with polyacrilate and administration of 80 mg atorvastatin daily. The five treatments were given in the above order, and each lasted at least 2 months. To compare the effectiveness of the different methods, the blood levels of total cholesterol, LDL-cholesterol and high-density lipoprotein (HDL)-cholesterol were measured before each session, and the percentage decreases in the blood levels of total cholesterol and LDL-cholesterol were recorded during sessions in Periods 1 and 2. In Periods 1 and 2, the biological effectiveness of LDL apheresis was comparable. Atorvastatin (40 mg daily) improved the blood levels of total cholesterol and LDL-cholesterol, but lowered HDL-cholesterol values. Increasing the daily dose of atorvastatin from 40 mg to 80 mg did not significantly improve LDL-cholesterol levels. When the time between two sessions was longer (Period 5), the total cholesterol and LDL-cholesterol values worsened and were comparable to those of Period 2 during which there was no atorvastatin treatment. In this case of homozygous FH, weekly sessions of LDL apheresis in association with atorvastatin at dose of 40 mg per day gave the best results.",2002.0,0,0 1282,11984212,"Angiographic intervention trial using HMG CoA reductase inhibitor to evaluate retardation of obstructive multiple atheroma in West Japan (ATHEROMA study): rationale, design and baseline.",Akito Kawaguchi; Kazuaki Mitsudo; Masakiyo Nobuyoshi; Ryouzo Minamino; Kazuya Hayasaki; Mitsuyoshi Nakashima; Akira Yamamoto; ATHEROMA Study Group,"The ATHEROMA study is a prospective, multicentre, randomized controlled study in Japan to assess the changes of coronary atherosclerosis of patients with pre-existing coronary artery disease (CAD) by cholesterol-lowering therapy (CLT) using pravastatin 10-20 mg per day for 3 years. The primary objective is to evaluate the changes in coronary minimum lumen diameters by quantitative coronary arteriography, and the secondary outcome is to observe morphological changes of plaques and clinical events including mortality, recurrence of CAD and the requirement of any coronary intervention. The primary objective will test the hypothesis that CLT results in a beneficial effect on coronary vessels in patients with coronary atherosclerosis in Japan, where the incidence of CAD is the lowest among industrialized countries. A total of 373 eligible patients were recruited from 799 patients and allocated to a dietary (n=187) and pravastatin regimen (n=186) by the minimization method. Clinical characteristics in the two groups were well matched and there were no differences in serum lipids and coronary status between them. The average +/- SD (range) of total, LDL and HDL cholesterol were 225.6 +/- 17.3 mg/dl, 141.9 +/- 21.2 mg/dl and 49.4 +/- 12.0 mg/dl, respectively. Three years of follow-up were completed in late 2000, and cine angiograms blinded through the study coordinating centre were interpreted at the angiographic core laboratory. The final results, which are due to be published in 2002, will reveal whether or not specifically designed prophylactic strategy based on different cultural background is required.",2002.0,0,0 1283,11984215,Atorvastatin versus four statin-fibrate combinations in patients with familial combined hyperlipidaemia.,Vasilios G Athyros; Athanasios A Papageorgiou; Valasia V Athyrou; Dimokritos S Demitriadis; Anthimos N Pehlivanidis; Athanasios G Kontopoulos,"Statin-fibrate combinations are very effective in the treatment of familial combined hyperlipidaemia (FCHL). Nonetheless, they have not been extensively used because of the fear of side effects. Thus, a therapeutic alternative is required for this lipid disorder. To compare the long-term (one-year) efficacy of atorvastatin monotherapy with those of four statin-fibrate combinations in 675 FCHL patients. Patients were randomly assigned to atorvastatin monotherapy (A 20 mg/day) n = 134, or pravastatin (P 20 mg/day)+gemfibrozil (G 1200 mg/day) n = 135, simvastatin (S 20 mg/day)+G (1200 mg/day) n = 137, P (20 mg/day)+ciprofibrate (C 100 mg/day) n = 135, and S (20 mg/day)+C (100 mg/day) n = 134. Twelve patients on statin-fibrate combinations were withdrawn from the study because of side effects: three because of CK elevation, two because of myalgia and seven due to increase in serum transaminase levels. One patient on A was withdrawn because of persistent epigastric discomfort. Atorvastatin reduced low density lipoprotein cholesterol and apoprotein B more than all four combinations (-45% vs. maximum -40% of S+C, and -39% vs. maximum -32% of the same combination, respectively, P < 0.001 for both), but had a lesser effect on triglycerides (-38% vs. maximum -53% of S+C, P = 0.0002) and high density lipoprotein cholesterol (6% vs. maximum 21% of S+G, P = 0.0003). The effect of A on plasma fibrinogen was analogous to that of G combinations (-8% vs. -9% of P+G and -11% of S+G, P = NS vs. baseline and among each other) and inferior to that of the ciprofibrate combinations (-8% vs. -24% of P+C, P = 0.0002 and -26% S+C, P = 0.0001). A had a lower treatment cost and better patient compliance, P = 0.04 vs. C combinations and P = 0.02 vs. G combinations. The data suggest that statin-fibrate combinations have a beneficial effect on all lipid parameters. Atorvastatin monotherapy has a better effect on LDL-C and apoprotein B than statin-fibrate combinations, but a lesser effect on HDL-C, TG and in the case of ciprofibrate combinations, fibrinogen. The clinical significance of these findings should be tested in a large, long-term survival study.",2002.0,0,0 1284,11989073,[Significance of the follow-up of patients with ischemic cardiopathy in the treatment with atorvastatin as secondary prevention. Pilot study].,F de la Iglesia Martínez; S Pita Fernández; V Ramos Polledo; C Pellicer Vázquez; R Nicolás Miguel; F Diz-Lois Martínez,"To determine the usefulness of different intensities of follow up when atorvastatin is used in the secondary prevention of ischemic heart disease. Design. Prospective study with balanced randomized allocation including a concurrent control group. Ambulatory care. 75 patients hospitalized because of acute coronary syndromes were administered atorvastatin as secondary prevention of ischemic heart disease and randomized either to intensive follow up or to a control visit 6 months apart. The intensive follow up group (40 patients) was controlled every 2 months as outpatients and a physical examine and lipid profile was done, enhancing diet and exercise and adjusting the statin dose. The control group was evaluated just once after a 6 six month period. 88% were males and the average age was 63.7 +/- 10 year. Basal characteristics, myocardial infarction, revascularized procedures and initial chemistry and lipid profile were similar in both groups, although there was a higher proportion of patients in the control group taking ACE. After 6 months total cholesterol, LDL cholesterol and triglycerides reduction was higher in the intensive follow up group (33 vs. 24, 34 vs. 26 y 51 vs. 24 mg/dl, respectively) without realising statistical significance. Hospital readmissions were lesser in the intensive group (7.3% vs. 19.4%, P = 0.114). There was one death in each group. Results show a tendency indicating that follow up planification is relevant to obtain the target lipid level recommended in the secondary prevention.",2002.0,0,0 1285,11994377,Mechanism of action of a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor on apolipoprotein B-100 kinetics in visceral obesity.,Dick C Chan; Gerald F Watts; P Hugh R Barrett; Trevor A Mori; Lawrence J Beilin; Trevor G Redgrave,"We examined the effect of atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the kinetics of apolipoprotein B-100 (apoB) metabolism in 25 viscerally obese men in a placebo-controlled study. Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB kinetics were measured using an iv bolus injection of [(2)H(3)]leucine. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry. Kinetic parameters were derived by using a multicompartmental model (SAAM-II). Compared with the placebo group, atorvastatin treatment resulted in significant (P < 0.001) decreases in total cholesterol (-34%), triglyceride (-19%), LDL cholesterol (-42%), total apoB (-39%), and lathosterol (-86%); VLDL-apoB, IDL-apoB, and LDL-apoB pool sizes also fell significantly (P < 0.002) by -27%, -22%, and -41%, respectively. This was associated with an increase in the fractional catabolic rates of VLDL-apoB (+58%, P = 0.019), IDL-apoB (+40%, P = 0.049), and LDL-apoB (+111%, P = 0.001). However, atorvastatin did not significantly alter the production and conversion rates of apoB in all lipoproteins. We conclude that in obese subjects, atorvastatin decreases the plasma concentration of all apoB-containing lipoproteins chiefly by increasing their catabolism and not by decreasing their production or secretion. This may be owing to up-regulation of hepatic receptors as a consequence of inhibition of cholesterogenesis.",2002.0,0,0 1286,11996199,Statins and osteoporosis: can these lipid-lowering drugs also bolster bones?,Abelardo C Cruz; Barry L Gruber,"The statins may not only lower cholesterol, they may stimulate bone formation, as suggested by a number of observational studies and animal research. Whether these drugs will be of benefit in treating osteoporosis awaits further clinical trials.",2002.0,0,0 1287,11996608,Low- and high-density lipoprotein cholesterol and ischemic cerebrovascular disease: the bezafibrate infarction prevention registry.,Nira Koren-Morag; David Tanne; Eran Graff; Uri Goldbourt,"Despite increasing evidence that beta-hydroxy-beta-methyglutaryl coenzyme A reductase inhibitors reduce the incidence of stroke in patients with coronary heart disease (CHD), the associations between blood lipid levels and cerebrovascular disease (CVD) are not clear. To evaluate whether blood cholesterol level and its fractions are risk factors for stroke in a large group of patients with CHD. We followed up 11 177 patients with documented CHD who were screened for but not included in the Bezafibrate Infarction Prevention study, a secondary prevention randomized clinical trial of lipid modification, and had no history of stroke for subsequent CVD. During a 6- to 8-year follow-up period, 941 patients were identified as having nonhemorrhagic CVD, of whom 487 had verified ischemic stroke or transient ischemic attack (TIA). Increases in age-adjusted rates of both nonhemorrhagic CVD and verified ischemic stroke or TIA were identified with increasing cholesterol and low-density lipoprotein cholesterol levels, decreasing high-density lipoprotein cholesterol levels, and decreasing percentage of total serum cholesterol contained in the HDL moiety. In logistic regression models, adjusting for clinical covariates, the following odds ratios (95% confidence intervals) were identified for lipid values in the upper vs lower tertile for the end point of nonhemorrhagic CVD: total cholesterol, 1.43 (1.20-1.70); low-density lipoprotein cholesterol, 1.52 (1.27-1.81), high-density lipoprotein cholesterol, 0.84 (0.70-1.00); and percentage of serum cholesterol contained in HDL, 0.69 (0.58-0.83). Similar trends appeared for the end point of verified ischemic stroke or TIA. These findings clearly support the role of total cholesterol and its fractions in prediction of ischemic CVD among patients with established CHD.",2002.0,0,0 1288,11996626,"Statins: balancing benefits, efficacy and safety.",Michael B Clearfield,"Coronary heart disease (CHD) is the leading cause of death in the US. The risk of CHD is substantially increased in people with elevated levels of low-density lipoprotein cholesterol (LDL-C). The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most effective drug class for lowering LDL-C. Long-term prospective studies have shown that statin therapy significantly reduces the risk of CHD morbidity and mortality in patients without or with evidence of established CHD (primary and secondary prevention, respectively). In 1988, treatment guidelines were first issued by the National Cholesterol Education Program Adult Treatment Panel I (NCEP-ATP I), then revised in 1993 (ATP II), to provide recommendations for the prevention and management of high cholesterol in adults. Despite these guidelines, recent national surveys have shown that effective therapies are being under-utilised and they often fail to achieve LDL-C goals established by NCEP-ATP II. The reasons appear to be multifactorial but include issues related to efficacy, safety, the potential for adverse drug reactions, failure to prescribe appropriate medication or dose and noncompliance with therapy. In the first major update of NCEP guidelines in almost a decade, the current ATP III recommendations have placed an increased number of Americans in the high-risk category, inviting even more aggressive therapy and escalating the challenge of reaching NCEP goals. New statins that may have even greater efficacy and less potential for drug interactions may help address some concerns associated with the failure to achieve treatment goals.",2002.0,0,0 1289,11996943,Effect of atorvastatin and bezafibrate on plasma levels of C-reactive protein in combined (mixed) hyperlipidemia.,Juan A Gómez-Gerique; Emilio Ros; Josefina Oliván; Jose M Mostaza; Miquel Vilardell; Xavier Pintó; Fernando Civeira; Antonio Hernández; Pedro Marqués da Silva; Antonio Rodriguez-Botaro; Daniel Zambón; Joan Lima; Cristina Díaz; Rosa Aristegui; Josep M Sol; José Chaves; Gonzalo Hernández; ATOMIX Investigators,"C-reactive protein (CRP) is a non-specific but sensitive marker of underlying systemic inflammation. High CRP plasma levels correlate with risk for future cardiovascular events. The present study evaluated the effects of atorvastatin (10-40 mg) and bezafibrate (400 mg) on CRP concentrations after 6 and 12 months of treatment in 103 patients with combined (mixed) hyperlipidemia. The number of cardiovascular risk factors present in a given patient was associated with baseline CRP levels. After 6 months and 1 year, atorvastatin treatment was associated with significant (P<0.001) decreases from baseline of CRP concentrations by 29 and 43%, respectively, while bezafibrate-treated patients showed non-significant reductions of 2.3 and 14.6%, respectively (P=0.056 and 0.005 for the respective differences between the two treatment arms at 6 months and 1 year). The magnitude of change in CRP after 1 year was directly related to baseline CRP levels. Covariance analysis showed that CRP decreases in the atorvastatin group were unrelated to total cholesterol and LDL cholesterol reductions; however, they were directly related to triglyceride changes (r=0.28, P=0.047) and inversely related to HDL cholesterol changes (r=-0.28, P=0.045). A model including baseline CRP values and treatment effect showed that atorvastatin use was a significant predictor of change in CRP levels over time (beta=0.82, P=0.023). These results suggest a potential anti-atherosclerotic additional benefit of atorvastatin in patients at a risk of cardiovascular disease.",2002.0,0,0 1290,11996956,A 16-week fenofibrate treatment increases LDL particle size in type IIA dyslipidemic patients.,Isabelle Lemieux; Luc Laperrière; Vladimir Dzavik; Gérald Tremblay; Joanne Bourgeois; Jean Pierre Després,"The objective of the present study was to compare the effects of a 16-week pharmacotherapy with fenofibrate (200 mg) or pravastatin (initially 20 mg for 8-weeks and, if necessary, increased to 40 mg) on low density lipoprotein (LDL) particle size assessed by gradient gel electrophoresis among patients with type IIa dyslipidemia. For that purpose, type IIa dyslipidemic patients (cholesterol, 7.45+/-1.18 (S.D.) mmol/l; LDL cholesterol, 5.57+/-1.16 mmol/l; triglycerides (TGs), 1.66+/-0.43 mmol/l) were randomized to either fenofibrate (n=36) or pravastatin (n=43) therapy for 16 weeks. Fasting plasma lipoprotein levels as well as the LDL peak particle size (using 2-16% polyacrylamide gel electrophoresis) were assessed at baseline and after the 16-week treatment period. Whereas significant improvements in the plasma lipoprotein-lipid variables were observed with both fenofibrate and pravastatin treatments, LDL peak particle size was only significantly increased with fenofibrate therapy (+2.11+/-5.18 A, P<0.05). Among patients under fenofibrate therapy, changes in TG levels were negatively associated with changes in LDL peak particle size (r=-0.54, P<0.0007), whereas no such association was found in pravastatin-treated patients. The prevalence of patients with small, dense LDL particles (as defined by LDL particle diameter <255.5 A) was reduced from 69.4 to 30.6% (P<0.05) among fenofibrate-treated patients as opposed to 81.4 to 72.1% (NS) in patients who received pravastatin. As pravastatin treatment had no effect on LDL size, it is suggested that the additional effect of fenofibrate therapy on LDL size may contribute to reduce the risk of coronary heart disease (CHD) beyond what can be expected from the reduction in LDL cholesterol concentration in type IIa dyslipidemic patients.",2002.0,0,0 1291,11996957,"A randomized, double-blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia.",Yasushi Saito; Nobuhiro Yamada; Tamio Teramoto; Hiroshige Itakura; Yoshiya Hata; Noriaki Nakaya; Hiroshi Mabuchi; Motoo Tushima; Jun Sasaki; Nobuya Ogawa; Yuichiro Goto,"Pitavastatin (p-INN) is a novel and fully synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, with a cholesterol-lowering action stronger than that of other statins currently in use. A 12-week, multi-center, randomized, double-blind, controlled study was conducted to confirm the efficacy and safety of pitavastatin compared with pravastatin, an agent for using to reduce low density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. Patients were recruited at 43 institutes in Japan. Following more than 4 weeks run-in period, 240 patients were randomized to receive 2 mg of pitavastatin or 10 mg of pravastatin daily. At 12 weeks post-randomization, the pitavastatin group showed significantly lower LDL-C levels by -37.6% from baseline compared with -18.4% in the pravastatin group (P<0.05). Pitavastatin also significantly lowered total cholesterol (TC) by -28.2% compared with -14.0% of pravastatin (P<0.05). The LDL-C target level of <140 mg/dl was attained in 75% of the patients treated with pitavastatin, compared with 36% of those in the pravastatin group (P<0.05). Pitavastatin also significantly reduced triglycerides (TG), apo B, C-II and C-III, compared with pravastatin, and increased HDL-C, apo A-I and A-II, to the same extent of pravastatin. Safety was assessed by monitoring adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. These results indicated that pitavastatin was more effective than pravastatin, and both drugs were well-tolerated in the treatment of hypercholesterolemia.",2002.0,0,0 1292,11999665,Effects of pravastatin on exercise electrocardiography test performance and cardiovascular mortality and morbidity in patients with hypercholesterolemia: Lipid Intervention Study in Kyoto.,Susumu Sasaki; Masao Nakagawa; Tetsuo Nakata; Akihiro Azuma; Shohei Sawada; Kazuo Takeda; Jun Asayama; Lipid Intrvention Study in Kyoto,"The long-term effects of the 3-hydoxy-3-methyl-glutaryl coenzyme A reductase inhibitor, pravastatin, on exercise electrocardiography (ECG) test performance and cardiovascular mortality and morbidity were compared with those of conventional lipid-lowering drugs in hypercholesterolemic patients with no history of myocardial infarction or stroke. One thousand two hundred and seventeen patients were randomly assigned with mean serum cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol levels of 6.98 +/- 0.91mmol/L, 2.08 +/- 1.87mmol/L, 1.38 +/- 0.44mmol/L, and 5.07 +/- 1.14 mmol/L, respectively, and received either pravastatin at a dose of 10-20mg/day (group P) or one of the conventional lipid-lowering drugs such as fibrates, nicotinic acid, and probucol (group C). The numbers of patients available for analysis in groups P and C were 305 and 278 at year 1, 261 and 216 at year 2, 206 and 184 at year 3, 159 and 122 at year 4, and 103 and 81 at year 5. Over the 3.2 year mean follow-up period, the reduction in serum LDL cholesterol levels was significantly greater (p<0.01) in group P (-24.3%) than in group C (-16.0%). Serum HDL cholesterol levels increased in group P (+11.6%), but decreased in group C (-0.3%) (p<0.01). There were no significant differences in the rate of patients who exhibited ischemic changes to exercise ECG test (ischemic responders) between the 2 groups. Coronary heart diseases (CHD) occurred in 6 patients in group P and 13 in group C; pravastatin significantly reduced CHD risk (reduction rate 0.369; 95% confidence interval 0.140-0.970; p<0.05). No significant differences existed between the treatment groups in terms of the number of strokes (group P, 6; group C, 7) or deaths unrelated to CHD (group P, 3; group C, 2). Although pravastatin did not improve the proportion of ischemic responders on exercise testing, it reduced CHD risk and serum LDL cholesterol levels more significantly than conventional lipid-lowering drugs without adversely affecting the risk of stroke and non-CHD death in hypercholesterolemic patients.",2002.0,0,0 1293,12000046,The cardiovascular event reduction tool (CERT)--a simplified cardiac risk prediction model developed from the West of Scotland Coronary Prevention Study (WOSCOPS).,G L'Italien; I Ford; J Norrie; P LaPuerta; J Ehreth; J Jackson; J Shepherd,"The clinical decision to treat hypercholesterolemia is premised on an awareness of patient risk, and cardiac risk prediction models offer a practical means of determining such risk. However, these models are based on observational cohorts where estimates of the treatment benefit are largely inferred. The West of Scotland Coronary Prevention Study (WOSCOPS) provides an opportunity to develop a risk-benefit prediction model from the actual observed primary event reduction seen in the trial. Five-year Cox model risk estimates were derived from all WOSCOPS subjects (n = 6,595 men, aged 45 to 64 years old at baseline) using factors previously shown to be predictive of definite fatal coronary heart disease or nonfatal myocardial infarction. Model risk factors included age, diastolic blood pressure, total cholesterol/ high-density lipoprotein ratio (TC/HDL), current smoking, diabetes, family history of fatal coronary heart disease, nitrate use or angina, and treatment (placebo/ 40-mg pravastatin). All risk factors were expressed as categorical variables to facilitate risk assessment. Risk estimates were incorporated into a simple, hand-held slide rule or risk tool. Risk estimates were identified for 5-year age bands (45 to 65 years), 4 categories of TC/HDL ratio (<5.5, 5.5 to <6.5, 6.5 to <7.5, > or = 7.5), 2 levels of diastolic blood pressure (<90, > or = 90 mm Hg), from 0 to 3 additional risk factors (current smoking, diabetes, family history of premature fatal coronary heart disease, nitrate use or angina), and pravastatin treatment. Five-year risk estimates ranged from 2% in very low-risk subjects to 61% in the very high-risk subjects. Risk reduction due to pravastatin treatment averaged 31%. Thus, the Cardiovascular Event Reduction Tool (CERT) is a risk prediction model derived from the WOSCOPS trial. Its use will help physicians identify patients who will benefit from cholesterol reduction.",2002.0,0,0 1294,12002257,Pleiotropic effects of HMG-CoA reductase inhibitors.,Nikos Werner; Georg Nickenig; Ulrich Laufs,"HMG CoA reductase inhibitiors (statins) have been shown to be effective lipid lowering agents and are able to significantly reduce cardiovascular mortality and morbidity in patients at risk for cardiovascular disease. Recent clinical and experimental data suggest that the benefit of statins may extend beyond their hepatic effects on serum cholesterol levels. This review summarizes the current evidence and the molecular mechanisms of the direct effects of statins on plaque stability, inflammation, endothelial function, oxidative stress, thrombosis and stroke. Furthermore, recent data on the effects of statins on bone marrow, bone density and dementia are described. In summary, statins have emerged as a novel and powerful tool to study cardiovascular biology, including protein isoprenylation, small G protein function, leukocyte activity and endothelial progenitor cells. These pleiotropic properties of statins may have important clinical implications in addition to lowering serum cholesterol.",2002.0,0,0 1295,12006915,Lipid modulation and liver function tests. A report of the Program on the Surgical Control of the Hyperlipidemias (POSCH).,Henry Buchwald; Stanley E Williams; John P Matts; James R Boen,"Statin drugs are known to cause dose-dependent abnormalities in liver function tests (LFTs), with elevations three times the upper limits of normal of the aminotransferase enzymes in up to 2.5% of patients on the highest prescribable doses. The Program on the Surgical Control of the Hyperlipidemias (POSCH) trial employed no hypocholesterolaemic drugs and used a surgical procedure, partial ileal bypass, as the intervention modality. Serum total bilirubin, alkaline phosphatase and serum glutamic-oxaloacetic transaminase (SGOT) (equivalent to aspartate aminotransferase [AST]), were the LFTs obtained in POSCH at baseline, 3 months, annually for 5 years, and at 7 or 10 years postrandomization. Abnormal values were found for total bilirubin in seven of 416 control group (CG) patients (1.68%) and in 34 of 373 intervention group (IG) patients (9.16%) (P = 0.001); for alkaline phosphatase, in 28 of 378 (7.41%) and in 41 of 326 (12.58%) (P = 0.0214); and for SGOT, in 102 of 412 (24.76%) and in 161 of 372 (43.28%) (P = 0.001). Values twice the upper limit of normal occurred in 1 CG and 1 IG patient for total bilirubin and for alkaline phosphatase, and in 11 CG and 7 IG patients for SGOT (NS). Values three times the upper limit of normal did not occur in any patient for total bilirubin or alkaline phosphatase, and occurred in 3 CG and 5 IG patients for SGOT (NS). In POSCH, the IG demonstrated statistically significant mild increases for total bilirubin, alkaline phosphatase and SGOT levels, with no significant increases in values twice or greater the upper limits of normal.",2002.0,0,0 1296,12006916,Declaring war on undertreatment: rationale for an aggressive approach to lowering cholesterol.,Marjel van Dam; Sanne van Wissen; John J P Kastelein,"Few things are better understood within the medical community than the relationship between elevated total and low-density lipoprotein cholesterol (LDL-C) levels, cardiovascular disease and death. There is consensus in the treatment guidelines of numerous national and international bodies that cholesterol levels in at-risk patients should be reduced to target levels that have been shown in population studies to be associated with low rates of coronary heart disease (CHD). However, dyslipidaemia continues to be underdiagnosed and undertreated. The 'landmark' statin trials have demonstrated unequivocally that effective lipid-lowering therapy significantly decreases CHD morbidity and mortality. Furthermore, these benefits of lipid-lowering therapy are not limited to middle-aged men, but extend across a broad range of patient populations. Recent trial data suggest that lowering LDL-C to target levels is possible in a substantial proportion of patients when statins are administered aggressively and results in a greater reduction in the risk of major coronary events. This reduction in events is seen in patients with stable coronary disease as well as those treated immediately after an acute coronary syndrome. Although strong clinical and angiographic evidence shows that intensive treatment prevents morbidity and saves lives, indications are that clinicians are still waiting too long to treat dyslipidaemia and when treatment is initiated it is often at inadequate dosages. Undertreatment of dyslipidaemia is an issue that the healthcare community can no longer ignore.",2002.0,0,0 1297,12007681,Percutaneous intervention for atherosclerotic disease in saphenous vein grafts.,Niall T Mulvihill; Jean Marco,The long term benefit of coronary artery bypass surgery (CABG) is limited by development of atherosclerotic disease in the bypass conduits. Percutaneous revascularisation is frequently the preferred method of treated symptomatic saphenous vein graft (SVG) atherosclerotic disease. The immediate and long term results of percutaneous intervention for SVGs is reviewed. Therapeutic considerations as well as novel technical advances are overviewed,2002.0,0,0 1298,12009719,Short-term effects of atorvastatin on C-reactive protein.,W F Riesen; H Engler; M Risch; W Korte; G Noseda,"To study the short-term effect of atorvastatin on C-reactive protein (CRP) in patients with or at risk for coronary heart disease. One hundred and fifty-five randomly selected patients from the SWiss Intervention Trial for lowering CHolesterol (SWITCH) were assessed for high sensitivity CRP, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides at baseline, and after 1 and 3 months of treatment with atorvastatin at various doses to reach pre-defined lipid target values. The median decrease of cholesterol was 28% after 1 month and 35% after 3 months. LDL-cholesterol was decreased by 37% and 45%, HDL-cholesterol was increased by 7% and 8%, respectively. Patients with a low CRP baseline concentration (lowest quartile <1.34 mg. l(-1)) displayed no significant change, whereas patients in the other quartiles showed a significant decrease, of 22% to 40% (P -value <0.05 to <0.001) at 1 month and of 32% to 36% after 3 months compared to baseline. The decrease in CRP lowering was thus fully established by 1 month and this response was independent of lipid and lipoprotein changes as well as atorvastatin doses. Atorvastatin significantly decreases CRP concentrations after 4 weeks of therapy. These results may be important with respect to the early benefit of statin therapy.",2002.0,0,0 1299,12010563,Statins as modulators of bone formation.,Christopher J Edwards; Tim D Spector,"The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) to reduce serum cholesterol is well described. However, the recent finding that statins have direct effects on bone was unexpected. A number of epidemiological studies have recently been published that explore the effects of statins on bone mineral density and risk of fracture in humans. Statins may act by directly stimulating the expression of bone morphogenetic protein-2 and increasing osteoblast differentiation or, like nitrogen-containing bisphosphonates, may have effects on the mevalonate pathway that leads to inhibition of osteoclast activity and osteoblast apoptosis. In addition, the demonstration that statins can inhibit inflammation and encourage angiogenesis offers other possibilities for action.",2002.0,0,0 1300,12014432,Early initiation of treatment with statins in acute coronary syndromes.,Anders G Olsson; Gregory G Schwartz,"Statins may act rapidly to reverse abnormalities of the arterial wall that may predispose to recurrent ischemic events after acute coronary syndromes. Such abnormalities are endothelial dysfunction, a local inflammatory response. and an exaggerated thrombogenic tendency. In one study almost 20,000 patients with first myocardial infarction were studied with regard to statin treatment (28%) or not. Baseline characteristics were adjusted using multivariate regression analysis including propensity analysis. One year mortality was 3.7/5.0% in statin/not statin groups, respectively, P = 0.001, relative risk 0.75. In another study of more than 20,000 patients, 18% were prescribed statin after an acute coronary syndrome and followed for six months. Propensity analysis was performed in this study as well. Deaths in statin/not statin groups were 1.7/3.5%, P<0.0001, relative risk 0.48. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL), a double-blind randomized, placebo-controlled intervention study, 3086 patient with acute non-Q-wave coronary syndromes were allocated immediately in hospital to receive atorvastatin 80 mg daily or placebo for four months. No lower limit for plasma LDL cholesterol was used. Primary endpoint was time to first occurrence of death, non-fatal myocardial infarction, cardiac arrest, and worsening angina with objective evidence of ischemia. This was significantly reduced compared to the placebo group by 2.4% (14.8 versus 17.2%, relative risk 0.84, P= 0.048). Atorvastatin also reduced significantly fatal or non-fatal strokes. Possible mechanisms behind these acute beneficial effects are discussed. The studies highlight the importance of treatment with a statin in the early management of acute coronary syndromes and the need to incorporate this therapeutic strategy in national guidelines and treatment recommendations.",2002.0,0,0 1301,12015788,Pharmacokinetics of lovastatin extended-release dosage form (Lovastatin XL) in healthy volunteers.,Michael Lamson; Gale Phillips; Jason Shen; Peter Lukacsko; Lawrence Friedhoff; Robert M Niecestro,"The purpose of this study was to evaluate pharmacokinetics and dose proportionality of lovastatin extended-release dosage form (ER-lovastatin) in the dosage levels of 10, 20 and 40 mg in 9 healthy male subjects. Each subject was randomized to receive a single oral dose of ER-lovastatin either 10, 20 or 40 mg in a three-way crossover design with a washout period of 7 days between the treatments. Subjects were served dinner at approximately 5:30 PM followed by dosing at approximately 10:00 PM in each study period. Serial plasma samples were collected up to 48 h after dosing and assayed for lovastatin and its active metabolite lovastatin acid using an LC/MS/MS method. The plasma concentration-time profiles of lovastatin and its active metabolite lovastatin acid exhibited delayed- and extended-release characteristics at each dose. Mean (+/-) values for the C(max) of lovastatin were 1.04+/-0.43, 2.03+/-0.65 and 4.03+/-3.02 ng/ml for the 10, 20 and 40 mg dosage, respectively. The corresponding values for the AUC(0-48 h) of lovastatin were 14.6+/-7.8, 34.1 +/-13.7, and 53.9+/-35.6 ng h/ml. The same tendency was also found for C(max) and AUC(0-48 h) values of lovastatin acid. Results from this study demonstrated as the dose of ER-lovastatin increased from 10 to 40 mg, the C(max) and AUC(0-48 h) values of lovastatin as well as lovastatin acid appeared to increase linearly.",2002.0,0,0 1302,12017224,Hyperlipidemia in children with type 2 diabetes mellitus.,Doris Taha,"Atherosclerosis is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (DM). The increased risk of coronary artery disease in patients with type 2 DM is partly due to the lipoprotein abnormalities associated with DM. Dyslipidemia outweighs all other risk factors for cardiovascular disease in adults with type 2 DM. Hypertriglyceridemia and low levels of high-density lipoprotein (HDL)-cholesterol are the most common abnormalities in adults with type 2 DM. These abnormalities may improve, but commonly persist, after optimal glycemic control has been achieved. Children with type 2 DM also have hypertriglyceridemia, low levels of HDL-, as well as elevated levels of total and low-density lipoprotein (LDL)-cholesterol levels. Screening for dyslipidemia is recommended in children with type 2 DM. Several adult clinical trials that included patients with DM have demonstrated the efficacy of lowering LDL-cholesterol in preventing death from coronary artery disease. Weight loss, changing dietary habits, increasing physical activity, and improving glycemic control are initial approaches to the treatment of hyperlipidemia in children with type 2 DM. When goals are not met, drug therapy should be considered.",2002.0,0,0 1303,12017409,A preliminary evaluation of neural network analysis for pharmacodynamic modeling of the dosing of the hydroxymethylglutaryl coenzyme A-reductase inhibitors simvastatin and atorvastatin.,Albert Moon; Timothy Smith,"Neural networks have been used in diagnosing and treating many diseases, including the diagnosis of myocardial infarction and insulin dosing in diabetes mellitus. The goal of this study was to develop a preliminary pharmacodynamic model for dosing of the hydroxymethylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors simvastatin and atorvastatin using neural network analysis. Using NeuralSIM neural network software (NeuralWare, Carnegie, Pa), lipid panels from patients at a hospital lipid clinic were entered as inputs for the model, and the doses of simvastatin or atorvastatin that achieved those lipid results were used as outputs. The network was trained using 2 different data sets and was run using a subset of the data as inputs. The results of the neural network run (predictions) were compared with the actual doses used as directed by the hospital pharmacist in accordance with the lipid clinic protocol. Complete data sets were available for 17 patients (11 men, 6 women). The mean age of these patients was 56.7 years (range, 40-67 years). The neural network model based on data set 1 predicted a dose that was within 95% of the actual dose 7 of 12 times and predicted use of the drug actually used 13 of 19 (68.4%) times. The neural network based on data set 2 predicted use of the drug actually used 10 of 17 (58.8%) times, but the predicted doses never approximated the actual doses by > or = 90%. A neural network model for the dosing of the HMG-CoA-reductase inhibitors simvastatin and atorvastatin demonstrated an ability to predict appropriate dosing, but inclusion of other factors (eg, age, body weight, sex) and a larger sample size may be necessary for development of a more accurate model.",2002.0,0,0 1304,12017803,,,,,0,0 1305,12018562,Evaluation of anti-atherosclerotic and vasculoprotective effect of long acting nifedipine in patients after PTCA.,S Vaidya; P Walwaikar; G Kadhe,"The anti-atherosclerotic and vasculoprotective effect of long acting nifedipine (nicardia retard 20) was evaluated on patients undergoing percutaneous transluminal coronary angioplasty (PTCA). This was a randomised, controlled, prospective clinical trial. A total of 30 patients fulfilling inclusion criteria were divided randomly in 2 groups of 15 each. One group was given long acting nifedipine while other group did not receive long acting nifedipine. The rest of the treatment was similar for both the groups. Clinical and angiographic parameters were evaluated regularly for a period of one year. The group receiving long acting nifedipine showed 20% restenosis as against 33% in group not receiving long acting nifedipine. Thus, from this trial, it can be concluded that long acting nifedipine can reduce the progress of reocclusion and thus demonstrates the anti-atherosclerotic and vasculoprotective action.",2002.0,0,0 1306,12018641,Lipids in end-stage renal disease.,Christoph Wanner,,2003.0,0,0 1307,12018878,Reducing global risk for cardiovascular disease: using lifestyle changes and pharmacotherapy.,Alan Cheng; Joel B Braunstein; Cheryl Dennison; Caitlin Nass; Roger S Blumenthal,"Cardiovascular disease (CVD) is the leading cause of death and disability in industrialized societies, due in large part to the lack of a comprehensive approach to control the risk factors for atherosclerosis. One strategy for reducing an individual's global CVD risk relies on a targeted approach that modifies each of the major independent risk factors prevalent in both symptomatic (secondary prevention) and asymptomatic (primary prevention) patients. These interventions include lipid lowering, smoking cessation, blood pressure control, glycemic control, regular exercise, and the use of various medications. This review offers an evidence-based strategy toward reducing an individual's global risk for CVD by addressing the modifiable, major independent risk factors.",2002.0,0,0 1308,12019599,Current indications for ACE inhibitors and HOPE for the future.,Stephanie Burch; Narith Ou,"Angiotensin-converting enzyme (ACE) inhibitors are effective in several disease states such as congestive heart failure, myocardial infarction, and diabetes. This article reviews the evidence supporting the clinical use, efficacy, and cost effectiveness of ACE inhibitors in these various disease states. With the findings of the Heart Outcomes Prevention Evaluation trial, these agents may now have a positive impact on the primary prevention of coronary artery disease. New and ongoing trials will provide more information about the role of ACE inhibitors in coronary artery disease.",2002.0,0,0 1309,12020174,Interaction between aspirin and ACE Inhibitors: resolving discrepancies using a meta-analysis.,Bahi Takkouche; Mahyar Etminan; Francisco Caamaño; Paula A Rochon,"Recently, studies have attempted to explore the interaction between ACE inhibitors and aspirin (acetylsalicylic acid) when both drugs are used concomitantly to reduce mortality in patients with coronary artery disease. Results have been conflicting due, in part, to sub-optimal methods used to explore this interaction. We reviewed systematically all studies on mortality in patients treated with ACE inhibitors and aspirin and conducted a meta-analysis in order to explore the interaction between both drugs and resolve discrepancies. To be included, each study had to provide data on mortality of patients who received both drugs, either drug and no drug. These data were necessary to calculate the synergy index (S) and its 95% confidence interval (CI) that we used to quantify the effect due to interaction between ACE inhibitors and aspirin. After testing for heterogeneity of effects, we pooled the S values from the individual studies into one summary measure. Subsequently, we compared our results with those obtained through the most common but incorrect method of evaluating interaction. This method uses significance testing of the relative risk of mortality when a 'product term' between ACE inhibitors and aspirin is entered in a logistic regression model. Eight studies met the inclusion criteria. The pooled synergy index S indicates slight but precise antagonism between ACE inhibitors and aspirin (S = 0.91; 95% CI 0.80 to 1.03). In contrast, the pooled 'product term' is not significant and would have lead to the conclusion of absence of interaction (p = 0.15). There seems to be an antagonistic interaction between ACE inhibitors and aspirin. Former discrepancies were due to inadequate assessment of interaction. Results from the Studies on Left Ventricular Dysfunction (SOLVD) and Heart Outcome Prevention Evaluation (HOPE) trials that assessed the effect of combined administration of ACE inhibitors and aspirin were not included in this meta-analysis because those trials did not provide enough data to compute the S statistic. It is possible that results from on-going trials such as Women's Atovarstatin Trial on Cholesterol (WATCH) will shed more light on ACE inhibitor and aspirin interaction in the future.",2002.0,0,0 1310,12020249,Treatment of patients with stroke.,Louis R Caplan,,2002.0,0,0 1311,12020481,Statins and chronic heart failure: do we need a large-scale outcome trial?,Henry Krum; John J McMurray,"Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are of proven clinical benefit in coronary heart disease, at least in those patients who do not have overt chronic heart failure (CHF). However, as there have been no prospective clinical trials of statins in CHF patients, the question arises as to whether the benefits observed in the absence of CHF can be necessarily inferred in those patients in whom CHF is established. In this review, the evidence base stating support of the use of statins in CHF is presented, as well as theoretical considerations as to why these agents may not necessarily be of benefit in this setting. The beneficial potential of statins clearly relates to their plaque stabilization properties and associated improvements in endothelial function, which together should reduce the risk of further infarction and, perhaps, the ischemic burden on the failing ventricle. Furthermore, these agents may have beneficial effects independent of lipid lowering. These include actions on neoangiogenesis, downregulation of AT(1) receptors, inhibition of proinflammatory cytokine activity and favorable modulation of the autonomic nervous system. The potential adverse effects of statins in CHF include reduction in levels of coenzyme Q10 (which may further exacerbate oxidative stress in CHF) and loss of the protection that lipoproteins may provide through binding and detoxifying endotoxins entering the circulation via the gut. In support of these possibilities are epidemiologic data linking a lower serum cholesterol with a poorer prognosis in CHF. These uncertainties indicate the need for a definitive outcome trial to assess the efficacy and safety of statins in CHF, despite their current widespread, non-evidence based use in this population.",2002.0,0,0 1312,12020548,Survival plots of time-to-event outcomes in clinical trials: good practice and pitfalls.,Stuart J Pocock; Tim C Clayton; Douglas G Altman,"Survival plots of time-to-event data are a key component for reporting results of many clinical trials (and cohort studies). However, mistakes and distortions often arise in the display and interpretation of survival plots. This article aims to highlight such pitfalls and provide recommendations for future practice. Findings are illustrated by topical examples and also based on a survey of recent clinical trial publications in four major journals. Specific issues are: should plots go up or down (we recommend up), how far in time to extend the plot, showing the extent of follow-up, displaying statistical uncertainty by including SEs or CIS, and exercising caution when interpreting the shape of plots and the time-pattern of treatment difference.",2002.0,0,0 1313,12021218,Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project.,Marc A Pfeffer; Anthony Keech; Frank M Sacks; Stuart M Cobbe; Andrew Tonkin; Robert P Byington; Barry R Davis; Carola P Friedman; Eugene Braunwald,"Therapeutic decisions regarding pharmacological therapy should be based on safety and tolerability as well as efficacy data. Clinical trials designed to assess efficacy are often insufficiently powered to generate reliable safety data. The West of Scotland Coronary Prevention Study (WOSCOPS), the Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies collectively accumulated >112 000 person-years of exposure in double-blind randomized trials comparing placebo and pravastatin (40 mg once daily). During 5 years of exposure, the incidence of fatal and nonfatal cancers was similar between pravastatin and placebo groups. No differences in noncardiovascular serious adverse events were detected. With >243 000 blood sample analyses, the percentage of patients with any abnormal liver function test after baseline sampling was similar (>3x the upper limit of normal for alanine aminotransferase: 128 [1.4%] versus 131 [1.4%] patients for pravastatin versus placebo, respectively). Study medication was withdrawn in 3 pravastatin and 7 placebo patients due to creatine phosphokinase elevations; no cases of mild or severe myopathy were reported. A Cox regression model considering treatment group, age, diabetes, smoking, whether primary or secondary prevention study, and cardiovascular serious adverse events indicates that the likelihood of discontinuing pravastatin was less than placebo. This prospective analysis indicates that during prolonged exposure, 40 mg of pravastatin is well tolerated, with no excess of noncardiovascular serious adverse events, including liver function abnormalities and laboratory and clinical evidence for myositis. These extensive safety and tolerability data provide important information for therapeutic decisions regarding this pharmacological agent.",2002.0,0,1 1314,12021938,Stroke prevention: management of modifiable vascular risk factors.,Didier Leys; Dominique Deplanque; Claire Mounier-Vehier; Marie-Anne Mackowiak-Cordoliani; Christian Lucas; Régis Bordet,"Stroke prevention is a crucial issue because (i) stroke is a frequent and severe disorder, and (ii) acute stroke therapies that are effective at the individual level have only a little impact in term of public health. Stroke prevention consists of the combination of 3 strategies: an optimal management of vascular risk factors, associated when appropriate with antithrombotic therapies, carotid surgery, or both. Primary prevention trials have shown that reducing blood pressure in hypertensive subjects reduces their vascular risk, including stroke. The association of perindopril plus indapamide reduces the vascular risk in patients who have had a stroke or TIA during the last 5 years, irrespective of their baseline blood pressure. Lowering serum cholesterol with statins or gemfibrozil in patients with hypercholesterolemia or coronary heart disease (CHD), reduces the risk of stroke. However, no trial of cholesterol-lowering therapy has been completed in stroke patients. A strict control of high cholesterol levels should be encouraged, because of benefits in terms of CHD. Statins should be prescribed for stroke patients with CHD, or increased cholesterol levels. Cigarette smoking is associated with an increased risk of stroke and should be avoided. Careful control of all risk factors, especially arterial hypertension in type 1 and type 2 diabetics is recommended, together with a strict glycemic control to reduce systemic microvascular complications. Estrogens prescribed in hormone replacement or oral contraceptive therapies are not recommended after an ischemic stroke. It is also recommended to reduce alcohol consumption and obesity, and to increase physical activity in patients at risk for first-ever or recurrent stroke. An optimal management of risk factors for stroke is crucial to reduce the risks of first-ever stroke, recurrent stroke, any vascular event after stroke and vascular death. One of the major public health issues for the coming years will be to focus more on risk factor recognition and management.",2002.0,0,0 1315,12022381,The CURE trial: using clopidogrel in acute coronary syndromes without ST-segment elevation.,Gregory P Gerschutz; Deepak L Bhatt,"In a large, randomized, placebo-controlled trial in centers that use a conservative approach to acute coronary syndromes, the antiplatelet drug clopidogrel (Plavix) decreased the rate of the combined end point of cardiovascular death, nonfatal myocardial infarction, or stroke by 20% in patients presenting with acute coronary syndromes without ST-segment elevation. The benefit was at the cost of an increase in bleeding, however. This strategy may need to be tailored in centers that use a more aggressive treatment strategy of early angiography and revascularization.",2002.0,0,0 1316,12024336,Atherothrombosis: plaque instability and thrombogenesis.,Frederick L Ruberg; Jane A Leopold; Joseph Loscalzo,"Hemostasis involves a carefully regulated balance between circulating and endothelium-derived prothrombotic and antithrombotic factors. The unstable or vulnerable plaque facilitates thrombosis, clinically manifest as an acute coronary syndrome (ACS), by creating an environment that favors thrombus formation over prevention of lysis. Endothelial cell dysfunction is integral to both the development of the atherosclerotic lesion as well as its destabilization. The transformation of a stable plaque to an unstable one involves complex interactions among T lymphocytes, macrophages, endothelial cells, and smooth muscle cells. Degradation of the fibrous cap of the atherosclerotic lesion as well as the overexpression of prothrombotic and underexpression of antithrombotic factors by cells within the plaque precede thrombus formation. Accordingly, pharmacological interventions for the treatment of ACS are directed against the initiation and propagation of thrombosis, as well as toward improvement of endothelial function.",2002.0,0,0 1317,12027926,Teaching patients to monitor their risk factors retards the progression of vascular complications in high-risk patients with Type 2 diabetes mellitus--a randomized prospective study.,R Rachmani; Z Levi; I Slavachevski; M Avin; M Ravid,"Intensive management of risk parameters in diabetic patients may retard the progression of both micro- and macrovascular complications. Intensified care requires expert staff and is expensive. The aim of the present study was to examine whether sharing the therapeutic responsibility with the patients will improve the outcome. A randomized prospective study of 165 patients with diabetes mellitus Type 2, hypertension (> 140/90 mmHg) and hyperlipidaemia (LDL-C > 120 mg/dl). Patients were randomly allocated to standard annual consultation (SC) or to a patient participation programme (PP). The medical care for both groups was administered by primary care physicians, who were unaware of the nature of the intervention. At 4 years the mean blood pressure was 148/88 (+/- 6.1/1.7) mmHg in the SC patients vs. 142/84 (+/- 5.8/1.8) mmHg in the PP group (P = 0.02). The mean LDL-C was 124 +/- 8 and 114 +/- 6 mg/dl (P = 0.01) and the mean HbA1c was 8.9 +/- 1.2% and 8.2 +/- 1.5% (P = 0.04) in the SC and PP groups, respectively. The average annual fall in estimated glomerular filtration rate was 3.5 ml/min per year in the SC group vs. 2.25 in the PP group (P < 0.05). Albumin/creatinine ratio > 300 mg/g developed in four SC patients vs. none of the PP patients. There was a total of 36 cardiovascular events in the SC group vs. 23 in the PP group (P = 0.04). All patients in the PP group received ACE inhibitors (or AII blockers) and statins vs. 52% and 43%, respectively, in the SC group. Glucose-lowering regimens were similar. Well-informed and motivated patients were more insistent to reach and maintain target values of the main risk factors of diabetic complications. The differences between the PP and SC groups were of the same order of magnitude as those between intensive and standard care groups in other studies albeit with, comparatively, a very modest cost.",2002.0,0,0 1318,12027977,Matrix metalloproteinases and atherosclerotic plaque instability.,Ian M Loftus; A R Naylor; P R F Bell; M M Thompson,"There is growing interest in the role of matrix metalloproteinases in atherosclerosis. Excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic plaque disruption, a frequent predeterminant of ischaemic cardiac events and stroke. These enzymes represent a potential target for therapeutic intervention to modify vascular pathology. The core of this review is derived from a Medline database literature search. There is convincing evidence of increased matrix metalloproteinase activity during acute plaque disruption. Evidence for an imbalance promoting increased matrix degradation is less well documented. However, studies of matrix metalloproteinase inhibition in models of vascular disease suggest a potential therapeutic benefit. In vivo studies of matrix metalloproteinase inhibition are required to study the potential for reversal or deceleration of the excessive tissue remodelling that accompanies acute plaque disruption.",2002.0,0,0 1319,12028227,Unanswered questions: the use of statins in older people to prevent cardiovascular event effects of statins on risk of coronary disease: a meta-analysis of randomized controlled trials.,Lorna M Birch,,2002.0,0,0 1320,12028504,Effects of micronized fenofibrate versus atorvastatin in the treatment of dyslipidaemic patients with low plasma HDL-cholesterol levels: a 12-week randomized trial.,J-P Després; I Lemieux; H Salomon; D Delaval,"Studies have suggested that raising low levels of high-density lipoprotein cholesterol (HDL-C) may be an important target for the prevention of coronary heart disease. To compare the ability of micronized fenofibrate and atorvastatin to increase plasma HDL-C levels. Multicentre, randomized open-label study. Settings. The study was conducted in 19 centres across the UK and Canada. One hundred and eighty-one patients were randomized and the full analysis set included 165 nondiabetic patients with low HDL-C (women <46 mg dL-1, i.e. 1.2 mmol L-1 and men <43 mg dL-1, i.e. 1.1 mmol L-1): 86 patients in the atorvastatin group and 79 patients in the micronized fenofibrate group. Interventions. Micronized fenofibrate (200 mg day-1, 87 patients) or atorvastatin (10 mg day-1, 94 patients) for a period of 12 weeks. Main outcome measures. Percent change in HDL-C levels. After 12 weeks of treatment, the mean percent change from baseline in HDL-C was significantly higher in the micronized fenofibrate group (13.3%) compared with the atorvastatin group (5.3%, P=0.0003). The magnitude of such relative change was inversely related to the baseline HDL-C levels only in the micronized fenofibrate group. Furthermore, in the fenofibrate treatment group, 50.9% of the patients (29 of 57 patients) with a baseline HDL-C <40 mg dL-1 achieved a plasma HDL-C level above 40 mg dL-1 after 12 weeks of treatment versus 27.9% of the patients (19 of 68 patients) in the atorvastatin group (P=0.01). On the basis of (1) the greater impact of fenofibrate than atorvastatin on HDL-C levels and (2) the greater proportion of dyslipidemic patients achieving HDL-C levels above 40 mg dL-1 with fenofibrate than atorvastatin, it is suggested that micronized fenofibrate should be considered as a good therapeutic option to treat dyslipidemic patients with low HDL-C and moderately elevated LDL-C concentrations.",2002.0,0,0 1321,12028507,Effect of apoE genotype on the hypolipidaemic response to pravastatin in an outpatient setting.,R Peña; C Lahoz; J M Mostaza; J Jiménez; E Subirats; X Pintó; M Taboada; A López-Pastor; Rap Study Group,"Considerable variability exists in the plasma lipid and lipoprotein response to statin treatment due, in part, to genetic factors. The gene for apolipoprotein E (ApoE) is polymorphic and the different genotypes modulate baseline lipid levels. The objective of the present study was to evaluate the effect of the apoE genotype on the lipoprotein response to pravastatin treatment in an outpatient population followed-up in several different clinics across Spain. Subjects and methods. Subjects (n=401; 56% female; mean age 57 years), who were hypercholesterolaemic despite a diet poor in saturated fat and cholesterol, were treated according to NCEP-ATP II guidelines. Plasma lipids and lipoproteins were measured centrally before and after 16 weeks of treatment with 20 mg day-1 of pravastatin. ApoE genotype distributions were 3.2% with varepsilon2/3, 73.1% with varepsilon3/3 and 22.4% with varepsilon3/4 or varepsilon4/4. ApoE genotype did not have any effect on baseline lipid levels except on triglycerides such that the carriers of the varepsilon2 allele had concentrations significantly greater than those subjects with varepsilon3/3 genotype and carriers of the varepsilon4 allele after adjustment for age, gender and body mass index (BMI) (P < 0.001). Once adjusted for age, gender, BMI and baseline lipid levels, the apoE polymorphism did not significantly influence the plasma lipid and lipoprotein response to pravastatin. ApoE genotype appears not to influence the hypolipidaemic effect of pravastatin in patients monitored in a general outpatient setting.",2002.0,0,0 1322,12028600,Reduction of coronary events with aspirin in older patients with prior myocardial infarction treated with and without statins.,Wilbert S Aronow; Chul Ahn,"In an observational prospective study of 1,410 patients (mean age, 81 +/- 9 years) with prior myocardial infarction, no contraindications to aspirin, and a serum low-density lipoprotein cholesterol level of 125 mg/dL or higher, 832 (59%) were treated with aspirin. At the 36-month follow-up evaluation, the incidence of new coronary events was 52% in persons treated with aspirin versus 70% in those who were not treated with aspirin (P < 0.0001). The stepwise Cox regression model showed that significant independent predictors of new coronary events were age (risk ratio, 1.05 for each 1-year increase), current cigarette smoking (risk ratio, 2.7), hypertension (risk ratio, 1.7), diabetes mellitus (risk ratio, 2.2), initial serum low-density lipoprotein cholesterol level (risk ratio, 1.01 for each 1-mg/dL increase), initial serum high-density lipoprotein cholesterol level (risk ratio, 0.96 for each 1-mg/dL increase), use of statins (risk ratio, 0.46), and use of aspirin (risk ratio, 0.48).",2003.0,0,0 1323,12029003,Effect of atorvastatin and fish oil on plasma high-sensitivity C-reactive protein concentrations in individuals with visceral obesity.,Dick C Chan; Gerald F Watts; P Hugh R Barrett; Lawrence J Beilin; Trevor A Mori,"Chronic low-grade inflammation may contribute to the increased risk of atherosclerosis in visceral obesity. Statin and fish oil have been reported to have antiinflammatory effects. We studied whether dyslipidemic, obese individuals have increased plasma high-sensitivity C-reactive protein (hs-CRP) concentrations and whether treatment with atorvastatin and fish oil lowered plasma hs-CRP concentrations. We compared plasma hs-CRP, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) concentrations in 48 obese individuals with the concentrations in 10 lean normolipidemic men. The obese individuals were then randomized to treatment with atorvastatin (40 mg/day), fish oil (4 g/day), atorvastatin plus fish oil, or matching placebo for 6 weeks. Compared with controls, obese individuals had increased hs-CRP [geometric mean, 2.19 mg/L (95% confidence interval, 2.15-3.15 mg/L) vs 0.49 mg/L (0.30- 0.93 mg/L); P <0.001] and IL-6 [351 pg/L (318-449 pg/L) vs 251 pg/L (211-305 pg/L); P <0.01]. Atorvastatin treatment had a significant main effect of decreasing plasma hs-CRP (-0.87 mg/L; 95% confidence interval, -0.10 to -1.60 mg/L; P <0.01) and IL-6 (-70 pg/L; 10 to -140 pg/L; P <0.01), but this was not seen with fish oil. The reductions in hs-CRP with atorvastatin were not significantly correlated to changes in plasma lipids, IL-6, insulin resistance, or cholesterogenesis. Plasma TNF-alpha concentrations in obese individuals, however, were neither statistically different from concentrations in the lean controls nor altered with atorvastatin or fish oil treatment. This study shows that visceral obesity is associated with increased plasma hs-CRP and IL-6 and, hence, a low-grade chronic inflammatory state and that treatment with atorvastatin or atorvastatin with fish oil, but not fish oil alone, reverses this abnormality.",2002.0,0,0 1324,12029990,[Results of clinical epidemiology and intervention trial of hyperlipidemia in Japan].,Hiroshige Itakura,"Recently, three large-scale clinical studies on hypercholesterolemia have been reported in Japan. The Kyushu Lipid Intervention Study(KLIS) was initiated investigate the effect of pravastatin, as compared with conventional hypolipidemic treatment, in the primary prevention of not only coronary events but also cerebral infarction in Japanese men with serum total cholesterol levels of 220 mg/dl or greater. A total of 5,640 patients were recruited. Adjusted relative risks of outcomes combined coronary events and cerebral infarction for pravastatin versus conventional treatment was 0.81(p = 0.08). The Pravastatin Anti-atherosclerosis Trial in the Elderly(PATE) is a prospective randomized controlled trial to determine the effectiveness of pravastatin on the incidence of cardiovascular events by comparing the effect of low dose(group L, 5 mg/day, n = 334) with the standard dose(group S, 10-20 mg/day, n = 331) in elderly patients aged more than 60 years old. The risk ratio for group S compared with group L was 0.674(95% confidence interval: 0.423-1.074). The Japan Lipid Intervention Trial(J-LIT) is the first nation-wide study conducted to determine a relationship between serum lipid concentrations and the development of CHD under simvastatin treatment. The J-LIT study enrolled 52,421 men and women with total cholesterol(TC) more than 220 mg/dl. Patients were treated with open-labeled simvastatin at a dose of 5 to 10 mg/day for 6 years. Simvastatin reduced serum concentrations of TC, LDL-C and TG by 18.4, 26.8 and 16.1%, respectively. LDL-C positively correlated with the CHD events and the relative risk of CHD was higher significantly more than 160 mg/dl of LDL-C.",2002.0,0,0 1325,12031698,A review of the carotid and femoral intima-media thickness as an indicator of the presence of peripheral vascular disease and cardiovascular risk factors.,Koon Sung Cheng; Dimitri P Mikhailidis; George Hamilton; Alexander M Seifalian,"Peripheral vascular disease (PVD) is a common condition often associated with cardiovascular risk factors and events. With the aid of B-mode ultrasound scanning, evidence is emerging that these risk factors and events are significantly related to an increased carotid and femoral intima-media thickness (IMT). More importantly, treatment of these risk factors is associated with a decrease or a diminished progression of the IMT, paralleled by a reduction in cardiovascular events and an improvement in the symptoms associated with PVD. This evidence is particularly strong for lipid lowering therapy. Additional predictors of cardiovascular risk like the IMT, could now influence the decision to intervene with medication.",2002.0,0,0 1326,12031729,,,,,0,0 1327,12031735,Comparison of extended-release niacin and atorvastatin monotherapies and combination treatment of the atherogenic lipid profile in diabetes mellitus.,Joanne T Van; Jianqiu Pan; Talat Wasty; Eve Chan; Xiaoshan Wu; M Arthur Charles,,2002.0,0,0 1328,12031821,Improved fibrinolysis after 1-year treatment with HMG CoA reductase inhibitors in patients with coronary heart disease.,Ingebjørg Seljeflot; Serena Tonstad; Ingvar Hjermann; Harald Arnesen,"The study was aimed to investigate the effect of two different statins on the levels of haemostatic variables reflecting procoagulant and fibrinolytic activity in patients with coronary heart disease (CHD), with the hypothesis that statins might beneficially modify these levels. Fifty-eight patients were randomized to treatment with atorvastatin (n=28) or simvastatin (n=30) for 1 year. The starting dose in both groups was 20 mg/day. Fasting blood samples were collected before and after 12-month treatment for determinations of fibrinogen, prothrombin fragment 1+2 (F1+2), plasma D-dimer, soluble tissue factor, tissue plasminogen activator (tPA) antigen, tPA activity, plasminogen activator inhibitor type-1 activity (PAI-1 activity) and serum D-dimer as a global test of fibrinolytic activity. In the total population, improved fibrinolytic activity was observed after 1 year with increased levels of serum D-dimer (P=.001) and tPA activity (P=.024) and a reduction in tPA antigen (P=.048). No statistically significant changes were observed in any of the measured coagulation variables. Separately examined, an improved fibrinolytic profile was seen in the atorvastatin group with a significant increase in serum D-dimer (P=.005), a borderline increase in tPA activity (P=.083) and a borderline reduction in tPA antigen (P=.069). Within the simvastatin group, a reduction in prothrombin F1+2 was observed (P=.038). The differences in changes between the groups were statistically significant only for global fibrinolysis (serum D-dimer, P=.046). In conclusion, an improved fibrinolytic profile was observed after statin treatment, most pronounced with atorvastatin. The results indicate that the drugs promote a profibrinolytic profile, and may in part explain the benefit of statin treatment rendered in the prevention of CHD.",2002.0,0,0 1329,12031849,"Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice.",Ulrich Laufs; Karen Gertz; Ulrich Dirnagl; Michael Böhm; Georg Nickenig; Matthias Endres,"HMG-CoA reductase inhibitors (statins) are cholesterol-lowering drugs and reduce the risk of myocardial infarction and stroke. In this study we investigated whether rosuvastatin, a new, potent HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide (NO) expression and activity and protects from cerebral ischaemia in mice. Endothelial cells in culture and 129/SV mice were chronically treated with rosuvastatin. The expression and activity of endothelial NO synthase (eNOS) was determined by reverse-transcriptase polymerase chain reaction (RT-PCR), Western blotting and arginine-citrulline assays. Cerebral ischaemia was induced by occlusion of the middle cerebral artery (MCAo) for 2 h and infarct size was determined after 22 h of reperfusion. Treatment of endothelial cells with rosuvastatin concentration- and time-dependently upregulated eNOS mRNA and protein expression. In aortas of 129/SV wild-type mice, treatment with 0.2, 2, and 20 mg kg(-1) rosuvastatin subcutaneously (s.c.) for 10 days significantly upregulated eNOS mRNA by 50, 142, and 205%, respectively. NOS activity was significantly increased by 75, 145, and 320%, respectively. Stroke volume after 2-h MCAo was reduced by 27, 56, and 50% (for 0.2, 2 and 20 mg kg(-1), respectively). Serum cholesterol and triglygeride levels were not significantly lowered by the treatment. The novel HMG-CoA reductase inhibitor rosuvastatin dose-dependently upregulates eNOS expression and activity and protects from cerebral ischaemia in mice. The effects are independent of changes in cholesterol levels and are equivalent or even superior to the protective effects by simvastatin and atorvastatin in this animal model.",2002.0,0,0 1330,12032266,A randomized crossover trial of combination pharmacologic therapy in children with familial hyperlipidemia.,Brian W McCrindle; Elizabeth Helden; Geraldine Cullen-Dean; William T Conner,"We sought to determine whether a low-dose combination of a bile acid-binding resin (colestipol) with an hydroxymethylglutaryl CoA reductase inhibitor (pravastatin) would result in improved acceptability, compliance, and effectiveness in lipid-lowering compared with conventional therapy with a higher dose of a bile acid-binding resin only, with fewer side effects. We performed a randomized, crossover open-label clinical trial with two 18-wk medication regimens separated by an 8-wk washout period in 36 children and adolescents with familial hypercholesterolemia or familial combined hyperlipidemia. The regimens included colestipol 10 g/d (10 pills) versus a combination of colestipol 5 g/d with pravastatin 10 mg/d (six pills). All patients were maintained on a fat-reduced diet. Acceptability was better with the combination regimen. Mean compliance was similar and suboptimal (approximately 60%) with all medication components. Mean relative LDL cholesterol lowering was significantly better with the combination regimen (-17 +/- 16% versus -10 +/- 13%; p = 0.045), although insufficient to achieve recommended target values in the majority of patients on either regimen. Both regimens were equally free of adverse effects, with no important effect on chemistry or hematologic values. Patient-reported adverse effects were more common with the conventional-dose colestipol-only regimen. Compliance with medication regimens using the bile acid-binding resins is suboptimal, although combination with a low dose of a statin may result in better lipid lowering.",2002.0,0,0 1331,12032397,High doses of atorvastatin do not affect activity of prothrombinase in patients with acute coronary syndromes.,L Olivotti; G Ghigliotti; P Spallarossa; S Leslie; P Rossettin; A Barsotti; C Brunelli,"Membrane-dependent coagulation processes play a key role in acute coronary syndromes (ACS), where the generation of thrombin depends on the complex of activated factors X and V (prothrombinase complex) assembled on activated platelets. The aim of the present study was to evaluate prothrombinase activity in patients with ACS and to examine the effect of treatment with 80 mg/day atorvastatin on prothrombinase activity. Blood samples were obtained at admission from 22 patients with ACS, and then again at 2 weeks and at 16 weeks after double-blind randomization to either placebo or atorvastatin. Prothrombinase activity was evaluated by measuring the generation of thrombin by in vitro reconstructed thrombi, and also by measuring plasma levels of prothrombin fragment F1 + 2. Twenty age-matched subjects with stable angina and 11 without coronary disease were used as controls. At admission, prothrombinase activity and F1 + 2 were significantly higher in ACS patients than in controls. Prothrombinase activity was still high at 2 weeks while it returned to normal levels at 16 weeks. F1 + 2 remained high both at 2 and at 16 weeks. Our data indicate that prothrombinase activity is high in patients with ACS, and that it is not affected by high-dose atorvastatin.",2003.0,0,0 1332,12034651,,,,,0,0 1333,12035870,Long-term protection in at-risk hypertensive patients--a role for nifedipine GITS?,Luis M Ruilope,"Hypertensive patients who are at high risk of developing cardiovascular (CV) complications have become the focus of modern treatment guidelines. The choice of antihypertensive therapies in these patients should be evidence-based: in particular, there should be evidence of a beneficial impact on CV events in addition to blood pressure-lowering effects. The International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) is the first, large, randomized, double-blind study undertaken exclusively in high-risk hypertensive patients, with CV events as a prospectively defined primary end-point. The choice of a diuretic (co-amilozide) as a comparator reflects the fact that this group of antihypertensive drugs has been shown to reduce CV events in high-risk hypertensive patients. Nifedipine, administered in a long-acting gastrointestinal-transport-system (GITS) formulation, and co amilozide were equally effective in preventing overall CV or cerebrovascular complications. This finding extended to the subgroup of patients with diabetes at baseline. Substudies to INSIGHT showed that, compared with coamilozide, nifedipine GITS was significantly more effective at preventing an increase in intima-media thickness in the carotid artery and significantly slowed the progression of coronary calcification. The results from INSIGHT support incorporating nifedipine GITS in the management of high-risk hypertensive patients to prevent atherosclerosis-related illness and death.",2002.0,0,0 1334,12036426,Cholesterol absorption inhibitors in development as potential therapeutics.,Kouji Kajinami; Noboru Takekoshi,"Drugs that lower low-density lipoprotein cholesterol through their actions in the gastrointestinal tract have been used for > 30 years. Bile acid sequestrants have very excellent safety profiles but their poor tolerability means they have limited clinical use. Recently developed new compounds are better tolerated in clinical trials and show greater benefit in reducing low-density lipoprotein cholesterol level, as compared to ""older"" sequestrants. Cholesterol absorption inhibitors and bile acid transporter inhibitors have recently been reported to show clinical efficacy and safety as novel gut-acting drugs for lowering cholesterol. Further advances in our understanding of the cholesterol absorption mechanism will provide novel therapeutic targets, such as the ATP-binding cassette transporter. This approach in the treatment of lowering cholesterol appears to play a more significant role in the clinical field of atherosclerotic vascular disease.",2002.0,0,0 1335,12036521,Fighting restenosis after coronary angioplasty: contemporary and future treatment options.,Marc Horlitz; Ulrich Sigwart; Josef Niebauer,"Despite the widespread use of coronary stents, prevention of restenosis after percutaneous transluminal coronary angioplasty (PTCA) remains a major challenge. The restenotic process is even higher after balloon angioplasty without stenting and has been shown to be in the range of 30-50%. Experimental data suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (""statins"") might have a beneficial effect on restenosis after coronary angioplasty. Proposed mechanisms include favorable effects on plasma lipoproteins, endothelial function, plaque architecture and stability, thrombosis and inflammation. Although statins have documented efficacy in reducing clinical events and angiographic disease progression in patients with coronary atherosclerosis, the results of subsequent large prospective clinical trials using different types of statins clearly demonstrate that statins do not have a short-to-medium term effect on prevention of restenosis after successful conventional PTCA. The underlying pathological reasons for this shortcoming as well as promising innovative approaches including gene therapy and local drug delivery of vasoactive substances will be discussed in this review.",2002.0,0,0 1336,12036525,Cardiac remodelling in the era of aggressive medical therapy: does it still exist?,Nicholas G Bellenger; Jonathan M A Swinburn; Kim Rajappan; Avijit Lahiri; Roxy Senior; Dudley J Pennell,"To delineate the natural history of left ventricular remodelling following large anterior myocardial infarction (MI), in the era of aggressive medical therapy. Seventeen selected patients underwent cardiovascular magnetic resonance (CMR) at 2 weeks and 1, 3, 6 and 12 months post infarction. There was a significant increase in left ventricular (LV) end-diastolic volume index (EDVI) and LV ESVI from 2 weeks to 1 month (P<0.05) but no significant change thereafter. The LV ejection fraction (EF) decreased from 2 weeks to 1 month (P<0.05) and then increased over the year (P=0.02). Throughout the study period the sphericity index increased. There was a significant and progressive decrease in LV mass index over the year, which was associated with a decrease in wall thickness at both the infarct and non-infarct sites. Independent predictors of an early increase in LVESVI were increasing age, increasing CK-MB and not receiving treatment with a statin. This study delineates the natural history of left ventricular remodelling in the modern medical era in those patients who have suffered a large anterior MI. Classical remodelling occurred up to 1 month, but thereafter was attenuated. These findings would suggest that remodelling is not as prevalent in the modern era, and that combined medical management with thrombolysis, ACEi, beta-blockers and statins may strongly influence the development of this remodelling.",2002.0,0,0 1337,12038594,Cardiovascular disease and osteoporosis: is there a link between lipids and bone?,John R Burnett; Samuel D Vasikaran,"Atherosclerotic heart disease and osteoporosis are both diseases of old age. Evidence is accumulating for a link between vascular and bone disease. Calcification is a common feature of atherosclerotic plaques, and osteoporosis is associated with both atherosclerosis and vascular calcification. However, the relationship of vascular calcification to the pathogenesis of atherosclerosis remains incompletely understood. Hormone replacement therapy has beneficial effects in the prevention of both atherosclerosis and osteoporosis. Bisphosphonates inhibit bone resorption and are used in the treatment of osteoporosis, whereas the statins inhibit cholesterol biosynthesis and are used for the treatment of atherosclerosis. We have reviewed recent advances in the knowledge of the actions of bisphosphonates and statins at the cellular, molecular and end-organ levels in order to examine the relationship between cardiovascular disease and osteoporosis and to explore the link between lipids and bones. These studies suggest that the mechanism of actions of these two classes of drugs at the cellular level may not be mutually exclusive. There are some early clinical data to complement these findings, suggesting that statins increase bone density and bisphosphonates may have a beneficial effect in vivo on plasma lipid levels and on the atherosclerotic process. Properly designed prospective studies that examine the effect of statins on bone density and fractures, as well as the effects of bisphosphonates on lipid profiles, atherosclerotic progression and cardiovascular morbidity and mortality are needed to define clearly the clinical effects and potential new roles for these agents.",2003.0,0,0 1338,12039487,Increased transforming growth factor-beta(1) circulating levels and production in human monocytes after 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibition with pravastatin.,Ettore Porreca; Concetta Di Febbo; Giovanna Baccante; Marcello Di Nisio; Franco Cuccurullo,"We sought to determine whether inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase with pravastatin affects transforming growth factor-beta(1) (TGF-beta(1)) circulating levels and its production in the monocytes of hypercholesterolemic patients. Transforming growth factor-beta(1) is a multifunctional growth factor/cytokine involved in many physiologic and pathologic processes, such as vascular remodeling and atherogenesis. Statins have been reported to have a modulatory role in cytokine expression in the monocytes of hyperlipidemic patients. We evaluated, in a cross-over study design, plasma TGF-beta(1) levels and ex vivo TGF-beta(1) production in the monocytes of hypercholesterolemic patients before and after four to six weeks of lipid-lowering treatment with diet or diet plus 40 mg/day of pravastatin. In addition, isolated blood monocytes were subjected to pravastatin treatment and evaluated for TGF-beta(1) messenger ribonucleic acid (mRNA) expression and TGF-beta(1) in vitro production. Lipid-lowering treatment significantly decreased total cholesterol and low-density lipoprotein cholesterol plasma levels. Pravastatin, but not a low lipid diet, induced a significant increase in TGF-beta(1) plasma levels (from 1.7 +/- 0.5 ng/ml to 3.1 +/- 1.1 ng/ml, p < 0.001) and in ex vivo monocyte production (from 1.8 +/- 0.8 ng/ml to 3.9 +/- 1.0 ng/ml, p < 0.001). The increase in TGF-beta(1) levels was not related to the changes in the lipid profile observed with pravastatin. An increase of approximately twofold in TGF-beta(1) production and in mRNA expression was also observed after in vitro treatment of human monocytes with pravastatin (5 microM). Co-incubation with mevalonate reversed the in vitro effect of pravastatin. 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition with pravastatin increases TGF-beta(1) plasma levels, as well as monocyte production, in hypercholesterolemic patients. The mevalonate pathway plays a role in the regulation of TGF-beta(1) expression in human monocytes. A possible implication in the biologic and clinical effects of statins can be suggested.",2002.0,0,0 1339,12039998,Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis.,Wulf Palinski; Sotirios Tsimikas,"Clinical trials with statins have demonstrated a marked reduction of cardiovascular mortality. However, it remains controversial whether these clinical benefits stem from powerful cholesterol-lowering effects of statins or whether they are due in part to their cholesterol-independent effects on vascular function, plaque growth, plaque rupture, or thrombosis. The identification of several mechanisms through which statins decrease the recruitment of monocytes and T cells into the arterial wall and inhibit T cell activation and proliferation in vitro have prompted speculations that immunomodulatory effects of statins may be beneficial in recipients of organ transplants. Hypercholesterolemia is frequent in these patients, and delayed-type hypersensitivity reactions in the arterial walls of the graft may be compounded by chronic inflammation associated with conventional atherogenesis. To assess the potential clinical relevance of immunomodulatory effects of statins, the role of the immune system in atherogenesis and the effects of statins in vitro in experimental models and in clinical trials will be reviewed. It is concluded that despite solid in vitro evidence, clinical evidence for an independent immunosuppressive effect of statins in organ transplant patients is presently insufficient; however, further investigation of their in vivo occurrence and clinical relevance is warranted.",2002.0,0,0 1340,12040732,Colesevelam hydrochloride.,Karen L Steinmetz,"The pharmacology, pharmacodynamics, clinical efficacy, drug interactions, adverse effects, and dosage and administration of colesevelam hydrochloride are reviewed. Colesevelam hydrochloride is a nonabsorbed lipid-lowering agent approved for use alone or in combination with hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors for the reduction of low-density-lipoprotein (LDL) cholesterol in patients with primary hypercholesterolemia. Colesevelam forms nonabsorbable complexes with bile acids in the gastrointestinal (GI) tract, resulting in changes in plasma lipid levels, including total, LDL, and high-density-lipoprotein cholesterol and triglycerides. Colesevelam has been reported to be four to six times as potent as traditional bile acid sequestrants (BASs), perhaps because of its greater binding affinity for glycocholic acid. Unlike cholestyramine and colestipol, colesevelam appears to reduce LDL cholesterol in a dose-dependent manner. In clinical trials, colesevelam demonstrated efficacy either alone or in combination with HMG-CoA reductase inhibitors in the treatment of primary hypercholesterolemia. Combination therapy appeared to be more effective than monotherapy. Although infection, headache, and GI adverse effects have been reported for colesevelam, the rates do not differ significantly from those occurring with placebo. The constipation that typically hinders compliance with traditional BASs is minimal. In one study, the rate of compliance with colesevelam was 93%. There is little evidence of clinically significant interactions involving colesevelam. The maintenance dosage is three 625-mg tablets twice daily or six tablets once daily, taken with meals. Colesevelam provides an effective alternative to cholestyramine and colestipol while offering the potential for fewer adverse effects and better compliance. Studies are needed to directly compare colesevelam with traditional BASs.",2002.0,0,0 1341,12040967,"Clinical efficacy of pitavastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in patients with hyperlipidemia. Dose-finding study using the double-blind, three-group parallel comparison.",Yasushi Saito; Nobuhiro Yamada; Tamio Teramoto; Hiroshige Itakura; Yoshiya Hata; Noriaki Nakaya; Hiroshi Mabuchi; Motoo Tushima; Jun Sasaki; Yuichiro Goto; Nobuya Ogawa,"Pitavastatin (CAS 147526-32-7, NK-104), the first totally synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor discovered in Japan, was examined. Pitavastatin significantly decreased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) at doses of 1 mg/day or more, and significant dose-dependence of the effect of this drug was observed within the dose range from 1 mg/day to 4 mg/day. It also significantly decreased the serum levels of triglycerides (TG) within this dose range. There was no dose-dependence of the incidence of adverse reactions to pitavastatin.",2002.0,0,0 1342,12043936,"Polymorphonuclear leukocyte membrane fluidity, at baseline and after in vitro activation, in obesity with or without diabetes mellitus.",R Lo Presti; D Sinagra; M Montana; A M Scarpitta; A Catania; G Caimi,"We studied a group of 28 obese subjects (mean age 38.2+/-13.5 years, body mass index 35.0+/-5.6 kg/m2) with insulin resistance demonstrated employing an euglycemic hyperinsulinemic clamp, subdivided into a subgroup with normal glucose tolerance (NGT) and a subgroup with type 2 diabetes mellitus (DM). We examined the polymorphonuclear leukocyte (PMN) membrane fluidity at baseline and after activation with 4-phorbol 12-myristate 13-acetate (PMA) or N-formyl-methionyl-leucylphenylalanine (fMLP). At baseline, PMN membrane fluidity was significantly decreased in both subgroups compared to normals. In obese subjects with NGT no correlation was found between this PMN determinant and the parameters reflecting the insulin-resistance degree (glucose disposal [M] and metabolic clearance rate of glucose [MCR]), while in type 2 DM subjects the PMN membrane fluidity was correlated to M and MCR. After activation with PMA and fMLP, no variation in PMN membrane fluidity was observed in normals, while in obese subjects with NGT an early decrease was present only after fMLP activation, and in obese subjects with type 2 DM there was a constant and significant decrease of this PMN parameter after activation with PMA and fMLP. Our interest in the study of the PMN membrane fluidity emerges from its known role in PMN function, especially considering that PMN cells, together with monocytes, may be mediators of vascular damage.",2002.0,0,0 1343,12044582,Statins and ischemic stroke.,James K Liao,"The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors or statins are potent inhibitors of cholesterol synthesis. Several large clinical trials have demonstrated that these agents reduce serum cholesterol levels and the incidence of cardiovascular diseases. However, overlap and meta-analyses of these clinical trials suggest that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels. Because statins also inhibit the synthesis of isoprenoid intermediates in the cholesterol biosynthetic pathway, they may have pleiotropic effects on the vascular wall. In particular, the ability of statins to decrease the incidence of ischemic stroke highlights some of their non-cholesterol effects since serum cholesterol levels are poorly correlated with the risk for ischemic stroke.",2002.0,0,0 1344,12044585,Postprandial lipemia--effect of lipid-lowering drugs.,Fredrik Karpe,"Exaggerated postprandial hyperlipidemia has been associated with cardiovascular disease. The mechanisms underlying this association are likely to depend on a multitude of effects. Potentially atherogenic remnants of triglyceride-rich lipoproteins (TRL) accumulate in the postprandial state. In addition, TRL may promote the formation of small dense LDL. There are some indications that the postprandial period is a hypercoagulable state and endothelial function seems to be hampered after acute fat intake. Conventional lipid lowering drugs such as statins and fibrates have the potency of reducing postprandial hyperlipidemia, but the fibrates seem to be more effective in this respect. There is a complete lack of prospective studies linking inefficient postprandial lipid metabolism with clinical endpoints and there is also a need to include investigations of postprandial lipid metabolism in the evaluation of novel drugs affecting lipid metabolism and insulin resistance.",2002.0,0,0 1345,12044587,The choice of hormone replacement therapy or statin therapy in the treatment of hyperlipidemic postmenopausal women.,Mary Seed,"Evidence based treatment of cardiovascular risk factors on outcome in women is still inconclusive given the very large numbers needed to achieve a significant difference in cardiovascular event. Although numerous studies of the effect of hormone replacement therapy (HRT) on risk factors have suggested benefit, the only data from a randomised control trial of HRT in secondary prevention was neutral. Coronary disease-primary prevention: (a) Statins: Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEX CAPS). The only randomised controlled trial (RCT) to include women. There were fewer coronary heart disease (CHD) events in women but no difference in mortality. (b) HRT: no completed RCT-the results from Womens Health Initiative (WHI) and Women Intervention Study of Long Duration of Oestrogen in the Menopause (WISDOM) are awaited, the former likely to complete in 2004. There are numerous reports of positive observational epidemiological studies for HRT. There is little evidence for statin use in women who will probably not qualify for treatment on global CHD risk assessment, familial hypercholesterolemia and type 2 diabetes excepted. HRT is, therefore, not only appropriate for its multiple effects on lipoproteins, vascular function and insulin sensitivity but also for prevention of osteoporosis. Coronary disease- (a) Statins: the major measurable effect of these drugs is to reduce total and LDL cholesterol. In RCT trials, the Scandanavian Simvastatin Survival Study (4S), the Cholesterol and Recurrent Event (CARE) and Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID), approximately 20% of subjects were female, in whom CHD events, but not CHD or total mortality were reduced. (b) HRT: there is data available from a single RCT of continuous combined premarin and medroxyprogesterone acetate (MPA) against placebo, The Heart Estrogen Replacement Study (HERS). A study of 2763 women and mean duration of 4.1 years. This study was neutral, with no reduction in CHD events or mortality. There were more events in the first year, and fewer in years 3-5. Other studies of HRT have been observational and positive for HRT. The effects of treatment on lipoproteins with statins, HRT and combination of statin and HRT have been investigated. In secondary prevention for hyperlipidemic women to achieve cholesterol <5, low density lipoprotein (LDL)<3 mmol/l statins will be first choice, possibly with HRT additionally for its other benefits on cardiovascular risk factors.",2002.0,0,0 1346,12045159,"Inflammatory biomarkers, statins, and the risk of stroke: cracking a clinical conundrum.",Paul M Ridker,,2002.0,0,0 1347,12045375,Premature termination of clinical trials--lessons learned.,D A Sica,"Controlled clinical trials in cardiovascular disease are the cornerstone for therapeutic advances in this field of medicine. Since the introduction of the concept of controlled clinical trials there has been substantial progress in the design, conduct, and analysis of such studies. A growing awareness of ethical issues emerging from such trials has heightened public awareness, increased investigator scrutiny, and reinforced the need for interim data analysis. A benefit of such interim analyses is that either an entire clinical trial or a specific treatment limb can be stopped if the observed findings argue for premature termination. For example, highly positive findings, as were noted in the HOPE Study (Heart Outcomes Prevention Evaluation), led to its being stopped after 4.5 years of treatment, which was 1 year early. Alternatively, the doxazosin treatment limb of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) and the amlodipine treatment limb of AASK (African American Study of Kidney Disease and Hypertension) were stopped early because of negative findings with each respectively. Finally, economic considerations can enter into the decision to close a study early as was the case in the CONVINCE (Controlled Onset Verapamil Investigation of Cardiovascular End Points) trial. Most such decisions rely heavily on information obtained from independent data and safety monitoring boards. Such boards ensure patient safety by providing an unbiased ongoing review of data, which would otherwise be unavailable until a study's completion. Early termination of a clinical trial can have important clinical implications and, in particular, can redirect patterns of clinical practice.",2002.0,0,0 1348,12046033,Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients.,Jai Won Chang; Won Seok Yang; Won Ki Min; Sang Koo Lee; Jung Sik Park; Soon Bae Kim,"A 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is recommended in hemodialysis (HD) patients with hypercholesterolemia to improve their lipid profiles. We evaluated effects of simvastatin on markers for inflammation, oxidative stress, and coagulation in HD patients. Sixty-two maintenance HD patients with serum cholesterol levels of 200 mg/dL or greater were randomly assigned to the treatment group (n = 31; 8 men, 23 women; age, 63 +/- 11 years) and administered simvastatin, 20 mg/d, for 8 weeks or to the control group (n = 31; 10 men, 21 women; age, 60 +/- 12 years). We measured cholesterol, albumin, high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA; an index of lipid peroxidation), and D-dimer (a marker of intravascular coagulation) in blood at baseline and again at 8 weeks. Fifty-eight of 62 patients completed the study. In the control group, total cholesterol, serum albumin, hs-CRP, MDA, and D-dimer levels did not change. In the treatment group, simvastatin administration for 8 weeks significantly reduced total cholesterol levels from 232 +/- 25 to 165 +/- 39 mg/dL (P < 0.001) and hs-CRP levels from a median of 0.23 mg/dL (range, 0.05 to 1.63 mg/dL) to 0.12 mg/dL (range, <0.006 to 1.45 mg/dL; P < 0.01), whereas it increased serum albumin levels from 3.4 +/- 0.3 to 3.6 +/- 0.4 g/dL (P < 0.001). Administration of simvastatin did not affect MDA and D-dimer levels. These results suggest that in addition to the lipid-lowering effect, simvastatin had an antiinflammatory effect in HD patients. Considering that atherosclerosis is inflammation of the vascular wall, simvastatin may have a beneficial effect on cardiovascular disease, in part because it alleviates inflammation.",2002.0,0,0 1349,12047796,"Mechanical or metabolic treatment for coronary disease: synergistic, not antagonistic, approaches.",Carol Gemayel; David Waters,"Cardiologists have traditionally focused on coronary narrowing as seen on angiography and have orientated treatment towards bypassing these lesions or widening them with angioplasty. In patients with stable coronary artery disease, percutaneous coronary interventions reliably relieve angina and myocardial ischemia, but do not prevent myocardial infarction or reduce mortality. Cholesterol lowering therapy has been shown, in several large, randomized trials reported over the past decade, to reduce mortality and coronary events, including the need for revascularization in a broad spectrum of patients. Mechanical and metabolic treatments for coronary disease should be used synergistically.",2002.0,0,0 1350,12048120,Rho/Rho-kinase is involved in the synthesis of tissue factor in human monocytes.,Kenji Nagata; Toshiyuki Ishibashi; Takayuki Sakamoto; Hiroshi Ohkawara; Joji Shindo; Keiko Yokoyama; Koichi Sugimoto; Sotaro Sakurada; Yoh Takuwa; Shin Nakamura; Tamio Teramoto; Yukio Maruyama,"Monocytes and macrophages synthesize tissue factor (TF) which plays a role in thrombogenicity in coronary artery disease. This study was conducted to investigate the effect of Rho/Rho-kinase inhibition on the synthesis of TF in cultured human monocytes. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), C3 exoenzyme and Rho-kinase inhibitors were added to isolated peripheral blood monocytes and the synthesis of TF was assessed by reverse transcriptase polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry. Rho activity was determined by measuring the GTP-bound form of Rho A. Cerivastatin and pravastatin reduced the levels of TF antigen and mRNA. The suppressive effect of statins on TF synthesis was reversed by geranylgeranylpyrophosphate (GGPP) and the restoring effect of GGPP was eliminated by C3 exoenzyme and Y-27632. Pravastatin decreased the activity of Rho A, suggesting that the suppression of TF synthesis by statins is mediated via inhibition of the geranylgeranylation of Rho. Moreover, inhibition of Rho and Rho-kinase downregulated the synthesis of TF. Our results suggest that Rho/Rho-kinase signaling is involved in the synthesis of TF in human monocytes and that inhibition of Rho/Rho-kinase may be useful for treating thrombogenicity in coronary artery disease.",2002.0,0,0 1351,12048134,"Long-term treatment with pitavastatin (NK-104), a new HMG-CoA reductase inhibitor, of patients with heterozygous familial hypercholesterolemia.",Yoshihiro Noji; Toshinori Higashikata; Akihiro Inazu; Atsushi Nohara; Kosei Ueda; Susumu Miyamoto; Kouji Kajinami; Tadayoshi Takegoshi; Junji Koizumi; Hiroshi Mabuchi; Hokuriku NK-104 Study Group,"The clinical efficacy and safety of pitavastatin (NK-104), a novel HMG-CoA reductase inhibitor, during long-term treatment, were examined in 25 patients (male/female=11/14, mean age=53+/-13 (mean+/-SD) years) with heterozygous familial hypercholesterolemia (FH). After a period on placebo of >4 weeks, 2 mg/day of pitavastatin was administered for 8 weeks, and the dose was increased to 4 mg/day for up to 104 weeks. Total cholesterol (TC) decreased by 31% from the initial value of 340+/-57 to 237+/-40 mg/dl (P<0.0001) at week 8. During treatment with the higher dose, TC decreased even further to 212+/-35 mg/dl at week 12; it decreased by 37% from the initial value (P<0.0001). Similarly, the baseline low-density lipoprotein (LDL)-cholesterol (LDL-C) decreased by 41% at week 8, and by 49% at week 12, from 267+/-61 mg/dl at baseline. These findings indicate a dose-dependent effect of the drug on TC and LDL-C concentrations. To examine whether the levels of circulating matrix metalloproteinases (MMPs) and their endogenous inhibitors (tissue inhibitors of metalloproteinases: TIMPs) are altered during lipid-lowering therapy, we also measured their plasma levels. The mean levels of MMP-2 and -3 were significantly increased. No significant alteration was found in MMP-9, TIMP-1 and -2 levels. As for the safety of pitavastatin, adverse reactions were observed in one case (4%) of subjective and objective symptoms. The effects of pitavastatin on TC and LDL-C were stable during long treatment of patients with heterozygous FH.",2002.0,0,0 1352,12048142,Long-term treatment with atorvastatin in adolescent males with heterozygous familial hypercholesterolemia.,Vasilios G Athyros; Athanasios A Papageorgiou; Athanasios G Kontopoulos,,2002.0,0,0 1353,12052144,Genes and their polymorphisms in mono- and multifactorial cardiomyopathies: towards pharmacogenomics in heart failure.,Philippe Charron; Michel Komajda,"Cardiomyopathies are diseases of the myocardium associated with cardiac dysfunction, and are classified as dilated cardiomyopathy (DCM), hypertropic cardiomyopathy (HCM) and restrictive cardiomyopathy. Heart failure and sudden death are the two major complications. Also, since DCM is the primary indication for heart transplantation and HCM the primary cause of sudden death in young athletes, the socioeconomic impact of these diseases is important. Recently, the role of the genetic background in both monogenic and multifactorial cardiomyopathies has been studied, which has led to a better understanding of the underlying mechanisms that promote the development and progression of these diseases. Preliminary data suggest interactions between pharmacological treatment and genetic polymorphisms, which appear to be the first steps towards the application of pharmacogenetics in heart failure.",2002.0,0,0 1354,12052268,Early use of statins in acute coronary syndromes.,Joshua M Spin; Randall H Vagelos; American College of Cardiology; American Heart Association,"This review examines the use of HMG-CoA reductase inhibitor (statin) medications early in the clinical course of acute coronary syndrome. Available data demonstrate that there are clear clinical benefits to this practice. Numerous previous studies have documented the primary and secondary benefits of statins in the prevention of coronary events. Recent trials show that when statins are used during hospital admissions for acute coronary syndrome (ACS), patients experience decreased recurrent myocardial infarction, lower death rates, and fewer repeat hospitalizations for ischemia or revascularization. Several studies suggest that the positive effects of statins on plaque stabilization, inflammation, thrombosis, and endothelial function may be independent of lipid levels. There is also an emerging view that beneficial lipid-lowering with statins in high-risk patients has no lower limit. This information suggests that all patients admitted for ACS should be treated with statins, regardless of cholesterol levels.",2002.0,0,0 1355,12052271,Lipid-lowering therapies in the management of acute coronary syndromes.,Lori Mosca; Angelo Biviano; National Cholesterol Education Program,"Despite the significant advances made in the treatment of acute coronary syndromes (ACS) with antiplatelet and antithrombotic therapy, the risk of serious complications remains high, especially in the first few months following an acute coronary event. Although lipid-lowering therapy in patients with significant risk factors (primary prevention) or stable coronary disease (secondary prevention) is known to improve long-term survival, patients with a recent ACS were specifically excluded from the early statin trials. However, the use of lipid-lowering agents (principally statins) during hospitalization or in the period immediately following an acute coronary event has recently been studied. Statin therapy in this setting has been shown to reduce angina, rehospitalization, and mortality. Improved outcomes associated with lipid-lowering therapy in ACS may be mediated through beneficial effects on plaque stabilization, endothelial function, inflammation, and thrombus formation. This paper reviews the evidence supporting the potential benefits and mechanisms of statin therapy in the management of ACS. Clinical guidelines to achieve optimal lipid management are also discussed.",2002.0,0,0 1356,12052282,Treatment of lipid disorders after stroke.,Joao A Gomes; Sander J Robins; Viken L Babikian,"The efficacy of lipid disorder therapy for the primary and secondary prevention of coronary heart disease is established. There are, however, no completed studies specifically directed at reducing the risk of stroke with lipid therapy. Although observational cohort studies have failed to demonstrate an association between lipid disorders and stroke incidence, recently completed trials of subjects at risk for coronary heart disease have shown that statins and fibric acid derivatives reduce not only the risk of myocardial infarction and death, but also that of brain infarction and transient ischemic attacks. Lipid drugs are well tolerated and treatment complications are relatively low. It seems prudent to conclude that the stroke patient with an undesirable lipid profile who has a history of coronary heart disease should receive specific treatment for the lipid disorder. Recommendations are more problematic for stroke patients with lipid disorders but no history of coronary heart disease; most should receive therapy for primary prevention of heart disease. Lipid treatment trials focused on stroke risk reduction are urgently needed.",2003.0,0,0 1357,12052467,Genetic polymorphisms: importance for response to HMG-CoA reductase inhibitors.,Anke Hilse Maitland-van der Zee; Olaf H Klungel; Bruno H Ch Stricker; W M Monique Verschuren; John J P Kastelein; Hubertus G M Leufkens; Anthonius de Boer,"Coronary artery disease is among the leading causes of death worldwide. Clinical trials show a protective effect of statins against the sequelae of coronary artery disease. The mean risk reductions for subjects using statins compared with placebo found in these trials is about 30%. These are average reductions for all patients included in the trials. Important factors in interpreting the variability in the outcome of drug therapy include the patient's health profile, prognosis, disease severity, quality of drug prescribing, compliance with prescribed pharmacotherapy and the genetic profile of the patient. This review aims to give an overview of the known polymorphisms (Cholesteryl Ester Transfer Protein polymorphism, Stromelysin-1 polymorphism, -455G/A and TaqI polymorphisms of the beta-fibrinogen gene, apoE4, Asp(9)Asn mutation in the lipoprotein lipase gene, the -514 CT polymorphism in the hepatic lipase gene and the ACE deletion type gene) that have an influence on the effects of statins in the general population. The expectation is that in the future a subject's genotype may determine whether he will be treated with statins or not. Determining the genotype will not deny therapy to a subject, but will help in deciding the therapy that will suit the patient best.",2002.0,0,0 1358,12052475,"Dose-dependent action of atorvastatin in type IIB hyperlipidemia: preferential and progressive reduction of atherogenic apoB-containing lipoprotein subclasses (VLDL-2, IDL, small dense LDL) and stimulation of cellular cholesterol efflux.",Maryse Guerin; Pascal Egger; Céline Soudant; Wilfried Le Goff; Arie van Tol; Reynald Dupuis; M John Chapman,"Type IIB hyperlipidemia is associated with premature vascular disease, an atherogenic lipoprotein phenotype characterised by elevated levels of triglyceride-rich VLDL and small dense LDL, together with subnormal levels of HDL. The dose-dependent and independent effects of a potent HMGCoA reductase inhibitor, Atorvastatin, at daily doses of 10 and 40 mg, were evaluated on triglyceride-rich lipoprotein subclasses (VLDL-1, VLDL-2 and IDL), on the major LDL subclasses (light LDL, LDL-1+LDL-2, D: 1.019-1.029 g/ml; intermediate LDL, LDL-3, D: 1.029-1.039 g/ml and small dense LDL, LDL-4+LDL+5, D: 1.039-1.063 g/ml), on CETP-mediated cholesteryl ester transfer from HDL to apoB-containing lipoproteins, on phospholipid transfer protein activity and on plasma-mediated cellular cholesterol efflux in patients (n=10) displaying type IIB hyperlipidemia. Plasma concentrations of triglyceride-rich lipoprotein subclasses (TRL: VLDL-1, Sf 60-400; VLDL-2, Sf 20-60 and IDL, Sf 12-20) and of LDL (D: 1.019-1.063 g/ml) were markedly diminished after 6 weeks of statin treatment at 10 mg per day (-31 and -36%, respectively; P<0.002) and by 42 and 51%, respectively at the 40 mg per day dose. Increasing doses of atorvastatin progressively normalised both the quantitative and qualitative features of the LDL subclass profile, in which dense LDL predominated at baseline. Indeed, dense LDL levels were reduced by up to 57% at the 40-mg dose, leading to a shift in the peak of the density profile towards larger, buoyant LDL particles typical of normolipidemic subjects. In addition, marked reduction in numbers of apoB100-containing particle acceptors led to a 30% decrease (P<0.02) in CETP-mediated CE transfer from HDL. Finally, a significant dose-dependent statin-mediated elevation (+15% at 10 mg; P=0.0003 and +35% at 40 mg; P<0.0001 compared to baseline) in the capacity of plasma from type IIB subjects to mediate free cholesterol efflux from Fu5AH hepatoma cells was observed. Moreover, atorvastatin (40 mg per day) significantly increased plasma apoAI levels (+24%; P<0.05), thereby suggesting that this statin enhances production of apoAI and with it, formation of nascent pre-beta HDL particles. Plasma PLTP activity was not affected by either dose of atorvastatin. We conclude that increasing the dose of atorvastatin leads to dose-dependent, preferential and progressive reduction in particle numbers of atherogenic VLDL-2, IDL and dense LDL, and concomitantly, to enhanced cellular cholesterol efflux in type IIB dyslipidemia, thereby diminishing the atherosclerotic burden in subjects characterised by high cardiovascular risk.",2002.0,0,0 1359,12053648,Aggressive secondary prevention: a perspective from the coronary interventional setting.,J N Patton; G Fletcher,,2002.0,0,0 1360,12054084,Fosamprenavir. Vertex Pharmaceuticals/GlaxoSmithKline.,Amanda H Corbett; Angela D M Kashuba,"Fosamprenavir, a Vertex Pharmaceuticals phosphate ester prodrug of the HIV protease inhibitor amprenavir, is under development by GlaxoSmithKline (GSK; formerly Glaxo Wellcome) for the potential treatment of HIV infection in adults and children. By November 2000, it was in phase III trials; a third phase III trial was initiated in April 2001. In October 2001, GSK expected filing in both the EU and US in 2002. In January 2002, Vertex anticipated an NDA filing during the second half of 2002. Fast-track status for fosamprenavir was received by Glaxo Wellcome in December 1999. As of January 2002, enrollment was complete for two of the three phase III trials, and an NDA was expected to be filed during 2002. Fosamprenavir was first synthesized at Vertex as part of a collaboration with Glaxo Wellcome and by 1999, it was being developed by Glaxo Wellcome as part of an ongoing agreement between the two companies. In September 2000 and January 2001, Merrill Lynch predicted a 2002 launch, with sales of pounds sterling 50 million in 2002, rising to pounds sterling 150 million in 2004.",2002.0,0,0 1361,12054090,Use of recombinant apolipoproteins in vascular diseases: the case of apoA-I.,Giulia Chiesa; Cesare R Sirtori,"Apolipoprotein (apo) A-I, because of its anti-atherogenic properties, represents a powerful approach to the management of vascular diseases. Infusion of apoA-I-containing synthetic high-density lipoprotein (HDL) inhibits atherosclerosis progression or prevents restenosis in experimental animals, and apoA-I liposomes are capable of stimulating reverse cholesterol transport in humans. Moreover, many experimental studies have been conducted with a molecular variant of apoA-I, apoA-I(Milano), characterized by a prolonged residence time in plasma and improved function, which may offer an even better approach to the therapeutic handling of arterial disease.",2002.0,0,0 1362,12056584,Issues concerning the monitoring of statin therapy in hypercholesterolemic subjects with high plasma lipoprotein(a) levels.,Angelo M Scanu; Janet Hinman,"Most studies on the topic have shown that statin therapy decreases plasma LDL levels but not those of lipoprotein(a) [Lp(a)]. This specificity of action, although previously noted, has not been systematically investigated. In the current study we approached this problem by monitoring LDL- and Lp(a) cholesterol in 80 hypercholesterolemic subjects with high Lp(a) levels, at entry and 8 mon after initiation of statin therapy. We found that commonly used direct and indirect LDL cholesterol assays gave an LDL cholesterol value that comprised both true LDL- and Lp(a) cholesterol. We estimated these two analytes from the values of Lp(a) protein determined by ELISA and from knowledge of the Lp(a) chemical composition, complemented by data from immunochemical and ultracentrifugal analyses. Statin therapy, while not affecting plasma Lp(a) protein levels (21.7+/-10.4, before, and 22.0+/-10.1 mg/dL, after), caused a decrease in the estimated or true LDL cholesterol (P < 0.0001) to values in some cases as low as 10 mg/dL. This drop in true LDL was validated by the decrease in the LDL band in the ultracentrifugation profiles, and its magnitude was proportional to the degree of total cholesterol lowering and to the pretreatment true LDL/Lp(a) cholesterol weight ratio. We conclude that true LDL but not Lp(a) cholesterol is affected by statin therapy and that this specific response cannot be monitored by current LDL cholesterol assays and must, rather, rely on estimates of these two analytes.",2002.0,0,0 1363,12056919,Hypertension and hypercholesterolaemia as risk factors for Alzheimer's disease: potential for pharmacological intervention.,Miia Kivipelto; Mikko P Laakso; Jaakko Tuomilehto; Aulikki Nissinen; Hilkka Soininen,"This paper focuses on hypertension and hypercholesterolaemia as risk factors for Alzheimer's disease and, as such, subjects for prevention. The long-term, prospective, population-based studies regarding the relationship between hypertension or hypercholesterolaemia and Alzheimer's disease, and the clinical studies regarding the association between antihypertensive or lipid-lowering medications and the risk of Alzheimer's disease, are reviewed. These studies provide evidence to suggest that elevated blood pressure and cholesterol levels earlier in life may have an important role in the development and expression of late-life Alzheimer's disease. Based on these data, we propose that proper, early interventions aimed at reducing these cardiovascular risk factors may have an impact on the future incidence and prevalence of Alzheimer's disease.",2002.0,0,0 1364,12058793,Short- and long-term changes of flow-mediated vasodilation in patients under statin therapy.,Matthias Frick; Hannes F Alber; Heike Hügel; Severin P Schwarzacher; Otmar Pachinger; Franz Weidinger,"Flow-mediated vasodilation (FMD) of the brachial artery (BA) has been shown to improve in response to lipid-lowering therapy and other therapeutic interventions, usually within 1 to 2 months. Whether FMD remains improved under therapy in the longer term is unknown. The aim of this study was to examine the short- and long-term changes of FMD under statin therapy. Flow-mediated vasodilation and nitroglycerin-mediated vasodilation (NMD) of the BA were measured with high-resolution ultrasound (13 MHz) at baseline and at 4 and 10 months in 18 consecutively recruited patients with coronary artery disease (CAD), in whom statin therapy was newly established. The decrease of total plasma cholesterol levels after 4 and 10 months of statin therapy (243 +/- 31 vs. 186 +/- 30 vs. 191 +/- 40 mg/dl; p < 0.001) was accompanied by an increase in FMD from 4.4 +/- 3.8% at baseline to 9.6 +/- 2.7% at 4 months and to 9.5 +/- 2.6% at 10 months (p < 0.001). Nitroglycerin-mediated vasodilation showed a trend toward improvement after 4 months (14.6 +/- 7.5 vs. 19.1 +/- 3.6 vs. 19.4 +/- 5.6%; NS). The FMD/NMD ratio also rose significantly after 4 months and remained improved after 10 months of statin therapy (0.31 +/- 0.25 vs. 0.52 +/- 0.16 vs. 0.50 +/- 0.14; p < 0.01). Statin therapy is associated with sustained improvement of endothelial function up to 10 months. These data support the utility of FMD for the assessment of vascular function in response to lipid-lowering therapy or other therapeutic interventions in long-term studies.",2003.0,0,0 1365,12058813,The medicinal chemistry of multidrug resistance (MDR) reversing drugs.,E Teodori; S Dei; S Scapecchi; F Gualtieri,"Multidrug resistance (MDR) is a kind of resistance of cancer cells to multiple classes of chemotherapic drugs that can be structurally and mechanistically unrelated. Classical MDR regards altered membrane transport that results in lower cell concentrations of cytotoxic drug and is related to the over expression of a variety of proteins that act as ATP-dependent extrusion pumps. P-glycoprotein (Pgp) and multidrug resistance protein (MRP1) are the most important and widely studied members of the family that belongs to the ABC superfamily of transporters. It is apparent that, besides their role in cancer cell resistance, these proteins have multiple physiological functions as well, since they are expressed also in many important non-tumoural tissues and are largely present in prokaryotic organisms. A number of drugs have been identified which are able to reverse the effects of Pgp, MRPI and sister proteins, on multidrug resistance. The first MDR modulators discovered and studied in clinical trials were endowed with definite pharmacological actions so that the doses required to overcome MDR were associated with unacceptably high side effects. As a consequence, much attention has been focused on developing more potent and selective modulators with proper potency, selectivity and pharmacokinetics that can be used at lower doses. Several novel MDR reversing agents (also known as chemosensitisers) are currently undergoing clinical evaluation for the treatment of resistant tumours. This review is concerned with the medicinal chemistry of MDR reversers, with particular attention to the drugs that are presently in development.",2002.0,0,0 1366,12059987,Allelic polymorphism -491A/T in apo E gene modulates the lipid-lowering response in combined hyperlipidemia treatment.,A-L García-Otín; F Civeira; R Aristegui; C Díaz; D Recalde; J M Sol; X Masramon; G Hernández; M Pocoví; ATOMIX Study Group. Atorvastatin in Mixed dyslipidemia,"Combined hyperlipidemia (CHL) is one of the dyslipidemias more frequently found in clinical practice, and lipid-lowering drugs are often necessary in its management. Some genetic loci have been associated with CHL expression, and some studies have shown modulation of drugs efficiency in the treatment of dyslipidemias by genetic polymorphisms. We have investigated whether common polymorphisms and mutations in the apolipoprotein (apo) E, lipoprotein lipase (LPL), and apo CIII genes influence atorvastatin or bezafibrate responses in patients with CHL. One hundred and sixteen subjects participating in the ATOMIX study (Atorvastatin in Mixed dyslipidemia) were randomized to treatment with either atorvastatin or bezafibrate. Apolipoprotein E genotype and common -491A/T and -219T/G polymorphisms in the apo E gene promoter region, Sst I polymorphism in the apo CIII gene (3238C/G), and D9N and N291S common mutations in the LPL gene were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. Statistical analysis showed the influence of the -491A/T polymorphism in atorvastatin and bezafibrate treatments. Subjects carrying the -491T allele showed an increased LDL-cholesterol-lowering effect with atorvastatin compared with -491T allele noncarriers (-35% vs. -27%, P = 0.037). Subjects carrying the -491T allele, when on bezafibrate treatment, showed a lower triglyceride reduction compared with -491T allele noncarriers (-23% vs. -39%, P = 0.05). In our study, the -491A/T polymorphism in the apo E gene promoter region modulated the lipid-lowering efficiency of atorvastatin and bezafibrate in CHL patients. Such influence might explain some of the interindividual response variabilities observed for the two drugs, and could help in CHL management.",2003.0,0,0 1367,12059988,Factorial study of the effects of atorvastatin and fish oil on dyslipidaemia in visceral obesity.,D C Chan; G F Watts; T A Mori; P H R Barrett; L J Beilin; T G Redgrave,"Dyslipidaemia may account for increased risk of cardiovascular disease in central obesity. Pharmacotherapy is often indicated in these patients, but the optimal approach remains unclear. We investigated the effects of atorvastatin and fish oil on plasma lipid and lipoprotein levels, including remnant-like particle-cholesterol and apolipoprotein C-III, in dyslipidaemic men with visceral obesity. We carried out a 6-week randomized, placebo-controlled, 2 x 2 factorial intervention study of atorvastatin (40 mg day(-1)) and fish oil (4 g day(-1)) on plasma lipids and lipoproteins in 52 obese men (age 53 +/- 1 years, BMI 33.7 +/- 0.55 kg m(-2)) with dyslipidaemia and insulin resistance. Treatment effects were analysed by general linear modelling. Atorvastatin had significant main effects in decreasing triglycerides (-0.38 +/- 0.02 mmol L(-1), P = 0.002), total cholesterol (-1.89 +/- 0.17 mmol L(-1), P = 0.001), LDL-cholesterol (-1.78 +/- 0.14 mmol L(-1), P = 0.001), remnant-like particle-cholesterol (-0.08 +/- 0.04 mmol L(-1), P = 0.035), apolipoprotein B (-49 +/- 4 mg dL(-1), P = 0.001), apolipoprotein C-III (-12.6 +/- 6.1 mg L(-1), P = 0.044) and in increasing HDL-cholesterol (+0.10 +/0- 0.04 mmol L(-1), P = 0.007). Fish oil had significant main effects in decreasing triglycerides (-0.38 +/- 0.11 mmol L(-1), P = 0.002) and in increasing HDL-cholesterol (+0.07 +/- 0.04 mmol L(-1), P = 0.041). There were no significant changes in weight or insulin resistance during the study. Atorvastatin and fish oil have independent and additive effects in correcting dyslipidaemia in viscerally obese men. Improvement in abnormalities in remnant lipoproteins may occur only with use of atorvastatin. Combination treatment with statin and fish oil may, however, offer an optimal therapeutic approach for globally correcting dyslipidaemia in obesity.",2003.0,0,0 1368,12060980,Antioxidant treatment of therapy-resistant idiopathic membranous nephropathy with probucol: a pilot study.,Martin Haas; Gert Mayer; Gerhard Wirnsberger; Herwig Holzer; Manfred Ratschek; Ullrich Neyer; Josef Neuweiler; Reinhard Kramar; Brigitte Schneider; Silvana Breiteneder-Geleff; Heinrich M Regele; Walter H Hörl; Dontscho Kerjaschki,"Proteinuria in Heymann's nephritis, an experimental rat model disease corresponding to membranous nephropathy, has been shown to be due to lipid peroxidation. Since the pathophysiology might be similar to idiopathic membranous nephropathy in humans, we performed a prospective multicenter trial to investigate the efficacy of the lipid peroxidation scavenger, probucol. Fifteen patients with biopsy-proven idiopathic membranous nephropathy resistant to conventional immunosuppressive therapy (n = 7) and/or ACEI treatment (n = 12) were recruited. Probucol (1 g/d orally) was administered for three months, followed by a washout period of four weeks, whereon lovastatin (10-20 mg/d orally) was administered for additional three months. A significant reduction in proteinuria was seen during the probucol treatment (median (range): 6.4 (3.8-9.1) g/d vs. 4.7 (1.3-16) g/d; P < 0.05), with partial remission achieved in four patients. Three of these patients had previously been resistant to immunosuppressive therapy. Median protein excretion increased to pretreatment values during the washout period (6.2 (1.9-15) g/d; P < 0.05) and was not significantly different after the intake of lovastatin (4.9 (1.8-19) g/d; P = NS). None of the patients achieved partial remission during lovastatin therapy (P < 0.05 vs. probucol). The present study led us to conclude that proteinuria can be reduced by probucol in some patients with idiopathic membranous nephropathy. A randomized multicenter study to further elucidate the influence of lipid peroxidation scavengers on membranous nephropathy is warranted.",2002.0,0,0 1369,12062375,Lipid lowering and the assessment of endothelial function.,Kaeng W Lee; Dirk C Felmeden; Gregory Y H Lip,,2002.0,0,0 1370,12062731,The liver and lovastatin.,Keith G Tolman,"The cholesterol-lowering agents, known as statins, have been in use for 15 years and are among the most commonly prescribed drugs. Animal studies and premarketing clinical trials have given signals of hepatotoxicity, primarily minor elevations in serum alanine aminotransferase enzyme (ALT) levels. For that reason, all of the cholesterol-lowering drugs have labeling that requires monitoring of liver enzymes. Postmarketing experience, however, suggests that hepatotoxicity is rare and thus it is timely to revisit the issue. The first of the statins, lovastatin, was approved in 1986 and has acquired 24 million patient-years of clinical experience. Minor elevations in liver enzymes, i.e., ALT 3 x the upper limit of normal (ULN) occur in 2.6% and 5.0% of patients on lovastatin doses of 20 and 80 mg/day, respectively. These elevations are reversible with continuing therapy, are dose related, and are probably related to cholesterol lowering per se. Rare cases of acute liver failure (ALF) have been reported with all of the cholesterol-lowering drugs. With lovastatin, the rate is approximately 1/1.14 million patient-treatment years, which is 9% of the background rate of all causes of ALF and approximately equal to the background rate of idiopathic ALF. Monitoring for hepatotoxicity has not been effective in preventing serious liver disease, largely because of its rarity and the poor predictive value of minor ALT elevations. In fact, it may increase patient risk because of needless discontinuation of cholesterol-lowering therapy for false-positive results in patients who are benefiting from treatment.",2002.0,0,0 1371,12062737,"Side effects of statins: hepatitis versus ""transaminitis""-myositis versus ""CPKitis"".",Carlos A Dujovne,,2002.0,0,0 1372,12064258,Transmission of prion disease.,Thomas Blättler,"The transmission of bovine spongiform encephalopathy to humans as variant Creutzfeldt-Jakob disease (vCJD) has focused public attention on how prion diseases are transmitted and how prions reach the brain after exposure. Prion diseases are characterised by transmissibility and neuropathological features of gliosis, neuronal loss and microscopic vacuoles, termed spongiosis. The principal component of prions is the glycoprotein PrP(Sc), which is a conformational modified isoform of the normal membrane protein PrP(C). How are prions transmitted and how do prions find their way once they have been ingested? Prion models in mouse and hamster point to lymphoreticular cells which support an early replication phase of prions before reaching the central nervous system via peripheral nerves. Whilst some key players seem to have been identified so far, the mechanisms of prion propagation to the brain are still not fully understood. Seemingly contradictory results have led to some confusion and have provoked discussion.",2002.0,0,0 1373,12067933,Use of statins in the secondary prevention of coronary heart disease: is treatment equitable?,F D A Reid; D G Cook; P H Whincup,"To investigate possible inequities in the use of statins for people with coronary heart disease according to a wide range of social and clinical factors. Cross sectional analysis of data from the Health Survey for England 1998, a population based survey. 760 adults with coronary heart disease. Only 19.9% of subjects with coronary heart disease were receiving lipid lowering drugs (151 of 760; 95% confidence interval (CI) 17.0% to 22.7%). The likelihood of receiving statins was greatly reduced for older age groups: compared with those aged less than 65 years, the odds of receiving statin treatment were 0.53 (95% CI 0.35 to 0.80) for subjects aged 65-74 years, and 0.11 (95% CI 0.06 to 0.21) for subjects aged 75 years and over. Statins were given less often to current cigarette smokers than to non-smokers (odds ratio 0.55, 95% CI 0.32 to 0.96), and to subjects with angina compared with those with a previous myocardial infarct (odds ratio 0.63, 95% CI 0.43 to 0.93). Lower levels of statin use were also seen with increasing time since diagnosis (p = 0.12). No clear associations were observed with social measures. Important inequalities were found in the use of statins among people with coronary heart disease, which could not be justified by evidence from the large statin trials. Proactive policies are required to ensure that the vast majority of (if not all) patients with coronary heart disease are receiving statins, regardless of age, sex, social class, smoking status, type of coronary heart disease, or time since diagnosis.",2002.0,0,0 1374,12067936,Low prevalence of lipid lowering drug use in older men with established coronary heart disease.,P H Whincup; J R Emberson; L Lennon; M Walker; O Papacosta; A Thomson,"To determine the prevalence and correlates of lipid lowering drug use among older British men with established coronary heart disease (CHD). Cross sectional survey within a cohort study (British regional heart study) carried out at 20 years of follow up in 1998-2000. General practices in 24 British towns. 3689 men aged 60-75 years (response rate 76%). Diagnoses of myocardial infarction and angina based on detailed review of general practice records. Lipid lowering drug use and blood cholesterol concentrations ascertained at 20 year follow up examination. Among 286 men with definite myocardial infarction, 102 (36%) were taking a lipid lowering drug (93 (33%) a statin); among 360 men with definite angina without myocardial infarction, 84 (23%) were taking a lipid lowering drug (78 (21%) a statin). Most men with documented CHD who were not receiving a lipid lowering drug had a total cholesterol concentration of 5.0 mmol/l or more (87% of those with myocardial infarction, 82% with angina). Fewer than half of men with CHD receiving a statin had a total cholesterol concentration below 5.0 mmol/l (45% of those with myocardial infarction and 47% of those with angina). Only one third of the men taking a statin were receiving trial validated dosages. Among men with CHD, a history of revascularisation, more recent diagnosis, and younger age at diagnosis were associated with a higher probability of receiving lipid lowering drug treatment. Among patients with established CHD, the prevalence of lipid lowering drug use remains low and statin regimens suboptimal. Major improvements in secondary prevention are essential if the benefits of statins are to be realised.",2002.0,0,0 1375,12069369,Future directions in lipid therapies.,Benjamin Ansell,"Cholesterol management to reduce the burden of cardiovascular disease is a major public health concern. Despite widespread recognition of lipid abnormalities as cardiovascular risk factors, significant cardiovascular event reductions with cholesterol-lowering therapies, and dissemination of treatment guidelines, most high-risk patients are not at target lipid levels. In addition to lifestyle changes, four major drug classes are available to modify lipid levels: fibrates, niacin, resins, and statins. High efficacy and tolerability in clinical trials make statins the most widely prescribed of these agents. Newer, more potent members of this class and novel formulations of niacin and resins may provide more effective therapy for dyslipidemia with fewer side effects. Several agents in development (cholesterol-absorption inhibitors and ACAT inhibitors) exploit mechanisms of action complementary to those of current treatments and combined with statins may produce greater improvements in lipid profiles than are now possible. These innovations should enable a greater number of patients to achieve more aggressive cholesterol goals, thereby reducing the risk of cardiovascular events.",2002.0,0,0 1376,12069671,Early statin initiation and outcomes in patients with acute coronary syndromes.,L Kristin Newby; Arni Kristinsson; Manjushri V Bhapkar; Philip E Aylward; Alexios P Dimas; Werner W Klein; Darren K McGuire; David J Moliterno; Freek W A Verheugt; W Douglas Weaver; Robert M Califf; SYMPHONY and 2nd SYMPHONY Investigators. Sibrafiban vs Aspirin to Yield Maximun Protection From Ischemic Heart Events Post-acute Coronary Syndromes,"The secondary prevention benefit of therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been clearly demonstrated; however, the role of early initiation of statins after acute coronary syndromes (ACSs) is unknown. To evaluate the association of early statin initiation (< or = 7 days) after ACS with 90-day and 1-year outcomes. Observational cohort from databases of 2 randomized clinical trials, SYMPHONY and 2nd SYMPHONY. Nine hundred thirty-one clinical centers in 37 countries. A total of 12,365 ACS patients randomized from August 1997 to August 1999 who were not taking statins prior to the index ACS and who either started statin therapy early (median, 2.0 [interquartile range, 1.0-3.1] days after ACS; n = 3952) or survived more than 5 days after ACS and never received statin therapy (n = 8413). Ninety-day incidence of death; death or myocardial infarction (MI); and death, MI, or severe recurrent ischemia; as well as 1-year incidence of death. Ninety-day and 1-year unadjusted mortality comparison suggested early statin benefit (1.2% for early statins vs 2.1% for no statins; hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.42-0.81 for 90-day comparisons and 2.3% for early statins vs 4.4% for no statins; HR, 0.52; 95% CI, 0.40-0.68 for 1-year comparison). However, no benefit was evident for 90-day death or MI (6.5% vs 6.9%; HR, 0.95; 95% CI, 0.82-1.11) or death, MI, or severe recurrent ischemia (9.2% vs 8.9%; HR, 1.04; 95% CI, 0.92-1.18). After propensity and covariate adjustment, there were no 90-day or 1-year differences between the early-statin group and the no-statin group. The 90-day adjusted HR for death was 1.08 (95% CI, 0.75-1.56); for death or MI, 1.08 (95% CI, 0.91-1.29); and for death, MI, or severe recurrent ischemia, 1.15 (95% CI, 0.99-1.34). One-year mortality-adjusted HR was 0.99 (95% CI, 0.73-1.33). Among 2711 patients with core laboratory lipid analysis, early statin was associated with higher adjusted risk for death or death or MI at cholesterol levels below treatment guidelines but was more favorable at higher levels. In this study, there was no relationship between early initiation of statin therapy and improved outcomes although our subset analysis suggests that outcomes after early statin initiation may vary with cholesterol levels. Confirmation of early treatment effects of statins on outcomes awaits the results of adequately powered randomized clinical trials.",2002.0,0,0 1377,12069677,Estimating treatment effects from observational data: dissonant and resonant notes from the SYMPHONY trials.,Karin B Michels; Eugene Braunwald,,2002.0,0,0 1378,12071579,Anti-inflammatory and antithrombotic effects of statins in the management of coronary artery disease.,Anetta Undas; Jan Brozek; Jacek Musial,"Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins), a potent class of cholesterol-lowering drugs, exert a number of pleiotropic effects, including anti-inflammatory and antithrombotic properties. Evidence is now accumulating that these effects are not related to the reduction in lipid levels. In vitro studies, supported recently by in vivo data, indicate that treatment with statins results in a significant decrease in the levels of inflammation markers, such as C-reactive protein, interleukin 6, and tumor necrosis factor alpha, which appear to be predictors of acute coronary events and help stratify cardiovascular risk. Up to now, only high-sensitive C-reactive protein testing has the potential to become an adjunctive method to assess the risk of coronary events in low- and high-risk individuals. Statins can also inhibit tissue factor expression, leading to impaired activation of the blood coagulation cascade, as evidenced by a decrease in thrombin generation in vivo. Interrelated inhibition of inflammation and thrombosis induced by statins is believed to largely contribute to clinical benefits from statin therapy, regardless of cholesterol levels. Further studies will answer the question whether markers of inflammation, other than C-reactive protein and possibly indices of thrombin formation, might improve cardiovascular risk stratification.",2003.0,0,0 1379,12071780,Signal generation in the New Zealand Intensive Medicines Monitoring Programme: a combined clinical and statistical approach.,David M Coulter,"The New Zealand Intensive Medicines Monitoring Programme (IMMP) undertakes prospective observational cohort studies on selected new drugs in the early postmarketing period using prescription-event monitoring (PEM) methodology with the purpose of identifying signals of previously unrecognised ADRs and establishing risk profiles for each drug. Events are reviewed by a physician and a relationship is established between each event and the drug. The events are then sorted into reactions and incidents. The latter are used to assist signal detection and control for bias. Rates for reports, reactions and incidents are used to assess the adequacy of reporting, signal detection and identification of confounders. Most signals are identified by clinical evaluation of the reports at a stage when statistical analyses are unlikely to have the power to detect them with confidence. The incident group is used for signal detection and controlling for bias. A low reporting rate indicates that certain types of event are unlikely to be reported. A systematic review of the original case reports at the site of collection provides the best opportunity for early signal detection. More resources need to be invested in the training and support of clinical evaluators. Categorising events into reactions and incidents gives added value to the data. Rates of reporting should be quoted with the results of cohort studies to facilitate assessment of their power to detect new signals.",2002.0,0,0 1380,12072338,Pravastatin treatment-associated reduction in plasma homocysteine in heart-transplanted patients.,P L Capecchi; P E Lazzerini; M Maccherini; F Guideri; G Lisi; M Acampa; A Cuomo; F Diciolla; M Toscano; F Laghi Pasini,,2002.0,0,0 1381,12072574,Valsartan therapy has additive anti-oxidative effect to that of fluvastatin therapy against low-density lipoprotein oxidation: studies in hypercholesterolemic and hypertensive patients.,Osamah Hussein; Julia Shneider; Mira Rosenblat; Michael Aviram,"In hypercholesterolemic and hypertensive patients, an increased propensity of their low-density lipoprotein (LDL) to oxidative modification has been observed. Because oxidized LDL (ox-LDL) plays a major role in atherosclerosis, the current study analyzed the anti-oxidative effect of valsartan (an angiotensin II receptor antagonist) therapy in combination with fluvastatin therapy in these patients. Administration of 40 mg/d of fluvastatin for 2 months to seven patients resulted in significant reduction in plasma total and LDL cholesterol (by 24-28%). Valsartan administration (80 mg/d for an additional 2-month period) in combination with fluvastatin did not further affect plasma cholesterol levels. Fluvastatin therapy inhibited the susceptibility of LDL to copper ion-induced oxidation, as shown by prolongation of the lag time by 22% and by a reduction of thiobarbituric acid-reactive substances (TBARS) levels by 14%, as compared with the patient's LDL baseline oxidation. The addition of valsartan to fluvastatin resulted in a further 17% prolongation of the lag time and in an additional reduction of 21% in TBARS levels. In a parallel study, the LDL from eight patients who were first treated with 80 mg/d of valsartan for 2 months demonstrated reduced susceptibility to copper ion-induced oxidation, as observed by prolongation of lag time by 23% and reduction in TBARS levels by 19%, compared with the baseline values. The administration of 40 mg/d of fluvastatin for an additional 2 months in combination with valsartan, however, demonstrated no further inhibitory effect on LDL oxidation. The anti-oxidative properties of fluvastatin and valsartan against LDL oxidation were also demonstrated in vitro and the combination of both drugs was shown to have an additive effect. Valsartan therapy in hypercholesterolemic and hypertensive patients has an additive anti-oxidative effect to that of fluvastatin therapy. This may be related both to the anti-oxidative properties of valsartan and to the blocking of angiotensin II-induced oxidative stress.",2003.0,0,0 1382,12073695,Statins for all?,John Hampton,,2002.0,0,0 1383,12073858,Managing hyperlipidemia: current and future roles of HMG-CoA reductase inhibitors.,Larry M Lopez,"The current and future roles of statins as antilipemic agents for the prevention and management of coronary artery disease (CAD) are reviewed. Therapy with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) substantially reduces total cholesterol and low-density-lipoprotein (LDL) cholesterol concentrations. Large clinical trials have documented the efficacy of statin therapy for both primary and secondary prevention of CAD. Nevertheless, many eligible patients are either untreated or inadequately treated with these agents. In one study, 61% of patients with documented CAD were not treated with a lipid-lowering agent. Large percentages of high-risk patients receiving such agents are not meeting cholesterol goals set by the National Cholesterol Education Program (NCEP). Populations at increased risk for coronary events include patients with diabetes, women, the elderly, and patients with established CAD. Comparative studies have not shown any one agent as clearly superior to the others. Future possibilities for statin use include early treatment of hypercholesterolemia and acute coronary syndromes consistent with guidelines established by NCEP. Many clinicians now believe that an aggressive approach to lowering LDL cholesterol may yield even greater reductions in coronary events. Treatment may reduce the risk of recurrent ischemic events when initiated within 96 hours of hospitalization for acute myocardial infarction or unstable angina and continued for up to four months. Another use may be the management of atherosclerotic cerebrovascular disease. Closer attention to potential adverse effects will be necessary before any expansion in statin use. Statins are highly effective for improving cardiovascular outcomes in high-risk patients but are frequently underused. Pharmacists can help extend the benefits of statins to more patients.",2002.0,0,0 1384,12074206,"Efficacy and safety of pioglitazone in type 2 diabetes: a randomised, placebo-controlled study in patients receiving stable insulin therapy.",J Rosenstock; D Einhorn; K Hershon; N B Glazer; S Yu; Pioglitazone 014 Study Group,"The glycaemic and lipid effects of treatment with pioglitazone in combination with a stable insulin regimen were evaluated in patients with type 2 diabetes. Patients (n=566) receiving stable insulin regimens for > or = 30 days yet who had HbA1c > or = 8.0% and C-peptide > 0.7 microg/l were randomised to receive once-daily 15 mg pioglitazone, 30 mg pioglitazone, or placebo in a 16-week multicentre, double-blind, placebo-controlled trial. Per study protocol, the insulin dose was to remain unchanged, but could be decreased in response to hypoglycaemia. At the end of double-blind treatment, patients receiving pioglitazone (15 mg or 30 mg) showed statistically significant mean decreases relative to baseline HbA1c (-1.0 and -1.3, respectively; p<0.0001) and fasting plasma glucose (FPG) (-34.5 mg/dl [-1.92 mmol/l] and -48.0 mg/dl [-2.67 mmol/l], respectively; p<0.0001); these differences compared with placebo were also significant (p<0.0001). Pioglitazone (15 or 30 mg) yielded significant increases in HDL-C levels (mean increases ranging from +7.1% to + 9.3%) compared with baseline or placebo (p<0.01). The 30 mg dose also significantly reduced mean triglyceride levels (-23.7%) compared with placebo (p=0.0218). No consistent changes in TC or LDL-C levels were observed. The incidence of adverse events was similar in all treatment groups, although the incidences of weight increase, hypoglycaemia and oedema were higher among patients receiving insulin plus pioglitazone. There was no evidence of hepatotoxicity or drug-induced elevations of serum ALT > or = 3 x ULN. Pioglitazone, when added to stable insulin regimens, significantly improved HbA1c and FPG in type 2 diabetes. Pioglitazone treatment also provided significant benefit with respect to plasma HDL-C and triglyceride levels. Whether these lipid changes have an impact on overall diabetic complications remains to be determined.",2002.0,0,0 1385,12074332,Various clinical approaches to minimise complications in peritoneal dialysis.,B Stegmayr,"The main reason for a failure of peritoneal dialysis is due to technical problems or infections. By starting PD immediately after the insertion of a dialysis catheter (instead of starting HD before optimal healing of the PD-catheter) it may be easier to achieve acceptance for PD by the patients. An easy and tight access is achieved when inserting the PD-catheter through the rectus muscle, fixing it with three purse string sutures, two of them fixing the inner cuff between the peritoneal membrane and the inner rectus fascia. Thereby early and late leakage will be rare and good drainage is normally achieved besides a low risk for exit site infections. Using Coloplast adhesive insulin can be injected into the PD bags in a simple way even by patients with bad vision. Using ultraviolet light, as additional exchange device (UV-box), the risk for peritonitis is reduced compared to classic manual connection. Using the Y-set or duo-bag system the risk for peritonitis is further lowered. Malfunction by dislocation of the intraperitoneal part of the catheters can often be corrected without surgery using a bent stylet. A controlled study showed that antibiotic prophylactics could significantly reduce the risk for peritonitis in the follow up after insertion of PD catheters. Additionally the risk for peritonitis is reduced using a special connector for the PET-sampling procedures. X-ray of catheter location in the abdominal cavity can be performed by injection of 20-ml contrast media into 100 ml of PD fluid residing in the PD-bag. After mixing, small portions of this fluid can be infused into the abdomen for X-ray determination of the location. An increased ultrafiltration failure during PD may be due to use of beta-blocker medication. After ceasing this medication recovery may occur. Avoiding pets in the room used for PD-exchange may lower the risk for peritonitis further. A devoted nurse and physician will keep up the patients' spirit and help to convert patients not suitable for PD to HD or the other way round. By such measures the incidence of peritonitis can be reduced to 1 in 40 treatment months or less.",2003.0,0,0 1386,12075242,Routine statin treatment after acute coronary syndromes?,Monica Acevedo; Dennis L Sprecher; Michael S Lauer; Gary Francis,,2002.0,0,0 1387,12075248,The SYNERGY trial: study design and rationale.,"SYNERGY Executive Committee. Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors","Enoxaparin was shown to be superior to unfractionated heparin in the patients with non-ST-segment elevation acute coronary syndromes (ACS) in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events study and the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. However, enoxaparin has had limited acceptance in clinical practice, in part because of the contemporary management of these patients, which includes glycoprotein IIb/IIIa inhibition and the use of early invasive management strategies. The Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is an 8000-patient, prospective, randomized, open-label, multicenter investigation of enoxaparin compared with unfractionated heparin in patients at high risk with non-ST-segment elevation ACS treated with an early invasive strategy. The primary efficacy end point is death or nonfatal myocardial infarction 30 days after enrollment. The SYNERGY trial is the largest study currently planned for the acute therapy of patients with non-ST-segment elevation ACS and the first large trial since the publication of the revised American College of Cardiology/American Heart Association guidelines for the management of these patients. In addition to evaluating the potential superiority of enoxaparin over unfractionated heparin, this investigation will provide important observations of current treatment strategies in patients with ACS.",2002.0,0,0 1388,12076217,Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.,Patrick W J C Serruys; Pim de Feyter; Carlos Macaya; Norbert Kokott; Jacques Puel; Matthias Vrolix; Angelo Branzi; Marcelo C Bertolami; Graham Jackson; Bradley Strauss; Bernhard Meier; Lescol Intervention Prevention Study (LIPS) Investigators,"Percutaneous coronary intervention (PCI) is associated with excellent short-term improvements in ischemic symptoms, yet only three fifths of PCI patients at 5 years and one third of patients at 10 years remain free of major adverse cardiac events (MACE). To determine whether treatment with fluvastatin reduces MACE in patients who have undergone PCI. Randomized, double-blind, placebo-controlled trial conducted at 77 referral centers in Europe, Canada, and Brazil. A total of 1677 patients (aged 18-80 years) recruited between April 1996 and October 1998 with stable or unstable angina or silent ischemia following successful completion of their first PCI who had baseline total cholesterol levels between 135 and 270 mg/dL (3.5-7.0 mmol/L), with fasting triglyceride levels of less than 400 mg/dL (4.5 mmol/L). Patients were randomly assigned to receive treatment with fluvastatin, 80 mg/d (n = 844), or matching placebo (n = 833) at hospital discharge for 3 to 4 years. Survival time free of MACE, defined as cardiac death, nonfatal myocardial infarction, or reintervention procedure, compared between the treatment and placebo groups. Median time between PCI and first dose of study medication was 2.0 days, and median follow-up was 3.9 years. MACE-free survival time was significantly longer in the fluvastatin group (P =.01). One hundred eighty-one (21.4%) of 844 patients in the fluvastatin group and 222 (26.7%) of 833 patients in the placebo group had at least 1 MACE (relative risk [RR], 0.78; 95% confidence interval [CI], 0.64-0.95; P =.01). This result was independent of baseline total cholesterol levels (above [RR, 0.76; 95% CI, 0.56-1.04] vs below [RR, 0.77; 95% CI, 0.57-1.02] the median). In subgroup analysis, the risk of MACE was reduced in patients with diabetes (n = 202; RR, 0.53; 95% CI, 0.29-0.97; P =.04) and in those with multivessel disease (n = 614; RR, 0.66; 95% CI, 0.48-0.91; P =.01) who received fluvastatin compared with those who received placebo. There were no instances of creatine phosphokinase elevations 10 or more times the upper limit of normal or rhabdomyolysis in the fluvastatin group. Fluvastatin treatment in patients with average cholesterol levels undergoing their first successful PCI significantly reduces the risk of major adverse cardiac events.",2002.0,1,1 1389,12076230,Statin therapy in older persons: pertinent issues.,Scott M Grundy,,2002.0,0,0 1390,12076239,Therapy with hydroxymethylglutaryl coenzyme a reductase inhibitors (statins) and associated risk of incident cardiovascular events in older adults: evidence from the Cardiovascular Health Study.,Rozenn N Lemaitre; Bruce M Psaty; Susan R Heckbert; Richard A Kronmal; Anne B Newman; Gregory L Burke,"Recommendations to treat older adults with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) for the primary prevention of coronary heart disease events are supported by a single clinical trial restricted to adults 73 years or younger with low levels of high-density lipoprotein cholesterol. We investigated the association of statin use with incident cardiovascular disease and all-cause mortality during up to 7.3 years' follow-up of 1250 women and 664 men from the Cardiovascular Health Study. Study participants were 65 years and older and free of cardiovascular disease at baseline. They received drug therapy to lower cholesterol levels at baseline or no treatment with a recommendation for therapy according to the National Cholesterol Education Program guidelines. Use of these drugs was assessed annually. We used proportional-hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for confounding variables. We found 382 incident cardiovascular events (159 myocardial infarctions, 159 strokes, and 64 deaths due to coronary heart disease) and 362 total deaths from June 1, 1989, to May 31, 1997. Compared with no use of drugs to lower cholesterol levels, statin use was associated with decreased risk of cardiovascular events (multivariate HR, 0.44; 95% CI, 0.27-0.71) and all-cause mortality (HR, 0.56; 95% CI, 0.36-0.88). Similar associations were observed among participants 74 years or older at baseline. Use of statins was associated with decreased risk of incident cardiovascular events among elderly adults. These findings lend support to the National Cholesterol Education Program guidelines, which recommend therapy for the lowering of cholesterol levels for older adults with hypercholesterolemia.",2002.0,0,0 1391,12077562,Lipid-lowering drugs: are adverse effects predictable and reversible?,Antonio Muscari; Giovanni M Puddu; Paolo Puddu,"Most of the currently available statins and fibric acid derivatives have been implicated in causing complications either in monotherapy or in combination therapy. Adverse events occur more often with the statins that are metabolized via the CYP enzyme system and its 3A4, 2C9 or 2C19 paths. All compounds interfering with the same cytochrome system may either impair or enhance the elimination of statins. Other factors predisposing to adverse effects are age, female sex, renal insufficiency, electrolyte disturbances, infections and trauma. Complications chiefly concern the hepatic function, skeletal muscles and peripheral nerves. The major adverse effect is myopathy, up to rhabdomyolysis with ensuing acute renal insufficiency. Fibrates bind to peroxisome proliferator-activated nuclear receptors alpha, with subsequent stimulation of fatty acid oxidation and reduction in the rate of hepatic lipid generation. Fibrates are associated with a number of adverse effects, including liver enzyme elevations, gastrointestinal side effects and rhabdomyolysis. The combination of statins with fibrates may cause serious complications and should be avoided when possible. In order to prevent or minimize adverse clinical outcomes, patients should be closely monitored and informed of the most common symptoms.",2002.0,0,0 1392,12079440,Lipid-lowering medication for secondary prevention of coronary heart disease in a German outpatient population: the gap between treatment guidelines and real life treatment patterns.,J Ruof; G Klein; W März; H Wollschläger; A Neiss; M Wehling,"Few published data in particular from the United States indicate that the implementation of guidelines for prevention of coronary heart disease (CHD) is far from optimal. The objective of our study was to identify the type and prevalence of lipid-lowering medications in a German outpatient CHD population and to examine the impact of applied treatment regimens on serum lipid levels. Retrospective analysis of the washout phase of 2,856 CHD patients requiring lipid-lowering medication. Data are derived from a multicenter, randomized, open-label, parallel group clinical trial comparing the safety and efficacy of atorvastatin versus simvastatin in 591 centers in Germany. Medical history, physical examination, and serum lipid levels were obtained at the beginning of the washout phase (Week -6) and at the end of the washout phase (Week -1, i.e., 5 weeks after the discontinuation of all prior lipid-lowering medications). The data at Week -6 represented the lipid levels under real life conditions. The difference from the data at Week -1 reflected the therapeutic effects achieved by the previous lipid-lowering treatment. The mean low-density lipoprotein cholesterol (LDL-C) level at Week -6 was 173.4 +/- 42.5 mg/dl. Only 176 (6.2%) of 2,856 CHD patients were found to meet the target LDL-C level of <115 mg/dl at Week -6, only 76 (2.7%) patients had LDL-C levels <100 mg/dl, and 363 (12.7%) patients had LDL-C levels <130 mg/dl. After discontinuation of all prior lipid-lowering medications, mean LDL-C increased to 187.2 +/- 44.0 mg. This means that only a marginal 7.4% reduction in LDL-C level was achieved under real life treatment conditions. This limited LDL-C reduction was due mainly to the low prevalence of lipid-lowering treatment (65.5% of patients did not receive any medication at all) and inadequate dosing. With respect to the effect on LDL-C and total cholesterol, statins alone were superior to fibrates. The study shows that there is a wide gap between treatment guidelines and real life treatment patterns in Germany. Awareness of the risks of high cholesterol levels has to be increased among both patients and physicians. Available treatment guidelines should be better implemented.",2002.0,0,0 1393,12079617,Lipid response to pioglitazone in diabetic patients: clinical observations from a retrospective chart review.,Allen B King; Dana U Armstrong,"The objective of this study was to determine whether improvements in the lipid profile observed in controlled clinical trials with pioglitazone are seen in the clinical practice setting, and to ascertain the influence of concurrent statin treatment. Charts of 100 consecutive patients with type 2 diabetes (mean age 56.8 years) treated with pioglitazone (45 mg/day) for 2-4 months were retrospectively analyzed for changes in serum lipids, glycemic parameters, and body weight. Subanalyses were performed on the relationship of lipid changes to baseline lipid values and to concurrent statin therapy. Pioglitazone was associated with statistically significant (p < 0.001) changes from baseline in HbA(1C) (mean decrease 1.09%), body weight (mean increase 1.76 kg), HDL cholesterol (HDL-C) levels (mean increase 15.6%), and triglycerides (mean decrease 9.9%). There was an increase (+ 1.09%) in mean individual LDL-C levels from baseline values, but this change was not statistically significant. The greatest absolute and percentage improvements in HDL-C and triglycerides were observed in patients who had the greatest lipid abnormalities at baseline: in patients with baseline HDL-C < 35 mg/dL, mean individual HDL-C values increased by 31% (p < 0.001); in those with baseline triglycerides >399 mg/dL, triglyceride levels decreased by 46% (p < 0.001); and in patients with baseline LDL-C > 129 mg/dL, mean individual LDL-C values decreased by 10.6% (p < 0.001). Subgroup analysis showed similar beneficial changes in HDL-C and triglycerides in patients who were not receiving concurrent statin therapy (n = 48) as in those who were receiving statins (n = 49). This observational study demonstrated that significant improvements in HDL-C and triglyceride levels can be achieved with pioglitazone in the clinical practice setting. The greatest improvements occurred in patients with the worst baseline lipid levels, and benefits were seen regardless of whether patients were receiving concurrent statin therapy.",2002.0,0,0 1394,12081213,"Bisphosphonates, statins, osteoporosis, and atherosclerosis.",Nelson Watts,,2002.0,0,0 1395,12081988,"Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS).",David M Herrington; Eric Vittinghoff; Feng Lin; Josephine Fong; Fran Harris; Donald Hunninghake; Vera Bittner; Helmut G Schrott; Roger S Blumenthal; Robert Levy; HERS Study Group,"Although effects of statins on cardiovascular outcomes are well established in men, fewer data exist for women. Furthermore, the effects of statins plus hormone replacement therapy (HRT) on cardiovascular outcomes are uncertain. We examined statin use, cardiovascular events, and total mortality in the Heart and Estrogen/progestin Replacement Study (HERS), a randomized clinical trial of estrogen plus progestin versus placebo in postmenopausal women with heart disease (n=2763). A nonrandomized comparison of statin users and nonusers revealed lower rates of the primary outcome, nonfatal myocardial infarction or coronary heart disease death (relative hazard [RH]=0.79, 95% confidence intervals [CI] 0.63 to 0.99, P=0.04), and total mortality (RH=0.67, 95% CI 0.51 to 0.87, P=0.003). Rates of venous thromboembolic events were also lower among statin users (RH=0.45, 95% CI 0.23 to 0.88, P=0.02). HRT resulted in a significant increase in early risk for primary events in women who did not use statins (RH=1.75, 95% CI 1.02 to 3.03, P=0.04) but not in statin users (RH=1.34, 95% CI 0.63 to 2.86, P=0.45). Adjustment for postrandomization statin use showed no effect of HRT on risk for the primary outcome (RH=0.96, 95% CI 0.77 to 1.29; P=0.72). In HERS, statin use was associated with lower rates of cardiovascular events, venous thromboembolic events, and total mortality. These data provide strong support for statin use in eligible women with coronary disease.",2002.0,0,0 1396,12083733,"Microalbuminuria: marker of vascular dysfunction, risk factor for cardiovascular disease.",Jay P Garg; George L Bakris,"Based on the data from large single and multi-center clinical trials, including the Heart Outcomes Prevention Evaluation (HOPE) study, it is clear that the presence of microalbuminuria is a signal from the kidney that cardiovascular risk is increased and that vascular responses are altered. This is exemplified by studies that have demonstrated that the compensatory vasodilation seen following relief from prolonged ischemia or infusion of vasodilators such as nitroglycerin is blunted in people with microalbuminuria. Thus, the presence of between 30 and 299 mg/day of albumin in the urine is associated with abnormal vascular responsiveness, which may be the result of more advanced atherosclerosis and not necessarily related to the presence of hypertension or renal disease. Agents known to reduce the rise in microalbuminuria or actually reduce the level of microalbuminuria, such as ACE inhibitors, angiotensin receptor blockers, HMG-CoA reductase inhibitors, beta blockers, non-dihydropyridine calcium channel blockers and diuretics, have all been shown to reduce cardiovascular mortality and in some cases preserve renal function. This article will present an overview of the data that support the assertion that a reduction in the rise of microalbuminuria is a significant consideration in the selection of agents to treat a given risk factor (cholesterol or blood pressure) to a recommended target goal. Achieving such a goal with agents that also impact microalbuminuria will provide for a more complete cardiovascular risk reduction.",2003.0,0,0 1397,12086554,Kaletra (lopinavir/ritonavir).,Amanda H Corbett; Michael L Lim; Angela D M Kashuba,"To review the pharmacology, virology, pharmacokinetics, efficacy, safety, and clinical use of lopinavir/ritonavir (Kaletra, Abbott Laboratories). English-language MEDLINE and AIDSline searches were performed (1966-July 2001) using lopinavir, ABT-378, and Kaletra as key words. Abstracts from infectious diseases and HIV scientific meetings were identified. Abbott Laboratories provided additional published and unpublished information. All publications, meeting abstracts, and unpublished information were reviewed and relevant items included. In vitro and preclinical studies were included as well as Phase II and III clinical trials. Lopinavir/ritonavir is a fixed-dose protease inhibitor (PI) combination used for the treatment of HIV-1 infection. Lopinavir, the active component of this combination, is extensively metabolized by CYP3A4 and produces low systemic concentrations when used alone. Ritonavir potently inhibits CYP3A4 and is used to enhance the systemic exposure of lopinavir. This combination results in lopinavir concentrations that greatly exceed those necessary in vitro to inhibit both wild-type and PI-resistant HIV isolates. In clinical trials with antiretroviral naïve and experienced patients, lopinavir/ritonavir was effective at suppressing HIV-RNA and increasing CD4+ T cell counts. Compared with other PIs, lopinavir/ritonavir may have advantages in the areas of pharmacokinetics, efficacy, and resistance. Toxicity, drug interactions, and medication adherence are important considerations surrounding its clinical use. Lopinavir/ritonavir is an effective option for the treatment of HIV-1-infected individuals when used in combination with other antiretroviral agents. It may be used as a component of initial therapy or salvage therapy; future studies will better define its place in therapy.",2002.0,0,0 1398,12086556,Orlistat use in type 2 diabetes.,Laura J Snider; Margaret Malone,"To review the use of orlistat in type 2 diabetes. A MEDLINE search of the English-language literature (1990-August 2001) was performed using the key terms orlistat, obesity, glucose, and diabetes. All articles pertaining to orlistat were considered for inclusion, with emphasis placed on randomized, placebo-controlled, double-blind clinical trials. In April 1999, orlistat was approved by the Food and Drug Administration for the treatment of obesity. Of 13 randomized, placebo-controlled studies, only 2 reported specific data in individuals with type 2 diabetes. Both reported significant weight reduction and improved glycemic control over placebo. Since weight loss is a difficult goal to achieve in patients with type 2 diabetes, orlistat can be a safe, effective addition to a multidisciplinary approach.",2002.0,0,0 1399,12087019,Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia.,Vasilios G Athyros; Athanasios A Papageorgiou; Valasia V Athyrou; Dimokritos S Demitriadis; Athanasios G Kontopoulos,"This study evaluated the effect of a atorvastatin-fenofibrate combination on lipid profile, in comparison to each drug alone, in patients with type 2 diabetes and combined hyperlipidemia (CHL). A total of 120 consecutive patients, who were free of coronary artery disease (CAD) at entry, were studied for a period of 24 weeks. These patients were randomly assigned to atorvastatin (20 mg/day, n = 40), micronized fenofibrate (200 mg/day, n = 40), or a combination of both (atorvastatin 20 mg/day plus fenofibrate 200 mg/day, n = 40). The effect of treatment on LDL cholesterol, triglycerides (TGs), HDL cholesterol, apolipoprotein A-I and B, lipoprotein(a), and plasma fibrinogen (PF) was recorded. Moreover, the percentage of patients that reached the American Diabetes Association treatment goals and the estimated CAD risk status were calculated. No patient was withdrawn from the study because of side effects. The atorvastatin-fenofibrate combination reduced total cholesterol by 37%, LDL cholesterol by 46%, TGs by 50%, and PF by 20%, whereas it increased HDL cholesterol by 22% (P < 0.0001 for all). These changes were significantly better than those of both monotherapies. Of the patients on drug combination, 97.5% reached the LDL cholesterol treatment goal of <100 mg/dl, 100% reached the desirable TG levels of <200 mg/dl, and 60% reached the optimal HDL cholesterol levels of >45 mg/dl. These rates were significantly higher than those of both monotherapies. Combined treatment reduced the 10-year probability for myocardial infarction from 21.6 to 4.2%. The atorvastatin-fenofibrate combination has a highly beneficial effect on all lipid parameters and PF in patients with type 2 diabetes and CHL. It improved patients' CAD risk status significantly more than each drug alone.",2002.0,0,0 1400,12087021,"Aggressive lipid lowering does not improve endothelial function in type 2 diabetes: the Diabetes Atorvastatin Lipid Intervention (DALI) Study: a randomized, double-blind, placebo-controlled trial.",Francine V van Venrooij; Marcel A van de Ree; Michiel L Bots; Ronald P Stolk; Menno V Huisman; J D Banga; DALI Study Group,"Endothelial dysfunction is considered an important early marker of atherosclerosis and cardiovascular risk and is currently used as a surrogate end point for cardiovascular risk in clinical trials. Type 2 diabetic patients show a characteristic dyslipidemia. Aggressive lipid lowering might be an effective method to improve endothelial function in these patients. A randomized, double-blind, placebo-controlled trial was completed to study the effect of 30 weeks' administration of atorvastatin 10 mg and 80 mg on endothelial function, as assessed by B-mode ultrasound of the brachial artery, in 133 patients with type 2 diabetes without a history of cardiovascular disease. Patients with diabetes and diabetic dyslipidemia had considerable endothelium-dependent and endothelium-independent dysfunction; mean flow-mediated vasodilation (SD) was 3.16% (3.56), and mean response on sublingual nitroglycerin was 6.58% (6.04). Despite substantial lowering of all atherogenic lipid parameters, no improvement of endothelium-dependent vasodilatation was found (P > 0.8). We observed considerable baseline endothelium-dependent and endothelium-independent dysfunction in patients with diabetes and diabetic dyslipidemia without a history of cardiovascular disease. Aggressive lipid lowering by administration of atorvastatin, resulting in substantial improvement of the lipid profile, did not reverse endothelial dysfunction.",2002.0,0,0 1401,12087027,Endothelial vasodilation effects of statins in type 2 diabetic patients: response to van Venrooij et al.,James R Sowers,,2002.0,0,0 1402,12087035,"Atorvastatin, diabetic dyslipidemia, and cognitive functioning.",Ingrid Berk-Planken; Inge de Konig; Ronald Stolk; Hans Jansen; Nicoline Hoogerbrugge,,2002.0,0,0 1403,12088769,A risk model derived from the National Registry of Myocardial Infarction 2 database for predicting mortality after coronary artery bypass grafting during acute myocardial infarction.,Jonathan G Zaroff; Dante G diTommaso; Hal V Barron,"The mortality risk associated with coronary artery bypass grafting (CABG) after acute myocardial infarction (AMI) remains controversial. Although elective CABG is quite safe, the effects of recent myocardial infarction, gender, and other clinical factors on perioperative mortality rates are not completely understood. The objective of this study was to determine in-hospital mortality rates for patients with AMI receiving CABG and to generate a model to predict the risk for any individual patient with specific risk factors. Using the National Registry of Myocardial Infarction 2 database, we identified 71,774 subjects (21,270 women) with AMI who underwent CABG; we excluded those subjects who received immediate surgery as reperfusion therapy. Multivariate logistic regression was used to quantify the independent effects of age, recent myocardial infarction, gender, and other covariates on mortality. A risk score was then generated from the regression model to quantify the mortality risk. The results of logistic regression modeling determined that age was an independent predictor of in-hospital death (adjusted odds ratio [OR] 3.05, 95% confidence interval [CI] 2.76 to 3.37 for age >75), as were previous CABG (OR 2.84, 95% CI 2.55 to 3.16), heart failure on presentation (OR 1.73, 95% CI 1.57 to 1.91 for Killip class II), and female gender (OR 1.58, 95% CI 1.45 to 1.71). The mortality risk score showed that 55% of patients had risk scores of 2 to 5 and mortality rates of 4% to 13%. This moderate risk group experienced 76% of the total predicted mortality. Thus, in-hospital CABG mortality rates after AMI are high compared with elective surgery. Using the described risk score, clinicians can quantify the impact of patient risk factors in making decisions about referral for and timing of CABG.",2002.0,0,0 1404,12088778,Impact of body mass index on outcome after percutaneous coronary intervention (the obesity paradox).,Hitinder S Gurm; Danielle M Brennan; Joan Booth; James E Tcheng; A Michael Lincoff; Eric J Topol,,2002.0,0,0 1405,12088789,Comparison of patients with syncope with left ventricular dysfunction and negative electrophysiologic testing to cardiac arrest survivors and patients with syncope and preserved left ventricular function and impact of an implantable defibrillator.,Paul LeLorier; Andrew D Krahn; George J Klein; Raymond Yee; Allan C Skanes,,2002.0,0,0 1406,12090553,Proteopathy: the next therapeutic frontier?,Lary C Walker; Harry LeVine,"The abnormal conformation and assembly of proteins is a probable cause of many degenerative diseases of old age. These proteopathies include such clinically disparate neurological disorders as Alzheimer's disease. Parkinson's disease and Creutzfeldt-Jakob disease, as well as a variety of non-neurological maladies. The involvement of protein pathology in these diseases is well established and we are beginning to understand the process whereby proteins self-assemble and injure tissues; however, we remain largely in the dark regarding the fundamental origins of the proteopathies. Our present knowledge suggests three broad therapeutic approaches to abrogating the proteopathic cascade: reduce the production of the offending proteins, prevent their self-assembly, or promote their removal.",2003.0,0,0 1407,12090723,,,,,0,0 1408,12090746,An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals at risk of coronary events. A WOSCOPS substudy.,H L White; A Maqbool; A D McMahon; L Yates; S G Ball; A S Hall; A J Balmforth,"The Glycine389 variant of the beta-1 adrenergic receptor generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant and may confer protection against coronary events similar to that observed with beta-blockers. The aim of this study was to ascertain whether this Glycine389 variant protects against coronary events. We identified the genotype at position 389 of the beta1AR in 1554 individuals taken from men enrolled in the West of Scotland Coronary Prevention Study. Men with a coronary event (event group) were each matched for age and smoking status with two control subjects from the same cohort who had not had a coronary event (control group). We compared the distribution of genotypes in the event and control groups. Conditional logistic regression was used to calculate odds ratios for each of the genotypes. The prevalence of the three genotypes in the entire cohort was ArgArg 53.5%, ArgGly 39.6%, GlyGly 6.9%. The Arg389Gly beta-1 adrenergic receptor polymorphism was not associated with coronary events. Using the ArgArg genotype as the reference, the odds ratio for the ArgGly genotype was 1.1 (95% CI, 0.88-1.38) and for the GlyGly genotype it was 1.05 (95% CI, 0.68-1.62). Our longitudinal case-control study demonstrates that the Glycine389 variant of the beta-1 adrenergic receptor does not protect against coronary events.",2002.0,0,0 1409,12090862,Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II).,Deborah Grady; David Herrington; Vera Bittner; Roger Blumenthal; Michael Davidson; Mark Hlatky; Judith Hsia; Stephen Hulley; Alan Herd; Steven Khan; L Kristin Newby; David Waters; Eric Vittinghoff; Nanette Wenger; HERS Research Group,"The Heart and Estrogen/progestin Replacement Study (HERS) found no overall reduction in risk of coronary heart disease (CHD) events among postmenopausal women with CHD. However, in the hormone group, findings did suggest a higher risk of CHD events during the first year, and a decreased risk during years 3 to 5. To determine if the risk reduction observed in the later years of HERS persisted and resulted in an overall reduced risk of CHD events with additional years of follow-up. Randomized, blinded, placebo-controlled trial of 4.1 years' duration (HERS) and subsequent unblinded follow-up for 2.7 years (HERS II) conducted at outpatient and community settings at 20 US clinical centers. A total of 2763 postmenopausal women with CHD and average age of 67 years at enrollment in HERS; 2321 women (93% of those surviving) consented to follow-up in HERS II. Participants were randomly assigned to receive 0.625 mg/d of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate (n = 1380), or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed at personal physicians' discretion during HERS II. The proportions with at least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6) in the hormone group, and increased from 0% (year 1) to 8% (year 6) in the placebo group. The primary outcome was nonfatal myocardial infarction and CHD death. Secondary cardiovascular events were coronary revascularization, hospitalization for unstable angina or congestive heart failure, nonfatal ventricular arrhythmia, sudden death, stroke or transient ischemic attack, and peripheral arterial disease. There were no significant decreases in rates of primary CHD events or secondary cardiovascular events among women assigned to the hormone group compared with the placebo group in HERS, HERS II, or overall. The unadjusted relative hazard (RH) for CHD events in HERS was 0.99 (95% confidence interval [CI], 0.81-1.22); HERS II, 1.00 (95% CI, 0.77-1.29); and overall, 0.99 (0.84-1.17). The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups (RH, 0.97; 95% CI, 0.82-1.14), and in analyses restricted to women who were adherent to randomized treatment assignment (RH, 0.96; 95% CI, 0.77-1.19). Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up. After 6.8 years, hormone therapy did not reduce risk of cardiovascular events in women with CHD. Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD.",2002.0,0,0 1410,12090974,Glucose-tolerance testing in acute myocardial infarction.,Steven M Haffner,,2002.0,0,0 1411,12091000,Disparity between angiographic regression and clinical event rates with hydrophobic statins.,Kazuo Ichihara; Kumi Satoh,,2002.0,0,0 1412,12091755,The importance of lipid evaluation and management in the prevention and treatment of acute myocardial infarction.,Monte Malach; Pascal James Imperato,"There is an obvious need to measure low-density lipoprotein cholesterol in all patients with acute myocardial infarction and coronary artery disease. The recent guidelines of the National Cholesterol Education Program have established the desired level for low-density lipoprotein cholesterol for such patients at <100 mg/dL. However, several studies have demonstrated a lack of low-density lipoprotein cholesterol measurement and lipid-lowering therapy with statins in patients with acute myocardial infarction and coronary artery disease. These findings point to a need for quality of care improvement efforts to foster both lipid measurement and statin use in such patients. Many studies have demonstrated the numerous beneficial effects of statin use. In addition to lipid lowering, these include plaque stability and ant platelet, ant macrophage, and antiatherothrombotic activities as well as enhanced endothelial activity. As a class of drugs, the statins have been shown to offer significant benefits with little in the way of associated risks.",2002.0,0,0 1413,12091773,Pharmacologic therapy of lipid disorders in the elderly.,W S Aronow,"Older men and women with coronary artery disease, prior stroke, peripheral arterial disease, and extracranial carotid arterial disease with a serum low-density lipoprotein (LDL) cholesterol > 125 mg/dL despite diet should be treated with lipid-lowering drug therapy, preferably with statins, to reduce the serum LDL cholesterol to < 100 mg/dL. If statin drug therapy does not lower the serum LDL cholesterol to < 100 mg/dL in older persons with coronary artery disease, a bile acid binding resin, such as cholestyramine, should be added, since this drug does not increase the incidence of myositis in persons taking statins. The physician should use statins to treat older persons without atherosclerotic cardiovascular disease with a serum LDL cholesterol > or = 160 mg/dL plus one major risk factor, or a serum LDL cholesterol greater than or equal to 130 mg/dL plus a serum high-density lipoprotein (HDL) cholesterol < 50 mg/dL. Gemfibrozil may be useful in reducing the incidence of coronary events in persons with coronary artery disease whose primary lipid abnormality is a low serum HDL cholesterol level. There are no good data supporting treatment of hypertriglyceridemia unassociated with increased LDL cholesterol or decreased HDL cholesterol for prevention of cardiovascular disease.",2002.0,0,0 1414,12095313,"Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study.",Kimmo Mäkinen; Hannu Manninen; Marja Hedman; Pekka Matsi; Hanna Mussalo; Esko Alhava; Seppo Ylä-Herttuala,"Vascular endothelial growth factor (VEGF) gene therapy may be useful for the treatment of lower-limb ischemia. The objectives of this study were to evaluate safety and angiographic and hemodynamic responses of local catheter-mediated VEGF gene therapy in ischemic lower-limb arteries after percutaneous transluminal angioplasty (PTA). For this study, we recruited patients with chronic lower-limb ischemia and atherosclerotic infrainguinal occlusion or stenosis suitable for PTA. In the study, 18 patients received 2x10(10) plaque-forming units (pfu) VEGF-adenovirus (VEGF-Ad), 17 patients received VEGF-plasmid/liposome (VEGF-P/L; 2000 microg of VEGF plasmid, 2000 microl of DOTMA:DOPE), and 19 control patients received Ringer's lactate at the angioplasty site. Digital subtraction angiography (DSA) was used to evaluate vascularity before, immediately after, and 3 months after the PTA. Clinical follow-up data, basic laboratory tests, and ankle-brachial index (ABI) were evaluated. Primary endpoint was DSA analysis of vascularity, and secondary endpoints were restenosis rate, Rutherford class, and ABI after 3 months follow-up. No major gene transfer-related side effects or differences in laboratory tests were detected between the study groups. However, anti-adenovirus antibodies increased in 61% of the patients treated with VEGF-Ad. For the primary endpoint, follow-up DSA revealed increased vascularity in the VEGF-treated groups distally to the gene transfer site (VEGF-Ad P=0.03, VEGFP/L P=0.02) and in the VEGF-Ad group in the region of the clinically most severe ischemia (P=0.01). As for the secondary endpoints, mean Rutherford class and ABI showed statistically significant improvements in the VEGF-Ad and VEGF-P/L groups, but similar improvements were also seen in the control patients. We conclude that catheter-mediated VEGF gene therapy is safe and well tolerated. Angiography demonstrated that VEGF gene transfer increased vascularity after PTA in both VEGF-Ad- and VEGF-P/L-treated groups.",2003.0,0,0 1415,12096273,Simvastatin inhibits human saphenous vein neointima formation via inhibition of smooth muscle cell proliferation and migration.,Karen E Porter; Jagjeeth Naik; Neil A Turner; Timothy Dickinson; Matthew M Thompson; Nicholas J M London,"Migration and proliferation of vascular smooth muscle cells (SMCs) contributes to intimal hyperplasia in saphenous vein (SV) bypass grafts, which leads to patency-threatening stenosis. Evidence for the involvement of basement membrane-degrading matrix metalloproteinases (MMPs) and growth factors in mediating SMC migration and proliferation has been presented in a number of in vitro and in vivo models. 3-Hydroxy-3 methylglutaryl CoA reductase inhibitors (statins) are widely used in patients with atherosclerosis and are claimed to have additional effects beyond cholesterol reduction. We therefore examined the effects of simvastatin, a commonly prescribed statin, on the proliferation and migration of cultured human SV SMC and on neointima formation and MMP activity in human SV organ cultures. To clarify its mode of action, we studied in parallel the effects of a specific MMP inhibitor, marimastat. Human SV specimens were obtained from patients who underwent coronary artery bypass grafting, and were cultured for 14 days in the presence of three concentrations of simvastatin and subsequently processed for measurement of MMP activity and neointimal thickness measurements. Cultured SV SMCs were used to construct growth curves in the presence of 10% fetal calf serum or 10% fetal calf serum supplemented with simvastatin or marimastat. Migration through a Matrigel basement-membrane matrix (invasion) was quantified with modified Boyden chambers. Simvastatin dose dependently reduced neointima formation (P =.004) in association with reduced MMP-9 activity (P =.03). SMC proliferation and invasion also were inhibited with simvastatin (P <.007 and P <.009, respectively). Marimastat dose dependently inhibited SMC invasion (P <.001) but importantly had no effect on SMC proliferation (P >.36). For effective control of neointimal development in vivo, a pharmacologic strategy should inhibit both SMC migration and proliferation. The ancillary properties of 3-Hydroxy-3 methylglutaryl CoA reductase inhibitors typified by simvastatin may be important in this regard.",2002.0,0,0 1416,12096274,,,,,0,0 1417,12098920,[Reduced mortality after acute myocardial infarction].,Per Mølstad; Kjell Andersen,"The mortality of cardiovascular disease has decreased substantially in later years though it is uncertain whether this decrease is due to a better profile of risk factors in the population or to improvements in medical treatment. In 1982 to 1984 and 1997 to 1999 all patients admitted to Hedmark Central Hospital in Norway, with acute myocardial infarction were registered and followed for reinfarction and survival over up to three years. A total of 1,236 patients were included in the study, 641 in the first time period and 595 in the second. A significant decrease in case fatality was observed in the second population. The seven days fatality rate decreased from 17.9% to 11.4%, and the one month fatality rate from 22.9% to 16.1%. The median number of days in hospital decreased from ten to six. A Kaplan-Meier estimate for survival in the total follow-up period showed a 43% higher relative death risk in the 1982-1984 cohort compared to the 1997-1999 cohort. A Cox regression revealed that this difference could not be explained by demographic differences between the populations. By evaluating variables registered during the course of infarction in the multivariate Cox model, it is concluded that improved survival in the recent cohort is related to modern treatment of acute myocardial infarction.",2002.0,0,0 1418,12099323,Beta blockers as cardioprotective agents: Part I--Insights into mechanisms of action.,Willima H Frishman,,2002.0,0,0 1419,12099325,Statins as cardioprotective agents.,Julie R Piskur; Neil J Stone,,2002.0,0,0 1420,12099384,Bilateral pharmacokinetic interaction between cyclosporine A and atorvastatin in renal transplant recipients.,A Asberg; A Hartmann; E Fjeldså; S Bergan; H Holdaas,"Atorvastatin is increasingly used as a cholesterol-lowering agent in solid organ transplant recipients receiving cyclosporine A (CsA). However, the potential bilateral pharmacokinetic interaction between atorvastatin and CsA in renal transplant recipients has not previously been examined. Baseline 12-h CsA pharmacokinetic investigation was performed in 21 renal transplant recipients and repeated after 4 weeks of atorvastatin treatment (10 mg/ d). At week 4, 24-h pharmacokinetics of atorvastatin was also performed. All patients received basiliximab induction followed by CsA and prednisolone immunosuppression. Compared with historic controls, CsA-treated patients showed, on average, sixfold higher plasma HMG-CoA reductase inhibitory activity after 4 weeks of atorvastatin treatment (p < 0.05). Atorvastatin had a moderate effect on the pharmacokinetics of CsA and reduced the AUC0-12 (area under curve, 0-12h) by 9.5 +/- 18% (p = 0.013) and Cmax (maximal concentration) by 13.5 +/- 24% (p =0.009), while C12 (trough level) was unchanged (p =0.42). Total and LDL cholesterol decreased by 26.8 +/- 8.4% (p < 0.0001) and 41.5 +/- 11.0% (p < 0.0001), respectively. Bilateral pharmacokinetic interaction between atorvastatin and CsA resulted in sixfold higher plasma HMG-CoA reductase inhibitory activity, but only a moderate decrease in systemic exposure of CsA.",2002.0,0,0 1421,12103251,"Physicians' interpretation of ""class effects"": a need for thoughtful re-evaluation.",Harold L Kennedy; Robert S Rosenson,"The concept of pharmacologic ""class effects"" exists across a broad range of medical products and is particularly pervasive with regard to cardiovascular agents. Evolution of the concept over the past two decades has shown the influence of physicians' practice patterns, pharmaceutical companies, health maintenance organizations and the Food and Drug Administration (FDA). Understanding the evolution of health care, social and economic policies, acknowledging the correction of medical misconceptions and inaccurate understanding and appreciating the emergence of new medical knowledge over the past decade should modify the clinician's viewpoint of ""class effects."" These revelations should signal caution in extrapolating the outcome efficacy or safety of one agent to another within a pharmacologic class. The authors urge clinicians, pharmaceutical companies, health maintenance organizations and the FDA to re-examine their concept of ""class effects."" An appeal is made for physicians to prescribe those pharmaceutical agents with definitive evidence of mortality and morbidity efficacy and safety established by appropriately scaled randomized clinical trials.",2002.0,0,0 1422,12103255,Projected life-expectancy gains with statin therapy for individuals with elevated C-reactive protein levels.,Gavin J Blake; Paul M Ridker; Karen M Kuntz,"We sought to estimate the potential gains in life expectancy achieved with statin therapy for individuals without overt hyperlipidemia but with elevated C-reactive protein (CRP) levels. Persons with low-density lipoprotein (LDL) cholesterol levels below current treatment guidelines and elevated CRP levels are at increased risk of cardiovascular disease and may benefit from statin therapy. We constructed a decision-analytic model to estimate the gains in life expectancy with statin therapy for individuals without overt hyperlipidemia but with elevated CRP levels. The annual risks of myocardial infarction (MI) and stroke, as well as the efficacy of statin therapy, were based on evidence from randomized trials. Estimates of prognosis after MI or stroke were derived from population-based studies. We estimated that 58-year-old men and women with CRP levels >or=0.16 mg/dl but LDL cholesterol <149 mg/dl would gain 6.6 months and 6.4 months of life expectancy, respectively, with statin therapy. These gains were similar to those for patients with LDL cholesterol >or=149 mg/dl (6.7 months for men and 6.6 months for women). In sensitivity analyses, we identified the baseline risk of MI and the efficacy of statin therapy for preventing MI as the most important factors in determining the magnitude of benefit with statin therapy. Our results suggest that individuals with elevated CRP levels, many of whom do not meet current National Cholesterol Education Program guidelines for drug treatment, may receive a substantial benefit from statin therapy. This analysis supports a crucial need for direct intervention trials aimed at subjects with elevated CRP levels.",2002.0,0,0 1423,12103306,Resource management in prevention of coronary heart disease: optimising prescription of lipid-lowering drugs.,James Shepherd,,2002.0,0,0 1424,12104065,,,,,0,0 1425,12105139,"Von Willebrand factor, soluble P-selectin, and target organ damage in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).","Charles G C Spencer; David Gurney; Andrew D Blann; D Gareth Beevers; Gregory Y H Lip; ASCOT Steering Committee, Anglo-Scandinavian Cardiac Outcomes Trial","To investigate the relationship between soluble markers of platelet, endothelial and rheological function, and target organ damage and their response to intensified management in a population of middle-age hypertensive patients at high risk of cardiovascular complications, we studied 382 consecutive patients (308 men; mean age, 63 years, SD 8) along with 60 normotensive controls free of cardiovascular disease. Patients were divided into those with target organ damage (TOD; n=107) and those free of end-organ damage. Plasma levels of soluble P-selectin (sP-sel), a marker of platelet activation, and von Willebrand factor (vWF), an index of endothelial damage/dysfunction (both enzyme-linked immunosorbent assay), and the rheological indices fibrinogen, plasma viscosity, hematocrit, platelet, and white cell count were measured. In 53 patients, variables were further measured after 6 months of intensified cardiovascular risk management. Patients with TOD had significantly higher vWF, 137 (SD 33) versus 125 (SD 33) IU/dL (P=0.002,) and a greater proportion of smokers, 31% versus 16% (P=0.002). There were no statistically significant differences in plasma viscosity, fibrinogen, hematocrit, white blood cell count, platelet count, or sP-sel between the 2 subgroups. In multivariate analysis, vWF was a significant independent predictor for TOD. After 6 months of intensified management in 53 patients who entered the trial, there were significant reductions in systolic blood pressure, total cholesterol, hematocrit, plasma viscosity, sP-sel, and vWF (all P<0.01) but no significant change in fibrinogen. In conclusion, there is a relationship between TOD and endothelial damage/dysfunction in hypertension. Intensified management results in improvements in hemorheology, endothelial and platelet function.",2002.0,0,0 1426,12105140,Effect of pravastatin on proteinuria in patients with well-controlled hypertension.,Tsung-Ming Lee; Sheng-Fang Su; Chang-Her Tsai,"Proteinuria is an important risk factor for cardiovascular and renal morbidity and mortality. The effects of 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitor (statin) therapy on proteinuria in normolipidemic patients with well-controlled hypertension have not been studied. A total of 63 normolipidemic (total cholesterol <240 mg/dL) and proteinuric (300 to 3000 mg/d) patients with well-controlled blood pressure (<140/90 mm Hg) were randomized to receive either placebo (n=32) or pravastatin (10 mg/d; n=31) after a 3-month placebo period. Pravastatin lowered proteinuria after 6 months by 54% (P<0.0001). Creatinine clearance was stable throughout the study in the 2 groups. Despite unchanged plasma endothelin-1 levels throughout the study, urinary excretion of the peptide was decreased and significantly correlated with improvement in urinary protein excretion in pravastatin-treated patients (r=0.64, P=0.001). The urinary excretion of retinol-binding protein decreased after pravastatin administration, probably reflecting an improvement in tubular function. In contrast, the urinary excretion of IgG did not change significantly throughout the study in either group. Multivariate analysis revealed that proteinuria was only significantly correlated with statin use (P<0.0001, R2= 0.66). Linear regression analysis in the statin-treated group did not show any correlation between changes in lipid profiles and proteinuria regression. Thus, in addition to their primary function of antilipidemia, the addition of pravastatin to treatment for well-controlled hypertension may have an additive effect on reducing proteinuria independent of hemodynamics and lipid-lowering effects, possibly through inhibiting renal endothelin-1 synthesis and improving tubular function.",2002.0,0,0 1427,12106834,Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial.,Robert S Rosenson; James D Otvos; David S Freedman,"Lipoprotein subclass measurements may enhance the prediction of coronary artery disease (CAD) risk, but clinical application of such information has been hindered by the relatively laborious and time-consuming nature of laboratory measurement methods. In this study, lipoprotein subclass analyses were performed on frozen plasma samples from 241 participants in the Pravastatin Limitation of Atherosclerosis in the Coronary arteries Trial using an automated nuclear magnetic resonance technique. The objective was to determine if levels of these subclasses provided additional information on the progression of CAD, based on the change in the minimum lumen diameter, over a 3-year period. After adjustment for race, sex, age, treatment group, baseline lumen diameter, and chemically measured levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol, on-trial predictors (p <0.05) of progression included an elevated LDL particle number, and levels of small LDL and small HDL. Within treatment groups, CAD progression was most strongly related to the LDL particle number (placebo) and levels of small HDL (pravastatin). In logistic regression models that adjusted for chemically determined lipid levels and other covariates, a small LDL level > or = 30 mg/dl (median) was associated with a ninefold increased risk of CAD progression (p <0.01) in the placebo group. These results indicate that levels of various lipoprotein subclasses may provide useful information on CAD risk even if levels of traditional risk factors are known.",2002.0,0,0 1428,12106843,The role of high-density lipoprotein (HDL) cholesterol in the prevention and treatment of coronary heart disease: expert group recommendations.,Frank M Sacks; Expert Group on HDL Cholesterol,,2002.0,0,0 1429,12106845,Frequency of congestive heart failure in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol > or = 125 mg/dl treated with statins versus no lipid-lowering drug.,Wilbert S Aronow; Chul Ahn,,2002.0,0,0 1430,12106850,Short-term effect of atorvastatin (80 mg) on plasma lipids of patients with unstable angina pectoris or non-Q-wave acute myocardial infarction.,Luis C L Correia; Andrei C Spósito; Luiz C S Passos; José C Lima; Júlio C Braga; Mário S Rocha; J Péricles Esteves; Argemiro D'Oliveira,,2002.0,0,0 1431,12106851,Effect of pravastatin on apolipoproteins B and C-III in very-low-density lipoproteins and low-density lipoproteins.,Frank M Sacks; Petar Alaupovic; Lemuel A Moye,,2002.0,0,0 1432,12106856,Two-year efficacy and safety of simvastatin 80 mg in familial hypercholesterolemia (the Examination of Probands and Relatives in Statin Studies With Familial Hypercholesterolemia [ExPRESS FH]).,Pernette R W de Sauvage Nolting; Rudolf J A Buirma; Barbara A Hutten; John J P Kastelein; Dutch ExPRESS Investigator Group,,2002.0,0,0 1433,12106923,Intravascular ultrasound evaluation of coronary plaque regression by low density lipoprotein-apheresis in familial hypercholesterolemia: the Low Density Lipoprotein-Apheresis Coronary Morphology and Reserve Trial (LACMART).,Masunori Matsuzaki; Katsuhiko Hiramori; Tsutomu Imaizumi; Akira Kitabatake; Hitoshi Hishida; Masanori Nomura; Takashi Fujii; Ichiro Sakuma; Kenichi Fukami; Takashi Honda; Hiroshi Ogawa; Masakazu Yamagishi,"We sought to assess the effects of low density lipoprotein (LDL)-apheresis (LDL-A) for regression of coronary plaque in familial hypercholesterolemia (FH), we set up a one-year follow-up multicenter trial using coronary angiography and intravascular ultrasound (IVUS). It is still unclear whether aggressive lipid-lowering therapy by LDL-A leads to the regression of coronary plaque in patients with FH. Eighteen patients with FH were assigned to one of two groups: medication + LDL-A (LDL-A group, n = 11) and medication only (medication group, n = 7). Total cholesterol, triglycerides, high density lipoprotein cholesterol and LDL cholesterol were measured in all subjects at the outset of treatment (baseline) and every three months thereafter. Coronary angiography and IVUS were performed at the outset and after the one-year follow-up period to measure minimal lumen diameter (MLD) by coronary angiogram and plaque area (PA) by IVUS. The LDL-A group showed 28.4% reduction in total cholesterol (from 275 +/- 27 mg/dl to 197 +/- 19 mg/dl) and 34.3% reduction in LDL cholesterol (from 213 +/- 25 mg/dl to 140 +/- 27 mg/dl) after one-year follow-up, while the medication group showed no changes in cholesterol levels. There were significant interactions between both treatments in total cholesterol (p = 0.0001), LDL cholesterol (p = 0.0001), MLD (p = 0.008) and PA (p = 0.017) using two-way repeated-measures analysis of variance by the SAS system (SAS Institute Inc., Cary, North Carolina). Significant differences were seen in net change in MLD (p = 0.004) and PA (p = 0.008) during the one-year follow-up period between both groups. These results suggest that aggressive lipid-lowering therapy using the combination of LDL-A and lipid-lowering drugs may induce regression of coronary atherosclerotic plaque in FH patients.",2002.0,0,0 1434,12106924,Coronary plaque regression: role of low density lipoprotein-apheresis.,Philip J Barter,,2002.0,0,0 1435,12107216,"Lowering low density lipoprotein cholesterol with simvastatin, a hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor, does not affect luteal function in premenopausal women.",Diane Plotkin; Sam Miller; Steven Nakajima; Edward Peskin; Ronald Burkman; David Richardson; Yale Mitchel; Joanne Waldstreicher; Minzhi Liu; Deborah Shapiro; Nanette Santoro,"In this double-blind, randomized, placebo-controlled study, normally cycling women (n = 86) with elevated low density lipoprotein cholesterol (LDL-C) levels were studied over six menstrual cycles. At the end of the screening phase, participants received placebo for the second menstrual cycle and subsequently were randomized to receive either placebo or simvastatin (40 mg/d) for the next four cycles. The second and sixth menstrual cycles were considered baseline and treatment cycles, respectively. Participants kept a menstrual diary throughout the study and provided daily first-void urine samples during cycles 2 and 6. Urine samples were assayed for LH and pregnanediol glucuronide (PdG). The primary end point was change in luteal phase duration as defined by the day of the urinary LH peak to the day preceding the onset of menstruation. Treatment with simvastatin (40 mg/d) effectively lowered LDL-C by 34.3% (P < 0.001). Simvastatin was generally well tolerated, and no meaningful difference in adverse event profile was observed between treatment groups. Compared with the placebo group, simvastatin did not have clinically relevant effects on luteal phase duration, peak PdG concentration, or integrated luteal phase PdG concentration. The results of this study demonstrate that treatment of healthy premenopausal women for approximately 4 months with simvastatin (40 mg/d) lowers LDL-C without adversely affecting reproductive gonadal function. Simvastatin should not be used during pregnancy or by nursing mothers.",2002.0,0,0 1436,12109340,The placebo effect and randomized trials: analysis of conventional medicine.,Mark A Moyad,"Randomized controlled trials are generally regarded as the gold standard of study designs to determine causality. The inclusion of a placebo group in these trials, when appropriate, is critical to access the efficacy of a drug or supplement. The placebo response itself has received some attention in the medical literature over the past fifty years. The recent increasing utilization of dietary supplements and herbal medications by patients makes it imperative to reevaluate the placebo response in conventional and alternative medicine. This article will review a whole series of unique conditions (allergies/asthma, alopecia, BPH, erectile dysfunction, osteoporosis, weight loss...) and the placebo response associated with them from conventional medical randomized trials.",2002.0,0,0 1437,12110017,Statin therapy improves brachial artery endothelial function in nephrotic syndrome.,Gursharan K Dogra; Gerald F Watts; Susan Herrmann; Mark A B Thomas; Ashley B Irish,"Patients with nephrotic syndrome have impaired endothelial function probably related to dyslipidemia. This study evaluated the effects of statin therapy on dyslipidemia and endothelial function in patients with nephrotic syndrome. A sequential, open-label study of the effects of statins on endothelial dysfunction in 10 nephrotic patients treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II (Ang II) receptor antagonist. Endothelial function was assessed at baseline, after 12 weeks of treatment with statins, and after an 8-week washout. Brachial artery endothelial function was measured as post-ischemic flow-mediated dilation (FMD) using ultrasonography. Endothelium-independent, glyceryl trinitrate-mediated vasodilation (GTNMD) also was measured. Serum lipids were significantly lower following statin: total cholesterol mean 8.2 +/- 0.4 (standard error) mmol/L versus 5.2 +/- 0.3 mmol/L, triglycerides 2.6 +/- 0.4 mmol/L versus 1.6 +/- 0.2 mmol/L, non-HDL-cholesterol 6.7 +/- 0.4 mmol/L versus 3.7 +/- 0.2 mmol/L (all P < 0.001). There was a trend to an increase in serum albumin (31.0 +/- 1.3 g/L vs. 33.8 +/- 1.5 g/L; P = 0.078) and FMD improved significantly following treatment (3.7 +/- 1.1% vs. 7.0 +/- 0.8%, P < 0.01). After washout, FMD deteriorated significantly to 3.5 +/- 1.4% (P < 0.05) versus week 12 FMD. GTNMD was unchanged. In multivariate regression, reduction in non-high-density lipoprotein (HDL)-cholesterol (beta - 0.736, P = 0.027) and increase in serum albumin (beta 0.723, P = 0.028), but not the on-treatment level of non-HDL-cholesterol, were significant independent predictors of improvement in FMD after adjusting for change in resting brachial artery diameter. Changes in serum lipoprotein and albumin concentrations off treatment were not associated with deterioration in FMD. Statin therapy significantly improves dyslipidemia and brachial artery endothelial function in patients with nephrotic syndrome. Improvement in brachial artery endothelial function may be in part related to a non-lipid effect of statins. The findings also suggest a role for dyslipidemia in endothelial dysfunction and the risk for cardiovascular disease in nephrotic syndrome.",2003.0,0,0 1438,12110758,Effect of HMG-CoA reductase inhibitors (statins) on bone mineral density.,Holly L Funkhouser; Tilahun Adera; Robert A Adler,"Recent studies have suggested that 3-hydroxy-3-methylglutaryl - coenzyme A (HMG-CoA) reductase inhibitors (statins) can increase the bone mineral density (BMD). Our objective was to determine if patients on statin drugs were more likely to have a greater bone mineral density and lower risk of osteoporosis than patients not taking these drugs. A computerized pharmacy system provided complete medication dispensing records for the 983 patients (697 men and 286 women) referred for bone mineral density testing at a single Veterans Affairs Medical Center. In an analysis of covariance model that adjusted for age, body mass index, race, and vitamin use, men using statin drugs were more likely to have a greater BMD of the spine (p < 0.005). The mean difference (effect size) was 0.05 g/cm2 (95% confidence interval of [CL] 0.02-0.09), about 5.3% greater BMD. In women, the association was not significant. The risk of osteoporosis (defined as a T-score < or = -2.5) was determined using logistic regression analysis after adjustment for potential confounding variables. Although not statistically significant, men who received statin drugs for more than 2 yr were approximately half as likely to develop osteoporosis (odds ratio [OR] =.55, 95% CI = 0.28-1.08). A similar effect was observed in women taking statins for any length of time (OR = 0.36, 95% CI = 0.12-1.07). This study suggests that statin drugs may decrease osteoporosis risk, warranting a randomized controlled trial.",2002.0,0,0 1439,12111013,Relation of statin use and bone loss: a prospective population-based cohort study in early postmenopausal women.,J Sirola; J Sirola; R Honkanen; H Kröger; J S Jurvelin; P Mäenpää; S Saarikoski,"Recent experimental and epidemiologic studies have suggested that the lipid-lowering drugs, statins, may have bone-protective effects. We studied the effects of statin use on the change in bone mineral density (BMD) in a prospective 4.5-year cohort study based on subjects from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study, Finland. Six hundred and twenty women aged 53-64 years were divided into four groups: 55 women reported continuous and 63 women occasional statin use during the follow-up; 142 non-users of statins reported hypercholesterolemia whereas 360 non-users did not. Spinal and femoral BMDs were measured by dual-energy X-ray densitometry in 1995-1996 and 1999-2000 and the BMD changes of the four groups were compared. Characteristics of the study population were obtained with postal inquiries. The mean annual spinal and femoral BMD changes of the study groups were 0.29% and -0.50% for the continuous statin users, 0.19% and -0.57% for the occasional statin users, 0.52% and -0.29% for the hypercholesterolemic non-users of statins, and 0.39% and -0.33% for the non-users of statins without hypercholesterolemia, ( p = 0.398 and p = 0.404) respectively. The corresponding BMD changes adjusted for age, years since menopause, body mass index, BMD at baseline, calcium intake, estrogen and cortisone therapy, duration of follow-up and statin use before the baseline were -0.20% and -0.47%, 0.19% and -0.54%, 0.54% and -0.32%, 0.47% and -0.33% ( p = 0.134 and p = 0.628), respectively. Our results suggest that statins do not protect from early postmenopausal bone loss. Randomized trials are needed to confirm these results.",2002.0,0,0 1440,12111445,Potential neurotoxic inflammatory responses to Abeta vaccination in humans.,G Münch; S R Robinson,"Studies in transgenic mouse models of Alzheimer's disease suggested the development of a vaccine that would induce the production of antibodies against amyloid-beta (Abeta) peptide, which in turn would stimulate microglia to phagocytose and remove senile plaques. However, some patients in the human clinical trials developed symptoms of brain inflammation, demonstrated by lymphocyte infiltration and elevated protein levels. These parameters are indicative of a breakdown of the blood-brain-barrier and entry of T-cells into the brain. Abeta-specific activated T-helper cells have the potential to amplify the existing pro-inflammatory conditions that are present in the brains of Alzheimer's disease patients. Cytotoxic T-cells might even attack the amyloid precursor protein which is present on the surface of many cells, including neurons. Before undertaking further vaccination trials there is a need to re-assess the risks associated with Abeta vaccination and with the therapeutic containment of a neuroinflammatory response. These risks may not be justified in the light of recent studies which have shown the efficacy of conventional, low-risk treatments in slowing the progress of AD.",2002.0,0,0 1441,12113263,Results from late-breaking clinical trial sessions at the American College of Cardiology 51st Annual Scientific Session.,Eric S Williams; John M Miller,,2002.0,0,0 1442,12113597,Assessment of the efficiency of treatment of dyslipidaemia in renal outpatients.,Kevin Harris; Mark Thomas; Colin Short; Richard Moore,"Lipid abnormalities, together with other co-existent risk factors, contribute to the accelerated atherosclerotic process, and consequently to the high incidence of cardiovascular disease, observed in end-stage renal patients. The objectives of this study were to determine the prevalence of dyslipidaemia and to assess how it is managed in a range of patients at four UK renal units. Patients with renal disease were recruited from the outpatient clinics of 4 UK hospitals. Individuals meeting the entry criteria were required to provide one sample of venous blood following a 12-hour fast. Lipid profiles were measured for each patient. The study population consisted of 677 patients of which 276 (40.8%) were pre-dialysis patients with existing renal disease, 233 patients (34.4%) were receiving haemodialysis and 168 patients (24.8%) were receiving CAPD. Analysis showed that 64% of all patients had hypercholesterolaemia (defined according to Joint British Societies guidelines as LDL-cholesterol [LDL-C] >3.0 mmol/L [115 mg/dL] and/or total cholesterol [TC] >5.0 mmol/L [190 mg/dLl). Despite the high incidence of hypercholesterolaemia, only 16% of study participants were receiving lipid-lowering therapy. An LDL-C goal of <3.0 mmol/L (115 mg/dL) was achieved in 50.0% of patients receiving lipid-lowering treatment. The widespread failure to treat hypercholesterolaemia in patients with renal dysfunction given their high risk of future cardiovascular events is a major cause for concern. The observation that many dialysis patients receiving lipid-lowering therapy had not achieved recommended LDL-C and TC levels suggests that more efficient treatment of dyslipidaemia may be indicated in this patient population.",2003.0,0,0 1443,12114036,"MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.",Heart Protection Study Collaborative Group,"Throughout the usual LDL cholesterol range in Western populations, lower blood concentrations are associated with lower cardiovascular disease risk. In such populations, therefore, reducing LDL cholesterol may reduce the development of vascular disease, largely irrespective of initial cholesterol concentrations. 20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average compliance: 85%) or matching placebo (average non-study statin use: 17%). Analyses are of the first occurrence of particular events, and compare all simvastatin-allocated versus all placebo-allocated participants. These ""intention-to-treat"" comparisons assess the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1.0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily). Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity. All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p=0.0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5.7%] vs 707 [6.9%]; p=0.0005), a marginally significant reduction in other vascular deaths (194 [1.9%] vs 230 [2.2%]; p=0.07), and a non-significant reduction in non-vascular deaths (547 [5.3%] vs 570 [5.6%]; p=0.4). There were highly significant reductions of about one-quarter in the first event rate for non-fatal myocardial infarction or coronary death (898 [8.7%] vs 1212 [11.8%]; p<0.0001), for non-fatal or fatal stroke (444 [4.3%] vs 585 [5.7%]; p<0.0001), and for coronary or non-coronary revascularisation (939 [9.1%] vs 1205 [11.7%]; p<0.0001). For the first occurrence of any of these major vascular events, there was a definite 24% (SE 3; 95% CI 19-28) reduction in the event rate (2033 [19.8%] vs 2585 [25.2%] affected individuals; p<0.0001). During the first year the reduction in major vascular events was not significant, but subsequently it was highly significant during each separate year. The proportional reduction in the event rate was similar (and significant) in each subcategory of participant studied, including: those without diagnosed coronary disease who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separately, women; those aged either under or over 70 years at entry; and--most notably--even those who presented with LDL cholesterol below 3.0 mmol/L (116 mg/dL), or total cholesterol below 5.0 mmol/L (193 mg/dL). The benefits of simvastatin were additional to those of other cardioprotective treatments. The annual excess risk of myopathy with this regimen was about 0.01%. There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause. Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularisation by about one-quarter. After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third. Hence, among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone.",2002.0,1,1 1444,12114037,"MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial.",Heart Protection Study Collaborative Group,"It has been suggested that increased intake of various antioxidant vitamins reduces the incidence rates of vascular disease, cancer, and other adverse outcomes. 20,536 UK adults (aged 40-80) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive antioxidant vitamin supplementation (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) or matching placebo. Intention-to-treat comparisons of outcome were conducted between all vitamin-allocated and all placebo-allocated participants. An average of 83% of participants in each treatment group remained compliant during the scheduled 5-year treatment period. Allocation to this vitamin regimen approximately doubled the plasma concentration of alpha-tocopherol, increased that of vitamin C by one-third, and quadrupled that of beta-carotene. Primary outcomes were major coronary events (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity. There were no significant differences in all-cause mortality (1446 [14.1%] vitamin-allocated vs 1389 [13.5%] placebo-allocated), or in deaths due to vascular (878 [8.6%] vs 840 [8.2%]) or non-vascular (568 [5.5%] vs 549 [5.3%]) causes. Nor were there any significant differences in the numbers of participants having non-fatal myocardial infarction or coronary death (1063 [10.4%] vs 1047 [10.2%]), non-fatal or fatal stroke (511 [5.0%] vs 518 [5.0%]), or coronary or non-coronary revascularisation (1058 [10.3%] vs 1086 [10.6%]). For the first occurrence of any of these ""major vascular events"", there were no material differences either overall (2306 [22.5%] vs 2312 [22.5%]; event rate ratio 1.00 [95% CI 0.94-1.06]) or in any of the various subcategories considered. There were no significant effects on cancer incidence or on hospitalisation for any other non-vascular cause. Among the high-risk individuals that were studied, these antioxidant vitamins appeared to be safe. But, although this regimen increased blood vitamin concentrations substantially, it did not produce any significant reductions in the 5-year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome.",2002.0,0,0 1445,12116743,Volumetric assessment of plaque progression with 3-dimensional ultrasonography under statin therapy.,U Schminke; L Hilker; L Motsch; B Griewing; C Kessler,"Lowering of serum cholesterol levels with HMG-CoA reductase inhibitors (statins) slowed the progression of atherosclerosis in the carotid arteries in several clinical trials using carotid artery intima media thickness as primary outcome measure. Whereas conventional ultrasonography is limited to thin 2-dimensional image planes, 3-dimensional (3D) ultrasonography provides quantitative measurement of the entire carotid artery plaque volume. This study aims to assess the feasibility of 3D ultrasonography to monitor plaque progression in hypercholesterolemic patients. The authors prospectively assessed the progression of 31 carotid artery plaques over 15.1 +/- 4.5 months in a study of 23 patients (6 women, 17 men; mean age = 61.7 +/- 7.5 years) with hypercholesterolemia under therapy with HMG-CoA reductase inhibitors. All patients were maintained on a lipid-lowering diet. Sixteen patients were additionally treated with statins. Quantitative measurements of carotid artery plaque volumes were performed after 3D reconstruction of exactly parallel transverse duplex ultrasound scans (slice distance = 0.1 mm) into volumetric 3D data sets and segmentation of voxels representing the carotid artery plaque. Within the treatment group, plaques were significantly less frequently progressive if they had a hypoechoic echogenicity (11%, n = 9 vs 64%, n = 14; P = .016) or if baseline serum cholesterol levels were above 8.0 mmol/L (9%, n = 11 vs 75%, n = 12; P = .002). Three-dimensional ultrasonography extends the measurement of the arterial wall thickness to the 3D volume of an entire atherosclerotic plaque including analysis of its morphology and configuration. However, further clinical trials with an adequate sample size to achieve sufficient statistical power are necessary to assess the effect of statin therapy on plaque progression.",2002.0,0,0 1446,12116890,Pharmacogenetics and cardiovascular disease: impact on drug response and applications to disease management.,Larisa M Humma; Steven G Terra,"The genetic polymorphisms that may affect individual responses to cardiovascular agents are reviewed, and the application of pharmacogenetics to cardiovascular disease management is discussed. Pharmacogenetics is the search for genetic polymorphisms that affect responses to drug therapy. Investigators have found many associations between genetic polymorphisms and responses to cardiovascular drugs. Some of these relationships have been demonstrated in large patient populations, such as patients with ischemic heart disease receiving statins. Study data consistently show a greater response to statins in ischemic heart disease patients with genotypes associated with worse prognoses. Studies of other polymorphisms, such as those in the genes encoding anglotensin-converting enzyme and beta 1-adrenergic receptors, have less consistently found relationships between these variations and cardiovascular drug responses. For gene-drug response associations for which the data are inconsistent, the interaction of multiple polymorphisms in multiple genes coding for proteins affected by drug therapy or influencing drug metabolism may prove to have a greater influence on drug responses than any one polymorphism. Once the polymorphisms that best determine the response to a particular drug are known and tests to rapidly identify these variations are available, individual patients may be screened for genetic polymorphisms before drug therapy is begun and the information used to choose agents with the greatest potential for efficacy and least potential for toxicity. Pharmacogenetics has many possible applications in the drug therapy of cardiovascular diseases. Much more must be learned, however, before pharmacogenetic factors can be routinely incorporated into therapeutic decisions.",2002.0,0,0 1447,12117017,Efficacy and safety of atorvastatin 10 mg every other day in hypercholesterolemia.,Chumpol Piamsomboon; Prasart Laothavorn; Sopon Saguanwong; Boonsert Chatlaong; Chanarong Nasawadi; Pravit Tanprasert; Kittika Pongsiri,"The authors sought to evaluate the safety and efficacy of atorvastatin administered every other day in patients with hypercholesterolemia. Statins have efficacy in lowering cholesterol and reducing cardiovascular events but their cost is a major disadvantage. Atorvastatin is the most potent statin and has a long half-life. Therefore, atorvastatin given on alternate days may be reasonable and cost effective, particularly in hypercholesterolemia patients. Sixty patients with hypercholesterolemia despite diet therapy were enrolled into the study. They received atorvastatin 10 mg every other day before bedtime. Duration of treatment was 8 weeks. A lipid profile was determined as baseline, at 4 weeks and again at 8 weeks. Atorvastatin every other day significantly reduced total cholesterol (TC), triglyceride (TG), and LDL-c versus baseline. The TC, TG, and LDL-c levels were lower by 23 per cent, 8 per cent, and 30 per cent. Increase in HDL-c level was not statistically significant. Three patients had drug side effects. One patient had increased serum transaminase and one patient had increased serum muscle enzyme. The other one had somnolence. In hypercholesterolemia patients, atorvastatin 10 mg every other day is safe and effective in lowering TC, TG, with LDL-c and a slight increase in HDL-c.",2002.0,0,0 1448,12118183,Novel therapeutic options for osteoporosis.,Diane M Biskobing; Angela M Novy; Robert Downs,"Osteoporosis remains a significant clinical problem despite effective therapies. Many patients cannot or will not take currently available therapies. For this reason, research continues in search of more effective and more tolerable agents. Arzoxifene and TSE-424 are investigational selective estrogen receptor modulators that have been shown to be effective in animal studies and are now in clinical studies. Tibolone is a tissue-specific steroid that is currently used in Europe for the prevention and treatment of osteoporosis. Multiple studies have shown efficacy in improving bone mineral density, but no fracture studies have been conducted to date. Although studies of the effect of isoflavones on bone mineral density have been encouraging, a large multicenter study in Europe recently showed no effect of isoflavones on fractures. The investigational bisphosphonates ibandronate and zoledronic acid may offer the advantage of less frequent dosing. The newly described agent osteoprotegerin has been shown in early studies to inhibit bone turnover. Finally, the issue of efficacy of statins in bone continues to be debated with no prospective, randomized studies yet to confirm the suggestion of benefit seen in epidemiologic studies.",2002.0,0,0 1449,12118490,Dose-expanded study in the reinforcement of efficacy of simvastatin.,Apichati Vichayanrat; Study Investigators of DESIRES-Z,"Two hundred and twenty two hyperlipidemic patients were recruited for a 12-week prospective, multicenter, open-label, titrate-to-goal study to evaluate the efficacy and safety of 20 to 40 mg per day of simvastatin in a Thai population. The efficacy on lipid lowering was evaluated at 4 weeks and 8 weeks after medication. Based on NCEP ATP II guideline and ADA position statement, subjects were categorized into three groups according to LDL-C goals; group I: patients without CHD and with < 2 CHD risk factors, group II: patients without CHD and with > or = 2 CHD risk factors and group III: CHD patients or diabetic patients with > or = 1 risk factors. Significant changes of all lipid parameters from baselines were noted at 4 weeks after medication except for HDL-C levels. Reduction of serum LDL-C, TC and TG by 40 per cent, 29 per cent and 16 per cent respectively and increase of serum HDL-C by 5 per cent were observed at 8 weeks of therapy (p<0.05). At 4 weeks after taking simvastatin 20 mg/day, 78.9 per cent of patients in group I, 67.4 per cent in group II and 40.9 per cent in group III achieved LDL-C goals. Seventeen per cent of the patients who were evaluated at 8 weeks increased the simvastatin dosage to 40 mg per day in the second month of treatment. At 8 weeks of therapy with simvastatin 20-40 mg/day, 90.1 per cent of patients in group I, 77.4 per cent in group II and 66.7 per cent in group III achieved LDL-C goals. Adverse symptoms during therapy, mostly mild, developed in 6.3 per cent of the 222 patients. Simvastatin 20-40 mg/day was effective and well tolerated in managing lipid parameters in Thai patients similar to other ethnic populations.",2002.0,0,0 1450,12118834,Lipid-lowering therapy and coagulation/fibrinolysis parameters in patients on peritoneal dialysis.,N Yorioka; T Masaki; T Ito; S Kushihata; Y Nishida; Y Taniguchi; H Oda; M Yamakido,"Patients on continuous ambulatory peritoneal dialysis (CAPD) often have abnormalities of lipid metabolism or coagulation and fibrinolysis, these patients may thus be more susceptible to atherosclerosis than those on hemodialysis. It has been reported that hypercoagulability and hyperfibrinolysis are correlated with abnormalities of lipid metabolism. Therefore, we investigated the effect of a decrease in lipids on the coagulation and fibrinolysis system in CAPD patients with hyperlipidemia who received lipid-lowering therapy. The patients included 5 men and 13 women, with a mean age of 52.5 years. Pravastatin sodium (10 mg/day) and ethyl icosapentate (1800 mg/day) were administered concomitantly for 8 weeks. Lipid levels and coagulation/fibrinolysis parameters were measured before and after therapy. The patients were divided into two groups depending on their response to therapy: responders showed a decrease in total cholesterol or triglycerides by at least 20% and non-responders showed less improvement. In the responders, the levels of protein C, tissue plasminogen activator/plasminogen activator inhibitor-I complex, factor XIII, alpha2-plasmin inhibitor, and D-dimer were significantly lower after therapy than before therapy. Protein C, factor XIII, and alpha2-plasmin inhibitor were also significantly decreased after therapy in non-responders, but the extent of the decrease was smaller. The plasminogen level was significantly increased after therapy in non-responders. These findings suggest that a decrease in lipid levels and/or some other action by lipid-lowering agents may correct abnormalities of coagulation and fibrinolysis in CAPD patients.",2002.0,0,0 1451,12118900,Effects of sirolimus on lipids in renal allograft recipients: an analysis using the Framingham risk model.,Conrad B Blum,"This report describes the effects of sirolimus on plasma lipids, and uses the Framingham risk model to assess the clinical importance of these effects. Lipid data from two large controlled studies of 1295 renal transplant patients were analyzed retrospectively. Sirolimus 2 mg/day and 5 mg/day were compared with placebo or azathioprine, and administered concomitantly with steroids and cyclosporine over 12 months. Hypercholesterolemia and hypertriglyceridemia occurred in all treatment groups and were maximal at 2-3 months. The sirolimus groups evidenced higher lipid levels than the controls, but the elevations diminished over time. At 1 year, the patients given sirolimus 2 mg/day had a mean cholesterol level 17 mg/dL greater and a mean triglyceride level 59 mg/dL greater than the controls. Among the patients given sirolimus 5 mg/day, mean cholesterol was 30 mg/dL greater and mean triglycerides were 103 mg/dL greater than the controls. Treatment with statins and fibrates was effective in reducing cholesterol and triglyceride levels, respectively, in the sirolimus-treated patients. The Framingham risk model predicted that the 17 mg/dL elevation in cholesterol would increase the incidence of coronary heart disease (CHD) by 1.5 new cases per 1000 persons per year and CHD death by 0.7 events per 1000 persons per year. Lipid elevations observed in the sirolimus-treated patients were manageable, improved over time, and responded to lipid-lowering therapy. Based on the Framingham risk model, the CHD risks associated with these cholesterol elevations are small compared with the baseline risks of the transplant population.",2003.0,0,0 1452,12119202,Influence of atorvastatin and simvastatin on apolipoprotein B metabolism in moderate combined hyperlipidemic subjects with low VLDL and LDL fractional clearance rates.,Lorne F Forster; Grace Stewart; Dorothy Bedford; James P Stewart; Elizabeth Rogers; James Shepherd; Chris J Packard; Muriel J Caslake,"Subjects with moderate combined hyperlipidemia (n=11) were assessed in an investigation of the effects of atorvastatin and simvastatin (both 40 mg per day) on apolipoprotein B (apoB) metabolism. The objective of the study was to examine the mechanism by which statins lower plasma triglyceride levels. Patients were studied on three occasions, in the basal state, after 8 weeks on atorvastatin or simvastatin and then again on the alternate treatment. Atorvastatin produced significantly greater reductions than simvastatin in low density lipoprotein (LDL) cholesterol (49.7 vs. 44.1% decrease on simvastatin) and plasma triglyceride (46.4 vs. 39.4% decrease on simvastatin). ApoB metabolism was followed using a tracer of deuterated leucine. Both drugs stimulated direct catabolism of large very low density lipoprotein (VLDL(1)) apoB (4.52+/-3.06 pools per day on atorvastatin; 5.48+/-4.76 pools per day on simvastatin versus 2.26+/-1.65 pools per day at baseline (both P<0.05)) and this was the basis of the 50% reduction in plasma VLDL(1) concentration; apoB production in this fraction was not significantly altered. On atorvastatin and simvastatin the fractional transfer rates (FTR) of VLDL(1) to VLDL(2) and of VLDL(2) to intermediate density lipoprotein (IDL) were increased significantly, in the latter instance nearly twofold. IDL apoB direct catabolism rose from 0.54+/-0.30 pools per day at baseline to 1.17+/-0.87 pools per day on atorvastatin and to 0.95+/-0.43 pools per day on simvastatin (both P<0.05). Similarly the fractional transfer rate for IDL to LDL conversion was enhanced 58-84% by statin treatment (P<0.01) LDL apoB fractional catabolic rate (FCR) which was low at baseline in these subjects (0.22+/-0.04 pools per day) increased to 0.44+/-0.11 pools per day on atorvastatin and 0.38+/-0.11 pools per day on simvastatin (both P<0.01). ApoB-containing lipoproteins were more triglyceride-rich and contained less free cholesterol and cholesteryl ester on statin therapy. Further, patients on both treatments showed marked decreases in all LDL subfractions. In particular the concentration of small dense LDL (LDL-III) fell 64% on atorvastatin and 45% on simvastatin. We conclude that in patients with moderate combined hyperlipidemia who initially have a low FCR for VLDL and LDL apoB, the principal action of atorvastatin and simvastatin is to stimulate receptor-mediated catabolism across the spectrum of apoB-containing lipoproteins. This leads to a substantial, and approximately equivalent, percentage reduction in plasma triglyceride and LDL cholesterol.",2002.0,0,0 1453,12120281,Ethical perspectives on pharmacogenomic profiling in the drug development process.,Amalia M Issa,"Pharmacogenomics, which is a field that encompasses the study of genetic polymorphisms that underlie individual differences in drug response, is rapidly advancing. The potential for the widespread use of pharmacogenomics in the drug development process merits an examination of its fundamental impact on clinical-trial design and practice. This article provides a critical analysis of some of the issues that pertain to pharmacogenomics in the drug development process. In particular, four areas will be discussed: clinical-trial design; subject stratification; some new social risks; and economic concerns. Recommendations are offered for addressing the issues that are discussed and anticipating the regulatory needs for pharmacogenomics-based trials.",2002.0,0,0 1454,12125500,A clinical and experimental study on the protective effects of jiangzhi tongmai fang on endothelial injury.,Yahong Wang; Fuling Niu; Mingjing Zhao; Bei Zhong; Jinghong Hao; Weihong Yan; Xiying Lu; Wei Wang; Qiang Li; Qian Lin; Yanyan Dai; Yong Zhao; Min Xiao; Ling Tang; Lanying He; Xueying Jiang; Weiqin Guo; Shuoren Wang; Weixing Lu,"31 cases of atherosclerosis (AS) were treated with Jiang Zhi Tong Mai Fang ([symbol: see text], formula of JZTMF), and its effect was compared with 30 cases treated with lovastatin in the control group. Clinically, the JZTMF formula showed an effect of regulating blood lipids, and therefore it was antiatherosclerotic. The mechanism is, probably, restoration of the function of endothelial cells (EC) by increasing the synthesis of 6-keto-PGF1 alpha and decreasing the release of endothelin (ET) as evidenced in the experimental study.",2003.0,0,0 1455,12126219,,,,,0,0 1456,12126462,Policosanol: a new treatment for cardiovascular disease?,Mark Janikula,"Policosanol is a mixture of alcohols isolated and purified from sugar cane. Recently, Cuban researchers found 5-20 mg daily of policosanol to be effective at improving serum lipid profiles. Policosanol is believed to decrease total cholesterol (TC), low-density lipoprotein (LDL), and increase high-density lipoprotein (HDL) by inhibiting cholesterol synthesis and increasing LDL processing. Lipid profile improvements are seen in healthy volunteers, patients with type II hypercholesterolemia, type 2 diabetics with hypercholesterolemia, postmenopausal women with hypercholesterolemia, and patients with combined hypercholesterolemia and abnormal liver function tests. Additionally, policosanol has performed equal to or better than simvastatin, pravastatin, lovastatin, probucol, or acipimox with fewer side effects in patients with type II hypercholesterolemia. Policosanol also decreases several other risk factors of cardiovascular disease by decreasing LDL oxidation, platelet aggregation, endothelial damage, and smooth muscle cell proliferation. Furthermore, policosanol decreases progression and increases regression of cardiovascular disease assessed by thallium-labeled myocardial perfusion scintigraphy (TL-MPS) and Doppler-ultrasound, and decreases symptoms of cardiovascular disease assessed by the Specific Activity Scale. In post-marketing studies, only 0.31 percent of patients have had adverse events. Furthermore, in animal toxicity studies doses up to 1500 times normal human doses (on the basis of body weight) have shown no negative effects on carcinogenesis, reproduction, growth, and development. However, despite the positive research on policosanol on Cubans, policosanol produced in Cuba is not available in the United States, and only Cuban subjects have been studied. Further research is needed to determine if the same effects will be obtained in U.S. populations with non-Cuban produced policosanol.",2002.0,0,0 1457,12127376,"Effects of short-term atorvastatin treatment on global fibrinolytic capacity, and sL-selectin and sFas levels in hyperlipidemic patients with coronary artery disease.",Enver Atalar; Ferhan Ozmen; Ibrahim Haznedaroglu; Tayfun Açil; Necla Ozer; Kenan Ovünç; Serdar Aksöyek; Sirri Kes,"The beneficial effects of HMG-CoA reductase inhibitors (statins) in patients with coronary artery disease (CAD) appear to be attributable not only to their lipid-lowering properties, but also to their therapeutic effects on the coagulation system, and anti-inflammatory effect. Furthermore, statins mitigate the apoptosis of vascular smooth muscle cells (VSMC) and macrophages in atherosclerotic plaques. The purpose of this study was to evaluate the effects of short-term atorvastatin treatment on the fibrinolytic system and systemic inflammatory status, and on apoptosis in hyperlipidemic patients with CAD. The study population consisted of 36 hyperlipidemic patients (14 women and 22 men, mean age 53+/-9 years) with stable CAD, untreated with lipid-lowering medications. Serum lipoproteins, fibrinogen levels, sFas and sL-selectin, and global fibrinolytic capacity (GFC) were measured at baseline and after 12 weeks of treatment with atorvastatin, 10 mg/day. Atorvastatin treatment decreased serum low-density lipoprotein (-39%, P=0.0001), total cholesterol (-32%, P=0.0001), and triglycerides (-22%, P=0.0001), and increased high-density lipoprotein (+13%, P=0.0001) at 12 weeks compared to baseline. These effects were associated with a decrease in plasma fibrinogen from 331+/-73 to 298+/-58 mg/dl (P=0.0001), and sL-selectin levels from 666+/-201 to 584+/-162 ng/ml (P=0.0001). sFas levels and GFC increased from 3754+/-1264 to 4873+/-1835 pg/ml and from 3.5+/-2.4 to 5.6+/-2.9 microg/ml, respectively (both P=0.0001). These results suggest that lipid lowering with atorvastatin therapy significantly increases GFC, decreases fibrinogen levels, and causes leukocyte deactivation. Our findings also suggest that atorvastatin treatment mitigates apoptosis of VSMC in the atherosclerotic plaque. These effects of atorvastatin may, in part, explain the early decrease in cardiovascular events observed in clinical trials of statins.",2002.0,0,0 1458,12127616,Effects of statins on six-month survival and clinical restenosis frequency after coronary stent deployment.,T Jared Bunch; Joseph B Muhlestein; Jeffrey L Anderson; Benjamin D Horne; Tami L Bair; Jeffrey D Jackson; Qunyu Li; Donald L Lappé,,2002.0,0,0 1459,12127920,Management of acute coronary syndromes. Variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE).,K A A Fox; S G Goodman; W Klein; D Brieger; P G Steg; O Dabbous; A Avezum,"Despite advances in the treatment of acute coronary syndromes based on randomized trial data and published guidelines, the extent to which such treatments are applied in practice remains uncertain. Data from clinical trials derive from selected geographical areas and in highly selected populations of patients, and hence may not reflect the overall population. The aim of the study was to investigate variations in hospital management and outcome using unselected data collected in the prospective Global Registry of Acute Coronary Events (GRACE). The 95 hospitals in GRACE were organized into 18 population-based clusters in 14 countries. Information was recorded about patient management and outcome during hospitalization and after discharge. Data on treatments administered were analysed by baseline condition, hospital type, by the presence or absence of a catheterization laboratory, and by geographical region. Of 11543 patients, 44% had an admission diagnosis of unstable angina, 36% presented with myocardial infarction, 9% were admitted to rule out a myocardial infarction, 7% had chest pain and 4% were hospitalized for 'other cardiac' and 'non-cardiac' diagnoses. Of the total GRACE population 38% had a final diagnosis of unstable angina, 30% ST-segment elevation myocardial infarction, 25% non-ST-segment elevation myocardial infarction, and 7% of 'other cardiac' and 'non-cardiac' final diagnoses. The event rates for hospital death or reinfarction were six and 2% for non-ST-segment elevation myocardial infarction, seven and 3% for ST-segment elevation myocardial infarction, and 3% hospital death for unstable angina. The use of aspirin was similar across all hospital types and geographical regions. In contrast, the use of percutaneous coronary intervention and glycoprotein IIb/IIIa inhibitors was higher (P<0.0001) in teaching hospitals and hospitals with catheterization laboratories and was also higher in the United States. At discharge a higher percentage (P<0.0001) of patients received angiotensin-converting enzyme inhibitors in hospitals without catheterization laboratories. The use of statins was lower in non-teaching hospitals and in centres without a catheterization laboratory. The GRACE study reveals substantial differences in the management of patients based on hospital type and geographical location. Further analyses will determine whether such variations translate into differences in longer term outcomes. GRACE provides a multinational reference for the implementation of therapies of proven efficacy.",2002.0,0,0 1460,12132975,Long-term persistence in use of statin therapy in elderly patients.,Joshua S Benner; Robert J Glynn; Helen Mogun; Peter J Neumann; Milton C Weinstein; Jerry Avorn,"Knowledge of long-term persistence with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy is limited because previous studies have observed patients for short periods of time, in closely monitored clinical trials, or in other unrepresentative settings. To describe the patterns and predictors of long-term persistence with statin therapy in an elderly US population. Retrospective cohort study including 34 501 enrollees in the New Jersey Medicaid and Pharmaceutical Assistance to the Aged and Disabled programs who were 65 years of age and older, initiated statin treatment between 1990 and 1998, and who were followed up until death, disenrollment, or December 31, 1999. Proportion of days covered (PDC) by a statin in each quarter during the first year of therapy and every 6 months thereafter; predictors of suboptimal persistence during each interval (PDC <80%) were identified using generalized linear models for repeated measures. The mean PDC was 79% in the first 3 months of treatment, 56% in the second quarter, and 42% after 120 months. Only 1 patient in 4 maintained a PDC of at least 80% after 5 years. The proportion of patients with a PDC less than 80% increased in a log-linear manner, comprising 40%, 61%, and 68% of the cohort after 3, 12, and 120 months, respectively. Independent predictors of poor long-term persistence included nonwhite race, lower income, older age, less cardiovascular morbidity at initiation of therapy, depression, dementia, and occurrence of coronary heart disease events after starting treatment. Patients who initiated therapy between 1996-1998 were 21% to 25% more likely to have a PDC of at least 80% than those who started in 1990. Persistence with statin therapy in older patients declines substantially over time, with the greatest drop occurring in the first 6 months of treatment. Despite slightly better persistence among patients who began treatment in recent years, long-term use remains low. Interventions are needed early in treatment and among high-risk groups, including those who experience coronary heart disease events after initiating treatment.",2002.0,0,0 1461,12132976,Adherence with statin therapy in elderly patients with and without acute coronary syndromes.,Cynthia A Jackevicius; Muhammad Mamdani; Jack V Tu,"Landmark clinical trials have demonstrated the survival benefits of statins, with benefits usually starting after 1 to 2 years of treatment. Research prior to these trials of older lipid-lowering agents demonstrated low levels of 1-year adherence. To compare 2-year adherence following statin initiation in 3 cohorts of patients: those with recent acute coronary syndrome (ACS), those with chronic coronary artery disease (CAD), and those without coronary disease (primary prevention). Cohort study using linked population-based administrative data from Ontario. All patients aged 66 years or older who received at least 1 statin prescription between January 1994 and December 1998 and who did not have a statin prescription in the prior year were followed up for 2 years from their first statin prescription. There were 22,379 patients in the ACS, 36,106 in the chronic CAD, and 85,020 in the primary prevention cohorts. Adherence to statins, defined as a statin being dispensed at least every 120 days after the index prescription for 2 years. Two-year adherence rates in the cohorts were only 40.1% for ACS, 36.1% for chronic CAD, and 25.4% for primary prevention. Relative to the ACS cohort, nonadherence was more likely among patients receiving statins in the chronic CAD (relative risk [RR], 1.14; 95% CI, 1.11-1.16) and primary prevention cohorts (RR, 1.92; 95% CI, 1.87-1.96). Elderly patients with and without recent ACS have low rates of adherence to statins. This suggests that many patients initiating statin therapy may receive no or limited benefit from statins because of premature discontinuation.",2002.0,0,0 1462,12133763,Alopecia associated with atorvastatin.,Alan S Segal,,2002.0,0,0 1463,12134620,Primary prevention of colorectal cancer: diet and drugs.,David Gatof; Dennis Ahnen,"Primary prevention of colonic adenomas and cancer through dietary interventions or chemoprevention has great appeal. This article discusses primary prevention goals and promising nutritional or chemopreventive strategies. There is substantial observational evidence that diets high in total calories and fat and or low in fruits and vegetables or total fiber as well as low levels of physical activity are related to the risk of colonic neoplasia. Similar observational data indicate that diets high in specific nutrients such as antioxidant vitamins or calcium may be protective. The article describes some of the newer chemopreventive agents and reviews the data linking diet and lifestyle to colorectal cancer risk, focusing on interventions that have also been studied in prospective clinical trials. Finally the evidence supporting the role of non-steroidal anti-inflammatory drugs for the chemoprevention of CRC is reviewed and the status of several other promising newer agents that are entering human trials is summarized.",2003.0,0,0 1464,12135935,Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy.,Francesco Cipollone; Andrea Mezzetti; Ettore Porreca; Concetta Di Febbo; Michele Nutini; Maria Fazia; Angela Falco; Franco Cuccurullo; Giovanni Davì,"Hypercholesterolemia is associated with inflammation and the prothrombotic state. CD40-CD40 ligand (CD40L) interactions promote a prothrombotic response in nucleated cells. The aim of this study was to characterize the in vivo expression of soluble CD40L (sCD40L) in hypercholesterolemia, to correlate it with the extent of the prothrombotic state, and to investigate whether it may be modified by statins. We studied 80 hypercholesterolemic patients and 80 matched healthy subjects. Hypercholesterolemic subjects had enhanced levels of sCD40L, factor VIIa (FVIIa), and prothrombin fragment 1+2 (F1+2) compared with healthy subjects. sCD40L correlated with total cholesterol and LDL cholesterol. Moreover, sCD40L was positively associated with in vivo platelet activation, as reflected by plasma P-selectin and urinary 11-dehydro-thromboxane B2, and with procoagulant state, as reflected by FVIIa and F1+2. Inhibition of cholesterol biosynthesis by pravastatin or cerivastatin was associated with comparable, significant reductions in sCD40L, FVIIa, and F1+2. This study suggests that sCD40L may represent the molecular link between hypercholesterolemia and the prothrombotic state and demonstrates that statin therapy may significantly reduce sCD40L and the prothrombotic state.",2002.0,0,0 1465,12137409,Endothelium-targeted pharmacotherapeutics for the treatment of stroke.,Gary Danton; Brant D Watson; Ricardo Prado; W Dalton Dietric,"The pathophysiology of stroke in humans is much more complex than what is typically studied in animal models. Embolic stroke models are more complex than pure ischemia models, but are more representative of human disease and may be particularly useful in the study of new therapeutic strategies. Vascular damage is a prominent feature of embolic stroke, and may be a useful therapeutic target. Serotonin antagonists, adenosine-regulating agents, free radical scavengers, matrix metalloproteinase inhibitors, and HMG-CoA reductase inhibitors are all potentially valuable agents in treating vascular damage after stroke. These agents facilitate decreased infarction volume, hemorrhage, and improved cerebral bloodflow.",2003.0,0,0 1466,12137445,The human and economic costs of undertreatment with statins.,P Durrington,"Several guidelines for the prevention and management of coronary heart disease (CHD) have been published. These generally recommend lipid-lowering therapy in patients with and without established CHD on the basis of their low-density lipoprotein cholesterol (LDL-C) levels and, for cases without established CHD, their risk-factor profile. Statins are the preferred lipid-lowering agent for the prevention of CHD because of overwhelming clinical trial evidence that they can significantly reduce the occurrence of CHD mortality and morbidity. Despite the guidelines, only approximately one-third of eligible patients receive lipid-lowering therapy in clinical practice--even for secondary prevention of CHD--and many treated patients fail to achieve their target LDL-C levels. This underuse must affect patients' clinical outcome and quality of life and has economic consequences for society. Reasons for the underuse may include physicians' and patients' attitudes and knowledge, and the perceptions of physicians and healthcare purchasers about economic factors. Health economic evaluations have confirmed that secondary prevention with statins is cost-effective, and that primary prevention is also reasonably cost-effective, depending on the absolute CHD risks in targeted individuals. Newer statins with greater efficacy in reducing LDL-C levels may allow patients to reach target levels more quickly and without the need for dose titration, thus improving clinical outcomes and being more cost-effective in the long term. This proposition should be testedin future clinical trials.",2002.0,0,0 1467,12137448,"Statin therapy: rationale for a new agent, rosuvastatin.",K Korlipara,"Cardiovascular disease (CVD) remains a major cause of death in industrialised societies, and elevated serum lipids are a significant, highly prevalent and undertreated risk factor for this condition. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have revolutionised the treatment of hyperlipidaemia, and results from large-scale, long-term clinical trials have shown that the substantial reductions in low-density lipoprotein cholesterol (LDL-C) achieved with these drugs are associated with dramatic decreases in cardiovascular risk. Results from recent comparative clinical trials that have included a new drug in this class, rosuvastatin (Crestor), have demonstrated that it is significantly superior to atorvastatin, pravastatin and simvastatin in reducing total cholesterol, LDL-C and apolipoprotein B (Apo B). It is also significantly more effective than atorvastatin in increasing high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I). Rosuvastatin was also superior to all these agents in helping patients meet European Atherosclerosis Society (EAS) and National Cholesterol Education Programme (NCEP) goals for LDL-C. The results of an increasing number of studies indicate that statins have a wide range of pleiotropic properties that almost certainly contribute to their ability to decrease cardiovascular risk and may also make them valuable for treatment of other diseases. These actions include plaque stabilisation, improvement of endothelial function, inhibition of smooth muscle cell proliferation and migration, reduction of expression of adhesion molecules, prevention of cholesterol esterification and accumulation, reduction of secretion of matrix metalloproteinases by macrophages, reduction of platelet activity, reduction of formation of thrombogenic factors, chemoprotection and induction of bone morphogenic protein-2 (BMP-2). Further exploration of these actions will provide key information about class effects and properties of specific members of this highly useful group of drugs.",2002.0,0,0 1468,12137559,Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same?,Marc Evans; Alan Rees,"The 3-hydroxy-3-methyl coenzyme A (HMG-CoA) reductase inhibitors or statins, specifically inhibit the enzyme HMG-CoA in the liver, thereby inhibiting the rate limiting step in cholesterol biosynthesis and so reducing plasma cholesterol levels. Numerous studies have consistently demonstrated that cholesterol lowering with statin therapy reduces morbidity and mortality from coronary heart disease, whilst recent evidence has demonstrated that benefits of statin therapy may also extend into stroke prevention. Since hypercholesterolaemia is a chronic condition, the long-term safety and tolerability of these agents is an important issue. Numerous large-scale clinical trials have consistently demonstrated a positive safety and tolerability profile for statins. Hepatic, renal and muscular systems are rarely affected during statin therapy, with adverse reactions involving skeletal muscle being the most common, ranging from mild myopathy to myositis and occasionally to rhabdomyolysis and death. Postmarketing data supports the positive safety and tolerability profile of statins, with an overall adverse event frequency of less than 0.5% and a myotoxicity event rate of less than 0.1%. The recent withdrawal of cerivastatin from the world market due to deaths from rhabdomyolysis has, however, focused attention on the risk of adverse events and in particular myotoxicity associated with statins. Indeed, initial clinical trial data supports postmarketing data, demonstrating a higher incidence of myotoxicity associated with cerivastatin, particularly when used in combination with fibrates. The potential mechanisms underlying statin-induced myotoxicity are complex with no clear consensus of opinion. Candidate mechanisms include intracellular depletion of essential metabolites and destabilisation of cell membranes, resulting in increased cytotoxicity. Cytochrome P450 3A4 is the main isoenzyme involved in statin metabolism. Reduced activity of this enzyme due to either reduced expression or inhibition by other drugs prescribed concomitantly such as cyclosporin or itraconazole may increase drug bioavailability and the risk of myotoxicity. Such factors may partly account for the interindividual variability in susceptibility to statin-induced myotoxicity, although other as of yet unclarified, genetic factors may also be involved. The risk of rhabdomyolysis is increased with combination fibrate-statin therapy, with initial evidence suggesting that gemfibrozil-statin combination may particularly increase the risk of myotoxicity, with pharmacodynamic as well as pharmacokinetic mechanisms being involved.",2002.0,0,0 1469,12138263,"Impact of treatment of dyslipidemia on renal function, fat deposits and scarring in patients with persistent nephrotic syndrome.",Osama Ashry Gheith; Mohamed Abel-Kader Sobh; Kefaia El-Sayed Mohamed; Mahmoud Abdo El-Baz; Fatma El-Husseini; Sana Sayed Gazarin; Hassan Abd-El-Hady Ahmed; Mahmoud Wageh Rasem; Galal Mohamed Amer,"In this study 43 patients with idiopathic nephrotic syndrome were randomly distributed into 2 age- and sex-matched groups. The first group was given fluvastatin while the second was used as control. The cases in the 2 groups were evaluated clinically, biochemically (creatinine clearance, albumin, 24-hour proteinuria, and lipogram), neurologically, and histopathologically (examination of renal biopsies obtained basally and after 1 year of treatment with fluvastatin). In the fluvastatin-treated group but not in the control group, we observed a significant reduction in cholesterol, low-density lipoprotein, and triglyceride. Clinical and laboratory assessment showed satisfactory tolerance of the drug by the patients. Proteinuria, serum albumin and creatinine clearance values were significantly better in the statin-treated patients. There was no difference in glomerular sclerosis between the 2 groups while interstitial fibrosis and renal fat deposits were less in the statin-treated group. The reduction in renal fat deposits in the statin-treated group was highly significant, while that of interstitial fibrosis was not. We conclude that: (1) statin can be safely and effectively used in the treatment of dyslipidemia in patients with persistent idiopathic nephrotic syndrome; (2) control of dyslipidemia in nephrotic patients is associated with better control of proteinuria and creatinine clearance; (3) statin treatment may cause regression of renal fat deposits in patients with nephrotic syndrome, and (4) longer term studies are still required to study further possible beneficial effects on renal histology and disease progression.",2003.0,0,0 1470,12138411,Antiatherosclerotic effects of calcium channel blockers.,G B John Mancini,"Over the past 30 years, a considerable body of experimental and clinical evidence has accumulated to support the suggestion that calcium channel blockers (CCBs) have significant antiatherosclerotic effects that are independent of their hypotensive effects. Early research using animal models of atherosclerosis and CCBs in concentrations that exceeded the normal therapeutic dose range showed definite antiatherosclerotic effects, especially in the development of new lesions. Investigations of these effects in humans have used quantitative coronary angiography and B-mode ultrasonography and have demonstrated some antiatherosclerotic effects. This article reviews the currently available evidence of antiatherosclerotic effects of CCBs in animal models and in clinical trials.",2002.0,0,0 1471,12142124,Simvastatin preserves myocardial perfusion and coronary microvascular permeability in experimental hypercholesterolemia independent of lipid lowering.,Piero O Bonetti; Stephanie H Wilson; Martin Rodriguez-Porcel; David R Holmes; Lilach O Lerman; Amir Lerman,"OBJECTIVES; This study was designed to assess the lipid-independent effects of simvastatin on myocardial perfusion (MP) and coronary microvascular permeability index (PI) at baseline and during episodes of increased cardiac demand in experimental hypercholesterolemia. Simvastatin preserves coronary endothelial function in experimental hypercholesterolemia independent of its lipid-lowering effect. However, the functional significance of this observation is unknown. Pigs were randomized to three groups: normal diet (N), high-cholesterol diet (HC) and HC diet plus simvastatin (HC+S) for 12 weeks. Subsequently, cardiac electron beam computed tomography was performed before and during intravenous infusion of adenosine and dobutamine, and MP and PI were calculated. Total and low density lipoprotein cholesterol levels were similarly and significantly increased in HC and HC+S animals compared with N. Basal MP was similar in all groups. Myocardial perfusion significantly increased in response to either adenosine or dobutamine in N and HC+S animals. Dobutamine also significantly increased MP in HC animals. However, the changes of MP in response to either drug were significantly lower in the HC group compared with the other two groups (p < 0.01 for adenosine and p < 0.05 for dobutamine vs. N and HC+S). Basal PI was similar in all groups and was not altered by either drug in N and HC+S animals. In contrast, PI significantly increased in HC pigs during infusion of either adenosine (p < 0.001) or dobutamine (p < 0.05). These findings demonstrate that chronic administration of simvastatin preserves myocardial perfusion response and coronary microvascular integrity during cardiac stress in experimental hypercholesterolemia independent of lipid lowering.",2002.0,0,0 1472,12145148,Regulatory effects of HMG CoA reductase inhibitor and fish oils on apolipoprotein B-100 kinetics in insulin-resistant obese male subjects with dyslipidemia.,Dick C Chan; Gerald F Watts; P Hugh R Barrett; Lawrence J Beilin; Trevor G Redgrave; Trevor A Mori,"Hepatic accumulation of lipid substrates perturbs apolipoproteinB-100 (apoB) metabolism in insulin-resistant, obese subjects and may account for increased risk of cardiovascular disease. In a placebo-controlled trial, we examined the independent and combined effects of decreasing cholesterol synthesis with atorvastatin (40 mg/day) and triglyceride synthesis with fish oils (4 g/day) on apoB kinetics. The subjects were 48 viscerally obese, insulin-resistant men with dyslipidemia who were studied in a fasted state. We found that atorvastatin significantly decreased plasma apoB-containing lipoproteins (P < 0.001, main effect) through increases in the fractional catabolic rate (FCR) of VLDL-, IDL-, and LDL-apoB (P < 0.01). Fish oils significantly decreased plasma levels of triglycerides and VLDL-apoB (P < 0.001), decreased the VLDL-apoB secretion rate (P < 0.01), but increased the conversion of VLDL to LDL (P < 0.001). Compared with placebo, combined treatment with atorvastatin and fish oils decreased VLDL-apoB secretion (P < 0.03) and increased the FCR of apoB in each lipoprotein fraction (P < 0.03) and the percent conversion of VLDL to LDL (P < 0.05). None of the treatments altered insulin resistance. In conclusion, in visceral obesity, atorvastatin increased hepatic clearance of all apoB-containing lipoproteins, whereas fish oils decreased hepatic secretion of VLDL-apoB. The differential effects of atorvastatin and fish oils on apoB kinetics support their combined use in correcting defective apoB metabolism in obese, insulin-resistant subjects.",2002.0,0,0 1473,12145176,Cerivastatin improves insulin sensitivity and insulin secretion in early-state obese type 2 diabetes.,J A Paniagua; J López-Miranda; A Escribano; F J Berral; C Marín; D Bravo; E Paz-Rojas; P Gómez; M Barcos; J A Moreno; F Pérez-Jiménez,"In a double-blind, placebo-controlled, randomized crossover study, 15 stable mild hyperglycemic patients without treatment and with features of metabolic syndrome were treated with cerivastatin (0.4 mg/day) or placebo for 3 months. The insulin sensitivity index during the euglycemic-hyperinsulinemic clamp (EHC; 5.4 mmol/l; 80 mU x m(-2) x min(-1)) was increased by cerivastatin treatment (66.39 +/- 3.9 nmol x lean body mass [LBM](-1) x min(-1) x pmol(-1) x l(-1)) as compared with placebo (58.37 +/- 3.69 nmol x LBM(-1) x min(-1) x pmol(-1) x l(- 1); P < 0.01) by 13.7%. Glucose oxidation during EHC was significantly higher with statin treatment (16.1 +/- 1.37 micromol x LBM(-1) x min(-1)) as compared with placebo (14.58 +/- 1.48 micromol x LBM(-1) x min(-1); P < 0.05). During hyperinsulinemia (approximately 800 pmol/l) in EHC steady-state, lipid oxidation was significantly decreased and respiratory quotient was significantly increased with statin treatment (0.33 +/- 0.05 mg x LBM(-1) x min(- 1), 0.94 +/- 0.01) as compared with placebo (0.48 +/- 0.06 mg x LBM(-1) x min(-1), 0.91 +/- 0.01; P < 0.01 and P < 0.05, respectively). During statin treatment, the first-phase insulin response increased from 2.07 +/- 0.28 to 2.82 +/- 0.38 pmol x l(-1) x pmol(-1) (P < 0.05). The second phase of insulin responses examined by C-peptide and insulin levels averaged during the hyperglycemic clamp (20 mmol/l) was unchanged. In conclusion, this study demonstrates that 0.4 mg cerivastatin therapy improves first-phase insulin secretion and increases insulin-mediated glucose uptake and respiratory quotient in the early state of obese type 2 diabetes.",2002.0,0,0 1474,12147960,A summary of the findings from the Post-CABG trial.,B J Hoogwerf; D B Hunninghake; G Knatterud; L Campeau,"The Post-CABG trial was designed to assess the effects of 2 different lipid lowering strategies and low dose warfarin vs placebo (2 x 2 factorial) design on the progression of atherosclerosis in saphenous vein grafts. Atherosclerotic progression was determined by comparing baseline and follow-up angiograms (mean interval: 4.3 years) using quantitative angiography. Significant progression of disease in SVG's was reduced with the aggressive lipid lowering strategy compared to the moderate strategy; significant progression in SVG's was not altered by low dose warfarin. The beneficial effects on angiographic changes were demonstrated in multiple subgroups of participants in the trial. The composite clinical end point of death, MI, stroke, PTCA or repeat CABG was analyzed at the end of the trial and 3 years (extended follow-up) after closure of the angiographic trial. At the time of the extended follow-up the aggressive lipid strategy was associated with reduced clinical events; low dose warfarin was also associated with reduced clinical events.",2002.0,0,0 1475,12149041,Who should receive HMG CoA reductase inhibitors?,Koon K Teo; Jeffrey R Burton,"During the last decade, the development of the HMG CoA reductase inhibitors, commonly referred to as 'statins', has contributed greatly to cholesterol lowering therapy and cardiovascular risk reduction. These agents are well tolerated and efficacious. Data on nearly 30,000 patients from five long-term randomised, placebo-controlled trials of statins have clearly demonstrated that a broad range of individuals can benefit from such therapy. These include men or women, younger or older individuals, those with elevated or normal cholesterol levels, with or without myocardial infarction or symptomatic coronary heart disease, with or without hypertension or diabetes mellitus, and those who are smokers or non-smokers. Benefits include reductions in the risks for myocardial infarction, and coronary, cardiovascular and all-cause mortality, stroke and the need for coronary revascularisation. Results of the recently completed Heart Protection Trial have clearly confirmed the results of the earlier trials and support the use of statin therapy in secondary prevention. The role of statins in acute coronary syndromes is being actively evaluated and appears promising. In primary prevention, the data are not as convincing and generalisations cannot be made as to whether, and in which subgroup, drug therapy to lower low density lipoprotein (LDL) cholesterol should be initiated. There are important cost implications to consider and the use of statin therapy has to be judged on an individual basis, particularly in those with high or very high LDL cholesterol levels and/or with multiple risk factors rendering them at high short- and long-term risk of coronary heart disease. There is evidence of a 'care gap' in translating trial data into practice, even in secondary prevention, and this needs closing in order to improve patient outcomes.",2002.0,0,0 1476,12150693,Pharmacotherapeutic options for the management of myocardial infarction.,Judy W M Cheng,"The pharmacological treatment of acute coronary syndrome (ACS), including unstable angina, non-ST- and ST-segment elevation myocardial infarction (MI) is dynamic and continues to evolve. Expert guidelines based on the results of clinical trials for the management of different types of ACS have been published. In both ST-segment elevation and non-ST-segment elevation MI, aspirin/clopidogrel, heparin/low molecular weight heparin/direct thrombin inhibitors, beta-blockers and angiotensin converting enzyme inhibitors are part of the routine regimens. In patients with ST-segment elevation MI, eligibility for thrombolytic therapy needs to be determined and utilised as soon as possible. In patients with non-ST-segment elevation MI, the risks of thrombolytic therapy outweigh the benefits. The use of glycoprotein IIb/IIIa inhibitors has become increasingly important. The use of antihyperlipidaemic agents for the prevention of secondary events in both types of patients continue to be essential and the early aggressive use of lipid-lowering therapy also plays a role in improving endothelial function and stabilising atherosclerotic plaques.",2003.0,0,0 1477,12151856,Non-invasive measurement of coronary heart disease using electron beam computed tomography.,Jonathan Valabhji; Robert S Elkeles,"Electron beam computed tomography is a non-invasive investigation that can quantify calcification within the walls of coronary arteries. Coronary arteries remodel to maintain luminal integrity, so that significant plaque may be present before the development of luminal stenoses. This has led to interest in techniques that assess the coronary artery wall, rather than the lumen. This review examines the power of coronary calcification detected by electron beam computed tomography to predict coronary heart disease events, and outlines recent studies in which it has been used as a surrogate marker for coronary heart disease. The predictive power of coronary calcification has been shown to exceed that of traditional coronary heart disease risk factors and possibly also coronary angiography. This may justify the use of coronary calcification as a surrogate marker for coronary heart disease, and studies have thus examined cross-sectional associations between coronary calcification and potential risk factors in healthy individuals and patients with diabetes, end-stage renal failure and familial hypercholesterolaemia. Intervention studies can use the rate of change of coronary calcification detected by serial electron beam computed tomography imaging as an end-point, rather than relying on coronary heart disease events. As every participant reaches an end-point, sufficient power can be attained with smaller numbers at substantially less cost. Coronary calcification detected by electron beam computed tomography may prove an invaluable tool in the selection of at-risk individuals suitable for primary prevention, and a useful surrogate marker for coronary heart disease in clinical trials.",2003.0,0,0 1478,12151857,The myotoxicity of statins.,Marc Evans; Alan Rees,"Since hypercholesterolaemia is a chronic condition, the long-term safety of statins is important. Adverse reactions involving skeletal muscle are the most common (reported incidence 1-7%). The recent withdrawal of cerivastatin because of deaths from rhabdomyolysis, of which 25% were related to gemfibrozil-cerivastatin combination therapy, has focused attention on myotoxicity associated with statins and in particular with statin-fibrate combinations. We review the safety profiles of the individual statins, and discuss the mechanisms that may account for myotoxicity associated with statins and these agents and how these may relate to the different myotoxic potential of individual agents. The statins, particularly the first-generation agents, have been well evaluated from the perspective of safety and efficacy. Cerivastatin was associated with a 10-fold higher incidence of myotoxicity than any other statin, suggesting that there may be differences in myotoxic potential between agents. Statin-associated myotoxicity is complex, involving effects on cell membrane structure and function, mitochondrial dysfunction and impaired myocyte duplication. Potential differences in myotoxicity between agents may relate to the physicochemical, pharmacokinetic and pharmacodynamic properties of individual drugs. The aetiology of myotoxicity associated with statin-fibrate combination therapy is complex and multifactorial, with recent studies suggesting that there may be differences in myotoxic potential between individual fibrates. Recent evidence suggests that there may be differences in myotoxic potential between individual agents. Thus, the choice of hypolipidaemic therapy needs to be based not only on outcome evidence and cost-effectiveness analysis, but also on safety considerations for individual agents.",2003.0,0,0 1479,12151864,High-sensitivity C-reactive protein and cardiovascular risk in patients with coronary heart disease.,Robert S Rosenson; Wolfgang Koenig,"High-sensitivity C-reactive protein levels have received widespread attention because of a multitude of prospective studies that have shown that high levels of high-sensitivity C-reactive protein identify increased risk of initial cardiovascular events in coronary heart disease patients and increased risk of recurrent cardiac events in patients with stable and unstable angina, patients with acute myocardial infarction, and patients undergoing elective coronary revascularization procedures. In contrast to several other inflammatory markers, high-sensitivity C-reactive protein measurements are standardized and reproducible. The clinical significance of a reliable inflammatory marker includes identification of high-risk individuals, a gauge to monitor the activity of the disease, and a potential therapeutic target to alter the inflammatory component of the disease process. This review focuses on the importance of high-sensitivity C-reactive protein in cardiovascular risk stratification in coronary heart disease patients and discusses several preventive therapies that may reduce cardiovascular risk through reduction in high-sensitivity C-reactive protein.",2002.0,0,0 1480,12152989,P-glycoprotein in acute myeloid leukaemia: therapeutic implications of its association with both a multidrug-resistant and an apoptosis-resistant phenotype.,Monica Pallis; Julie Turzanski; Yutaro Higashi; Nigel Russell,"P-glycoprotein (Pgp) expression is an independent prognostic factor for response to remission-induction chemotherapy in acute myeloblastic leukaemia, particularly in the elderly. There are several potential agents for modulating Pgp-mediated multi-drug resistance, such as cyclosporin A and PSC833, which are currently being evaluated in clinical trials. An alternative therapeutic strategy is to increase the use of drugs which are unaffected by Pgp. However, in this review, we explain why this may be more difficult than it appears. Evidence from in vitro studies of primary AML blasts supports the commonly held supposition that chemoresistance may be linked to apoptosis-resistance. We have found that Pgp has a drug-independent role in the inhibition of in vitro apoptosis in AML blasts. Modulation of cytokine efflux, signalling lipids and intracellular pH have all been suggested as ways by which Pgp may affect cellular resistance to apoptosis; these are discussed in this review. For a chemosensitising agent to be successful, it may be more important for it to enhance apoptosis than to increase drug uptake.",2003.0,0,0 1481,12153549,Effect of Simvastatin on markers of triglyceride-rich lipoproteins in familial hypercholesterolaemia.,C A Dane-Stewart; G F Watts; J C L Mamo; P H R Barrett; I J Martins; S B Dimmitt; T G Redgrave,"We have previously shown elevated fasting plasma concentrations of intestinal remnants, as reflected by apolipoprotein (apo) B-48 and remnant-like particle-cholesterol (RLP-C) in patients with heterozygous familial hypercholesterolaemia (FH). We now investigate the effect of an HMG-CoA reductase inhibitor (simvastatin) on chylomicron remnant metabolism using the measurement of fasting apoB-48 and RLP-C in FH patients after long- and short-term simvastatin therapy and after a wash-out period. We also piloted the response of a breath test, involving the measurement of the fractional catabolic rate (FCR) of an intravenously injected chylomicron remnant-like emulsion labeled with cholesteryl (13)C-oleate. Fifteen FH patients were studied after > 6 months 40 mg day(-1) simvastatin treatment (long-term), a wash-out period (4 weeks), and 4 weeks of simvastatin treatment (short-term). Apolipoprotein B-48 was determined by SDS-PAGE and Western blotting/enhanced chemiluminescence and RLP-C by an immunoseparation assay. The FCR of the chylomicron remnant-like emulsion was determined from the appearance of (13)CO(2) in the breath and by multicompartmental mathematical modelling. Both long- and short-term treatment with simvastatin were associated with decreases in the plasma concentration of apoB-48 (P < 0.05) and RLP-C (P < 0.001), but there was no significant change in the FCR of the emulsion. We suggest that long- and short-term treatments with simvastatin have comparable effects in decreasing the plasma concentration of triglyceride-rich remnants in heterozygous FH, as measured by fasting apoB-48 and RLP-C. The mechanisms for this may involve decreased production of hepatic and possibly intestinal lipoproteins, and/or up-regulation of hepatic receptor clearance pathways, but these changes are apparently not associated with a change in remnant clearance as measured kinetically by the (13)CO(2) breath test.",2003.0,0,0 1482,12153554,Effects of combined treatment with pravastatin and ursodeoxycholic acid on hepatic cholesterol metabolism.,C-G Hillebrant; B Nyberg; U Gustafsson; S Sahlin; I Björkhem; M Rudling; C Einarsson,"Treatment with ursodeoxycholic acid and also, to some degree, statins reduces cholesterol saturation of bile. The present study aimed [1] to study the effects of combined treatment with ursodeoxycholic acid and pravastatin on hepatic cholesterol metabolism and [2] to evaluate if the addition of pravastatin to ursodeoxycholic acid treatment has beneficial effects on the lipid composition of gallbladder bile in gallstone patients. Nineteen patients with cholesterol gallstones were subjected to combined treatment with ursodeoxycholic acid (500 mg bid) and pravastatin (20 mg bid) for three weeks before cholecystectomy. Eleven patients received ursodeoxycholic acid only and 20 untreated gallstone patients served as controls. Gallbladder bile was collected, and for both the patients receiving combined treatment and the controls a liver biopsy was also obtained peroperatively. The cholesterol saturation of bile averaged 59% in the patients on combined treatment, 60% in the ursodeoxycholic acid-treated patients, and 130% in the untreated controls. In the patients receiving ursodeoxycholic acid, this bile salt constituted approximately 60% of all bile salts. The patients receiving combined treatment had reduced cholesterol synthesis, as reflected by a 45% reduction in serum lathosterol. The activity and the mRNA levels of cholesterol 7 alpha-hydroxylase and the mRNA levels for the low density lipoprotein-receptor were not significantly affected. Pravastatin does not further reduce the cholesterol saturation of bile in gallstone patients treated with ursodeoxycholic acid, although hepatic cholesterol synthesis is inhibited. The study supports the important concept that de novo synthesized cholesterol is not particularly important for biliary cholesterol secretion in humans.",2003.0,0,0 1483,12162466,,,,,0,0 1484,12162932,Clinical implications of statin event trials.,Anne Carol Goldberg,"Event trials using statin therapy have shown a beneficial effect on rates of cardiovascular events. The three statins that have been used in long-term trials have shown generally similar effects on rates of myocardial infarction, stroke, revascularizations, and mortality. Safety data appear to be comparable for lovastatin, pravastatin, and simvastatin. Long-term trials of other statins are in progress or pending. The question of how much low-density lipoprotein cholesterol should be lowered may be answered by studies currently in progress.",2003.0,0,0 1485,12162933,New targets for medical treatment of lipid disorders.,Margaret E Brousseau; Ernst J Schaefer,"Coronary heart disease (CHD) is the leading cause of death and disability in the industrialized world. Included among the risk factors for CHD are an elevated level of low-density lipoprotein (LDL) cholesterol and a low level of high-density lipoprotein (HDL) cholesterol. The discovery of drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins), the rate-limiting enzyme in cholesterol biosynthesis, constituted a major advance in the treatment of patients with elevated plasma concentrations of LDL cholesterol. However, although the statins are potent LDL-lowering agents, they may not be the therapy of choice for all dyslipidemic patients. This is particularly true for subjects whose primary lipid abnormality is a low level of HDL cholesterol with or without hypertriglyceridemia, a group that includes about one half of patients with CHD. In this report, we review emerging options for the treatment of patients with lipid disorders, including inhibitors of cholesterol absorption, acyl coenzyme A-cholesterol acyltransferase, microsomal triglyceride transfer protein, and cholesteryl ester transfer protein, as well as liver X receptor agonists that up-regulate the expression of ATP-binding cassette transporter A1.",2003.0,0,0 1486,12163127,"Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis.",Helen Vosper; Guennadi A Khoudoli; Tracey L Graham; Colin N A Palmer,"Dyslipidaemia is a major risk factor in the development of atherosclerosis, and lipid lowering is achieved clinically using fibrate drugs and statins. Fibrate drugs are ligands for the fatty acid receptor peroxisome proliferator-activated receptor (PPAR)alpha, and the lipid-lowering effects of this class of drugs are mediated by the control of lipid metabolism, as directed by PPARalpha. PPARalpha ligands also mediate potentially protective changes in the expression of several proteins that are not involved in lipid metabolism, but are implicated in the pathogenesis of heart disease. Clinical studies with bezafibrate and gemfibrozil support the hypothesis that these drugs may have a significant protective effect against cardiovascular disease. The thiazolidinedione group of insulin-sensitising drugs are PPARgamma ligands, and these have beneficial effects on serum lipids in diabetic patients and have also been shown to inhibit the progression of atherosclerosis in animal models. However, their efficacy in the prevention of cardiovascular-associated mortality has yet to be determined. Recent studies have found that PPARdelta is also a regulator of serum lipids. However, there are currently no drugs in clinical use that selectively activate this receptor. It is clear that all three forms of PPARs have mechanistically different modes of lipid lowering and that drugs currently available have not been optimised on the basis of PPAR biology. A new generation of rationally designed PPAR ligands may provide substantially improved drugs for the prevention of cardiovascular disease.",2003.0,0,0 1487,12163182,Diabetes and the role of isoprenoid biosynthesis.,Emile G Bliznakov,,2002.0,0,0 1488,12163444,Isoprenoids as mediators of the biological effects of statins.,James K Liao,,2002.0,0,0 1489,12164161,Are some statins more equal than others.,,,2003.0,0,0 1490,12164995,Effect of statin (HMG-Co-A-Reductase Inhibitor) use on 1-year mortality and hospitalization rates in older patients with cardiovascular disease living in nursing homes.,Charles B Eaton; Kate L Lapane; John B Murphy; Anne L Hume,"To quantify the effect of statins on 1-year mortality, hospitalizations, and decline in physical function among patients with cardiovascular disease (CVD) aged 65 and older living in nursing homes. Retrospective cohort study. All Medicare/Medicaid certified nursing homes (N = 1,492) in Maine, New York, Mississippi, and South Dakota. We identified 51,559 older patients with CVD from a population database that merged sociodemographic data and functional, clinical, and drug treatments from more than 300,000 newly admitted nursing home residents from 1992 to 1997. Statin users (n = 1,313) were matched with nonusers (n = 1,313) in the same facilities. All-cause mortality, hospitalization, combined endpoint of mortality or hospitalization, and decline in physical function were determined at 1 year, and survival analysis was performed. Prevalence of statin use in this frail older cohort with CVD was 2.6%. Statin use varied by age, gender, comorbid condition, medication use, and cognitive and physical function. One-year mortality was 229/1,000 person-years in the statin group and 404/1,000 person-years in the nonusers, with an adjusted hazard rate ratio (HRR) of 0.69, 95% confidence interval (CI) = 0.58-0.81. The estimated number needed to treat was seven (95% CI = 5-13). This association with improved all-cause mortality was evident for women and men and for age groups 75 to 84, and 85 and older. Statin therapy is associated with improved clinical outcomes, including reduction in 1-year all-cause mortality, and the combined endpoint of death or hospitalization in a frail older population with CVD. Some caution should be taken in interpreting these results because potential bias from residual confounding could affect these results.",2002.0,0,0 1491,12166344,The effects of combination therapy with niceritrol and pravastatin on hyperlipidaemia.,M Kinoshita; Y Mikuni; M Kudo; M Mori; E Horie; T Teramoto; T Matsushima,"In the present study, we evaluated the effects of combination therapy with niceritrol and pravastatin in patients with hyperlipidaemia. A total of 62 patients with hyperlipidaemia, defined as total cholesterol levels above 220 mg/dl or triglyceride levels above 150 mg/dl, were recruited. Patients were divided into two groups: Group N received initial therapy with niceritrol 750-1500 mg/day, and those in Group P, pravastatin 10 mg/day. After 8 weeks, pravastatin 10 mg/day was added to the Group N treatment regimen for a further 8 weeks, while patients in Group P were given niceritrol 750-1500 mg/day in addition to pravastatin for 8 weeks. After the 8-week combination therapy study period, total cholesterol levels were 209.6 mg/dl in Group N and 220.7 mg/dl in Group P. Decreased triglyceride and lipoprotein(a) levels and increased high-density lipoprotein cholesterol levels, neither of which were achieved by pravastatin administration alone, were achieved with the combination of pravastatin and niceritrol. We conclude that when a single lipid-lowering drug fails to show therapeutic value, attempting combination therapy with a nicotinic acid preparation and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) is worthwhile.",2003.0,0,0 1492,12167391,The effect of carvedilol in patients with impaired left ventricular systolic function following an acute myocardial infarction. How do the treatment effects on total mortality and recurrent myocardial infarction in CAPRICORN compare with previous beta-blocker trials?,Jan Erik Otterstad; Ian Ford,"In previous beta-blocker trials, post-myocardial infarction (MI) patients were essentially treated with a beta-blocker or placebo. In the CAPRICORN trial, patients were selected on the basis of a left ventricular (LV) ejection fraction (EF) <40% following the index MI and randomised to carvedilol or placebo, in addition to modern secondary prophylaxis with ACE inhibitors, aspirin and statins. In 1959 patients with a mean LVEF of 33%, treatment with carvedilol over a mean follow-up period of 15 months reduced total mortality from 15.3% with placebo to 11.9% with carvedilol [relative risk reduction (RRR) =23%, absolute risk reduction (ARR) =3.4%]. The incidence of recurrent MI was reduced from 5.8 to 2.3% (RRR 41%, ARR 2.3%). The number needed to treat (NNT) to prevent one death was 28 for the entire study period and 43 for 1 year of treatment. The results of the CAPRICORN trial are compared with three previous beta-blocker post-MI trials: the Gothenburg metoprolol trial (GMT), the Norwegian timolol trial (NTT) and the beta-blocker heart attack trial (BHAT). The RRRs for total mortality were 36% in the GMT and NTT, and 27% in BHAT. The respective NNTs for total mortality were 32, 18 and 38. NNT for 1 year of treatment was 25 in NTT and 80 in BHAT. The RRR for recurrent MIs were 28% in NTT and 16% in BHAT. The reduction of mortality and recurrent MIs in CAPRICORN is within the range of previous post-MI beta-blocker studies. In post-MI patients with LVEF<40%, add-on treatment with a beta-blocker should be given >48 h after initiation with an angiotensin-converting enzyme inhibitor (ACEI) and then with a slow dose escalation as applied in CAPRICORN.",2002.0,0,0 1493,12168612,,,,,0,0 1494,12169073,Sertraline treatment of major depression in patients with acute MI or unstable angina.,Alexander H Glassman; Christopher M O'Connor; Robert M Califf; Karl Swedberg; Peter Schwartz; J Thomas Bigger; K Ranga Rama Krishnan; Louis T van Zyl; J Robert Swenson; Mitchell S Finkel; Charles Landau; Peter A Shapiro; Carl J Pepine; Jack Mardekian; Wilma M Harrison; David Barton; Michael Mclvor; Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group,"Major depressive disorder (MDD) occurs in 15% to 23% of patients with acute coronary syndromes and constitutes an independent risk factor for morbidity and mortality. However, no published evidence exists that antidepressant drugs are safe or efficacious in patients with unstable ischemic heart disease. To evaluate the safety and efficacy of sertraline treatment of MDD in patients hospitalized for acute myocardial infarction (MI) or unstable angina and free of other life-threatening medical conditions. Randomized, double-blind, placebo-controlled trial conducted in 40 outpatient cardiology centers and psychiatry clinics in the United States, Europe, Canada, and Australia. Enrollment began in April 1997 and follow-up ended in April 2001. A total of 369 patients with MDD (64% male; mean age, 57.1 years; mean 17-item Hamilton Depression [HAM-D] score, 19.6; MI, 74%; unstable angina, 26%). After a 2-week single-blind placebo run-in, patients were randomly assigned to receive sertraline in flexible dosages of 50 to 200 mg/d (n = 186) or placebo (n = 183) for 24 weeks. The primary (safety) outcome measure was change from baseline in left ventricular ejection fraction (LVEF); secondary measures included surrogate cardiac measures and cardiovascular adverse events, as well as scores on the HAM-D scale and Clinical Global Impression Improvement scale (CGI-I) in the total randomized sample, in a group with any prior history of MDD, and in a more severe MDD subgroup defined a priori by a HAM-D score of at least 18 and history of 2 or more prior episodes of MDD. Sertraline had no significant effect on mean (SD) LVEF (sertraline: baseline, 54% [10%]; week 16, 54% [11%]; placebo: baseline, 52% [13%]; week 16, 53% [13%]), treatment-emergent increase in ventricular premature complex (VPC) runs (sertraline: 13.1%; placebo: 12.9%), QTc interval greater than 450 milliseconds at end point (sertraline: 12%; placebo: 13%), or other cardiac measures. All comparisons were statistically nonsignificant (P> or = .05). The incidence of severe cardiovascular adverse events was 14.5% with sertraline and 22.4% with placebo. In the total randomized sample, the CGI-I (P =.049), but not the HAM-D (P =.14), favored sertraline. The CGI-I responder rates for sertraline were significantly higher than for placebo in the total sample (67% vs 53%; P =.01), in the group with at least 1 prior episode of depression (72% vs 51%; P =.003), and in the more severe MDD group (78% vs 45%; P =.001). In the latter 2 groups, both CGI-I and HAM-D measures were significantly better in those assigned to sertraline. Our results suggest that sertraline is a safe and effective treatment for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.",2002.0,0,0 1495,12172500,Ecteinascidin 743: a novel anticancer drug with a unique mechanism of action.,Gregory J Aune; Takahisa Furuta; Yves Pommier,"Ecteinascidin 743 (Et743) is an interesting compound in phase II/III clinical trials. Its chemistry is complex, its mechanism of action is original and it is active in human cancers, such as sarcomas refractory to conventional chemotherapy. The present review describes the discovery of the drug, its specific interactions with DNA and its reversible alkylation mechanism with guanine N2 in the DNA minor groove. Et743 is a selective transcription inhibitor, which has the unique characteristic of poisoning transcription-coupled nucleotide excision repair. Understanding the molecular pharmacology of Et743 should help in deciding which patients should receive Et743 treatments and which agents should be most useful in association.",2003.0,0,0 1496,12172771,Use of atorvastatin in hyperlipidemic hypertensive renal transplant recipients.,Rafael T Krmar; Jorge R Ferraris; José A Ramirez; Patricia Sorroche; Susana Legal; Amely Cayssials,"The aim of the present short-term study was to evaluate the use of a new HMG-CoA reductase inhibitor, atorvastatin, in the treatment of hyperlipidemia and the effect on blood pressure in a group of hypertensive stable renal transplant recipients with hypercholesterolemia who received kidney grafts before 18 years of age. Eight patients (aged 10.8-30.1 years) with inadequately controlled total cholesterol (TC) levels by a lipid-lowering diet (8 weeks) were treated daily for 12 weeks with atorvastatin at an initial dose of 2.5 mg. The dose was increased monthly by 2.5 mg in order to lower TC levels to less than 200 mg/dl. Serum lipoprotein profile, cyclosporin A (CsA), serum creatinine (SCr), and liver and muscle enzyme levels were measured before starting the lipid-lowering diet, at the start of treatment (baseline), and during treatment. Ambulatory blood pressure monitoring (ABPM) (24-h) was carried out in each patient at both baseline and the end of the follow-up. During the lipid-lowering diet, no significant changes in lipoprotein parameters were observed. Atorvastatin was tolerated well and no clinical side effects were noted during the follow-up. The final dose of atorvastatin ranged from 2.5 to 7.5 mg/day. At the end of the study, TC was reduced by 32.2% ( P<0.05), low-density lipoprotein cholesterol (LDL-C) by 41.8% ( P<0.05), and apo B by 29.5% ( P<0.05). No significant changes in HDL-C, VLDL-C, apolipoprotein AI, and lipoprotein(a) were observed. SCr and CsA levels were unaffected. Overall, no significant changes in mean 24-h, daytime, and nighttime ABPM values between the first and the second recordings were observed. However, both daytime and nighttime systolic and diastolic ABPM values dropped in four patients. In conclusion, low-dose atorvastatin appears to be safe, well tolerated, and effective in the treatment of post-transplant hyperlipidemia. In addition, the capacity of atorvastatin to reduce blood pressure, whether or not related to its lipid-lowering action, deserves further investigation.",2003.0,0,0 1497,12176592,Calcineurin-inhibitor withdrawal in heart transplantation recipients (the case against).,Mandeep R Mehra; P A Uber,,2003.0,0,0 1498,12176600,Cardiac allograft vasculopathy: prevention and treatment options.,Michael Weis,,2003.0,0,0 1499,12176948,,,,,0,0 1500,12176951,Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study.,G Rioufol; G Finet; I Ginon; X André-Fouët; R Rossi; E Vialle; E Desjoyaux; G Convert; J F Huret; A Tabib,"To test the hypothesis of general atherosclerotic plaque destabilization during acute coronary syndrome (ACS), the present study sought to analyze the 3 coronary arteries by systematic intravascular ultrasound scan (IVUS). Seventy-two arteries were explored in 24 patients referred for percutaneous coronary intervention after a first ACS with troponin I elevation. Fifty plaque ruptures (mean, 2.08 per patient; range, 0 to 6) were diagnosed by the association of a ruptured capsule with intraplaque cavity. Plaque rupture on the culprit lesion was found in 9 patients (37.5%). At least 1 plaque rupture was found somewhere other than on the culprit lesion in 19 patients (79%). These lesions were in a different artery than the culprit artery in 70.8% and were in both other arteries in 12.5% of these 24 patients. Complete IVUS examination of all 3 coronary axes in patients who had experienced a first ACS revealed that multiple atherosclerotic plaque ruptures were detected by IVUS; these multiple ruptures were present simultaneously with the culprit lesion; they were frequent and located (in three quarters of cases) on the 3 principal coronary trunks; and the multiple plaque ruptures in locations other than on the culprit lesion were less severe, nonstenosing, and less calcified. Although one single lesion is clinically active at the time of ACS, the syndrome seems nevertheless associated with overall coronary instability.",2002.0,0,0 1501,12177634,Therapy for cardiovascular disease in patients with chronic kidney disease: appropriate caution or the absence of data.,Donal N Reddan,,2002.0,0,0 1502,12181210,Adherence to statin treatment and readmission of patients after myocardial infarction: a six year follow up study.,L Wei; J Wang; P Thompson; S Wong; A D Struthers; T M MacDonald,"To investigate patients' adherence to statin treatment prescribed following their first myocardial infarction (MI) and to estimate the effect of adherence to statins on recurrence of MI and all cause mortality. Cohort study using a record linkage database. Tayside, Scotland, UK. Patients who experienced their first MI between January 1990 and November 1995. Percentage of statin use and adherence to statins by patients after an MI and the relative risk of hospitalisation for recurrent MI. The effect of adherence on all cause mortality was also examined. The covariates used were age, sex, socioeconomic deprivation, serum cholesterol concentration, diabetes mellitus, cardiovascular drug use, and other hospitalisations. Of 5590 patients who experienced an incident MI, 717 (12.8%) experienced at least one further MI. Only 7.7% of patients used statins after an MI during the study period. Compared with those not taking statins, those who had 80% or better adherence to statin treatment had an adjusted relative risk of recurrent MI of 0.19 (95% confidence interval (CI) 0.08 to 0.47) and all cause mortality of 0.47 (95% CI 0.22 to 0.99). There was no significant reduction in either end point for those who were less than 80% adherent to statins. Despite the infrequent use of statin during the study period, good adherence to statin treatment was associated with lower risk of recurrent MI.",2002.0,0,0 1503,12181212,Long term efficacy and safety of atorvastatin in the treatment of severe type III and combined dyslipidaemia.,M van Dam; M Zwart; F de Beer; A H M Smelt; M H Prins; M D Trip; L M Havekes; P J Lansberg; J J P Kastelein,"Fibric acid derivatives and HMG-CoA reductase inhibitors are effective in combination for treating patients with familial dysbetalipoproteinaemia and severe combined dyslipidaemia, but combination therapy affects compliance and increases the risk of side effects. To evaluate the efficacy and safety of monotherapy with atorvastatin, an HMG-CoA reductase inhibitor with superior efficacy in lowering low density lipoprotein cholesterol and triglyceride concentrations, in patients with dysbetalipoproteinaemia and severe combined dyslipidaemia. Atorvastatin was tested as single drug treatment in 36 patients with familial dysbetalipoproteinaemia and 23 patients with severe combined dyslipidaemia. After 40 weeks of 40 mg atorvastatin treatment decreases in total cholesterol, triglycerides, and apolipoprotein B of 40%, 43%, and 41%, respectively, were observed in the combined dyslipidaemia group, and of 46%, 40%, and 43% in the dysbetalipoproteinaemic patients. Target concentrations of total cholesterol (< 5 mmol/l) were reached by 63% of the patients, and target concentrations of triglycerides (< 3.0 mmol/l) by 66%. Treatment with atorvastatin was well tolerated and no serious side effects were reported. Atorvastatin is very effective as monotherapy in the treatment of familial dysbetalipoproteinaemia and severe combined dyslipidaemia.",2002.0,0,0 1504,12184961,Clinical inquiries. Should we treat elevated cholesterol in elderly patients?,Neil Korsen; Edward Nowicki; Ann Thering; Nicholas Solomos,,2002.0,0,0 1505,12186124,Comparison of the efficacy and safety of pravastatin and simvastatin in heart transplantation.,K Vivekananthan; M R Mehra; P A Uber; H DeGruiter; C J Lavie; R V Milani,"Data on the safety and efficacy of HMG CoA reductase inhibitors in managing dyslipidemia in heart transplant recipients is inadequate. We undertook this study to evaluate the comparative safety and efficacy of simvastatin and pravastatin in lowering lipids in heart transplant recipients. Forty eight patients (38 males) who received heart transplantation between 1995 and 1997, and who had no contraindications to statin therapy or history of myopathy were randomized to receive either pravastatin (n=24) or simvastatin (n=24) for six months. Detailed fasting lipid profiles, hepatic function tests, and serum creatinine phosphokinase were obtained regularly. Baseline and six month characteristics were compared using the unpaired student t test for continuous variables and Chi-square analysis or Fisher's exact test, as appropriate. Baseline total cholesterol levels, LDL cholesterol levels, HDL cholesterol levels, and triglyceride levels were similar in the two groups. At six months, the total cholesterol, LDL cholesterol, and triglyceride levels were greatly reduced in both groups, with greater reductions in the simvastatin group than in the pravastatin group. Only modest increases were noted in HDL cholesterol levels in the two groups. No significant adverse effects were noted, and no complications with drug withdrawals occurred. Patient compliance exceeded 97%. Simvastatin and pravastatin are safe and very effective in total cholesterol and LDL cholesterol lowering in heart transplant recipients, with simvastatin being more efficacious than pravastatin in lipid lowering in this group of patients.",2002.0,0,0 1506,12186809,Principles from clinical trials relevant to clinical practice: Part I.,Robert M Califf; David L DeMets,,2002.0,0,0 1507,12187312,Interactions between hypercholesterolemia and hypertension: implications for therapy.,Claudio Borghi,"The purpose of the present review is to summarize the available information that supports the therapeutic role for the concomitant and aggressive management of hypercholesterolemia and hypertension. A concomitant management of hypertension and high-plasma cholesterol has been suggested to significantly reduce the extent of cardiovascular complications. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been demonstrated to be very effective in the treatment of patients with hypercholesterolemia where they reduce the rate of coronary and cerebrovascular complications. This benefit is largely extended to the hypertensive population. Very recently some studies have demonstrated the capacity of statins to improve blood pressure control in patients with hypertension and this effect, which has not been demonstrated for the other lipid-lowering drugs, could be very important in the clinical management of overall cardiovascular risk. These findings confirm that the prevention of cardiovascular diseases should be based on the aggressive treatment of many different risk factors. This is particularly true for patients with hypertension and hypercholesterolemia for whom the negative interaction between risk factors could be effectively managed by an appropriate choice of both antihypertensive and lipid-lowering drugs.",2003.0,0,0 1508,12191598,Tumor necrosis factor-alpha in cardiovascular biology and the potential role for anti-tumor necrosis factor-alpha therapy in heart disease.,Michael Sack,"The functional role of tumor necrosis factor (TNF)-alpha in the heart has been extensively studied over the last 15 years. Collectively, these studies have demonstrated that TNF-alpha has both diverse and potentially conflicting roles in cardiac function and pathology. These include beneficial effects, such as cardioprotection against ischemia, myocarditis, and pressure overload, as well as potentially adverse effects, such as the development of atherosclerosis, reperfusion injury, hypertrophy, and heart failure. TNF-alpha antagonist therapy recently has been demonstrated to be clinically applicable in inflammatory conditions, and clinical trials are currently in progress in the use of these agents in cardiovascular diseases. The scope for clinical applications of anti-TNF-alpha therapy in cardiovascular diseases is potentially extensive. Hence, this review has been undertaken to evaluate the cardiovascular effects of this pleiotropic cytokine and to evaluate the potential of targeting this cytokine in cardiovascular therapeutics. An overview of the TNF-alpha peptide and its associated signaling are described. This is followed by a discussion of the known roles of TNF-alpha in cardiac physiology and in a diverse array of cardiac pathologies. Reference to experimental and clinical studies using anti-TNF-alpha therapies are described where applicable. The postulated role of TNF-alpha signaling concerning innate cardiac cellular processes that may have direct adaptive effects in the heart will be reviewed with respect to future research directions. Finally, the author postulates that attenuation of TNF-alpha biosynthesis in selected individuals will need to be tested if true benefits of this therapeutic approach are to be realized in the management of cardiovascular diseases.",2003.0,0,0 1509,12193764,New therapies. New Alzheimer's treatments that may ease the mind.,Laura Helmuth,,2002.0,0,0 1510,12196129,Cholesterol and Alzheimer's disease.,B Wolozin,"Accumulation of a 40-42-amino acid peptide, termed amyloid-beta peptide (A beta), is associated with Alzheimer's disease (AD), and identifying medicines that inhibit A beta could help patients with AD. Recent evidence suggests that a class of medicines that lower cholesterol by blocking the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), termed statins, can inhibit A beta production. Increasing evidence suggests that the enzymes that generate A beta function best in a high-cholesterol environment, which might explain why reducing cholesterol would inhibit A beta production. Studies using both neurons and peripheral cells show that reducing cellular cholesterol levels, by stripping off the cholesterol with methyl-beta-cyclodextrin or by treating the cells with HMG-CoA reductase inhibitors, decreases A beta production. Studies performed on animal models and on humans concur with these results. In humans, lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce A beta levels in blood of patients by up to 40%. The putative role of A beta in AD raises the possibility that treating patients with statins might lower A beta, and thereby either delay the occurrence of AD or retard the progression of AD. Two large retrospective studies support this hypothesis. Both studies suggest that patients taking statins had an approx. 70% lower risk of developing AD. Since statins are widely used by doctors, their ability to reduce A beta offers a putative therapeutic strategy for treating AD by using medicines that have already been proved safe to use in humans.",2003.0,0,0 1511,12196332,Influence of lipid-lowering therapy on the progression of coronary artery calcification: a prospective evaluation.,Stephan Achenbach; Dieter Ropers; Karsten Pohle; Alexander Leber; Christian Thilo; Andreas Knez; Theresa Menendez; Ralph Maeffert; Magda Kusus; Matthias Regenfus; Andrea Bickel; Ralph Haberl; Gerhard Steinbeck; Werner Moshage; Werner G Daniel,"Coronary calcification measured by fast computed tomography techniques is a surrogate marker of coronary atherosclerotic plaque burden. In a cohort study, we prospectively investigated whether lipid-lowering therapy with a cholesterol synthesis enzyme inhibitor reduces the progression of coronary calcification. In 66 patients with coronary calcifications in electron beam tomography (EBT), LDL cholesterol >130 mg/dL, and no lipid-lowering treatment, the EBT scan was repeated after a mean interval of 14 months and treatment with cerivastatin was initiated (0.3 mg/d). After 12 months of treatment, a third EBT scan was performed. Coronary calcifications were quantified using a volumetric score. Cerivastatin therapy lowered the mean LDL cholesterol level from 164+/-30 to 107+/-21 mg/dL. The median calcified volume was 155 mm3 (range, 15 to 1849) at baseline, 201 mm3 (19 to 2486) after 14 months without treatment, and 203 mm3 (15 to 2569) after 12 months of cerivastatin treatment. The median annualized absolute increase in coronary calcium was 25 mm3 during the untreated versus 11 mm3 during the treatment period (P=0.01). The median annual relative increase in coronary calcium was 25% during the untreated versus 8.8% during the treatment period (P<0.0001). In 32 patients with an LDL cholesterol level <100 mg/dL under treatment, the median relative change was 27% during the untreated versus -3.4% during the treatment period (P=0.0001). Treatment with the cholesterol synthesis enzyme inhibitor cerivastatin significantly reduces coronary calcium progression in patients with LDL cholesterol >130 mg/dL.",2002.0,0,0 1512,12197306,Osteoporosis: challenges and new opportunities for therapy.,David P Rotella,"Osteoporosis is a chronic disease that affects a large number of both men and women and is characterized by a decrease in bone mass, as well as weakened bones. It causes a significant amount of morbidity and mortality in patients and is often only diagnosed after a fracture occurs. This review will highlight recent advances in the development of novel anabolic approaches for treatment of osteoporosis, such as parathyroid hormone (PTH), calcium sensing receptor modulators, statins and prostanoid receptor agonists. Selected antiresorptive targets (cathepsin K inhibitors and vitronectin receptor antagonists) will also be surveyed.",2003.0,0,0 1513,12199980,[Effects of statins on angiogenesis and vasculogenesis].,Joan Llevadot; Takayuki Asahara,"Statins promote the proliferation, migration, and survival of endothelial cells and bone marrow-derived endothelial progenitor cells (angioblasts) by stimulating the serine/threonine protein kinase Akt (also known as protein kinase B) pathway. Like vascular endothelial growth factor (VEGF), the statins promote angiogenesis and vasculogenesis. Therefore, Akt activation may explain some of the beneficial effects of the statins, including postnatal neovascularization.",2002.0,0,0 1514,12200817,Patient survival after renal transplantation III: the effects of statins.,Fernando G Cosio; Todd E Pesavento; Ronald P Pelletier; Mitchell Henry; Ronald M Ferguson; Sunny Kim; Stanley Lemeshow,"Kidney transplant recipients have high cardiovascular risk and an unfavorable cardiovascular risk profile, which frequently includes hyperlipidemia. Although the use of HMG-CoA reductase inhibitors (statins) is associated with improved survival in the general population, the effects of these drugs on the survival of kidney transplant recipients have not been established. In this study, we determined which factors were associated with the use of statins in a population of 1,574 adult, kidney allograft recipients, transplanted in one institution. A risk factor analysis of patient survival was done with a primary focus on the possible relationship between statin use and survival. The percent of patients treated with statins increased progressively from 1982 to 1996. Statins were used significantly more often in whites (30%) than in blacks (20%, P = 0.001) and in older individuals. These differences in statin use were not due to differences in lipid levels among the patient groups. As expected, the group of patients treated with statins had significantly higher serum lipid levels than untreated patients. Patient survival was significantly better in patients treated with statins than in untreated patients. That relationship became apparent, however, only after controlling for three additional factors: recipient age, transplant year, and serum cholesterol levels. In a multivariable Cox survival model, patient survival was associated significantly with statin use (hazard ratio [HR] = 0.76; confidence interval [CI], 0.6 to 0.96; P = 0.02), recipient age (HR = 1.05; CI, 1.04 to 1.06; P < 0.0001), and transplant year (HR = 1.05; CI, 1.01 to 1.08; P = 0.001). The serum cholesterol level was not associated significantly with patient survival in this model, but cholesterol significantly modified the relationship between statin use and patient survival. Renal transplant recipients treated with statins have a 24% better survival than patients who do not receive these drugs.",2002.0,0,0 1515,12201488,A novel high-through-put assay for screening of pro-apoptotic drugs.,Maria Hägg; Kenneth Bivén; Takayuki Ueno; Lars Rydlander; Peter Björklund; Klas G Wiman; Maria Shoshan; Stig Linder,"Screening for anti-cancer substances is commonly conducted using viability assays. An inherent problem with this approach is that all compounds that are toxic and growth inhibitory, irrespective of mechanism of action, will score positive. It would be beneficial to be able to screen for compounds that specifically induce apoptosis. We here describe an ELISA-assay based on a monoclonal antibody (M30) which recognizes a neo-epitope on cytokeratin 18 exposed after cleavage by caspases during apoptosis. We show that this assay detects apoptosis in epithelial cells and that the sensitivity is sufficient for screening in the 96-well format. We used the M30-ELISA assay to screen 500 low molecular weight compounds from a chemical library from the National Cancer Institute and identified 16 drugs with strong pro-apoptotic activity, suggesting that the assay is a useful tool for discovery of pro-apoptotic drugs.",2003.0,0,0 1516,12201623,Treatment with atorvastatin to the National Cholesterol Educational Program goal versus 'usual' care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study.,Vasilios G Athyros; Athanasios A Papageorgiou; Bodosakis R Mercouris; Valasia V Athyrou; Athanasios N Symeonidis; Elias O Basayannis; Dimokritos S Demitriadis; Athanasios G Kontopoulos,"Atorvastatin is very effective in reducing plasma low-density lipoprotein cholesterol (LDL-C) levels. However, there is no long-term survival study that evaluated this statin. To assess the effect of atorvastatin on morbidity and mortality (total and coronary) of patients with established coronary heart disease (CHD), 1600 consecutive patients were randomised either to atorvastatin or to 'usual' medical care. The dose of atorvastatin was titrated from 10 to 80 mg/day, in order to reach the National Cholesterol Education Program (NCEP) goal of LDL-C <100 mg/dl (2.6 mmol/l). All patients were followed up for a mean period of 3 years. Primary endpoints of the study were defined as death, non-fatal myocardial infarction, unstable angina, congestive heart failure, revascularisation (coronary morbidity) and stroke. Secondary endpoints were the safety and efficacy of the hypolipidaemic drugs as well as the cost-effectiveness of atorvastatin. The mean dosage of atorvastatin was 24 mg/day. This statin reduced total chlesterol by 36%, LDL-C by 46%, triglycerides by 31%, and non-high-density lipoprotein cholesterol (non-HDL-C) by 44%, while it increased HDL-C by 7%; all these changes were significant. The NCEP LDL-C and non-HDL-C treatment goals were reached by 95% (n = 759) and 97% (n = 776), respectively, of patients on atorvastatin. Only 14% of the 'usual' care patients received any hypolipidaemic drugs throughout the study and 3% of them reached the NCEP LDL-C treatment goal. The cost per quaility-adjusted life-year gained with atorvastatin was estimated at $US 8350. During this study 196 (24.5%) CHD patients on 'usual' care had a CHD recurrent event or died vs. 96 (12%) CHD patients on atorvastatin; risk ratio (RR) 0.49, confidence interval (CI) 0.27-0.73, p < 0.0001. In detail, atorvastatin reduced, in comparison to 'usual' care, total mortality (RR 0.57, CI 0.39-0.78, p = 0.0021), coronary mortality (RR 0.53, CI 0.29-0.74, p = 0.0017), coronary morbidity (RR 0.46, CI 0.25-0.71, p < 0.0001), and stroke (RR 0.53, CI 0.30-0.82, p = 0.034). All subgroups of patients (women, those with diabetes mellitus, arterial hypertension, age 60 to 75 years, congestive heart failure, recent unstable angina or prior revascularisation) benefited from treatment with atorvastatin. Withdrawal of patients because of side-effects from the atorvastatin group was low (0.75%) and similar to that of the 'usual' care group (0.4%). Long-term treatment of CHD patients with atorvastatin to achieve NCEP lipid targets significantly reduces total and coronary mortality, coronary morbidity and stroke, in comparison to patients receiving 'usual' medical care. Treatment with atorvastatin is well tolerated and cost-effective.",2003.0,1,1 1517,12202841,Vascular oxidative stress and antioxidant protection in atherosclerosis: what do the clinical trials say?,John F Keaney; Joseph A Vita,,2002.0,0,0 1518,12204790,The use of antioxidant supplements in coronary heart disease.,Leonard Kritharides; Roland Stocker,"There is clear evidence of lipoprotein oxidation in atherosclerotic lesions. Animal studies and observational prospective human cohort studies have been interpreted as supporting a role for antioxidants in the prevention of coronary heart disease (CHD). However, firm recommendations to take antioxidant supplements to treat or prevent CHD require evidence derived from randomised controlled studies. In primary prevention studies, low dose alpha-tocopherol does not reduce the incidence of coronary events (ATBC study), and beta-carotene either has no effect or increases the incidence of coronary events and cancer death (ATBC, CARET, Physician's Health studies). Secondary preventions, those with smaller populations and shorter duration of follow up have shown some benefit from alpha-tocopherol (CHAOS, SPACE), but larger randomised studies indicate no benefit from treatment with alpha-tocopherol (HOPE, GISSI, PPP). Recent studies with antioxidant combinations also show no benefit (HATS, MPS). On the basis of these data, supplements of alpha-tocopherol and beta-carotene cannot be recommended for the treatment or prevention of CHD. Fundamental and applied research may yet find a role for antioxidant supplements in the treatment of coronary disease. However, this will require positive results from combined antioxidant studies currently in progress, and the targeting of oxidative processes that operate in the artery wall and cause or contribute to disease.",2003.0,0,0 1519,12204802,Atorvastatin lowers lipoprotein(a) but not apolipoprotein(a) fragment levels in hypercholesterolemic subjects at high cardiovascular risk.,Sophie Gonbert; Sophie Malinsky; Andrei C Sposito; Hervé Laouenan; Chantal Doucet; M John Chapman; Joëlle Thillet,"The effect of statins on Lp(a) levels is controversial; furthermore, the potential action of statins on apo(a) fragmentation is indeterminate. We therefore determined the circulating levels of Lp(a) and of apo(a) fragments in hypercholesterolemic patients before and after treatment (6 weeks) with Atorvastatin 10 mg/day (A10) or Simvastatin 20 mg/day (S20). In a double blind study, hypercholesterolemic patients (n=391) at high cardiovascular risk (LDL-C>=4.13 mmol/l; TG<2.24 mmol/l; 34% with documented CHD; 45% hypertensive; and 29% current smokers) were assigned to treatment with A10 (n=199) or S20 (n=192). Plasma Lp(a) and apo(a) fragment levels (n=206) were measured prior to and after treatment. At baseline, A10 and S20 groups did not differ in plasma levels of lipids, Lp(a) (A10: 0.45+/-0.48 mg/ml, S20: 0.46+/-0.5), and apo(a) fragments (A10: 3.88+/-5.22 microg/ml; S20: 3.25+/-3), and equally in apo(a) isoform size (A10: 26+/-5 kr, S20: 25.5+/-5.3). After treatment, both statins significantly reduced Lp(a) levels (A10: 0.42+/-0.47 mg/ml, 6% variation, P<0.001; S20: 0.45+/-0.53 mg/ml, 0.02% variation, P=0.046). A10 and S20 did not significantly differ in their efficacy to lower Lp(a) levels. In a multivariate logistic regression analysis, the reduction of Lp(a) levels was independently associated with Lp(a) baseline concentration, but not to other variables, including LDL-C reduction. Plasma levels of apo(a) fragments were not modified by either statin. In conclusion, both A10 and S20 significantly lowered Lp(a), although this effect was of greater magnitude in atorvastatin-treated patients.",2003.0,0,0 1520,12204807,Baseline lipid values partly determine the response to high-dose simvastatin in patients with familial hypercholesterolemia. The examination of probands and relatives in Statin studies with familial hypercholesterolemia (ExPRESS FH).,Pernette R W de Sauvage Nolting; Rudolf J A Buirma; Barbara A Hutten; John J P Kastelein; Dutch ExPRESS investigators Group,"Statins decrease low-density lipoprotein cholesterol (LDL-C), and additionally, reduce triglycerides (TG) and raise high-density lipoprotein cholesterol (HDL-C) levels. This study evaluated the frequency of abnormal TG and HDL-C levels in patients with classical familial hypercholesterolemia (FH) and assessed therapeutic response at different baseline levels of these lipoproteins after 1 year of statin therapy. A total of 508 FH patients were included and mean LDL-C levels (8.37+/-2.12 mmol l(-1)) were severely elevated. After a washout period of 6 weeks, all patients started monotherapy with 80 mg simvastatin. Remarkably, LDL-C reduction was dependent on baseline LDL-C levels ranging from 51.1 to 45.5% in the top versus the bottom third of the LDL-C distribution. Unexpected in FH, elevated baseline TG levels were seen in 30% and low HDL-C levels in 15% of all patients. Also, changes in these lipoproteins were dependent on baseline levels; TG reduction was 40.7 versus 22.2% in patients with elevated versus normal levels, while HDL-C increase was 29.1 versus 11.4% in patients with low versus normal HDL-C levels. In conclusion, FH patients with the worst lipoprotein profile showed the greatest benefit from high-dose simvastatin treatment, since changes in these parameters were partly determined by baseline lipid levels.",2003.0,0,0 1521,12204809,Comparing the effects of five different statins on the HDL subpopulation profiles of coronary heart disease patients.,Bela F Asztalos; Katalin V Horvath; Judith R McNamara; Paul S Roheim; Joel J Rubinstein; Ernst J Schaefer,"We compared the effects of five different statins (atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin) on the lipid, lipoprotein, and apolipoprotein (apo) A-I-containing high-density lipoprotein (HDL) subpopulation profiles of 86 coronary heart disease (CHD) patients. Patients with established CHD, and low density lipoprotein (LDL) cholesterol (C)>130 mg/dl, and triglyceride (TG)<400 mg/dl, were treated with atorvastatin 20, 40, and 80 mg/day and one of the other four statins at 20, 40, and when available 80 mg/day in increasing doses (4 weeks of each dose) in a randomized crossover fashion. There was an 8-week placebo controlled washout period between different drug treatments. All five statins on each dose resulted in significant reductions in total- and LDL-C compared to placebo treatment. There were also decreases in plasma TG and increases in HDL-C and apoA-I concentrations, but not all treatments changed these parameters significantly. Each statin except fluvastatin improved the HDL subpopulation profile by increasing the concentrations of the large, cholesterol-rich, LpA-I alpha-1 and prealpha-1 HDL subpopulations. CHD patients have significantly lower concentration of the large, LpA-I alpha-1 HDL particles compared to controls. Our data indicate that statins which are the most effective in lowering LDL-C and TG are also the most effective agents in modifying the HDL subpopulation profile in CHD patients towards the patterns found in healthy individuals. The order of efficacy of statins in increasing alpha-1 HDL subpopulation was: atorvastatin, simvastatin, pravastatin, lovastatin and fluvastatin.",2003.0,0,0 1522,12205648,"Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial.",Mikael Simons; Frank Schwärzler; Dieter Lütjohann; Klaus von Bergmann; Konrad Beyreuther; Johannes Dichgans; Henning Wormstall; Tobias Hartmann; Jörg B Schulz,"In a randomized, placebo-controlled, double-blind study, we investigated whether statins alter cholesterol metabolites and reduce Abeta levels in the cerebrospinal fluid of 44 patients with Alzheimer's disease. Individuals were given up to 80mg simvastatin daily or placebo for 26 weeks. Overall, simvastatin did not significantly alter cerebrospinal fluid levels of Abeta40 and Abeta42. In post hoc analysis, simvastatin significantly decreased Abeta40 levels in the cerebrospinal fluid of patients with mild Alzheimer's disease. The reduction of Abeta40 correlated with the reduction of 24S-hydroxycholesterol. These changes were not observed in more severely affected patients.",2002.0,0,0 1523,12207553,Outcomes of lipid-lowering treatment in postmenopausal women.,John C LaRosa,"Elevated triglycerides and low high-density lipoprotein (HDL) levels are more important coronary risk factors in women, and elevated low-density lipoprotein (LDL) levels less important in women, than men. There is clear-cut evidence in clinical trials that the benefit of cholesterol lowering in women and men is virtually identical. Modifiers of lipids and lipoproteins in women include diabetes mellitus, bodyweight and its distribution, and menopausal status. Diabetes is a more powerful predictor of risk in women than men. This may relate to the importance of elevated triglycerides as a risk factor in women, and to the effects of lipoprotein glycosylation, which lead to increased susceptibility to arterial deposition of LDL and decreased reverse cholesterol transport with HDL. Therapy for lipoprotein disorders in women and men is identical. For the overwhelming majority of patients, treatment with statin therapy is both highly efficacious and well tolerated.",2002.0,0,0 1524,12208152,Policosanol safely down-regulates HMG-CoA reductase - potential as a component of the Esselstyn regimen.,M F McCarty,"Many of the wide-ranging health benefits conferred by statin therapy are mediated, not by reductions in LDL cholesterol, but rather by inhibition of isoprenylation reactions essential to the activation of Rho family GTPases; this may be the mechanism primarily responsible for the favorable impact of statins on risk for ischemic stroke, senile dementia, and fractures, as well as the anti-hypertensive and platelet-stabilizing actions of these drugs. Indeed, the extent of these benefits is such as to suggest that most adults would be wise to take statins; however, owing to the significant expense of statin therapy, as well as to the potential for dangerous side effects that mandates regular physician follow-up, this strategy appears impractical. However, policosanol, a mixture of long-chain aliphatic alcohols extractable from sugar cane wax, has shown cholesterol-lowering potency comparable to that of statins, and yet appears to be devoid of toxic risk. Recent evidence indicates that policosanol down-regulates cellular expression of HMG-CoA reductase, and thus has the potential to suppress isoprenylation reactions much like statins do. Consistent with this possibility, the results of certain clinical and animal studies demonstrate that policosanol has many effects analogous to those of statins that are not likely explained by reductions of LDL cholesterol. However, unlike statins, policosanol does not directly inhibit HMG-CoA reductase, and even in high concentrations it fails to down-regulate this enzyme by more than 50% - thus likely accounting for the safety of this nutraceutical. In light of the fact that policosanol is quite inexpensive and is becoming available as a non-prescription dietary supplement, it may represent a practical resource that could enable the general public to enjoy health benefits comparable to those conferred by statins. In a long-term clinical study enrolling patients with significant symptomatic coronary disease, Esselstyn has demonstrated that a low-fat, whole-food vegan diet, coupled with sufficient statin therapy to maintain serum cholesterol below 150 mg/dL, can stop the progression of coronary disease and virtually eliminate further risk for heart attack. A comparable regimen, in which policosanol is used in place of statins, may represent a practical strategy whereby nearly everyone willing to commit to health-protective eating can either prevent coronary disease, or prevent pre-existing coronary disease from progressing to a life-threatening event.",2003.0,0,0 1525,12208171,Minor thalassemia as a protective factor against cerebrovascular accidents.,Mohammad Reza Namazi,"Hypertension, hypercholesterolemia, and coronary artery disease are among the risk factors of cerebrovascular accidents. After age, hypertension is the most powerful stroke risk factor. Abnormalities of serum lipids are regarded as risk factors for cerebrovascular accidents. A significant reduction in stroke risk among persons treated with cholesterol-reducing medicines known as statins are reported. Stroke risk nearly doubles in those with antecedent coronary artery disease. Moreover, polycythemia and high hematocrit levels are considered to be potential stroke risk factors. Minor thalassemia is associated with decreased prevalence of arterial hypertension and myocardial infarction (the second effect observed only in males.) Total cholesterol and LDL levels are lower in minor thalassemics, as is the blood viscosity. Therefore, it could be hypothesized that minor thalassemia could afford some protection against cerebrovascular accidents.",2003.0,0,0 1526,12208415,Reassessment of National Cholesterol Education Program Adult Treatment Panel-III guidelines: one year later.,Benjamin J Ansell; David D Waters; National Cholesterol Education Program Adult Treatment Panel-III Guidelines,,2002.0,0,0 1527,12208470,Regulation of interleukin-8 expression by HMG-CoA reductase inhibitors in human vascular smooth muscle cells.,Takayuki Ito; Uichi Ikeda; Keiji Yamamoto; Kazuyuki Shimada,"Interleukin-8 (IL-8) is a potent chemotactic factor that has been implicated in atherogenesis. HMG-CoA reductase inhibitors (statins) may reduce the cardiovascular risk and vulnerability of atherosclerotic plaque through nonlipid mechanisms such as inhibition of cytokine expression. In this study, we investigated the effects of statins on IL-8 synthesis in human vascular smooth muscle cells (VSMCs). Addition of angiotensin II (Ang II) increased IL-8 production in VSMCs in a time (0-24 h)- and dose (10(-8)-10(-6) mol/l)-dependent manner with increased IL-8 mRNA accumulation. The Ang II type 1 receptor (AT1R) antagonist candesartan, but not the Ang II type 2 receptor (AT2R) antagonist PD123319, significantly blocked Ang II-induced IL-8 production. Addition of fluvastatin decreased the basal and Ang II-induced IL-8 production in VSMCs in a dose (10(-8)-10(-5) mol/l)-dependent manner with a decrease in IL-8 mRNA accumulation. The effect of fluvastatin on IL-8 production was completely reversed in the presence of mevalonate or geranylgeranyl-pyrophosphate, but not in the presence of squalene or farnesyl-pyrophosphate. Lipophilic cerivastatin also significantly decreased IL-8 production, while hydrophilic pravastatin showed no effect on IL-8 levels. In conclusion, we demonstrated for the first time that Ang II increased IL-8 production and fluvastatin decreased the basal and Ang II-induced IL-8 production in human VSMCs. These findings suggested that Ang II may exacerbate atherosclerosis through induction of IL-8 in VSMCs, while statins may exert therapeutic effects by modulating IL-8 synthesis in patients with atherosclerotic disease.",2002.0,0,0 1528,12208479,The effects of lovastatin and simvastatin on the diurnal periodicity of plasma mevalonate concentrations in patients with heterozygous familial hypercholesterolemia.,Anuradha S Pappu; D Roger Illingworth,"Animal and human studies have shown that the biosynthesis of cholesterol exhibits diurnal periodicity with nocturnal increases in the level of cholesterol precursors. Dietary cholesterol, which increases the intracellular pool of cholesterol and plasma cholesterol levels, has been shown to blunt the nocturnal increases in cholesterol biosynthesis. Patients with heterozygous familial hypercholesterolemia (FH) have very high levels of plasma low-density lipoprotein cholesterol (LDL) due to their reduced ability to metabolize LDL particles. The present studies were carried out to determine whether diurnal variations in cholesterol synthesis occur in FH patients and to test the effects of 3-hydroxy-3-methyl glutaryl CoA (HMG CoA) reductase inhibitors on the diurnal cycle of cholesterol biosynthesis in these patients. Diurnal rates of cholesterol synthesis were assessed by measuring the plasma concentrations of mevalonate, an intermediate in the pathway of cholesterol biosynthesis. Female FH patients exhibited a diurnal pattern in plasma mevalonate levels similar to that previously reported in controls with peak values occurring at night. Treatment with lovastatin and simvastatin (40 mg b.i.d.) significantly reduced 24-h mean plasma mevalonate levels from baseline values. Administration of lovastatin in the evening reduced the nocturnal increases in mevalonate levels, and the administration of simvastatin completely abolished the nighttime rise. These results demonstrate that inhibition of cholesterol biosynthesis by lovastatin and simvastatin modifies the normal diurnal rhythm of cholesterol biosynthesis in female FH patients.",2002.0,0,0 1529,12208481,Association of the factor XII 46C>T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study.,Francesco Zito; Gordon D O Lowe; Ann Rumley; Alex D McMahon; Steve E Humphries; WOSCOPS Study Group West of Scotland Coronary Prevention Study,"To evaluate the contribution of the 46C>T polymorphism of the Factor XII (FXII) gene to risk for coronary heart disease (CHD) in the West of Scotland Coronary Prevention Study (WOSCOPS) of men with high cholesterol. WOSCOPS is a primary prevention trial that demonstrated the effectiveness of pravastatin in reducing morbidity and mortality from CHD. FXII is a protein of the contact system that plays a key role in both coagulation and fibrinolysis. Elevated activated FXII (FXIIa) levels have been previously associated with CHD. Plasma FXIIa levels are strongly determined by a 46C>T polymorphism in the FXII gene. 441 CHD cases and 990 controls were genotyped. The frequency of TT homozygotes was 8.3% in controls and 11.8% in cases (P=0.04). When compared with the CC+CT group (after adjustment for age, blood pressure, BMI, fibrinogen and lipid levels) the TT genotype was an independent risk factor for CHD (OR 1.48 95% CI 1.01-2.17), an effect that was only significant in the pravastatin group (OR 1.95 95% CI 1.09-3.47) and not in the placebo group (OR 1.20, 95%CI 0.72-2.02). Compared with risk in the placebo group as a whole (reference group), and after adjustment for other risk factors, men with the CC or CT genotype, but not the TT genotype showed a significant benefit from pravastatin treatment (OR, respectively, 0.61 (0.46-0.81) and 0.56 (0.40-0.79) compared with 1.10 (0.64-1.96). In a subgroup of these men, subjects with the TT genotype had, as expected, baseline levels of FXIIa that were 50% lower than those with the CC genotype, with CT subjects having intermediate levels (P<0.001 by Kruskal-Wallis test). The TT genotype of the FXII 46C>T polymorphism is associated with a high risk of CHD in men with high cholesterol. We hypothesise that reduced fibrinolysis in these men, as a consequence of lower plasma FXIIa, may be the mechanism leading to higher risk, and that pravastatin treatment may enhance this effect.",2002.0,0,0 1530,12208482,Association of factor VII levels with inflammatory parameters in hypercholesterolemic patients.,Ettore Porreca; Concetta Di Febbo; Augusto di Castelnuovo; Giovanna Baccante; Concetta Amore; Antonio Angelini; Marcello Di Nisio; Maria Donati; Franco Cuccurullo; Licia Iacoviello,"Inflammatory markers have been demonstrated to be associated with increased risk of cardiovascular events. In this setting, C-reactive protein (CRP) was shown to add predictive value to cholesterol levels. We investigated hypercholesterolemic patients and related their inflammatory variables and their coagulation state focusing on factor VII, a coagulation protein which plays an established role in thrombogenesis. We examined the relationship between factor VII clotting activity (FVIIc), FVII antigen (FVIIAg) and activated FVII (FVIIa) levels against CRP, interleukin-6 soluble receptor (IL-6sR), P-selectin, soluble intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-beta(1) (TGF-beta(1)), in fifty-eight hypercholesterolemic subjects. Patients were subjected to 6-8 weeks of lipid lowering treatment with diet or diet plus pravastatin (40 mg/day). Univariate analysis showed that FVII levels were positively associated with CRP (FVIIAg: r=0.56, P<0.0001; FVIIc: r=0.57, P<0.0001; FVIIa: r=0.39, P<0.001) and IL-6sR (FVIIAg: r=0.59, P<0.0001; FVIIc: r=0.52, P<0.0001; FVIIa: r=0.47; P<0.001). CRP was still correlated, at the baseline, with FVIIAg and FVIIc levels after multiple stepwise regression analysis (FVIIAg: P<0.0001; FVIIc: P<0.0001, respectively) and with FVIIAg at the end of lipid lowering treatment (P<0.0001). Our data indicate that the FVII level is independently associated with inflammatory variables and suggest their pathophysiological link in hypercholesterolemic patients.",2002.0,0,0 1531,12208585,Use of cardiovascular medications in the elderly.,Jaffar Ali Raza; Assad Movahed,"Cardiovascular disease is the leading cause of death in patients aged 65 and above. Although elderly persons represent only 12.4% of the US population, they account for about a third of drug expenditures. However the appropriate use of cardiovascular medications in these patients has been shown to reduce the rate of cardiovascular morbidity and mortality. The normal aging and the disease process in the elderly result in significant changes at the structural and molecular level in the elderly. The changes that take place in the autonomic nervous system, the kidneys, and the liver in the elderly modify the metabolism and clinical effects of most medications. Elderly patients are also susceptible to side effects and adverse drug reactions. Physicians should have a clear understanding of the normal aging processes, the abnormal changes due to disease process and the changes in the pharmacology of drugs in the elderly to deliver proper care to the elderly patient.",2002.0,0,0 1532,12208794,"Death following creatine kinase-MB elevation after coronary intervention: identification of an early risk period: importance of creatine kinase-MB level, completeness of revascularization, ventricular function, and probable benefit of statin therapy.",Stephen G Ellis; Derek Chew; Albert Chan; Patrick L Whitlow; Jakob P Schneider; Eric J Topol,"Creatine kinase (CK)-MB elevation after percutaneous coronary intervention (PCI) has been associated with subsequent cardiac death. The patients at risk, the timing of risk, and potential treatment implications are uncertain. Eight thousand, four hundred nine consecutive non- acute myocardial infarction patients with successful PCI and no emergency surgery or Q-wave myocardial infarction were followed for 38+/-25 months; 1446 (17.2%) had post-PCI CK-MB above normal on routine ascertainment. Patients were prospectively stratified into those with CK-MB 1 to 5x or CK-MB >5x normal. No patient with CK-MB 1 to 5x normal died during the first week after PCI, and excess risk of early death for patients with CK-MB elevation occurred primarily in the first 3 to 4 months. The actuarial 4-month risk of death was 8.9%, 1.9%, and 1.2% for patients with CK-MB >5x, CK-MB 1 to 5x, and CK-MB < or =1x normal (P<0.001). Death within 4 months was independently correlated with the degree of CK-MB elevation, creatinine > or =2 mg%, post-PCI C-reactive protein, low ejection fraction, age, and congestive heart failure class (P<0.01 for all). In a matched subset analysis, incomplete revascularization (P<0.001), congestive heart failure class (P=0.005), and no statin treatment at hospital discharge (P=0.009) were associated with death. Patients with CK-MB elevation after PCI are at excess risk of death for 3 to 4 months, although prolonging hospitalization for CK-MB 1 to 5x is unlikely to modify risk. CK-MB >5x normal, incomplete revascularization, elevated C-reactive protein, heart failure, the elderly, and hospital discharge without on statin therapy increases risk. Several of these factors suggest that inflammation may play a part in the excess risk of death.",2002.0,0,0 1533,12208795,Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment.,Antonio Ceriello; Claudio Taboga; Laura Tonutti; Lisa Quagliaro; Ludovica Piconi; Bruno Bais; Roberto Da Ros; Enrico Motz,"Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease. Evidence suggests that postprandial hypertriglyceridemia and hyperglycemia induce endothelial dysfunction through oxidative stress; however, the distinct role of these two factors is a matter of debate. Thirty type 2 diabetic patients and 20 normal subjects ate 3 different meals: a high-fat meal; 75 g glucose alone; and high-fat meal plus glucose. Glycemia, triglyceridemia, nitrotyrosine, and endothelial function were assayed during the tests. Subsequently, diabetics took 40 mg/d simvastatin or placebo for 12 weeks. The 3 tests were performed again at baseline, between 3 to 6 days after the start, and at the end of each study. High-fat load and glucose alone produced a decrease of endothelial function and an increase of nitrotyrosine in normal and diabetic subjects. These effects were more pronounced when high fat and glucose were combined. Short-term simvastatin treatment had no effect on lipid parameters but reduced the effect on endothelial function and nitrotyrosine observed during each different test. Long-term simvastatin treatment was accompanied by a lower increase in postprandial triglycerides, which was followed by smaller variations of endothelial function and nitrotyrosine during the tests. This study shows an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function, suggesting oxidative stress as common mediator of such effect. Simvastatin shows a beneficial effect on oxidative stress and endothelial dysfunction, which may be ascribed to a direct effect as well as the lipid-lowering action of the drug.",2002.0,0,0 1534,12208797,Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women.,Andrea Decensi; Umberto Omodei; Chris Robertson; Bernardo Bonanni; Aliana Guerrieri-Gonzaga; Francesca Ramazzotto; Harriet Johansson; Serena Mora; Maria Teresa Sandri; Massimiliano Cazzaniga; Massimo Franchi; Sergio Pecorelli,"The increase in C-reactive protein (CRP) during oral conjugated equine estrogen (CEE) may explain the initial excess of cardiovascular disease observed in clinical studies. Because the effect of transdermal estradiol (E2) on CRP is unclear, we compared CRP changes after 6 and 12 months of transdermal E2 and oral CEE in a randomized 2x2 retinoid-placebo trial. A total of 189 postmenopausal women were randomized to 50 microg/d transdermal E2 and 100 mg BID of the retinoid fenretinide (n=45), 50 microg/d transdermal E2 and placebo (n=49), 0.625 mg/d oral CEE and 100 mg BID fenretinide (n=46), or 0.625 mg/d oral CEE and placebo (n=49) for 1 year. Sequential medroxyprogesterone acetate was added in each group. Relative to baseline, CRP increased by 10% (95% CI -9% to 33%) and by 48% (95% CI 22% to 78%) after 6 months of transdermal E2 and oral CEE, respectively. The corresponding figures at 12 months were 3% (95% CI -14% to 23%) for transdermal E2 and 64% (95% CI 38% to 96%) for oral CEE. Fenretinide did not change CRP levels at 6 and 12 months relative to placebo. Relative to oral CEE, the mean change in CRP after 12 months of transdermal E2 was -48% (95% CI -85% to -7%, P=0.012), whereas fenretinide was associated with a mean change of -1% (95% CI -34% to 40%, P=0.79) compared with placebo. In contrast to oral CEE, transdermal E2 does not elevate CRP levels up to 12 months of treatment. The implications for early risk of coronary heart disease require further studies.",2002.0,0,0 1535,12211217,,,,,0,0 1536,12211221,A review of the pharmacologic and pharmacokinetic aspects of rosuvastatin.,C Michael White,"Rosuvastatin is a new HMG-CoA reductase inhibitor with unique pharmacologic and pharmacokinetic properties. It has additional HMG-CoA reductase enzyme-binding interactions that cause tighter binding, has substantial active transport into hepatocytes, and has the lowest IC50 for sterol synthesis in hepatocytes. Rosuvastatin 10 mg and 80 mg dosages have superior low-density lipoprotein (LDL) cholesterol-lowering efficacy as compared to atorvastatin 10 mg and 80 mg. Rosuvastatin 10 mghas also been shown to have superior LDL reductions to 20 mg of both simvastatin and pravastatin. This agent can raise high-density lipoprotein (HDL) 8% to 12% and lower triglycerides by 10% to 35%. Rosuvastatin is a hydrophilic agent with poor penetration in extrahepatic tissue such as human umbilical vein endothelial cells and fibroblasts. It also has a low potential for cytochrome P450 drug interactions and can be dosed in the morning or night. In conclusion, rosuvastatin is an agent with molecular alterations that provide it with unique pharmacologic and phannacokinetic effects. As such, it is a novel and unique HMG-CoA reductase inhibitor for the treatment of hyperlipidemia.",2003.0,0,0 1537,12212758,The potential of pill splitting to achieve cost savings.,Randall S Stafford; David C Radley,"To present a methodology for identifying specific medications for which pill splitting is clinically appropriate and cost saving, to present data from a commercial managed care population on current pill-splitting practices, and to estimate additional cost savings from extended use of this strategy. Retrospective pharmacy claims analysis. Pharmacy claims data from a commercial managed care health plan covering 19,000 lives and national drug data were used to compile a list of frequently prescribed medications. Excluding medications in which packaging, formulation, and potential adverse pharmacologic outcomes prohibited splitting, we performed a cost analysis of medications amenable to splitting. Eleven medications amenable to pill splitting were identified based on potential cost savings and clinical appropriateness: clonazepam, doxazosin, atorvastatin, pravastatin, citalopram, sertraline, paroxetine, lisinopril, nefazadone, olanzapine, and sildenafil. For these medications, pill splitting is currently infrequent, accounting for annual savings of $6200 (or $0.03 per member per month), just 2% of the potential $259,500 (or $1.14 per member per month) that more comprehensive pill-splitting practices could save annually. Pill splitting can be a cost-saving practice when implemented judiciously using drug- and patient-specific criteria aimed at clinical safety, although this strategy is used infrequently.",2002.0,0,0 1538,12215067,Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia.,Gillian M Keating; Douglas Ormrod,"Micronised fenofibrate is a synthetic phenoxy-isobutyric acid derivative (fibric acid derivative) indicated for the treatment of dyslipidaemia. Recently, a new tablet formulation of micronised fenofibrate has become available with greater bioavailability than the older capsule formulation. The micronised fenofibrate 160mg tablet is bioequivalent to the 200mg capsule. The lipid-modifying profile of micronised fenofibrate 160mg (tablet) or 200mg (capsule) once daily is characterised by a decrease in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels, a marked reduction in plasma triglyceride (TG) levels and an increase in high-density lipoprotein cholesterol (HDL-C) levels. Micronised fenofibrate 200mg (capsule) once daily produced greater improvements in TG and, generally, in HDL-C levels than the hydroxymethylglutaryl coenzyme A reductase inhibitors simvastatin 10 or 20 mg/day, pravastatin 20 mg/day or atorvastatin 10 or 40 mg/day. Combination therapy with micronised fenofibrate 200mg (capsule) once daily plus fluvastatin 20 or 40 mg/day or atorvastatin 40 mg/day was associated with greater reductions from baseline than micronised fenofibrate alone in TC and LDL-C levels. Similar or greater changes in HDL-C and TG levels were seen in combination therapy, compared with monotherapy, recipients. Micronised fenofibrate 200mg (capsule) once daily was associated with significantly greater improvements from baseline in TC, LDL-C, HDL-C and TG levels than placebo in patients with type 2 diabetes mellitus enrolled in the double-blind, randomised Diabetes Atherosclerosis Intervention Study (DAIS) [> or =3 years follow-up]. Moreover, angiography showed micronised fenofibrate was associated with significantly less progression of coronary atherosclerosis than placebo. Micronised fenofibrate has also shown efficacy in patients with metabolic syndrome, patients with HIV infection and protease inhibitor-induced hypertriglyceridaemia and patients with dyslipidaemia secondary to heart transplantation. Micronised fenofibrate was generally well tolerated in clinical trials. The results of a large (n = 9884) 12-week study indicated that gastrointestinal disorders are the most frequent adverse events associated with micronised fenofibrate therapy. Elevations in serum transaminase and creatine phosphokinase levels have been reported rarely with micronised fenofibrate. In conclusion, micronised fenofibrate improves lipid levels in patients with primary dyslipidaemia; the drug has particular efficacy with regards to reducing TG levels and raising HDL-C levels. Micronised fenofibrate is also effective in diabetic dyslipidaemia; as well as improving lipid levels, the drug reduced progression of coronary atherosclerosis in patients with type 2 diabetes mellitus. The results of large ongoing studies (e.g. FIELD with approximately 10 000 patients) will clarify whether the beneficial lipid-modifying effects of micronised fenofibrate result in a reduction in cardiovascular morbidity and mortality.",2002.0,0,0 1539,12215193,Effect of early statin therapy after acute coronary syndromes: a concise review of the recent data.,Kevin A Bybee; R Scott Wright; Stephen L Kopecky,"HMG Co-A reductase inhibitors(statins) have been shown, in three large randomized trials, to decrease adverse cardiac events in patients with clinically evident coronary artery disease. All of these trials have excluded patients with an acute coronary syndrome within the three months prior to enrollment. Statin therapy is thought to stabilize coronary plaque and decrease the risk of plaque rupture. Statins have been shown to quickly reduce levels of LDL-C in addition to altering systemic inflammatory responses, improving endothelial function, and reducing platelet aggregation and activation. These mechanisms are potentially beneficial in the setting of acute coronary syndromes, a time of profound plaque instability. There is a growing body of evidence supporting the early initiation of statin therapy in the setting of acute coronary syndromes. This paper reviews the available data from randomized-controlled trials and observational studies evaluating the effect of early statin initiation during, or soon following, an acute coronary syndrome.",2002.0,0,0 1540,12215472,Mitogenic activity of oxidized lipoprotein (a) on human vascular smooth muscle cells.,Norio Komai; Ryuichi Morishita; Shingo Yamada; Mitsuru Oishi; Sota Iguchi; Motokuni Aoki; Minako Sasaki; Ikunosuke Sakurabayashi; Jitsuo Higaki; Toshio Ogihara,"Although oxidized lipoproteins may play an important role in the progression of atherosclerosis, no report has mentioned the significance of oxidized lipoprotein (a) (Lp[a]) in the pathogenesis of cardiovascular disease. Initially, we compared the mitogenic actions of Lp(a) and oxidized Lp(a) on human vascular smooth muscle cells (VSMC). Lp(a) significantly stimulated the growth of human VSMC in a dose-dependent manner, whereas oxidized Lp(a) showed a stronger stimulatory action on VSMC growth than native Lp(a). Interestingly, antioxidants probucol and fluvastatin inhibited the oxidation of Lp(a). Moreover, the stimulatory effect of oxidized Lp(a) on human VSMC growth was significantly inhibited by probucol. Finally, we elucidated the molecular mechanisms of how Lp(a) stimulated the growth of VSMC. Extracellular signal-regulated kinase (ERK), as those controlled by kinases, modulate critical cellular functions such as cell growth, differentiation, and apoptosis, was transiently phosphorylated by oxidized Lp(a) as well as native Lp(a) from 5 minutes, and the phosphorylation disappeared within 30 minutes. The degree of ERK phosphorylation by oxidized Lp(a) was much higher than that by native Lp(a). Administration of a specific inhibitor of MEK, PD 98059, significantly attenuated VSMC growth induced by native Lp(a) or oxidized Lp(a) in a dose-dependent manner (P<0.01). The current study demonstrated that oxidized Lp(a) is more potent than native Lp(a) in stimulating VSMC growth. Oxidized Lp(a) may play an important role in the pathogenesis of vascular disease.",2002.0,0,0 1541,12215610,ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins.,"Richard C Pasternak; Sidney C Smith; C Noel Bairey-Merz; Scott M Grundy; James I Cleeman; Claude Lenfant; American College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute",,2002.0,0,0 1542,12222546,Daily dosing versus alternate-day dosing of simvastatin in patients with hypercholesterolemia.,Heather R Copher; Robert D Stewart,"To compare the efficacy of daily simvastatin administration with that of alternate-day therapy at double the daily dose. Nonrandomized, before-after comparison trial. Outpatient clinic of a Veterans Affairs medical center. Fifteen men with hyperlipidemia. The simvastatin regimen for patients with a low-density lipoprotein cholesterol (LDL) level at their established National Cholesterol Education Program goal was converted from daily dosing to double the daily dose given every other day for 8 weeks. Baseline laboratory values were obtained for patients receiving daily simvastatin therapy After 8 weeks of alternate-day therapy, follow-up laboratory values were obtained and assessed for efficacy and toxicity. The LDL-lowering effect of the daily dosing regimen was compared with that of the alternate-day dosing regimen. Paired t tests were computed to compare LDL concentrations before and after the study using a 95% confidence interval. No statistically significant difference was observed. Alternate-day dosing of simvastatin may be an effective alternative to daily dosing.",2003.0,0,0 1543,12222700,Early use of pravastatin in patients with acute myocardial infarction undergoing coronary angioplasty.,Meral Kayikçioğlu; Levent Can; Hakan Kültürsay; Serdar Payzin; Cüneyt Turkoğlu,"To determine whether statin therapy initiated early in acute myocardial infarction together with thrombolytic therapy in patients with acute myocardial infarction results in clinical benefit through early plaque stabilization. The study population consisted of 77 patients who underwent coronary balloon angioplasty of the infarct-related artery during the first month of acute myocardial infarction. These patients belonged to the cohort of the Pravastatin Turkish Trial (PTT). Forty of them were assigned randomly to have immediate pravastatin (40 mg/day) therapy adjunctive to thrombolytic therapy regardless of serum lipid levels and received statin treatment throughout the study. Lipid levels were determined immediately after admission and before angioplasty and at the end of 6 months. Patients were re-evaluated clinically and angiographically for cardiovascular adverse events and restenosis after a 6-month follow-up period. The baseline angiographic and clinical characteristics of the two groups were similar. The incidence of angina was significantly lower in the pravastatin group (30.0%, 12 patients) compared to the control group (59.5%, 22 patients) (p = 0.018). The cumulative major adverse cardiac events in the pravastatin group were significantly lower when compared to the control group (32.5% vs. 75.6%, p = 0.0001). Early initiation of pravastatin therapy immediately after an acute myocardial infarction significantly decreased the frequency of major cardiac adverse events. Such early potential clinical benefits further strengthen the rationale for starting statin treatment as soon as possible after acute coronary events particularly in patients in whom invasive intervention is planned.",2003.0,0,0 1544,12223056,"Variagenics, inc.",Ann E Ferentz; Joseph S Mohr,"Variagenics, Inc. develops molecular diagnostic tests by identifying genetic markers associated with response to cancer therapies, with the goal of optimizing patient care. Toward this end, the company analyzes genetic variations in both normal and tumor cells, including SNPs, haplotypes, loss of heterozygosity, and gene expression levels. The company's approach of analyzing multiple types of genetic variations increases the likelihood of finding significant associations with drug response and successfully developing diagnostics. Variagenics is pursuing marker identification and diagnostic development through both biopharmaceutical collaborations and internal research programs.",2003.0,0,0 1545,12224342,Update on the management of dyslipidemia.,Brian K Irons; Kathleen A Snella; Kenneth McCall; Eric J MacLaughlin; Maumi Villarreal,"The third edition of guidelines from the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) is discussed. The most recent classifications for low-density-lipoprotein (LDL) cholesterol, high-density-lipoprotein (HDL), total cholesterol, and triglycerides are provided. LDL cholesterol goals, cardiovascular risk assessment, therapeutic goals, and pharmacologic treatment options are discussed for both primary and secondary prevention of cardiovascular disease. In addition, the management of dyslipidemia in patients with diabetes and metobolic syndrome is addressed, and the differences between the old and new guidelines are highlighted. The ATP III guidelines may help health care professionals to better screen and categorize patients on the basis of their coronary heart disease (CHD) risk. The updated guidelines recommend more intensive lipid-lowering treatments for primary prevention in patients with two or more risk factors.",2003.0,0,0 1546,12224668,Aggressive lipid-lowering in stable patients with coronary artery disease.,B Supanich,,2002.0,0,0 1547,12224718,Cardiology's 10 greatest discoveries of the 20th century.,Nirav J Mehta; Ijaz A Khan,"We present a brief summary of the 10 greatest cardiologic developments and discoveries of the 20th century Described are electrocardiography; preventive cardiology and the Framingham Study; ""lipid hypotheses"" and atherosclerosis; coronary care units; echocardiography; thrombolytic therapy; cardiac catheterization and coronary angiography; open-heart surgery; automatic implantable cardiac defibrillators; and coronary angioplasty. These topics are the personal choices of the authors.",2003.0,0,0 1548,12225707,Statin treatment following coronary artery stenting and one-year survival.,Albert Schömig; Julinda Mehilli; Heidrun Holle; Karin Hösl; Dorejd Kastrati; Jürgen Pache; Melchior Seyfarth; Franz-Josef Neumann; Josef Dirschinger; Adnan Kastrati,"We assessed the influence of statin therapy given after the procedure on one-year survival of patients treated with coronary artery stenting. Coronary artery stenting is currently a common treatment option for patients with symptomatic coronary artery disease (CAD). Although several secondary prevention trials have demonstrated improved survival achieved with statin therapy in conservatively treated patients with CAD, it is not known whether this benefit can also be expected in patients undergoing percutaneous coronary interventions with intraluminal stenting. This study included 4,520 patients younger than 80 years who underwent coronary artery stenting and were discharged from the hospital in the period October 1995 through September 1999. We compared one-year mortality of 3,585 patients who received statins after stenting with that of 935 patients who did not. The mortality rate at one year was 2.6% among patients who received statins and 5.6% among those who did not. Thus, statin therapy at discharge was associated with an unadjusted odds ratio (OR) of 0.46 (95% confidence interval [CI], 0.33 to 0.65), indicating a 54% reduction in the risk of death at one year. After adjusting for other covariates, the risk reduction associated with statin therapy was 49%, OR 0.51 (95% CI, 0.36 to 0.71). This reduction was observable in most of the subgroups of patients. The results of this nonrandomized study show that statin therapy improves survival after coronary artery stenting independent of patient characteristics recorded on the day of the intervention.",2002.0,0,0 1549,12227864,Japanese familial hypercholesterolaemia with a 327insC mutation in the LDL receptor gene.,Ryoji Hirota; Nobuhiko Kubo; Kazumasa Hikiji; Kumiko Nakajima; Yoshiya Hata; Ikunosuke Sakurabayashi,"Mutations in the LDL receptor (LDLR) cause familial hypercholesterolaemia (FH) in an autosomal dominant manner. The condition frequently progresses to coronary atherosclerosis. We describe a patient with FH, but without ischaemic heart disease, who had a novel frameshift mutation (327insC) in exon 4 of the LDLR gene. This mutation introduced a premature termination codon (TGA, codon 158). The patient was a 59-year-old man who had presented with hypercholesterolaemia and a plasma total cholesterol (TC) concentration of 12.2 mmol/L at age 44 years. The mutation 327insC in this patient was heterozygous and hypercholesterolaemia was common within his family. Despite taking lipid-lowering medications (probucol and pravastatin) for more than 20 years, his TC concentration hardly fell below 7.8 mmol/L. However, neither the patient nor anyone else in his family developed characteristic symptoms of ischaemic heart disease or xanthoma. This patient was discovered by an intensive mutation survey among 22 unrelated Japanese with FH mainly in the Kanto area of Japan, suggesting a low incidence of the mutation in the area.",2003.0,0,0 1550,12228849,Renin-angiotensin system antagonism and lipid-lowering therapy in cardiovascular risk management.,Jun R Chiong; Alan B Miller,"The renin-angiotensin system (RAS) and dyslipidaemia have been shown to be involved in the genesis and progression of atherosclerosis. Manipulation of the RAS has been effective in modifying human coronary artery disease progression. Similarly, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors or statins have been shown to reduce cholesterol and lower cardiovascular events in primary and secondary prevention trials in coronary artery disease. In addition to their primary mode of action, statins and blockers of the RAS possess common additional properties that include restoration of endothelial activity and inhibition of cellular proliferation. This article reviews the current data on the common properties of these classes of drugs in which the beneficial effects extend beyond their antihypertensive and lipid-lowering properties.",2003.0,0,0 1551,12231607,Intensive statin treatment improves baroreflex sensitivity: another cardioprotective mechanism for statins?,D Patterson; J B C Dick; A D Struthers,,2002.0,0,0 1552,12233907,Antiinflammatory effect of simvastatin in patients with rheumatoid arthritis.,Hiroko Kanda; Ken Hamasaki; Kanae Kubo; Shoko Tateishi; Aki Yonezumi; Yoshinobu Kanda; Kazuhiko Yamamoto; Toshihide Mimura,,2003.0,0,0 1553,12234946,Simvastatin lowers C-reactive protein within 14 days: an effect independent of low-density lipoprotein cholesterol reduction.,Julie K Plenge; Teri L Hernandez; Kathleen M Weil; Paul Poirier; Gary K Grunwald; Santica M Marcovina; Robert H Eckel,"The early response of C-reactive protein to initiation of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) is not known. The purpose of this study was to determine the rate at which highly sensitive C-reactive protein (hsCRP) levels change after initiation of simvastatin and whether this occurs independently of the change in LDL cholesterol. The study was a crossover, double-blind design including 40 subjects with elevated LDL cholesterol. Subjects were randomly assigned to 1 of 2 groups: simvastatin 40 mg for 14 days, then placebo for 14 days, or placebo first, then simvastatin. Simvastatin decreased LDL cholesterol by 56+/-4 mg/dL (P<0.0001) at day 7 and by an additional 8+/-3 mg/dL (P=0.02) at day 14. Baseline log(hsCRP) levels were similar in the 2 groups. By day 14, log(hsCRP) was significantly lower in patients on simvastatin when compared with placebo (P=0.011). Although there was no significant difference in fibrinogen levels, simvastatin produced a modest increase in log[lipoprotein(a)] (P=0.03) at days 7 and 14. There were no relationships between the decrease in LDL cholesterol and the decrease in hsCRP. Simvastatin lowers hsCRP by 14 days, independent of its effect on LDL cholesterol. This rapid impact of a statin on hsCRP has potential implications in the management of acute coronary syndromes.",2002.0,0,0 1554,12235098,Malformation syndromes due to inborn errors of cholesterol synthesis.,Forbes D Porter,,2002.0,0,0 1555,12235178,Effect of atorvastatin on plasma apoE metabolism in patients with combined hyperlipidemia.,Jeffrey S Cohn; Michel Tremblay; Rami Batal; Hélène Jacques; Lyne Veilleux; Claudia Rodriguez; P Hugh R Barrett; Denise Dubreuil; Madeleine Roy; Lise Bernier; Orval Mamer; Jean Davignon,"Atorvastatin, a synthetic HMG-CoA reductase inhibitor used for the treatment of hyperlipidemia and the prevention of coronary artery disease, significantly lowers plasma cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. It also reduces total plasma triglyceride and apoE concentrations. In view of the direct involvement of apoE in the pathogenesis of atherosclerosis, we have investigated the effect of atorvastatin treatment (40 mg/day) on in vivo rates of plasma apoE production and catabolism in six patients with combined hyperlipidemia using a primed constant infusion of deuterated leucine. Atorvastatin treatment resulted in a significant decrease (i.e., 30-37%) in levels of total triglyceride, cholesterol, LDL-C, and apoB in all six patients. Total plasma apoE concentration was reduced from 7.4 +/- 0.9 to 4.3 +/- 0.2 mg/dl (-38 +/- 8%, P < 0.05), predominantly due to a decrease in VLDL apoE (3.4 +/- 0.8 vs. 1.7 +/- 0.2 mg/dl; -42 +/- 11%) and IDL/LDL apoE (1.9 +/- 0.3 vs. 0.8 +/- 0.1 mg/dl; -57 +/- 6%). Total plasma lipoprotein apoE transport (i.e., production) was significantly reduced from 4.67 +/- 0.39 to 3.04 +/- 0.51 mg/kg/day (-34 +/- 10%, P < 0.05) and VLDL apoE transport was reduced from 3.82 +/- 0.67 to 2.26 +/- 0.42 mg/kg/day (-36 +/- 10%, P = 0.057). Plasma and VLDL apoE residence times and HDL apoE kinetic parameters were not significantly affected by drug treatment. Percentage decreases in VLDL apoE concentration and VLDL apoE production were significantly correlated with drug-induced reductions in VLDL triglyceride concentration (r = 0.99, P < 0.001; r = 0.88, P < 0.05, respectively, n = 6). Our results demonstrate that atorvastatin causes a pronounced decrease in total plasma and VLDL apoE concentrations and a significant decrease in plasma and VLDL apoE rates of production in patients with combined hyperlipidemia.",2003.0,0,0 1556,12236852,Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin.,Teddy Kosoglou; Ingo Meyer; Enrico P Veltri; Paul Statkevich; Bo Yang; Yali Zhu; Lillian Mellars; Stephen E Maxwell; James E Patrick; David L Cutler; Vijay K Batra; Melton B Affrime,"The primary aims of these two single-centre, randomized, evaluator-blind, placebo/positive-controlled, parallel-group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective. Eighty-two healthy men with low-density lipoprotein cholesterol (LDL-C) >or=130 mg dl-1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11-12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady-state pharmacokinetics of simvastatin and its beta-hydroxy metabolite were evaluated in Study 1 only. In both studies, reported side-effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL-C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose-dependent reduction in LDL-C and total cholesterol, with no apparent effect on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean -17%, 95% CI -27.7, -6.2, and -18%, -28.4, -7.4, respectively) in LDL-C than simvastatin alone. The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL-C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted.",2003.0,0,0 1557,12236985,[Surrogate end points as a clinical and public health problem. The cerivastatin case].,Juan Gérvas; Mercedes Pérez Fernández,,2003.0,0,0 1558,12241128,Oxidation injury in patients receiving HMG-CoA reductase inhibitors: occurrence in patients without enzyme elevation or myopathy.,Helmut Sinzinger; Fahdi Chehne; Graziana Lupattelli,"Myopathy in its severe forms including rhabdomyolysis is a very rare adverse effect occurring during monotherapy with the HMG-CoA reductase inhibitors ('statins') and is associated with pronounced signs of oxidation injury. This has been found at a local (muscle) as well as at a systemic level (blood). Several lines of evidence indicate that even mild forms of myopathy during statin treatment may be associated with in vivo oxidation injury. In contrast, statin therapy has been shown to be associated with a decrease in oxidation injury. The aim of this study was to investigate whether patients with heterozygous familial hypercholesterolaemia who did not exhibit any symptoms or abnormalities in safety parameters during 6 months of treatment with various statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) did exhibit a change in oxidation injury as assessed by the isoprostane levels. Blood (plasma and serum) as well as urine was tested before and 1, 3 and 6 months after starting statin therapy. Out of 111 treated patients (63 males, 48 females; aged 19 to 58 years) who did not experience any adverse effects during statin treatment, 11 (seven males, four females; aged 24 to 51 years) showed a pronounced increase in 8-epi-prostaglandin (PG) F(2alpha) in all the compartments examined. In the remaining 100 patients (56 males, 44 females; aged 19 to 58 years) there was either no change in or even an apparent decrease in 8-epi-PGF(2alpha). This increase was monitored with all the statins administered. If elevated, the increase in 8-epi-PGF(2alpha) remained without change throughout the entire follow-up period. No sex difference or differential response between smokers and nonsmokers was observed. These findings indicate that in the absence of other clinically observable adverse effects, in some of the patients, for an as yet unknown reason, statin therapy may be associated with increased oxidation injury. The fact that changing to another statin is apparently not necessarily associated with an identical response raises the question of a specific predisposition for certain compounds in a given patient. These data add a further piece of evidence that mild adverse effects of statins that are difficult to assess might be much more prevalent than widely considered. The clinical relevance and consequence of these findings still remains to be assessed.",2002.0,0,0 1559,12243373,Hyperhomocyst(e)inemia: is this a novel risk factor in hypertension?,Agostino Virdis; Lorenzo Ghiadoni; Guido Salvetti; Daniele Versari; Stefano Taddei; Antonio Salvett,"Homocysteine is an intermediate sulfur-containing amino acid formed during intracellular metabolism of methionine. Circulating homocyst(e)ine can be increased by genetic deficiency of enzymatic pathways involved in its catabolism as well as by environmental factors including nutritional deficiencies, life style factors, physiological conditions, drugs and some diseases, which mainly induce deficiency of folate, vitamin B12 and vitamin B6. Therefore plasma homocyst(e)ine can be reduced by vitamin therapy with folate and vitamin B12. Although hyperhomocyst(e)inemia exerts a prothrombotic and proatherosclerotic effect, its relevance in the genesis of the atherosclerotic lesions, as well in the first occurrence of cardiovascular events in normotensive and even more so in hypertensive patients is still to be established. However available data indicate that hyperhomocyst(e)inemia could be an independent risk factor for the recurrence of cardiovascular events in patients with coronary artery disease and in elderly high risk patients. Finally, the possibility that a reduction in plasma homocyst(e)ine induced by vitamin therapy can diminish the risk of cardiovascular events is under evaluation in several controlled longitudinal studies focusing mainly on secondary prevention.",2003.0,0,0 1560,12243374,Do ancillary properties of antihypertensive drugs explain the outcome results of recent trials?,Jan A Staessen; Jiguang Wang,"In a quantitative overview of published trials, we investigated whether some pharmacological properties of antihypertensive drugs, besides reduction in blood pressure, explain cardiovascular outcomes in hypertensive or high-risk patients. Across trials, using meta-regression, we correlated odds ratios with differences in systolic blood pressure between study groups. We then compared odds ratios of benefit observed in recent trials with those predicted by metaregression on the basis of the differences in systolic pressure between randomised groups. Significant differences in systolic pressure between randomised groups (experimental minus reference) were observed in the ALLHAT (-2/+1), CAPPP(-3/-1) and NORDIL (-3.1/+0.2) trials. Furthermore, the differences in achieved systolic and/or diastolic pressure between study groups were also significant in the hypertension trials which involved untreated control patients, as well as in MIDAS (-3.5/ approximately 0 mm Hg), HOPE (-3.3/-1.0 mm Hg), PART2 (-5/-4 mm Hg), and SCAT (4/-2 mm Hg) (1). The differences between the observed odds ratios and those predicted by the meta-regression between outcome and difference in systolic pressure did not reach statistical significance except for the NORDIL trial, in which the risk of stroke was lower on diltiazem than on the older drugs despite a 3.1 mm Hg higher systolic pressure on the calcium-channel blocker. The finding that in the reviewed trials blood pressure reduction largely accounted for outcome emphasizes the desirability of blood pressure control. The hypothesis that converting-enzyme inhibitors or alpha-blockers might influence cardiovascular prognosis over and beyond their antihypertensive effect remains unproved.",2003.0,0,0 1561,12243615,Role of antibiotics for the prevention of cardiovascular disease.,Michael P Gabay; Rupali Jain,"To evaluate the data regarding the use of antibiotic therapy for the prevention of cardiovascular events. Pertinent literature was identified through a MEDLINE search (1966-September 2001) and through other secondary literature databases and/or bibliographies of pertinent articles. Cardiovascular disease is a common cause of morbidity and mortality among the general population, with well-defined risk factors (e.g., diabetes, hypertension, hyperlipidemia, cigarette smoking, genetic predisposition). Clinical data evaluating the association between the aforementioned risk factors and the development of atherosclerosis and subsequent cardiovascular disease are substantial; however, these risk factors may only partially explain the high prevalence of cardiovascular disease. The presence of Chlamydia pneumoniae within atherosclerotic lesions has been documented and may be an additional risk factor for the development and progression of cardiovascular disease. The results of primary and secondary prevention trials have shown conflicting evidence with regard to the beneficial effects of antibiotic therapy to reduce cardiovascular events. Currently, the lack of certainty in published data does not support the use of antibiotics for the prevention of cardiovascular disease. Clinicians should continue to emphasize interventions proven to reduce adverse cardiovascular events such as smoking cessation, reduction of hyperlipidemia, and control of hypertension.",2003.0,0,0 1562,12243846,Beyond lipid lowering: the role of statins in vascular protection.,James K Liao,"The introduction of the hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in 1987 was a major advance in the prevention and treatment of cardiovascular disease. Several landmark clinical trials have demonstrated the benefit of lipid lowering with statins for the primary and secondary prevention of coronary heart disease (CHD), namely The Scandinavian Simvastatin Survival Study (4S), Cholesterol And Recurrent Events (CARE), Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), West of Scotland Coronary Prevention Study (WOSCOPS) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Although it is widely accepted that the majority of clinical benefit obtained with statins is a direct result of their lipid-lowering properties, these agents appear to display additional cholesterol-independent or pleiotropic effects on various aspects of cardiovascular disease, including improving endothelial function, decreasing vascular inflammation and enhancing plaque stability. Although the full impact of statin therapy on each of these processes is not fully understood, ongoing studies with current and new statins are likely to shed further light on the potential cholesterol-independent benefits of these agents.",2002.0,0,0 1563,12269853,Rosuvastatin.,Christopher I Carswell; Greg L Plosker; Blair Jarvis,"Rosuvastatin is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used in the treatment of patients with dyslipidaemia. Rosuvastatin is not extensively metabolised and has a low propensity for drug interactions. In well designed trials of between 6 and 52 weeks' duration, rosuvastatin was superior to atorvastatin, simvastatin and pravastatin in improving the lipid profile of patients with hypercholesterolaemia. In a 1-year dose-titration study, rosuvastatin 13.4mg daily (mean dose) allowed more patients to achieve US National Cholesterol Education Program (Adult Treatment panel II)[NCEP] target low-density lipoprotein (LDL)-cholesterol levels than atorvastatin 20.8mg daily (98 vs 87%) with the difference most marked in high-risk patients (97 vs 61%). Similarly, when compared with pravastatin and simvastatin 20 mg/day in a further 1-year trial, 88% of rosuvastatin recipients [9.5 and 13.8 mg/day (mean doses)] achieved NCEP target serum LDL-cholesterol levels compared with 60 and 73% of pravastatin and simvastatin recipients, respectively, with the difference more marked in high-risk patients. In further clinical trials, rosuvastatin improved the lipid profile of patients with heterozygous or homozygous familial hypercholesterolaemia, hypertriglyceridaemia or mixed dyslipidaemias. Rosuvastatin was well tolerated in clinical trials of up to 1 years' duration.",2002.0,0,0 1564,12270465,Hyperlipidemia and graft loss.,A Stephan; A Barbari; A Karam; H Kilani; G Kamel; A Masri,,2003.0,0,0 1565,12270846,Reducing the risk for stroke in patients with myocardial infarction: a Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy.,Antonio M Gotto; John A Farmer,,2002.0,0,0 1566,12270864,Effects of atorvastatin on stroke in patients with unstable angina or non-Q-wave myocardial infarction: a Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy.,David D Waters; Gregory G Schwartz; Anders G Olsson; Andreas Zeiher; Michael F Oliver; Peter Ganz; Michael Ezekowitz; Bernard R Chaitman; Sally J Leslie; Theresa Stern; MIRACL Study Investigators,"This report describes the effect of intensive cholesterol lowering with atorvastatin on the incidence of nonfatal stroke, a secondary end point, in a randomized, placebo-controlled trial of patients with unstable angina or non-Q-wave myocardial infarction. The primary end point, a composite of death, nonfatal myocardial infarction, resuscitated cardiac arrest, or recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalization, was reduced from 17.4% in the placebo group to 14.8% in the atorvastatin group over the 16 weeks of the trial (P=0.048). Strokes were adjudicated by a blinded end-point committee using standard clinical and imaging criteria. The outcomes of nonfatal stroke and fatal plus nonfatal stroke were analyzed by time to first occurrence during the 16-week trial. Of 38 events (in 36 patients) adjudicated as fatal or nonfatal strokes, 3 were classified as hemorrhagic, one as embolic, and 29 as thrombotic or embolic; 5 could not be categorized. Nonfatal stroke occurred in 9 patients in the atorvastatin group and 22 in the placebo group (relative risk, 0.40; 95% confidence intervals, 0.19 to 0.88; P=0.02). Fatal or nonfatal stroke occurred in 12 atorvastatin patients and 24 placebo patients (relative risk, 0.49; 95% confidence intervals, 0.24 to 0.98; P=0.04). All 3 hemorrhagic strokes occurred in the placebo group. Intensive cholesterol lowering with atorvastatin over 16 weeks in patients with acute coronary syndromes reduced the overall stroke rate by half and did not cause hemorrhagic stroke. These findings need to be confirmed in future trials.",2002.0,0,0 1567,12296991,"Pharmacokinetics and disposition of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in rat.",K Nezasa; A Takao; K Kimura; M Takaichi; K Inazawa; M Koike,"1. The pharmacokinetics and disposition of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, were investigated following single administration of (14)C-rosuvastatin in the Sprague-Dawley rat. 2. Following oral administration of (14)C-rosuvastatin at 1, 5 and 25 mg kg(-1), the C(max) and AUC of the radioactivity in the plasma increased more than the increase in dose ratio. 3. Excretion of radioactivity was 98.0% of the dose in the faeces and 0.4% in the urine up to 168 h after oral administration in the intact rat, and was 55.1% in the bile and 0.5% in the urine up to 48 h post-dosing in the bile duct-cannulated rat. The unchanged compound mainly accounted for the radioactivity in the bile and faeces. 4. In the tissue distribution study, the concentration of the radioactivity in the liver was markedly higher than those in the other tissues, and the radioactivity concentration ratios of the liver to the plasma were between 8 and 25 up to 48 h after oral administration. The liver-specific distribution of rosuvastatin was similarly recognized in whole-body autoradiography. 5. Metabolic profiling studies indicated that rosuvastatin would not be metabolized by CYP enzymes. 6. These results clarified that rosuvastatin selectively distributed in the liver - the target organ - and was excreted in the bile mainly as the unchanged compound.",2002.0,0,0 1568,12298341,The pursuit of secondary prevention targets in Czech coronary patients. A comparison of EuroAspire I and II surveys.,O Mayer; J Simon; H Rosolová; Dirk De Bacquer; EuroAspire I and II Study Groups,"Definite evidence has been established, that coronary patients benefit from appropriate secondary prevention measures, as recommended by the European and National Guidelines. EuroAspire I (1995) and EuroAspire II (1999) were surveys aimed to evaluate the state of the implementation of guidelines into the every-day medical practice in several European countries, including Czech Republic. We wondered to what extent the practice in secondary prevention of Czech physicians, since the guidelines were published, changed during 5 years, to pursue the targets. We compared two surveys, undertaken in the same geographical areas of the Czech Republic. Consecutive patients, males and females, less than 71 years of age were indentified following acute coronary event or revascularisation procedure and were interviewed and examined at least 6 months after hospitalization. The Czech surveys included 331 patients in EuroAspire I and 410 in EuroAspire II. In EuroAspire II, the total number of smokers decreased in males, but increased in females. The patients were more obese, had higher glucose levels as well, while blood pressure, total and LDL cholesterol and triacylglycerols were lower, than in EuroAspire I. Corresponding changes also occurred in the prevalence of hypertension and hyperlipidaemias by definitions. There was a significant increase in the use of betablockers, ACE inhibitors and hypolipidemic drugs, mainly statins. In conclusion, in spite that the compliance with the recommendations for secondary prevention improved, achievement of targets remained rather unsatisfactory, likewise in other European countries.",2003.0,0,0 1569,12325048,Thinking preventively about dementia: a review.,Brian Cooper,"The dementias of late life now constitute a major public health challenge to our society. To examine the contributions of neuroscience, clinical treatment and health-care policy to the building of a national programme for preventive approaches to dementia. Critical review of the literature, making use of international databases (Medline, Embase, Psychlit) and British official publications. Recent developments in a number of research fields afford prospects for advances in primary and secondary prevention. These include findings from case-control and cohort studies of associations with earlier head injury and vascular disease, possibilities of pharmacological protection for persons at high risk for Alzheimer's disease, and the use of more effective anti-dementia drugs in the mild to moderate stages of severity. Research aimed at tertiary prevention is lagging behind, but there are some indications that the worst features of late-stage decline could already be mitigated by improvements in community support services and nursing-home care. Containment of the growing social and economic burdens of dementia calls for a national policy to ensure that new research findings can be translated into practice and applied to the benefit of all old people who stand in need. For this purpose the most appropriate conceptual framework is supplied by a preventive model, broadly similar to those already developed for some other forms of chronic degenerative disease.",2002.0,0,0 1570,12325099,Regulatory perspectives on data monitoring.,Robert T O'Neill,"Data monitoring is a critical component of the conduct of clinical trials that provide the evidence of efficacy and safety of investigational drugs. These trials may be conducted either by a pharmaceutical sponsor or by the government, especially those large trials that assess the impact of therapies on serious morbidity and/or mortality. While not extensive, I will review a regulatory history of FDA's evolving concerns and positions on data monitoring. I will review the key aspects of data monitoring and interim analysis of clinical trials contained in the recently published International Conference on Harmonization's statistical guidance as well as some other issues being considered for a draft guidance on data monitoring. Finally, some suggestions for improving and enhancing tools and statistical methods for monitoring clinical trials for safety assessment will be offered. This latter area deserves more consideration by statisticians than it has received to date.",2003.0,0,0 1571,12325106,The role of covariates in estimating treatment effects and risk in long-term clinical trials.,Ian Ford; John Norrie,"This paper reviews previously published work showing that the impact of including covariates in models used to estimate the magnitude of treatment effects in long-term clinical trials is different from what would be predicted from results for the normal linear model. Typically, models with and without covariates cannot simultaneously be valid. A case is made for the use of data from clinical trials to model the future risk and potential benefits of treatment in individual subjects. The methods and results are illustrated using data from the West of Scotland Coronary Prevention Study.",2003.0,0,0 1572,12325110,Policy developments in regulatory approval.,Robert Temple,"Although radical changes in drug regulation are rare (e.g., the Federal Food, Drug and Cosmetic Act of 1938 and the 1962 amendment to the Act creating an effectiveness requirement), regulations and guidance do evolve significantly in the face of new problems and accumulating experience. Recent changes have been driven by the Food and Drug Administration Modernization Act (FDAMA), user fee legislation, the International Conference on Harmonization, recent safety related drug withdrawals, and concerns about trial ethics and investigator conflict of interest. FDAMA and guidance developed in response to it has helped circumstances in which FDA would rely on a single study to support effectiveness and the circumstances in which surrogate endpoints could support approval. An ICH Document 'Choice of control group and related design issues in clinical trials' focussed attention on the ethics of placebo controls (acceptable, even if there is existing therapy, when the placebo-treated patient will suffer no irreversible injury) and the design of 'equivalence' or 'non-inferiority' trials. There has been greatly increased attention to obtaining good dose-response information and to assessing need for modifying treatment in demographic (age, gender, race) and concomitant disease (renal or hepatic function abnormalities) subgroups, and in assessing drug-drug interactions. Other important trends are increasing reliance on non-U.S. data, increasing numbers of FDA-industry meetings during drug development, and new focus on risk assessment and risk management.",2003.0,0,0 1573,12349850,Insulin resistance and risk for stroke.,W N Kernan; S E Inzucchi; C M Viscoli; L M Brass; D M Bravata; R I Horwitz,"Resistance to insulin-mediated glucose uptake by peripheral tissues is a cardinal defect in type 2 diabetes mellitus. Insulin resistance is also common among nondiabetic individuals, and may be an important risk factor for stroke in both populations. The authors review the definition, epidemiology, and treatment of insulin resistance. The authors searched Medline (1977-2001) and reviewed bibliographies to identify pertinent English-language publications. Insulin resistance is present in most patients with type 2 diabetes. It is also common among elderly persons, certain ethnic groups, and persons with hypertension, obesity, physical deconditioning, and vascular disease. The principal pathophysiologic defect is impaired intracellular signaling in muscle tissue leading to defective glycogen synthesis. Insulin resistance is associated with numerous metabolic, hematologic, and cellular events that promote atherosclerosis and coagulation. The association between insulin resistance and risk for stroke has been examined in four case-control studies and five prospective observational cohort studies. Six of the nine studies are methodologically sound and provide evidence that insulin resistance is associated with risk for stroke. Insulin resistance may be a prevalent risk factor for stroke. New drugs can safely reduce insulin resistance and may have a role in stroke prevention.",2002.0,0,0 1574,12351996,Metabolic and drug-induced muscle disorders.,Guglielmo Scarlato; Giacomo P Comi,"The inherited disorders of muscle metabolism affect both substrate utilization and the final intramitochondrial oxidation through the Krebs cycle and the respiratory chain. Almost every step of these complex biochemical pathways can be affected by inborn errors, whose expression depends on peculiar tissue-specific or systemic gene expression. This review updates current knowledge in this broad field. New inherited defects are still being discovered, such as the beta-enolase deficiency in glycogenosis type XIII and mutations in the gene encoding an esterase/lipase/thioesterase protein in Chanarin-Dorfman syndrome, a multisystem triglyceride storage disease. Therapeutic approaches to the metabolic myopathies are still lagging behind, although remarkable observations have been made on the rare coenzyme Q10 deficiency syndrome. However, transgenic animal models may offer the opportunity both to investigate muscle pathogenesis and explore therapeutic targets. Finally, human myotoxicity may provide novel paradigms for naturally occurring muscle disorders.",2002.0,0,0 1575,12352024,Therapy and clinical trials.,Asim K Duttaroy,,2003.0,0,0 1576,12353340,"Comparing the efficacy and safety of atorvastatin and simvastatin in Asians with elevated low-density lipoprotein-cholesterol--a multinational, multicenter, double-blind study.",Chau-Chung Wu; Rody Sy; Vichai Tanphaichitr; Arthur Tan Teow Hin; Slamet Suyono; Yuan-Teh Lee,"There have been few reports on the efficacy and safety of statins in the Asian population. The study objectives were to compare the efficacy and safety of atorvastatin and simvastatin in Asian people. This was a 16-week, double-blind, double-dummy, randomized, multicenter study involving eight medical centers in six Asian countries or areas. After a 6-week, diet-controlled, placebo lead-in period, 157 patients with low-density lipoprotein cholesterol (LDL-C) of between 160 and 250 mg/dL and serum triglyceride (TG) of less than 400 mg/dL were randomized to receive 10 mg of either atorvastatin (n = 79) or simvastatin (n = 78). After 8 weeks of treatment, all patients had the dose of study medication increased to 20 mg, irrespective of LDL-C concentration. Data obtained by monitoring lipid profiles, adverse events, and laboratory tests during the 16 weeks of study were used to assess the efficacy and safety of both treatments. After 8 weeks of treatment, LDL-C concentrations were reduced by 42.5% from baseline in patients receiving atorvastatin and 34.8% in those receiving simvastatin (p = 0.0006). Patients treated with atorvastatin also had a significantly greater reduction in very-low-density lipoprotein cholesterol (VLDL-C), TG, and total cholesterol (TC) after 8 weeks of treatment. The significantly greater reductions in LDL-C, VLDL-C, TG, and TC from baseline achieved with atorvastatin were still observed after an additional 8 weeks of treatment with 20 mg study medication. Both drugs increased high-density lipoprotein cholesterol (HDL-C) concentrations after 16 weeks of treatment, with no significant difference between the two treatments. After 16 weeks of treatment, 93% of atorvastatin and 85% of simvastatin patients had achieved their National Cholesterol Education Program LDL-C goals. No deaths occurred in the study population and the incidence of treatment-emergent adverse events was the same in the two groups (28%). Only one patient who was treated with simvastatin had a transaminase or creatine phosphokinase concentration that was more than three-fold the upper limit of normal. Asian people with primary hypercholesterolemia treated with atorvastatin had lower LDL-C, VLDL-C, TG, and TC after 8 weeks and 16 weeks of treatment than those treated with simvastatin. Both drugs demonstrated acceptable safety profiles.",2002.0,0,0 1577,12353945,Statin-associated myopathy with normal creatine kinase levels.,Paul S Phillips; Richard H Haas; Sergei Bannykh; Stephanie Hathaway; Nancy L Gray; Bruce J Kimura; Georgirene D Vladutiu; John D F England; Scripps Mercy Clinical Research Center,"Muscle symptoms in patients who are treated with statins and have normal creatine kinase levels are not well understood. To report biopsy-confirmed myopathy and normal creatine kinase levels associated with statin use. Case reports from preliminary analysis of an ongoing clinical trial. Clinical research center in a community hospital. Four patients with muscle symptoms that developed during statin therapy and reversed during placebo use. 1) Patients' ability to identify blinded statin therapy and 2) standard measures of functional capacity and muscle strength. All four patients repeatedly distinguished blinded statin therapy from placebo. Strength testing confirmed weakness during statin therapy that reversed during placebo use. Muscle biopsies showed evidence of mitochondrial dysfunction, including abnormally increased lipid stores, fibers that did not stain for cytochrome oxidase activity, and ragged red fibers. These findings reversed in the three patients who had repeated biopsy when they were not receiving statins. Creatine kinase levels were normal in all four patients despite the presence of significant myopathy. Some patients who develop muscle symptoms while receiving statin therapy have demonstrable weakness and histopathologic findings of myopathy despite normal serum creatine kinase levels.",2002.0,0,0 1578,12354174,Are early clinical effects of cholesterol lowering mediated through effects on inflammation?,A G Olsson; G G Schwartz; L Jonasson; C Linderfalk,"In a randomized, double-blind trial in 3086 patients with unstable angina pectoris or non-Q wave myocardial infarction we investigated if 80 mg of atorvastatin daily could improve outcome of cardiovascular events during a short period of time (16 weeks) compared with placebo. Baseline LDL cholesterol was 3.2 mmol L-1 (124 mg dL-1) and decreased by 40% to 1.9 mmol L-1 (72 mg dL-1) during atorvastatin treatment. The primary endpoint, which was a composite of death, non-fatal acute myocardial infarction, cardiac arrest with resuscitation or recurrent symptomatic myocardial ischaemia with objective evidence and requiring emergency rehospitalization occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group. The relative risk was 0.84 and 95% confidence interval was 0.70-1.00 (P = 0.048). Thus for patients with acute coronary syndromes, lipid-lowering therapy with high dose atorvastatin reduces recurrent ischaemic events in the short-term. A possible mechanism behind this rapid clinical effect induced by statin treatment is on inflammatory processes. Recent studies strongly suggest that acute T-cell activation is involved in the pathogenesis of unstable angina. In another study we investigated whether circulating T cells showed signs of activation in patients with stable angina pectoris (SA). Systemic venous blood samples were taken from 38 men with SA and 42 healthy controls. The T-cell receptor expression was assessed by three-colour flow cytometry using monoclonal antibodies against CD3,CD4, CD8, CD25 and human leucocyte antigen (HLA)-DR. Soluble interleukin-2 receptor (sIL-2R) was measured as the circulating form in serum. Levels of circulating CD3+ and CD4+ T cells tended to be higher in patients compared with controls. Patients were also shown to have a significant increase in CD4+ T cells expressing the activation markers CD25 (P < 0.05) and HLA-DR (P < 0.01). Furthermore, serum levels of sIL-2R were significantly higher (P < 0.001) in patients than in controls. We also observed that the T-cell response was more pronounced in patients without simvastatin treatment (n = 18) compared with simvastatin-treated patients (n = 20). In conclusion, our findings indicate that a continuous immune system activation takes place in patients with chronic angina pectoris, predominantly involving proliferation of CD4+ T cells. Statin treatment seems to be able to decrease this inflammatory response.",2003.0,0,0 1579,12354446,"Direct vascular and cardioprotective effects of rosuvastatin, a new HMG-CoA reductase inhibitor.",Steven P Jones; Michael F Gibson; David M Rimmer; Terrie M Gibson; Brent R Sharp; David J Lefer,"We examined the possible effects of a novel 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, rosuvastatin, on endothelial nitric oxide (NO) production and myocardial ischemia-reperfusion injury. Recent studies suggest that HMG-CoA reductase inhibitors promote vascular endothelial function through enhanced endothelial NO production. However, it is unclear whether all statins share this beneficial side effect or whether this effect is limited to the ""natural"" statins. Wild-type mice (n = 158) were subjected to 30 min of regional myocardial ischemia and 24 h of reperfusion. Mice were treated with various doses of rosuvastatin (0.1, 0.5, 1.0, 2.0, and 5.0 mg/kg) 18 h before myocardial ischemia and reperfusion. Rosuvastatin significantly increased NO production from the vascular endothelium following acute administration to mice. In addition, rosuvastatin increased myocardial endothelial nitric oxide synthase (eNOS) messenger ribonucleic acid levels. Myocardial necrosis was reduced by approximately 40% with rosuvastatin therapy. Rosuvastatin attenuated myocardial injury when it was administered 6 h, but not 0 h or 3 h, before myocardial ischemia. In additional studies, rosuvastatin did not affect myocardial infarct size in eNOS-deficient mice compared to vehicle-treated eNOS mice. These data demonstrate that rosuvastatin increases vascular endothelial NO production and attenuates myocardial necrosis following ischemia and reperfusion in mice.",2002.0,0,0 1580,12354476,Rituximab for idiopathic membranous nephropathy.,Giuseppe Remuzzi; Carlos Chiurchiu; Mauro Abbate; Verusca Brusegan; Mario Bontempelli; Piero Ruggenenti,"Treatments for idiopathic membranous nephropathy, a common cause of nephrotic syndrome, can be very toxic. In view of the pathogenic potential of B cells in this disease, we studied the effects of four weekly infusions of rituximab (375 mg/m(2)-- the monoclonal antibody to B-cell antigen CD20--in eight patients who had idiopathic membranous nephropathy with persistent nephrotic syndrome. At weeks 4 and 20, urinary protein decreased from mean (SE) 8.6 g/24 h (1.4) to 3.8 (0.8) and 3.7 (0.9), respectively (p<0.0001). At week 20, albuminuria and albumin fractional clearance decreased by 70% and 65%, and serum albumin increased by 31%. CD20 B lymphocytes fell below normal ranges up to study end. The short-term risk-benefit profile of rituximab seems more favourable to that of any other immunosuppressive drug used to treat idiopathic membranous nephropathy.",2002.0,0,0 1581,12355111,"New enzymes for ""warheads"".",David H Sherman,,2003.0,0,0 1582,12356379,Effects of atorvastatin on fasting and postprandial lipoprotein subclasses in coronary heart disease patients versus control subjects.,Ernst J Schaefer; Judith R McNamara; Timothy Tayler; Jennifer A Daly; Joi A Gleason; Leo J Seman; Andrea Ferrari; Joel J Rubenstein,"The effects of atorvastatin at 20, 40, and 80 mg/day on plasma lipoprotein subclasses were examined in a randomized, placebo-controlled fashion over 24 weeks in 103 patients in the fasting state who had coronary heart disease (CHD) with low-density lipoprotein (LDL) cholesterol levels >130 mg/dl. The effects of placebo and atorvastatin 40 mg/day were examined in 88 subjects with CHD in the fasting state and 4 hours after a meal rich in saturated fat and cholesterol. These findings were compared with results in 88 age- and gender-matched control subjects. Treatment at the 20, 40, and 80 mg/day dose levels resulted in LDL cholesterol reductions of 38%, 46%, and 52% (all p <0.0001), triglyceride reductions of 22%, 26%, and 30% (all p <0.0001), and high-density lipoprotein (HDL) cholesterol increases of 6%, 5%, and 3%, respectively (all p <0.05 at the 20- and 40-mg doses). The lowest total cholesterol/HDL cholesterol ratio was observed with the 80 mg/day dose of atorvastatin (p <0.0001 vs placebo). Remnant-like particle (RLP) cholesterol decreased 33%, 34%, and 32%, respectively (all p <0.0001). Lipoprotein(a) [Lp(a)] cholesterol decreased 9%, 16%, and 21% (all p <0.0001), although Lp(a) mass increased 9%, 8%, and 10%, respectively (all p <0.01). In the fed state, atorvastatin 40 mg/day normalized direct LDL cholesterol (29% below controls), triglycerides (8% above controls), and RLP cholesterol (10% below controls), with similar reductions in the fasting state. At this same dose level, atorvastatin treatment resulted in 39%, 35%, and 59% decreases in fasting triglyceride in large, medium, and small very LDLs, as well as 45%, 33%, and 47% reductions in cholesterol in large, medium, and small LDL, respectively, as assessed by nuclear magnetic resonance (all significant, p <0.05), normalizing these particles versus controls (77 cases vs 77 controls). Moreover, cholesterol in large HDL was increased 37% (p <0.001) by this treatment. Our data indicate that atorvastatin treatment normalizes levels of all classes of triglyceride-rich lipoproteins and LDL in both the fasting and fed states in patients with CHD compared with control subjects.",2002.0,0,0 1583,12356386,Factors affecting low-density lipoprotein and high-density lipoprotein cholesterol response to pravastatin in the West Of Scotland Coronary Prevention Study (WOSCOPS).,Leanne Streja; Chris J Packard; James Shepherd; Stuart Cobbe; Ian Ford; WOSCOPS Group,"Statins are regarded as efficacious in general but there is a wide variation in individual response. We sought demographic and lifestyle factors that influenced the response to pravastatin 40 mg/day in moderately hypercholesterolemic men in the West Of Scotland Coronary Prevention Study (WOSCOPS). Changes in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol after 6 months of treatment were examined in 1,604 highly compliant subjects. LDL cholesterol decreased by a mean of 30.4%. The magnitude of the change was influenced, albeit to a small extent, by baseline plasma triglyceride levels and alcohol intake and age; subjects with low plasma triglyceride levels, older subjects, and subjects with low alcohol intake had the greatest reductions. The mean response in HDL cholesterol in the group was an 8.3% increase (0.09 mmol/L). The percent increase in HDL cholesterol was affected by baseline HDL level, plasma triglyceride levels, decrease in plasma triglyceride levels during the administration of pravastatin, and body mass index. The absolute increase in HDL cholesterol was influenced by the decrease in plasma triglyceride levels, body mass index, and alcohol intake. All of these associations were weak (r <0.2) although highly significant. In conclusion, plasma lipid phenotype, obesity, and alcohol consumption appear to influence the response of LDL and HDL cholesterol to statin treatment. The absolute increment in HDL cholesterol is relatively constant across a range of baseline values, hence the percent change is largely a function of the starting value.",2002.0,0,0 1584,12356387,Additive effect of plant sterol-ester margarine and cerivastatin in lowering low-density lipoprotein cholesterol in primary hypercholesterolemia.,Leon A Simons,"The objective of this study was to evaluate whether plant sterol-ester margarine has an additive or interactive effect on low-density lipoprotein (LDL) cholesterol reduction when ingested in combination with a statin drug. This was a multicenter, randomized, double-blind study with 4 parallel treatment arms in a balanced 2 x 2 factorial design. The 4 daily treatment options were: (1) placebo plus regular margarine 25 g (n = 38); (2) placebo plus sterol-ester margarine 25 g (2 g of plant sterol) (n = 39); (3) cerivastatin 400 microg plus regular margarine 25 g (n = 38); and (4) cerivastatin 400 microg plus sterol-ester margarine 25 g (n = 37). The study was conducted in men and women with primary hypercholesterolemia with baseline LDL cholesterol >/=97 mg/dl (mean 206). The primary efficacy parameter was the percent change in LDL cholesterol between baseline and at the end of 4 weeks' treatment. Cerivastatin (vs placebo) reduced LDL cholesterol by 32% (95% confidence intervals 28% to 36%, p <0.0001) and sterol-ester margarine (vs regular margarine) by 8% (95% confidence interval 4% to 12%, p <0.0001). The effect of sterol-ester margarine and cerivastatin together was additive (39% reduction in LDL cholesterol), but there was no significant interactive effect between sterol-ester margarine and cerivastatin (p = 0.29). The treatments were generally well tolerated with no major differences in adverse events between groups. In subjects with primary hypercholesterolemia, statin and sterol-ester margarine used together produce a purely additive effect on LDL cholesterol reduction. The addition of sterol-ester margarine to statin therapy offers LDL cholesterol reduction equivalent to doubling the dose of statin.",2002.0,0,0 1585,12356389,Effect of atorvastatin on endothelium-dependent vasodilation in postmenopausal women with average serum cholesterol levels.,Giuseppe Mercuro; Sandra Zoncu; Francesca Saiu; Cristiano Sarais; Giuseppe M C Rosano,"After menopause, most healthy women show an impairment of peripheral vasodilation and an increase of plasma cholesterol levels. Statins have been shown to improve endothelial function in hypercholesterolemic men and women. The present study tests whether atorvastatin (10 mg) influences endothelium-dependent vasodilation in postmenopausal normocholesterolemic women. Twenty-eight healthy, postmenopausal women (mean age 51 +/- 2 years) with serum total cholesterol and low-density lipoprotein cholesterol within the desirable range entered a double-blind, single-crossover study. Postmenopausal women were randomized to receive either atorvastatin (10 mg/day) or placebo for 10 days and then crossed to the complementary treatment. Endothelium-dependent and -independent responses were assessed by means of strain-gauge plethysmography before and after intra-arterial infusion of acethylcholine (ACh) and sodium nitroprusside, in comparison to physiologic saline. The nitric oxide pathway was evaluated by repeating the infusion of ACh during admininstration of L-arginine and (G)-monomethyl-L-arginine (L-NMMA). Serum lipoproteins were not significantly modified by the active treatment. The vasodilation induced by ACh was significantly higher in the atorvastatin-treated women compared with the placebo-treated group (24 +/- 3 vs 13 +/- 2 ml/100 ml tissue/min, p <0.01). In contrast, responses to the endothelium-independent vasodilator sodium nitroprusside were not significantly modified by atorvastatin. The ACh-stimulated vasodilation induced by atorvastatin was additionally potentiated by L-arginine (800 +/- 105% vs 370 +/- 60%, p <0.05) and blunted by L-NMMA. No correlation was found between changes in plasma cholesterol and improvement in forearm blood flow. Our data show that the beneficial effect of atorvastatin on endothelium-dependent vasodilation is independent from changes in the lipid profile.",2002.0,0,0 1586,12356401,Effect of morning versus evening intake of simvastatin on the serum cholesterol level in patients with coronary artery disease.,Tor M Lund; Harald Torsvik; Dagfinn Falch; Bjørn Christophersen; Rita Skårdal; Lars Gullestad,,2002.0,0,0 1587,12356402,Effect of atorvastatin (80 mg) initiated at the time of coronary artery stent implantation on C-reactive protein and six-month clinical events.,Achille Gaspardone; Francesco Versaci; Igino Proietti; Fabrizio Tomai; Luca Altamura; Olga Skossyreva; Luigi Chiariello,,2002.0,0,0 1588,12356403,Frequency of new coronary events in older persons with peripheral arterial disease and serum low-density lipoprotein cholesterol > or = 125 mg/dl treated with statins versus no lipid-lowering drug.,Wilbert S Aronow; Chul Ahn,,2002.0,0,0 1589,12356647,ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina).,Eugene Braunwald; Elliott M Antman; John W Beasley; Robert M Califf; Melvin D Cheitlin; Judith S Hochman; Robert H Jones; Dean Kereiakes; Joel Kupersmith; Thomas N Levin; Carl J Pepine; John W Schaeffer; Earl E Smith; David E Steward; Pierre Theroux; Raymond J Gibbons; Joseph S Alpert; David P Faxon; Valentin Fuster; Gabriel Gregoratos; Loren F Hiratzka; Alice K Jacobs; Sidney C Smith; American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina),,2002.0,0,0 1590,12356809,A prospective study of the clarithromycin-digoxin interaction in elderly patients.,P Zapater; S Reus; A Tello; D Torrús; M Pérez-Mateo; J F Horga,The study was a prospective observational trial carried out to assess the clarithromycin-digoxin interaction in elderly patients chronically taking digoxin. Digoxin concentrations were determined before and after concomitant treatment with clarithromycin. A Bayesian approach was used to calculate digoxin pharmacokinetics. In the seven patients who were studied there was a significant increase in digoxin concentration after 4-7 days of clarithromycin treatment; digoxin clearance and elimination rate constant were 56-60% lower and elimination half-life was 82% longer. The pharmacokinetic clarithromycin-digoxin interaction in the elderly may be much more frequent than has been assumed up to now.,2003.0,0,0 1591,12357127,Management of dyslipidemia in the primary prevention of coronary heart disease.,Balkrishna K Singh; Jawahar L Mehta,"Coronary heart disease is a leading cause of death in industrialized nations. Hyperlipidemia with elevated serum total cholesterol, LDL cholesterol, and triglycerides is a known major cardiovascular risk factor. HDL cholesterol is considered to be protective, so low HDL cholesterol is being recognized as an independent cardiovascular risk factor that contributes to the development of atherosclerosis and related adverse cardiovascular events. The recognition of insulin resistance and metabolic syndrome is a step further in understanding these risk factors. Attempts at reducing serum cholesterol with different strategies in the past have met with limited success until the development of statins. The advent of statins has revolutionized the management of hyperlipidemia. The post-statins era has seen major clinical trials demonstrating the benefit of cholesterol reduction in the setting of both primary and secondary prevention. In general, there appears to be a 25% to 40% relative risk reduction in major adverse cardiovascular events such as death, myocardial infarction, and stroke. The recent megatrials further suggest that aggressive management of cholesterol in patients with high cardiovascular risk may be beneficial. Though the concept of the-lower-the-better may be looming, the question of ""How low is good enough?"" remains controversial. The results of recent megatrials such as the Heart Protection Study go a step further than the NCEP guidelines and suggest that statin therapy may benefit patients at high risk of cardiovascular disease regardless of their baseline values. We summarize the results of the available large clinical trials in our understanding of the management of dyslipidemia in a setting of primary prevention.",2003.0,0,0 1592,12358579,Epidemiological modelling (including economic modelling) and its role in preventive drug therapy.,Danny Liew; John J McNeil; Anna Peeters; Stephen S Lim; Theo Vos,"In contrast to curative therapies, preventive therapies are administered to largely healthy individuals over long periods. The risk-benefit and cost-benefit ratios are more likely to be unfavourable, making treatment decisions difficult. Drug trials provide insufficient information for treatment decisions, as they are conducted on highly selected populations over short durations, estimate only relative benefits of treatment and offer little information on risks and costs. Epidemiological modelling is a method of combining evidence from observational epidemiology and clinical trials to assist in clinical and health policy decision-making. It can estimate absolute benefits, risks and costs of long-term preventive strategies, and thus allow their precise targeting to individuals for whom they are safest and most cost-effective. Epidemiological modelling also allows explicit information about risks and benefits of therapy to be presented to patients, facilitating informed decision-making.",2002.0,0,0 1593,12360153,Design features of the Avasimibe and Progression of coronary Lesions assessed by intravascular UltraSound (A-PLUS) clinical trial.,Jean-Claude Tardif; Jean Grégoire; Jacques Lespérance; Jean Lambert; Philippe L L'Allier; Josep Rodés; Todd Anderson; John W Blue; James Imus; Therese Heinonen,"Although statins have been shown to be beneficial in the management of hyperlipidemia and the reduction of cardiovascular morbidity and mortality, rates of major cardiovascular events remain high despite their use. Inhibition of the acyl coenzyme A: cholesterol acyltransferase (ACAT) enzyme in the arterial wall may prevent excess accumulation of cholesteryl esters in macrophages. In addition to ACAT inhibitor monotherapy, combination of a statin with an ACAT inhibitor may be a promising approach to further prevent the progression of atherosclerosis. This report describes the design and methodologic features of a double-blind, randomized, placebo-controlled trial to assess the effect of the ACAT inhibitor avasimibe at 50-, 250-, and 750-mg daily dosages on the progression of coronary atherosclerosis as assessed by intravascular ultrasound (IVUS). All patients receive background lipid-lowering therapy when necessary. The study population consists of patients with at least one 20% to 50% diameter stenosis in a coronary artery with a reference diameter of > or =2.5 mm. IVUS and coronary angiography are performed at baseline and repeated at 24 months. The primary study end point is the change from baseline in plaque volume in a 30-mm segment of the coronary artery assessed by 3-dimensional IVUS. Several other IVUS and angiographic end points are measured. The Avasimibe and Progression of coronary Lesions assessed by intravascular UltraSound (A-PLUS) trial is among the first large imaging trials to use IVUS as a primary end point and assesses the effects of the ACAT inhibitor avasimibe on atherosclerosis progression.",2002.0,0,0 1594,12360164,Is alternate daily dose of atorvastatin effective in treating patients with hyperlipidemia? The Alternate Day Versus Daily Dosing of Atorvastatin Study (ADDAS).,Mazen S Matalka; Marcus C Ravnan; Prakash C Deedwania,"The objective of this pilot study was to evaluate the comparative efficacy of alternate-day dosing of atorvastatin compared with the standard once-daily dose based on mean low-density lipoprotein (LDL) reduction from baseline at 6 and 12 weeks of treatment. In a double-blind, placebo-controlled design, 35 eligible patients who met the National Cholesterol Education Program (NCEP) Adult Treatment Panel II (ATP II) guidelines for drug therapy, depending on their risk factors, were randomly assigned to receive 10 mg of atorvastatin as an initial dose every day or every other day. Patients were assessed at 6 and 12 weeks as to whether they met the LDL-C goal, and the dose was doubled if the goal was not reached. LDL-C decreased by 27% and 38%, in the every-other-day (n = 15) and every-day (n = 15) groups, respectively, at 6 weeks. At 12 weeks, the LDL-C was reduced by 35% and 38% in the every-other-day and every-day groups, respectively (P =.49). The mean dose was 18 mg (9 mg/d) in the alternate-day group (n = 14) and 12 mg/d in the every-day group (n = 12) at the end of the 12 weeks (P =.001). Although higher doses of atorvastatin were used on alternate days, these results suggest that the alternate-day administration of atorvastatin can produce a reduction in LDL-C comparable to that of daily administration in patients with hypercholesterolemia, and yet provide some cost savings.",2002.0,0,0 1595,12361185,Homocysteine and ADMA--emerging risk factors for cardiovascular disease?,Thomas Hedner; Anders Himmelmann; Lennart Hansson,,2003.0,0,0 1596,12361824,Myocardial infarction and heart failure-a dangerous intersection.,Marc Pfeffer,,2002.0,0,0 1597,12361836,Understanding and treating vein graft atherosclerosis.,Jennifer M Sarjeant; Marlene Rabinovitch,"Vein grafts have been used as bypass conduits for coronary artery disease since the 1960s. This widely used treatment, however, is complicated by the development of changes in the vein graft, which resemble atherosclerosis and are often termed as such. They occur at about 10 years, which leads to the need for reoperation in some patients. The purpose of this review is to summarize the knowledge regarding the pathophysiology of vein graft ""atherosclerosis,"" as well as promising new treatments for this disease. The relevant literature relating to the epidemiology, histology, cell and molecular pathophysiology and treatment of vein graft atherosclerosis is reviewed. The development of vein graft atherosclerosis differs from arterial atherosclerosis. Studies have examined the role of trauma, lipids, vasoactive mediators, smooth muscle cell mitogens, smooth muscle cells apoptosis, adhesion molecules and proteases. Therapies have been developed to prevent vein graft atherosclerosis based on these studies and have been tested using animal models and in patients. Promising new therapies have been developed based on current knowledge and further applications of genomics will allow for the further identification of risk factors and mechanistic insights. The use of arterial grafts such as the internal mammary artery, which have higher patency rates at 10 years compared with vein grafts as well as approaches to revascularize infarcted myocardium may one day replace the use of vascular conduits.",2003.0,0,0 1598,12362926,No effect of age or gender on the pharmacokinetics of rosuvastatin: a new HMG-CoA reductase inhibitor.,Paul D Martin; Aaron L Dane; Olise M Nwose; Dennis W Schneck; Mike J Warwick,"The effects of age and gender on the pharmacokinetics of rosuvastatin (Crestor) were assessed in healthy young (18-35 years) and elderly (> 65 years) males and females in this open, nonrandomized, noncontrolled, parallel-group trial. Sixteen males and 16 females (8 young and elderly volunteers per gender group) were enrolled. Mean (range) ages were 24 (18-33) and 68 (65-73) years for young and elderly volunteers, respectively. Volunteers were given a single oral 40 mg dose of rosuvastatin. Blood samples for measurement of rosuvastatin plasma concentration were collected up to 96 hours following dosing. Age and gender effects were assessed by constructing 90% confidence intervals (CIs) around the ratios of young/elderly and male/female geometric least square means (glsmeans) for AUC(0-t) and Cmax (derived from ANOVA of log-transformed parameters). Small differences in rosuvastatin pharmacokinetics were noted between age and gender groups. Glsmean AUC(0-t) was 6% higher (90% CI = 0.86-1.30) and glsmean Cmax, 12% higher (90% CI = 0.83-1.51) in the young compared with the elderly group. Glsmean AUC(0-t) was 9% lower (90% CI = 0.74-1.12) and glsmean Cmax 18% lower (90% CI = 0.61-1.11) in the male compared with the female group. These small differences are not considered clinically relevant, and dose adjustments based on age or gender are not anticipated. Rosuvastatin was well tolerated in all volunteers.",2003.0,0,0 1599,12362931,The effect of erythromycin and clarithromycin on the pharmacokinetics of intravenous digoxin in healthy volunteers.,Kimiko Tsutsumi; Tsutomu Kotegawa; Masae Kuranari; Yasukiyo Otani; Takuya Morimoto; Shunji Matsuki; Shigeyuki Nakano,"Several case reports have suggested an interaction between digoxin and macrolide antibiotics. The authors investigated the effect of erythromycin and clarithromycin on the pharmacokinetics of intravenously administered digoxin (0.5 mg) in healthy subjects. Nine male subjects participated in three studies (digoxin alone, digoxin with erythromycin, and digoxin with clarithromycin). Subjects took erythromycin (800 mg per day) or clarithromycin (400 mg per day) on the day before digoxin dosing and during the kinetic study, Neither of the macrolides affected serum digoxin concentration-time curves. However, more than 1.3-fold increases in urinary digoxin excretions were observed during erythromycin and clarithromycin coadministration compared with digoxin alone. There were significant differences in renal clearance between macrolide coadministration and the control condition (digoxin alone: 98.4 ml/min; digoxin with erythromycin: 137.3 ml/min; digoxin with clarithromycin: 133.6 ml/min). In conclusion, neither erythromycin nor clarithromycin has a significant effect on serum digoxin disposition after an intravenous administration. Renal digoxin excretion is not inhibited but rather enhanced by both macrolides.",2003.0,0,0 1600,12364554,Effects of atorvastatin on the HDL subpopulation profile of coronary heart disease patients.,Bela F Asztalos; Katalin V Horvath; Judith R McNamara; Paul S Roheim; Joel J Rubinstein; Ernst J Schaefer,"We investigated the effects of atorvastatin on the lipid and the apoA-I-containing HDL subpopulation profiles in 86 patients with established coronary heart disease (CHD). The entire drug treatment period lasted 12 weeks (4-week periods of 20 then 40, then 80 mg/day). Each dose of atorvastatin treatment resulted in significant reductions in plasma total-C, LDL-C, and triglyceride (TG), and non-significant increases in HDL-C levels compared with placebo treatment. ApoA-I levels did not change significantly during any of the treatment periods. Despite the modest increase of HDL-C (6%, 7%, 5%) and no change in apoA-I levels, the distribution of the apoA-I-containing HDL subpopulations changed significantly during each treatment period. There were significant increases in the concentrations of the large LpA-I alpha-1 (24%, 39%, 26%) and pre alpha-1 (51%, 61%, 63%) subpopulations at the expense of the small lipoprotein LpA-I:A-II alpha-3 subpopulations which decreased on all doses, and the decreases were significant on the 40 and 80 mg/day doses (6%, 5%). Atorvastatin influences the lipid-related risk for CHD in two ways: first, it significantly decreases LDL-C and TG levels while increasing HDL-C, and second, it significantly shifts the HDL subpopulation profile of CHD patients toward that observed in subjects without CHD.",2003.0,0,0 1601,12365855,Statins and renal function.,Moses Elisaf; Dimitri P Mikhailidis,"Renal disease is often associated with an increased risk of vascular events. Moreover, an accelerated form of atherosclerosis commonly occurs in these patients. The reasons for these associations are not clearly defined but include the widespread presence of several established risk factors (eg, dyslipidemia, hypertension, and diabetes). Other predictors of atherosclerotic disease may also be abnormally elevated (eg, homocysteine, fibrinogen, and lipoprotein a). In addition, there is evidence that impaired renal function per se predicts vascular risk. Despite this high-risk background, the potential benefit of treatment with statins has not been widely investigated in these patients. The present review considers the evidence (experimental and clinical) that statins exert beneficial effects in patients with different types of renal disease. This includes improved renal function, decreased microalbuminuria, and a fall in blood pressure. Statins may also improve renal allograft survival. The potential mechanisms mediating these effects are considered. The interactions between statins and several risk factors that may be present in patients with impaired renal function are also considered. There is an urgent need to define the role of statins in these high-risk patients. Which is the statin of choice? This question is relevant because impaired renal function can interfere with statin pharmacokinetics. Furthermore, other drugs administered to these patients may cause serious interactions with statins.",2002.0,0,0 1602,12366601,Inflammatory bio-markers and cardiovascular risk prediction.,G J Blake; P M Ridker,"Inflammatory processes are now recognized to play a central role in the pathogenesis of atherosclerosis and its complications. Plasma levels of several markers of inflammation have been found to be associated with future cardiovascular risk in a variety of clinical settings. These markers include cell adhesion molecules, cytokines, pro-atherogenic enzymes and C-reactive protein (CRP). Initially thought of as an inactive downstream marker of the inflammatory cascade, emerging evidence suggests that CRP may be directly involved in atherogenesis, and that arterial plaque can produce CRP, independent of traditional hepatic pathways. In addition to being a strong predictor of future cardiovascular risk amongst patients presenting with acute coronary syndromes, numerous studies have found that baseline levels of CRP are associated with risk of future myocardial infarction, stroke, peripheral vascular disease and cardiovascular death amongst apparently healthy populations. The combination of measurement of a marker of inflammation with lipid testing may improve upon risk stratification based on lipid testing alone, and intensification of programmes for exercise, weight loss, and smoking cessation is recommended for those with elevated CRP levels. Further trials are needed to confirm the potential benefits of statins amongst individuals with elevated CRP levels.",2002.0,0,0 1603,12368073,Statins as anti-inflammatory agents.,Gabriele Weitz-Schmidt,"The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in cardiovascular disease have generally been attributed to their cholesterol-lowering property. However, an increasing number of in vitro and in vivo studies indicate that statins have direct anti-inflammatory effects that are not mediated by their hypocholesterolemic activity. In this article, the HMG-CoA-reductase-dependent and -independent mechanisms by which statins might affect leukocyte adhesion and migration to sites of inflammation are reviewed and the implications for the design of new statin-derived drugs are discussed.",2002.0,0,0 1604,12369881,Clinical significance of pleiotropic effects of statins: lipid reduction and beyond.,J Auer; R Berent; T Weber; B Eber,"Statins significantly reduce cardiovascular-related morbidity and mortality in patients with and without coronary artery disease. The potential of this drug class has yet to be fully explored. Accumulating evidence from basic research and clinical trials indicates that statins have pleiotropic effects that may largely account for the clinical benefits observed. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. Statins have been shown to stabilize unstable plaques, improve vascular relaxation, and promote new vessel formation. Clinical trials and animal studies have shown that these agents reduce cardiovascular disease (CVD) risks and events, progression of nephropathy, development of diabetes, and fracture rates; these are benefits that go beyond lipid lowering alone. Potential beneficial effects are due to the positive impact on vascular and glomerular nitric oxide (NO) production and attenuation of vascular inflammation. Effects on bone, including fracture reduction, are thought to be mediated by direct action on bone formation. Moreover, potential reduction in the development of diabetes as observed in the West of Scotland Coronary Prevention Study (WOSCOPS) may relate to the improvement in insulin sensitivity. These actions are mediated, in part, by the effects on small G-proteins, modulation of signaling cascades, transcription, and gene expression. In particular, the inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall. The clinical relevance of these effects is beginning to be recognized, and ongoing studies will be able to answer these many questions in the near future. Actions of statins on vascular, glomerular, bone, and insulin-sensitive tissue as well as effects of statins on cognitive function and oncoprotection will be discussed in this review.",2003.0,0,0 1605,12370211,Missed opportunities to treat atherosclerosis in patients undergoing peripheral vascular interventions: insights from the University of Michigan Peripheral Vascular Disease Quality Improvement Initiative (PVD-QI2).,Debabrata Mukherjee; Prasanth Lingam; Stanley Chetcuti; P Michael Grossman; Mauro Moscucci; Ann E Luciano; Kim A Eagle,"Peripheral vascular disease is a manifestation of systemic atherosclerosis and is associated with an increased risk of cardiovascular morbidity and mortality. We examined clinical outcomes in 66 consecutive patients undergoing peripheral vascular interventions at our institution between January 2001 and October 2001. At hospital discharge and at 6 months, lifestyle modifications and use of evidence-based therapy was suboptimal. At 6 months, a significant proportion continued to smoke (22.7%) and only half of the patients exercised, controlled their weight, or modified their diet for lipid control. The use of antiplatelet therapy was 77.2%; of angiotensin-converting enzyme, 35.9%; of beta-blockers, 42.5%; and of statins, 50%. Twelve of the 66 patients (18.2%) had a clinical event of death, myocardial infarction, or stroke. An appropriateness algorithm for use of secondary prevention measures was created with the use of evidence-based therapy guidelines, and a composite appropriateness variable was also created. The use of evidence-based therapy was associated with a significant reduction of the composite of death, myocardial infarction, and stroke at 6 months (OR 0.02, 95% CI 0.01 to 0.44, P=0.01). Atherosclerosis risk factors are very prevalent in patients with peripheral vascular disease, but these patients receive less than optimal treatment after a predominantly technical vascular intervention. Effective secondary prevention with appropriate lifestyle interventions and evidence-based medical therapy needs to be strongly encouraged and implemented in these patients.",2002.0,0,0 1606,12370451,Statins as immunomodulators: comparison with interferon-beta 1b in MS.,O Neuhaus; S Strasser-Fuchs; F Fazekas; B C Kieseier; G Niederwieser; H P Hartung; J J Archelos,"Recent data suggest that statins may be potent immunomodulatory agents. In order to evaluate the potential role of statins as immunomodulators in MS, the authors studied their immunologic effects in vitro and compared them to interferon (IFN)beta-1b. Peripheral blood mononuclear cells (PBMC) obtained from untreated or IFN beta-1-treated patients with relapsing-remitting MS or from healthy donors (HD) and T cells were stimulated with concanavalin A, phytohemagglutinin, or antibody to CD3 in the presence of lovastatin, simvastatin, mevastatin, IFN beta-1b, or statins plus IFN beta-1b. The authors analyzed proliferative activity of T cells and B cells, cytokine production and release, activity of matrix metalloproteinases (MMP), and surface expression of activation markers, adhesion molecules, and chemokine receptors on both T and B cells. All three statins inhibited proliferation of stimulated PBMC in a dose-dependent manner, with simvastatin being the most potent, followed by lovastatin and mevastatin. IFN beta-1b showed a similar effect; statins and IFN beta-1b together added their inhibitory potentials. Furthermore, statins reduced the expression of activation-induced adhesion molecules on T cells, modified the T helper 1/T helper 2 cytokine balance, reduced MMP-9, and downregulated chemokine receptors on both B and T cells. Besides strong anti-inflammatory properties, statins also exhibited some proinflammatory effects. Statins are effective immunomodulators in vitro that merit evaluation as treatment for MS.",2002.0,0,0 1607,12371982,Incident acute coronary syndromes in chronic dialysis patients in the United States.,Fernando C Trespalacios; Allen J Taylor; Lawrence Y Agodoa; Kevin C Abbott,"Patients on dialysis have a disproportionately high rate of cardiovascular disease (CVD). However, the incidence and risk factors for incident acute coronary syndromes (ACS) have not been previously assessed in dialysis patients. We analyzed the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave II in a historical cohort study of ACS. Data from 3374 patients who started dialysis in 1996 with valid follow-up times were available for analysis, censored at the time of renal transplantation and followed until March 2000. Cox regression analysis was used to model factors associated with time to first hospitalization for ACS (ICD9 code 410.x or 411.x) adjusted for comorbidities, demographic factors, baseline laboratory values, blood pressures and cholesterol levels, type of vascular access, dialysis adequacy, and cardioprotective medications (angiotensin-converting enzyme inhibitors, calcium channel blockers, HMG-CoA reductase inhibitors (statins), beta blockers, and aspirin). Follow-up was 2.19 +/- 1.14 years. The incidence of ACS was 29/1000 person-years. Factors associated with ACS were older age, the extreme high and low ranges of serum cholesterol level, history of coronary heart disease (CHD), male gender, and diabetes. No cardioprotective medications including statins had a significant association with ACS in this study. However, medications known to reduce mortality after ACS were used in less than 50% of patients with known CHD at the start of the study, and statins were used in less than 10% of patients with CHD. Dialysis patients had similar risk factors for ACS compared to the general population. Cardioprotective medications were not associated with a significant benefit, possibly due to their striking underutilization in this at-risk population.",2003.0,0,0 1608,12372576,Usefulness of lipid-lowering therapy in elderly patients.,Nanette K Wenger,,2002.0,0,0 1609,12372577,Effects of atorvastatin 80 mg daily early after onset of unstable angina pectoris or non-Q-wave myocardial infarction.,Furio Colivicchi; Vincenzo Guido; Marco Tubaro; Fabrizio Ammirati; Nicola Montefoschi; Antonio Varveri; Massimo Santini,,2002.0,0,0 1610,12372582,Effectiveness of multiple antilipidemic agents on Vertical Auto Profile II guided treatment of dyslipoproteinemia.,Christopher M Rembold; Rongrong Fan; Karen E Rembold; Carlos R Ayers,,2002.0,0,0 1611,12374252,Statin lipid-lowering therapy for acute myocardial infarction and unstable angina: efficacy and mechanism of benefit.,R Scott Wright; Joseph G Murphy; Kevin A Bybee; Stephen L Kopecky; Jean-Marc LaBlanche,"The use of statin agents in patients with acute coronary syndromes (ACSs) remains an area of intense clinical interest. Statin therapy has an established secondary preventive benefit in patients with coronary artery disease, and its extension to ACS seems logical. A number of observational studies have shown an association between initiation of statin therapy early in ACS and improved clinical outcome. Additionally, 4 randomized controlled trials have examined the use of statin therapy for ACS: the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, the Pravastatin Turkish Trial, the Fluvastatin on Risk Diminishing After Acute Myocardial Infarction (FLORIDA) study, and the Lipid-Coronary Artery Disease (L-CAD) study. Three of these trials showed a benefit with early initiation of statin therapy, whereas 1 trial demonstrated neither benefit nor harm. All the available trials lacked the power and design to sufficiently evaluate whether early initiation of statin therapy reduces mortality and reinfarction in patients with ACS. Four ongoing trials have been designed and sufficiently powered to determine whether statin therapy reduces the risk of death and reinfarction when initiated early in ACS treatment. A body of evidence suggests that the pleiotropic actions of statin agents might modulate benefit in ACS. This article summarizes the available data and provides a rationale for early initiation of statin therapy for patients with ACS.",2002.0,0,0 1612,12374669,Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors.,Ramzi Dagher; Martin Cohen; Gene Williams; Mark Rothmann; Jogarao Gobburu; Gabriel Robbie; Atiqur Rahman; Gang Chen; Ann Staten; Donna Griebel; Richard Pazdur,"Imatinib mesylate (Gleevec; Novartis, East Hanover, NJ)is a receptor tyrosine kinase inhibitor approved previously in 2001 by the United States Food and Drug Administration for the treatment of chronic myelogenous leukemia in blast crisis, accelerated phase, or in chronic phase after failure of IFN-alpha therapy. We review herein the clinical profile of this drug and the regulatory review leading to the approval of a supplemental New Drug Application for the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors (GISTs). We discuss the efficacy and side effects of imatinib mesylate in a Phase II trial of 147 patients with metastatic and/or unresectable malignant GISTs, the basis for marketing approval, and postmarketing commitments by the drug's manufacturer. Imatinib was assessed in a single, open-label trial involving one European center and three centers in the United States. Seventy-three patients were randomly allocated to receive 400 mg of imatinib daily, and 74 patients received 600 mg daily. At the study report cutoff date, an objective response was confirmed in 56 patients; the overall response rate for the combined study arms was 38% (95% confidence interval, 30-46%). These responses were all partial responses. There was no statistically significant difference in response rates between the two dose groups. Adverse events included edema, fluid retention, nausea, vomiting, diarrhea, myalgias, skin rash, bone marrow suppression, bleeding, and elevations in aspartate aminotransferase, alanine aminotransferase, or bilirubin. Bleeding into the gastrointestinal tract or intratumoral sites occurred in 7 patients (5%) and was not correlated with thrombocytopenia or tumor bulk. The pharmacokinetics of imatinib in GIST patients were similar to those of chronic myelogenous leukemia patients. On February 1, 2001, imatinib mesylate was approved by the United States Food and Drug Administration for the treatment of malignant metastatic and/or unresectable GISTs. The recommended dose is 400 or 600 mg daily.",2003.0,0,0 1613,12375804,Inflammatory predictors of mortality in the Scandinavian Simvastatin Survival Study.,Filippo Crea; Claudia Monaco; Gaetano A Lanza; Elena Maggi; Francesca Ginnetti; Domenico Cianflone; Giampaolo Niccoli; Thomas Cook; Giorgio Bellomo; John Kjekshus,"The predictive value of specific markers of infection and autoimmunity for coronary events, such as the effects of statins on inflammation, is still controversial. A case-control design was used to compare C-reactive protein (CRP) levels, seropositivity for Chlamydia pneumoniae and Helicobacter pylori, and anti-oxidized low-density lipoprotein (oxLDL) antibody levels in prerandomization blood samples from 129 participants in the Scandinavian Simvastatin Survival Study who died (cases), and from 129 matched participants who were alive during 5-year follow-up (controls). Patients with CRP levels in the highest quartile had an increased risk of death compared with those in the first through third quartile (odds ratio [OR] = 2.51, 95% confidence interval [CI] 1.3-4.8). Seropositivity for Chlamydia pneumoniae or Helicobacter pylori and anti-oxLDL antibody levels were similar in cases and controls (p = NS). At a 4-month control, simvastatin reduced CRP levels (p = 0.009) while placebo did not (p = NS). However, the risk of death associated with high baseline CRP levels was similar in patients randomized to placebo (OR = 2.36, 95% CI 1.06-5.26) or simvastatin (OR = 3.13, 95% CI 1.06-9.21). Elevated CRP levels, but not seropositivity for Chlamydia pneumoniae or Helicobacter pylori, nor levels of anti-oxLDL antibodies, predict the risk of death in patients with stable ischemic heart disease. Simvastatin treatment reduces CRP levels, but without affecting the increased risk conferred by higher CRP levels at baseline.",2003.0,0,0 1614,12379573,ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness.,Allen J Taylor; Steven M Kent; Patrick J Flaherty; Louis C Coyle; Thor T Markwood; Marina N Vernalis,"Whether marked LDL reduction to levels well below 100 mg/dL would further reduce the burden of cardiovascular disease is controversial. We compared the effects of 2 statins with widely differing potencies for LDL reduction (pravastatin 40 mg/d and atorvastatin 80 mg/d) on carotid intima-media thickness (CIMT). This was a single-center, randomized, clinical trial of 161 patients (mean age, 60 years; 71.4% male; 46% with known cardiovascular disease) that met National Cholesterol Education Program (NCEP) II criteria for lipid-lowering therapy. The effects of atorvastatin (80 mg/d; n=79) and pravastatin (40 mg/d; n=82) on CIMT were compared using blinded, serial assessments of the far wall of the distal common carotid artery. Baseline CIMT and other characteristics were similar between study groups. As anticipated, atorvastatin was substantially more potent for LDL reduction after 12 months: in the atorvastatin group, LDL cholesterol was 76+/-23 mg/dL after 12 months (-48.5%); LDL cholesterol was 110+/-30 mg/dL in the pravastatin group (-27.2%; P<0.001). Atorvastatin induced progressive CIMT regression over 12 months (change in CIMT, -0.034+/-0.021 mm), whereas CIMT was stable in the pravastatin group (change of 0.025+/- 0.017 mm; P=0.03). Marked LDL reduction (<100 mg/dL) with a high-potency statin provides superior efficacy for atherosclerosis regression at 1 year. This early effect on CIMT, a surrogate for clinical benefit, suggests that marked LDL reduction with synthetic statins may provide enhanced reduction in clinical coronary event rates.",2002.0,0,0 1615,12381235,HIV disease and advanced age: an increasing therapeutic challenge.,Roberto Manfredi,"The mean age of patients at both first HIV detection and AIDS diagnosis is progressively rising over time. However, reliable epidemiological estimates, clinical data or controlled therapeutic and outcome figures are lacking for elderly patients, especially with regard to laboratory and clinical response to antiretroviral therapy, treatment tolerability, drug-drug interactions, short- and long-term toxicity, and interactions with underlying illnesses and concurrent pharmacological treatment. In fact, the large majority of randomised, controlled trials evaluating and comparing new antiretroviral drugs or anti-HIV therapeutic strategies, as well as antimicrobial treatment or chemoprophylaxis of HIV-related complications, either excluded patients with advanced age and/or concurrent disorders or did not offer substudies or detailed data analysis focusing on older patients compared with younger ones. The life expectancy of HIV-infected persons receiving highly active antiretroviral therapy (HAART) is now extended (approaching that of the general population), so that the definition of AIDS has lost its epidemiological and clinical significance thanks to the immune reconstitution resulting from potent antiretroviral therapy. However, an ever-increasing number of individuals aged > or =50 years with HIV infection is expected in the coming years, as a result of both increased survival of patients with treated disease and delayed recognition of individuals with occult HIV disease. The limited data available about combined antiretroviral therapy in the elderly seem to show an overlapping virological success rate but a slower and blunted immune recovery compared with younger patients. Thymic output, however, seems somewhat preserved even in adulthood and may contribute to the reconstitution of most of the quantitative and functional T cell abnormalities caused by HIV disease. More attention must be paid to underlying end-organ disorders, as well as expected pharmacological interactions and combined drug toxicity that may interfere with HAART efficacy and patients' compliance with recommended regimens and could lead to increased adverse effects. The available guidelines for antiretroviral treatment and therapy and prophylaxis of AIDS-related illnesses should be regularly updated and should include problems related to HIV disease in an aging population. Specific trials or substudies focusing on older people are warranted to obtain controlled data on all issues of antiretroviral therapy in the elderly, including time and mode of initiation, and modification and salvage HAART regimens. Antiretroviral drug dosage adjustment to take into account underlying pathological conditions or other pharmacological treatments is another emerging issue.",2002.0,0,0 1616,12381246,The Heart Protection Study: implications for clinical practice. The benefits of statin therapy do not come without financial cost.,Ian Hamilton-Craig,,2002.0,0,0 1617,12381248,"Clinical trials and ""real-world"" medicine. Trial evidence best informs real-world medicine when it is relevant to the clinical problem.",R John Simes,,2002.0,0,0 1618,12381252,Cholesterol-lowering therapy with pravastatin in patients with average cholesterol levels and established ischaemic heart disease: is it cost-effective?,Paul P Glasziou; Simon D Eckermann; Sarah E Mulray; R John Simes; Andrew J Martin; Adrienne C Kirby; Jane P Hall; Susan Caleo; Harvey D White; Andrew M Tonkin,"To measure the cost-effectiveness of cholesterol-lowering therapy with pravastatin in patients with established ischaemic heart disease and average baseline cholesterol levels. Prospective economic evaluation within a double-blind randomised trial (Long-Term Intervention with Pravastatin in Ischaemic Disease [LIPID]), in which patients with a history of unstable angina or previous myocardial infarction were randomised to receive 40 mg of pravastatin daily or matching placebo. 9014 patients aged 35-75 years from 85 centres in Australia and New Zealand, recruited from June 1990 to December 1992. Cost per death averted, cost per life-year gained, and cost per quality-adjusted life-year gained, calculated from measures of hospitalisations, medication use, outpatient visits, and quality of life. The LIPID trial showed a 22% relative reduction in all-cause mortality (P < 0.001). Over a mean follow-up of 6 years, hospital admissions for coronary heart disease and coronary revascularisation were reduced by about 20%. Over this period, pravastatin cost $A4913 per patient, but reduced total hospitalisation costs by $A1385 per patient and other long-term medication costs by $A360 per patient. In a subsample of patients, average quality of life was 0.98 (where 0 = dead and 1 = normal good health); the treatment groups were not significantly different. The absolute reduction in all-cause mortality was 3.0% (95% CI, 1.6%-4.4%), and the incremental cost was $3246 per patient, resulting in a cost per life saved of $107 730 (95% CI, $68 626-$209 881) within the study period. Extrapolating long-term survival from the placebo group, the undiscounted cost per life-year saved was $7695 (and $10 938 with costs and life-years discounted at an annual rate of 5%). Pravastatin therapy for patients with a history of myocardial infarction or unstable angina and average cholesterol levels reduces all-cause mortality and appears cost effective compared with accepted treatments in high-income countries.",2002.0,0,0 1619,12383389,[Methods of reporting research-results and their influence on decision-making by cardiologists prescribing drugs for primary and secondary prevention].,Carlos Brotons; Irene Moral; Aida Ribera; Purificación Cascant; Manuel Iglesias; Gaietà Permanyer-Miralda; Ignacio Ferreira González; Jordi Soler-Soler,"To assess the influence of the form of presentation of the results of clinical trials on the quantitative perceptions of cardiologists regarding the efficacy of drugs for the primary and secondary prevention of coronary heart disease and their likelihood of prescribing them. We conducted a survey of 1,408 cardiologists in Spain who were randomly allocated of three questionnaires that used different measurements to evaluate the impact of published clinical trials. Five-hundred and fifty-nine questionnaires (40%) were suitable for analysis. On a scale of 0 to 10, the following mean efficacy estimates were obtained from questionnaire items that focused, respectively, on the results of clinical trials in terms of relative risk reduction, absolute risk reduction, and number needed to treat: primary prevention with statins: 6.79, 6.38 and 5.43; primary prevention with aspirin: 6.84, 5.06 and 4.25; secondary prevention with statins: 8.16, 7.76 and 7.54; secondary prevention with ACE inhibitors: 7.11, 7.81 and 7.19, and secondary prevention with beta-blockers: 7.22, 7.43 and 6.98. The likelihood that a drug treatment would be prescribed was not influenced very much by the form of presentation of the trial results. Presenting the results of clinical trials in the form of relative risk reduction, as compared with presenting results in terms of absolute risk reduction or number needed to treat, led to overestimation of the efficacy of interventions without influencing the likelihood of prescribing a given drug therapy.",2003.0,0,0 1620,12383588,ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).,Eugene Braunwald; Elliott M Antman; John W Beasley; Robert M Califf; Melvin D Cheitlin; Judith S Hochman; Robert H Jones; Dean Kereiakes; Joel Kupersmith; Thomas N Levin; Carl J Pepine; John W Schaeffer; Earl E Smith; David E Steward; Pierre Theroux; Raymond J Gibbons; Joseph S Alpert; David P Faxon; Valentin Fuster; Gabriel Gregoratos; Loren F Hiratzka; Alice K Jacobs; Sidney C Smith; American College of Cardiology; American Heart Association. Committee on the Management of Patients With Unstable Angina,,2002.0,0,0 1621,12384626,Drug-eluting stent: the emerging technique for the prevention of restenosis.,I Sheiban; L Carrieri; B Catuzzo; P Destefanis; E Oliaro; C Moretti; G P Trevi,"Percutaneous coronary interventions (PCI) have surpassed coronary artery bypass grafting as the most common means for treating coronary artery disease, because of materials improvement, the use of stent and pharmacotherapy. However, despite the variety of mechanical techniques such as dilatation, debulking or conventional stent implantation, the incidence of restenosis on short and mid-term follow-up is still representing an important limitation to PCI. Restenosis is mainly due to elastic recoil, negative vessel remodelling and neointimal proliferation, as a response to vessel injury induced by angioplasty devices. The use of conventional stents has provided an efficient method to avoid elastic recoil and negative vessel remodelling, thus partially reducing restenosis as compared to conventional balloon dilatation. However, neointimal proliferation (biological vessel response to injury caused by stent implantation) is not affected by stenting technique. Thus, the extensive use of coronary stent, even in complex lesions, have produced again a ""new"" disease: the in-stent restenosis especially in some patients' subset (diabetics) or in some lesion subset (bifurcations, long lesions, small vessels, total occlusions, diffuse disease). Therefore, the main target of today's interventional cardiologists is to resolve this problem. The combination between mechanical control of elastic recoil and negative remodelling (stent) and the control of neointimal proliferation - biological response to vessel injury - (antiproliferative drugs) is the emerging approach against restenosis. This emerging approach consists in using the stent as drug carrier to the target site. Local delivery of antiproliferative or immunosuppressive agents using a drug-coated stent is supposed to inhibit in stent restenosis. The first antiproliferative agents being used successfully in clinical trials are sirolimus and paclitaxel and, so far, the data available of these trials demonstrated a marked reduction of restenosis using sirolimus- and paclitaxel-coated stents as compared to conventional stents. However, many questions are still to be answered and several other clinical trials with drug-eluting stents are ongoing, evaluating safety and efficacy of sirolimus and paclitaxel in a larger number of patients and in different subset of coronary lesions type and morphology. Based on the very impressive results available at the present time, we can expect, in the very near future, remarkable changes in our clinical practice and the beginning of a new ""era"" of interventional cardiology.",2003.0,0,0 1622,12385592,Role of oxidative stress and antioxidants in neurodegenerative diseases.,A V Rao; B Balachandran,"Neurodegenerative diseases (NDD) are a group of illness with diverse clinical importance and etiologies. NDD include motor neuron disease such as amyotrophic lateral sclerosis (ALS), cerebellar disorders, Parkinson's disease (PD), Huntington's disease (HD), cortical destructive Alzheimer's disease (AD) and Schizophrenia. Numerous epidemiological and experimental studies provide many risk factors such as advanced age, genetic defects, abnormalities of antioxidant enzymes, excitotoxicity, cytoskeletal abnormalities, autoimmunity, mineral deficiencies, oxidative stress, metabolic toxicity, hypertension and other vascular disorders. Growing body of evidence implicates free radical toxicity, radical induced mutations and oxidative enzyme impairment and mitochondrial dysfunction due to congenital genetic defects in clinical manifestations of NDD. Accumulation of oxidative damage in neurons either primarily or secondarily may account for the increased incidence of NDD such as AD, ALS and stroke in aged populations. The molecular mechanisms of neuronal degeneration remain largely unknown and effective therapies are not currently available. Recent interest has focused on antioxidants such as carotenoids and in particular lycopene, a potent antioxidant in tomatoes and tomato products, flavonoids and vitamins as potentially useful agents in the management of human NDD. The pathobiology of neurodegenerative disorders with emphasis on genetic origin and its correlation with oxidative stress of neurodegenerative disorders will be reviewed and the reasons as to why brain constitutes a vulnerable site of oxidative damage will be discussed. The article will also discuss the potential free radical scavenger, mechanism of antioxidant action of lycopene and the need for the use of antioxidants in the prevention of NDD.",2003.0,0,0 1623,12386502,,,,,0,0 1624,12387706,Fabry disease: recent advances in enzyme replacement therapy.,Dominique P Germain,"Fabry disease is an X-linked inherited disorder of metabolism due to mutations in the gene encoding alpha-galactosidase A, a lysosomal enzyme. The enzymatic defect leads to the systemic accumulation of incompletely metabolised glycosphingolipids, primarily globotriaosylceramide, in plasma and lysosomes within various tissues. Inability to prevent the progression of glycosphingolipid deposition causes significant morbidity, associated with significant impact on quality of life and diminished lifespan from early onset strokes, heart attack and progressive renal failure. The disease manifests primarily in hemizygous males; however, there is increasing recognition that heterozygous (carrier) females may also develop disease-related complications. Indeed, most heterozygotes present with cardiac, renal or neurological symptoms, although with later-onset and to a lesser extent than is observed in hemizygotes. Until recently, medical management was symptomatic, consisting of partial pain relief with analgesic drugs (carbamazepin, gabapentin), kidney and vascular protection with angiotensin-converting enzyme inhibitors, statins and folic acid, whereas renal transplantation or dialysis is available for patients experiencing end stage renal failure. The ability to produce high doses of alpha-galactosidase A has opened the way to preclinical studies, and enzyme replacement therapy has recently been validated as a therapeutic agent in clinical trials. Long-term safety and efficacy of replacement therapy are currently being investigated. Increasing knowledge of the natural history of Fabry disease and greater experience with enzyme therapy should enable optimal patient care. The complexity and relative rarity of Fabry disease necessitates a multi-disciplinary team approach that may be facilitated by a disease registry.",2003.0,0,0 1625,12389871,Combination antiplatelet therapy: implications for pharmacists.,Robert L Talbert; Sarah A Spinler; Jean M Nappi; Michael B Bottorff,"To present two case reports of patients who received suboptimal oral antiplatelet therapy and to review recent changes in national guidelines for management of acute coronary syndromes. Personal observation by the authors, and clinical practice guidelines and related clinical trials of the American Heart Association and the American College of Cardiology. The American College of Cardiology and the American Heart Association revised the guidelines for administration of antiplatelet and anticoagulant therapy in patients with unstable angina and non-ST-segment elevation myocardial infarction in March 2002. Two cases observed by the authors illustrate the consequences of suboptimal antiplatelet therapy when a combination of two antiplatelet drugs should have been administered. Evidence from recent randomized controlled trials led to changes in the national guidelines for administration of oral antiplatelet therapy in patients with acute coronary syndromes. Pharmacists should be aware of these changes and counsel patients about appropriate administration of antiplatelet drugs.",2003.0,0,0 1626,12389877,Modification of high-density lipoprotein cholesterol in the management of cardiovascular risk.,Jim Koeller; Robert L Talbert,"Although several clinical trials clearly demonstrate a decrease in mortality and morbidity rates for various patient populations with cardiovascular disease, this disease continues to be the leading cause of death in the United States. Based on various practice surveys and descriptive reports, clinicians apparently are not identifying patients at risk or not treating them to established goals set by national guidelines. Most evidence, including the updated National Cholesterol Education Program Adult Treatment Panel III guidelines, support low-density lipoprotein cholesterol (LDL) as the principal target for intervention. The guidelines also emphasize that a low level of high-density lipoprotein cholesterol (HDL) alone or in association with hypertriglyceridemia increases the risk of cardiovascular disease; also, epidemiologic data taken as a whole signify that a 1% decrease in HDL levels is associated with a 2-3% increase in risk of coronary heart disease. Low HDL levels occur more frequently than once thought, especially in selected populations such as patients with type 2 diabetes and men. Therapeutic lifestyle changes should be implemented first for any lipid disorder. In patients for whom this approach is not adequate, LDL levels need to be lowered to goals based on risk assessment. In addition, low HDL levels and/or hypertriglyceridemia should be managed with a niacin or fibrate product. However, increases in HDL levels and reductions in triglyceride levels are modest with fibrates compared with the dose-related changes seen with niacin products. Reformulation of niacin into an extended-release form minimizes common adverse effects seen with crystalline or sustained-release niacin, and the beneficial effects on the lipid profile are maintained.",2003.0,0,0 1627,12389882,Cyclooxygenase-2 inhibitor-associated acute renal failure: case report with rofecoxib and review of the literature.,Enid Morales; Jeffrey J Mucksavage,"Cyclooxygenase (COX)-2 inhibitors are widely prescribed for their antiinflammatory and analgesic effects. The potential for COX-2 inhibitors to exert deleterious effects on renal function similar to those of traditional nonsteroidal antiinflammatory drugs is not well defined. Until recently, COX-1 was considered responsible for the synthesis of renal prostaglandins. However, COX-2 is also constitutively expressed in the human kidney Clinical studies have reported a significant decrease in glomerular filtration rate in young and elderly sodium-depleted volunteers given COX-2 inhibitors. We describe the case of a 71-year-old woman who developed acute renal failure after receiving a 50-mg dose of the selective COX-2 inhibitor rofecoxib.",2003.0,0,0 1628,12390056,Health-related quality of life and long-term therapy with pravastatin and tocopherol (vitamin E) in older adults.,Cynthia M Carlsson; Kristi Papcke-Benson; Molly Carnes; Patrick E McBride; James H Stein,"Concerns about the effects of HMG-CoA reductase inhibitors ('statins') on health-related quality of life may contribute to their underuse in older adults with and at risk for cardiovascular disease. These concerns also may prevent clinicians from enrolling older patients in clinical trials assessing the efficacy of statins as a preventive therapy for Alzheimer's disease. To determine the effects of pravastatin and tocopherol (vitamin E), alone and in combination, on health-related quality of life in older adults. Double-blind, randomised, placebo-controlled, crossover study. Forty-one community-dwelling men and women aged > or = 70 years with low-density lipoprotein-cholesterol (LDL-C) > or = 3.62 mmol/L (140 mg/dl) participated. Subjects received pravastatin for 6 months then pravastatin plus tocopherol for an additional 6 months (group 1), or tocopherol for 6 months then pravastatin plus tocopherol for an additional 6 months (group 2). Dosages were pravastatin 20 mg daily and tocopherol 400 IU daily. The following health-related quality-of-life measures were assessed at baseline, after 6 months and after 1 year: health perception, depression, physical function, cognitive function and sleep behaviour. In addition, data on adverse effects and laboratory abnormalities were obtained. Pravastatin reduced levels of total cholesterol (-21%, p < 0.001) and LDL-C (-29%, p < 0.001). Health-related quality-of-life scores, physical adverse effects, muscle enzyme levels and liver function tests did not change after 12 months of therapy with pravastatin, tocopherol or their combination. Both pravastatin and tocopherol have a good safety profile, are well tolerated and do not adversely affect health-related quality of life in older patients with hypercholesterolaemia. Given the significant beneficial cardiovascular effects of statin therapy in older adults and the potential role of statins in prevention of Alzheimer's disease, concerns about adverse effects on quality of life should not deter use of these medications in this population.",2003.0,0,0 1629,12390104,Risk of upper gastrointestinal bleeding in patients taking low-dose aspirin for the prevention of cardiovascular diseases.,P Serrano; A Lanas; M T Arroyo; I J Ferreira,"Most patients with vascular-occlusive diseases benefit from low-dose aspirin (75-325 mg/day). However, they have an increased risk of upper gastrointestinal bleeding (UGIB). To analyse the incidence and factors influencing the occurrence of UGIB in patients taking low-dose aspirin for the prevention of cardiovascular diseases outside clinical trials. We studied 903 consecutive patients discharged on low-dose aspirin from the Cardiology Department of a general hospital. Data were collected from medical charts and structured telephone interviews. Forty-one patients (4.5%) presented with UGIB requiring hospitalization during follow-up (45 +/- 22 months). The incidence of UGIB was uniform during follow-up (1.2 UGIB per 100 patient years). Multivariate analysis showed that a history of peptic ulcer or UGIB [risk ratio: 3.1, 95% CI: (1.5-6.5)] and aspirin dose (per 100 mg/day) [1.8 (1.5-2.9)] was associated with higher risk of UGIB. On the other hand, antisecretory [0.22 (0.07-0.75)] and nitrovasodilator drugs [0.73 (0.55-0.96)] were associated with a decreased risk. Cardiovascular patients on long-term low-dose aspirin have a stable risk of major UGIB, which is higher than published controlled clinical trials. Antisecretory and nitrovasodilator drugs protect from UGIB, whereas previous peptic ulcer or UGIB and higher doses of aspirin increase the risk.",2003.0,0,0 1630,12390557,Evaluation and management of dyslipidemia in patients with HIV infection.,Michael L Green,"Persons with HIV infection develop metabolic abnormalities related to their antiretroviral therapy and HIV infection itself. The objective of this study was to summarize the emerging evidence for the incidence, etiology, health risks, and treatment of dyslipidemias in HIV disease. Systematic review of original research with quantitative synthesis. Dyslipidemia is common in persons with HIV infection on highly active antiretroviral therapy (HAART), but methodologic differences between studies preclude precise estimates of prevalence and incidence. The typical pattern includes elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides, which may be markedly elevated. The dyslipidemia may be associated with lipodystrophy, insulin resistance, and, rarely, frank diabetes mellitus. Exposure to protease inhibitors (PIs) is associated with this entire range of metabolic abnormalities. PI-naïve patients on nucleoside reverse transcriptase inhibitors (NRTIs) may develop lipodystrophy, insulin resistance, hypercholesterolemia, and possibly modest elevations in triglycerides but not severe hypertriglyceridemia, which appears to be linked to PIs alone. Most studies have not found an association between CD4 lymphocyte count or HIV viral load and lipid abnormalities. The pathogenesis is incompletely understood and appears to be multifactorial. There are insufficient data to definitively support an increased coronary heart disease risk in patients with HIV-related dyslipidemia. However, some of the same metabolic abnormalities remain firmly established risk factors in other populations. Patients on HAART with severe hypertriglyceridemia may develop pancreatitis or other manifestations of the chylomicronemia syndrome. Some of the metabolic derangements (particularly hypertriglyceridemia) may improve upon replacing a PI with a non-nucleoside reverse transcriptase inhibitor. The limited experience suggests that fibrates, pravastatin, and atorvastatin can safely treat lipid abnormalities in HIV-infected patients. Patients with HIV infection on HAART should be screened for lipid disorders, given their incidence, potential for morbidity, and possible long-term cardiovascular risk. Treatment decisions are complex and must include assessments of cardiac risk, HIV infection status, reversibility of the dyslipidemia, and the effectiveness and toxicities of lipid-lowering medications. The multiple potential drug interactions with antiretroviral or other HIV-related medications should be considered in lipid-lowering drug selection and monitoring.",2003.0,0,0 1631,12390944,Preprocedural statin medication reduces the extent of periprocedural non-Q-wave myocardial infarction.,Joerg Herrmann; Amir Lerman; Dietrich Baumgart; Lothar Volbracht; Rainer Schulz; Clemens von Birgelen; Michael Haude; Gerd Heusch; Raimund Erbel,"Stenting-related myocardial injury has been recognized as a frequent and prognostically important event, the extent of which depends on microcirculatory impairment in association with platelet aggregation, inflammation, and increased oxidative stress. Recent studies underscored the non-lipid-lowering effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) with antithrombotic, antiinflammatory, and antioxidative aspects. Thus, we tested the hypothesis that preprocedural statin therapy is associated with a reduction in the extent of stenting-related myocardial injury. We stratified 296 consecutive patients who were undergoing stenting of a de novo stenosis according to the preprocedural status of statin therapy (229 statin-treated and 67 control patients). Incidence of periprocedural myocardial injury was assessed by analysis of creatine kinase (CK; upper limit of normal [ULN] 70 IU/L for women, 80 IU/L for men) and cardiac troponin T (cTnT; bedside test; threshold 0.1 ng/mL) before and 6, 12, and 24 hours after the intervention. Relative to control patients, the incidence of CK elevation >3x ULN was more than 90% lower in statin-treated patients (0.4% versus 6.0%, P=0.01). Statin therapy was the only factor independently associated with a lower risk of CK elevation >3x ULN (OR: 0.08, 95% CI: 0.01 to 0.75; P=0.03). The overall incidences of CK and cardiac troponin T elevation were slightly lower in statin-treated than in control patients (14.4% versus 20.9%, P=0.3, and 17.9% versus 22.4%, P=0.5, respectively). Preprocedural statin therapy is associated with a reduction in the incidence of larger-sized, stenting-related myocardial infarctions. Prospective, randomized trials are warranted to further assess this cardioprotective effect of statins in coronary intervention.",2002.0,0,0 1632,12390953,"Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin.",Saskia de Jongh; Leiv Ose; Tamás Szamosi; Claude Gagné; M Lambert; Russell Scott; P Perron; Dries Dobbelaere; M Saborio; Mary B Tuohy; Michael Stepanavage; Aditi Sapre; Barry Gumbiner; Michele Mercuri; A S Paul van Trotsenburg; Henk D Bakker; John J P Kastelein; Simvastatin in Children Study Group,"A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate LDL cholesterol-lowering efficacy, overall safety, and tolerability and the influence on growth and pubertal development of simvastatin in a large cohort of boys and girls with heterozygous familial hypercholesterolemia (heFH). A total of 173 heFH children (98 boys and 75 girls) were included in this study. After a 4-week diet/placebo run-in period, children with heFH were randomized to either simvastatin or placebo in a ratio of 3:2. Simvastatin was started at 10 mg/d and titrated at 8-week intervals to 20 and then 40 mg/d. During a 24-week extension period, the patients continued to receive simvastatin (40 mg) or placebo according to their assignment. After 48 weeks of simvastatin therapy, there were significant reductions of LDL cholesterol (-41%), total cholesterol (-31%), apolipoprotein B (-34%), VLDL cholesterol (-21%), and triglyceride (-9%) levels. HDL cholesterol and apolipoprotein A-I levels were increased by 3.3% and 10.4%, respectively (not significant). No safety issues became evident. Except for small decreases in dehydroepiandrosterone sulfate compared with placebo, there were no significant changes from baseline in adrenal, gonadal, and pituitary hormones in either treatment group. Simvastatin significantly reduced LDL cholesterol, total cholesterol, triglyceride, VLDL cholesterol, and apolipoprotein B levels and was well tolerated in children with heFH. There was no evidence of any adverse effect of simvastatin on growth and pubertal development. Therefore, simvastatin at doses up to 40 mg is a well-tolerated and effective therapy for heFH children.",2002.0,0,0 1633,12391360,Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide.,K Fassbender; M Stroick; T Bertsch; A Ragoschke; S Kuehl; S Walter; J Walter; K Brechtel; F Muehlhauser; K Von Bergmann; D Lütjohann,"Cerebral cholesterol metabolism has been linked with production of amyloid peptide (Abeta) crucial in AD. The association between use of cholesterol-lowering drugs (statins) and AD disease is currently being intensely discussed. In this case-control study on elderly nondemented subjects, the authors provide the first evidence that statins in clinically relevant dosages indeed affect cerebral cholesterol metabolism. However, these changes were not associated with altered intrathecal secretion of Alzheimer Abeta.",2002.0,0,0 1634,12391603,Neuroplasticity in Alzheimer's disease.,Bruce Teter; J Wesson Ashford,"Ramon y Cajal proclaimed in 1928 that ""once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult centers the nerve paths are something fixed, ended and immutable. Everything must die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree."" (Ramon y Cajal, 1928). In large part, despite the extensive knowledge gained since then, the latter directive has not yet been achieved by 'modern' science. Although we know now that Ramon y Cajal's observation on CNS plasticity is largely true (for lower brain and primary cortical structures), there are mechanisms for recovery from CNS injury. These mechanisms, however, may contribute to the vulnerability to neurodegenerative disease. They may also be exploited therapeutically to help alleviate the suffering from neurodegenerative conditions.",2002.0,0,0 1635,12392286,Cardiovascular toxicities of immunosuppressive agents.,Leslie W Miller,"Cardiovascular disease is one of the major causes of morbidity and mortality following solid organ transplantation. Many of the current immunosuppressive drugs are associated with an increase of one or more risk factors for the development of atherosclerosis. This review compares the mechanism by which individual immunosuppressive agents may impact on these risk factors and the differential contribution of cyclosporine, tacrolimus, mycophenolate, azathioprine, and Rapamycin to these individual risk factors. Attention to the potential cardiovascular toxicities of individual immunosuppressive agents may help design strategies for maintenance of immunosuppression tailored to individual patients.",2003.0,0,0 1636,12392587,Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects.,Hisako Omori; Hirotaka Nagashima; Yukio Tsurumi; Atsushi Takagi; Naoko Ishizuka; Nobuhisa Hagiwara; Masatoshi Kawana; Hiroshi Kasanuki,"HMG-CoA reductase inhibitors (statins) have been demonstrated to have in vitro vascular effects. The aim of this study was to determine whether statins actually have in vivo vascular effects independent of their cholesterol-lowering effect. We investigated the effect of a single dose of cerivastatin on vascular endothelial function by measuring flow-mediated dilatation of the brachial artery on ultrasound in 30 healthy volunteers with normal serum cholesterol concentrations. They were randomized to either placebo group (n = 15) or cerivastatin group (n = 15), and flow-mediated dilatation and endothelium-dependent dilatation were evaluated at before and 1 h, 3 h, 6 h, and 12 h after administration of placebo or cerivastatin. There were no differences in total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, malondialdehyde-LDL, and high-sensitivity C-reactive protein before and after administration of placebo or cerivastatin. Cerivastatin significantly increased flow-mediated dilatation at 3 h (P < 0.001), and this increase rapidly returned to the baseline level 6 h after administration. Endothelium--independent dilatation of brachial artery was not altered. A single dose of cerivastatin increased vascular endothelial responsiveness. Our data suggest that cerivastatin has a direct effect on the blood vessels that is independent of its lipid-lowering effect, and thus can be considered as a vascular statin.",2003.0,0,0 1637,12394319,Imaging of atherosclerosis. Coronary wall imaging with MRI.,Robin P Choudhury; Zahi A Fayad,"Contrast arteriography is routinely used in the diagnosis and management of coronary atherosclerosis. However, it is recognized that conventional arteriography can not image plaque directly or provide prognostic information based on plaque characterization. Noninvasive, high-resolution magnetic resonance has the potential to image coronary plaque and to determine its composition and microanatomy. This review summarizes the rationale for coronary plaque imaging, and describes the characteristics of plaque using existing MRI techniques. Current and future applications of MRI, including the development of new contrast agents, targeted molecular imaging and the application of MRI to percutaneous coronary intervention are also discussed.",2003.0,0,0 1638,12394329,Prevalence of modifiable cardiovascular risk factors remain high after coronary bypass graft surgery: a multicentre study among Turkish patients.,Mehmet Baltali; Hidayet Tarik Kiziltan; Mehmet Emin Korkmaz; Semra Topçu; Mustafa Demirtaş; Mehmet Metin; M Sah Topçuoğlu; Ahmet Birand; Haldun Müderrisoğlu,"The measures of secondary prevention in patients undergoing coronary bypass graft surgery (CABG) remains largely undetermined in Turkey. We designed a multicentre cross-sectional study to estimate the prevalence of cardiovascular risk factors in patients after CABG and to evaluate the association of demographic-socio-economic factors with secondary prevention in these patients. A total of 622 patients who underwent CABG between 1 January 1999 and 15 January 2000 at four centres in Adana, Turkey; 273 (ages 35-77, 208 men) were interviewed and examined 1.0-2.2 years after the procedure. Of 273 patients interviewed, 81.5% were overweight, 65.5% had unhealthy food choices for a lipid-lowering diet, 56.0% were physically inactive, 28.8% were obese and 17.6% were current smokers. Hypercholesterolaemia, elevated blood pressure and fasting blood glucose were found in 65.6, 34.1 and 19.8%, respectively. Of diabetic patients, 63.8% had elevated fasting blood glucose. The use of angiotensin-converting enzyme inhibitors, beta-blockers and statins was low. Women had a higher rate of obesity and physical inactivity; smoking was less prevalent in females. More women were taking antihypertensive and lipid-lowering drugs than men. Logistic regression analysis revealed an association between hypercholesterolaemia and low educational level. Turkish patients have a high prevalence of modifiable risk factors related to unhealthy lifestyle and ineffective prophylactic drug use 1 year or more after CABG. Low educational level has a significant influence in this situation.",2003.0,0,0 1639,12394605,Sirolimus (Rapamune) in renal transplantation.,Robert W G Johnson,"There has been a necessary change in attitude to transplantation; there is much less concern with short-term outcome and more concern with long-term kidney function, overall health and quality of life. Nephrotoxicity is an invariable consequence of long-term treatment with calcineurin antagonists and it is one of the most underestimated causes of late graft loss; it has been reported as a serious threat to both patient and graft survival following heart, liver and bone marrow transplantation. Sirolimus has been shown in many recent studies to be of great value in allowing patients to be weaned from cyclosporine with excellent patient and graft survival at 24 months a significant improvement in renal function with resolution of hirsutism and gum hyperplasia. Patients maintained on the combined regime of cyclosporine and sirolimus had significantly higher blood pressure, much more cyclosporine nephrotoxicity and hyperuricaemia at 12 months. The experimental studies have found cyclosporine and sirolimus potentiate with each other's good and adverse effects. Cyclosporine therefore augments hyperlipidaemia caused by sirolimus, and sirolimus augments nephrotoxicity caused by cyclosporine. The results of these studies indicate that sirolimus is a suitable replacement for cyclosporine or tacrolimus for long-term maintenance therapy. By contrast the use of sirolimus in combination with cyclosporine results in potentiation of side effects. The principal disadvantages being increased cyclosporine associated nephrotoxicity and sirolimus associated hyperlipidaemia",2003.0,0,0 1640,12394655,The effect of Mediterranean diet on the risk of the development of acute coronary syndromes in hypercholesterolemic people: a case-control study (CARDIO2000).,Christos Pitsavos; Demosthenes B Panagiotakos; Christina Chrysohoou; John Skoumas; Ioanna Papaioannou; Christodoulos Stefanadis; Pavlos K Toutouzas,"Hypercholesterolemia has been identified as a major risk factor for the development of coronary artery disease. The aim of this study was to assess the effect of a Mediterranean diet on the development of non-fatal acute coronary syndromes (ACS) in hypercholesterolemic people, with or without statin treatment. During 2000-2001, 848 randomly selected patients with a first event of coronary heart disease and 1078 cardiovascular disease-free people, matched to the patients by sex, age and region, were studied. Treatment of hypercholesterolemia with statin and the adoption of a Mediterranean diet were recorded. Hypercholesterolemia was present in 534 (63%) out of 848 coronary patients and 399 (37%) out of 1078 control participants. One hundred and seventy-one (32%) of the hypercholesterolemic patients and 168 (42%) of the hypercholesterolemic control participants were treated with statins and also followed a Mediterranean diet. The analysis showed that the combination of a Mediterranean diet and statin medical therapy is associated with an additional reduction of the coronary risk (odds ratio = 0.57, P < 0.01), independently from cholesterol levels and the other cardiovascular factors. The adoption of a Mediterranean diet by hypercholesterolemic people seems to reinforce the benefits from statin treatment on lipid levels and reduces the risk of developing ACS. However, it is hard to claim that our findings suggest causal evidence, and in order to explain the potential common mechanism between diet and statin treatment much remains to be learned.",2003.0,0,0 1641,12395203,"Drug-eluting stent: the ""magic bullet"" for prevention of restenosis?",Christoph Hehrlein; Amina Arab; Christoph Bode,"The need for repeat interventions after initially successful PTCA due to restenosis has been called the ""Archilles heel"" of a percutaneous revascularization procedure. The incidence of restenosis varies between 20-50 % depending on the stent material, the presence of risk factors, and the location of vascular disease. Some risk factors such as diabetes have been clearly identified, others are currently debated. After years of failures trying to reduces restenosis rates, locally administered antiproliferative means have been shown to successfully inhibit excessive cell growth in response to PTCA. Local radiotherapy of in-stent restenosis results in a reduction of recurrent stenosis versus a conventional PTCA procedure. However, long-term evaluation indicated that restenosis may only be delayed with radiation therapy. Moreover, the restenosis rates were reduced, but the restenotic process was not eliminated. Coronary stents eluting the anti-proliferative agent rapamycin have demonstrated for the first time, that restenosis rates of zero percent are achievable after percutaneous revascularization procedures. Thus, it is intriguing to believe that the elimination of restenosis may have become reality. The purpose of this review is to discuss, whether a stent eluting drugs should be considered as the ""magic bullet"" for prevention of restenosis after PTCA.",2003.0,0,0 1642,12396226,Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia.,Thomas Sudhop; Klaus von Bergmann,"The benefits of lipid lowering therapy on coronary heart disease have been clearly established in many clinical trials on primary and secondary prevention. Despite the availability of potent lipid lowering drugs, many patients do not reach the current treatment goals. This paper reviews new therapeutic approaches in lipid lowering drugs focusing on compounds which lower cholesterol absorption. The role of plant sterols and stanols, new acyl-CoA:cholesterol O-acyl transferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, and ezetimibe are summarised. Although the lipid lowering effect of plant sterols and plant stanols is only moderate, their use as functional foods is beneficial for patients with mild hypercholesterolaemia and is able to enhance the lipid lowering effect of HMG-CoA reductase inhibitors (statins). The role of ACAT inhibitors that might also inhibit cholesterol absorption remains unclear. Avasimibe, the first oral bioavailable ACAT inhibitor, has entered phase III trials. However, the presently available data in humans do not indicate a clear clinical benefit. The role of MTP inhibitors, which exhibit remarkable effects on all plasma lipids, also remains unclear, as safety concerns must first be addressed. Ezetimibe, the first available 2-azetidinone, succeeded in phase III trials showing remarkable effects in inhibition of cholesterol absorption as well as cholesterol lowering. The synergistic effect of co-administration of ezetimibe with statins seemingly offers a new approach in reaching the therapeutic goals.",2003.0,0,0 1643,12398573,Early statin therapy for acute coronary syndromes.,Simon De Denus; Sarah A Spinler,"To review the clinical benefit of statins in the early management of acute coronary syndromes (ACSs) and their possible mechanisms of benefit. A MEDLINE search (1966-September 2001) was conducted using the following terms: pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, statins, hydroxymethylglutaryl coenzyme A reductase inhibitor, acute coronary syndromes, unstable angina, and myocardial infarction. Pertinent articles referenced in these publications were also reviewed. French- and English-language human and animal studies were selected and analyzed. In addition to their lipid-lowering properties, statins produce several nonlipid-related properties. These pleiotropic properties include improved endothelial function, reduction of inflammation at the site of the atherosclerotic plaque, inhibition of platelet aggregation, and anticoagulant effects, all of which may result in clinical benefit during ACSs. Preliminary studies and retrospective analyses of large clinical trials support the hypothesis that statins may be of benefit in ACSs. A recently published randomized, double-blind, multicenter trial evaluated the clinical impact of high-dose atorvastatin in patients with ACSs. Use of atorvastatin resulted in a decrease in a combined endpoint of cardiovascular events. Furthermore, initiation of statin therapy during hospitalization improves long-term compliance and may significantly improve clinical outcome. Early use of statins in ACSs appears to decrease cardiovascular events. We believe statin therapy should be initiated early (at the latest before hospital discharge) in all patients who have been hospitalized for ACSs. Ongoing studies will clarify the benefit of these agents in ACSs, the importance of their nonlipid-lowering properties, and the optimal cholesterol-target concentrations.",2003.0,0,1 1644,12398818,Greek technology or mythology?,P G Hugenholtz,,2003.0,0,0 1645,12398959,Effects of simvastatin on C-reactive protein in mixed hyperlipidemic and hypertriglyceridemic patients.,Harold E Bays; Evan A Stein; Arvind K Shah; Darbie L Maccubbin; Yale B Mitchel; Michele Mercuri,"This study examined the effects of simvastatin on C-reactive protein (CRP) and other inflammatory markers in study subjects with significant elevations in triglyceride (TG) blood levels. CRP, vascular cellular adhesion molecule (VCAM), serum amyloid A (SAA), and interleukin 6 (IL-6) were measured in archived plasma samples from 2 multicenter, randomized, double-blind, placebo-controlled studies designed to examine the lipid-altering efficacy of simvastatin in study subjects with elevated TGs. In the first study, 130 study subjects with mixed hyperlipidemia (low-density lipoprotein [LDL] cholesterol > or =130 mg/dl; TGs 300 to 700 mg/dl) received placebo or simvastatin 40 or 80 mg once daily for three 6-week periods in a complete-block crossover design. In the second study, 195 study subjects with hypertriglyceridemia (TGs 300 to 900 mg/dl) received daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. Significant but weak correlations were observed between baseline CRP values and baseline levels of LDL cholesterol and high-density lipoprotein (HDL) cholesterol, but not with TGs. CRP was also correlated with body mass index and fasting levels of glucose and insulin. Treatment with simvastatin 20, 40, and 80 mg led to significant reductions in CRP plasma levels versus placebo (p <0.05). Although CRP change was weakly correlated with changes in LDL cholesterol, TGs, and HDL cholesterol, results of regression analyses showed that only baseline CRP and treatment allocation were significant predictors of CRP response after 6 weeks of study drug administration. Simvastatin had no effect on VCAM, SAA, or IL-6. In summary, simvastatin significantly reduced CRP in patients with mixed hyperlipidemia and hypertriglyceridemia.",2002.0,0,0 1646,12398960,Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus.,Martin I Freed; Robert Ratner; Santica M Marcovina; Margaret M Kreider; Nandita Biswas; Beth R Cohen; John D Brunzell; Rosiglitazone Study 108 investigators,"This study evaluated the effects of rosiglitazone therapy on lipids and the efficacy and safety of rosiglitazone in combination with atorvastatin in patients with type 2 diabetes mellitus. Three-hundred thirty-two patients entered an 8-week, open-label, run-in treatment phase with rosiglitazone 8 mg/day, and 243 were randomized to a 16-week, double-blinded period of continued rosiglitazone plus placebo, atorvastatin 10 mg/day, or atorvastatin 20 mg/day. With rosiglitazone alone, a modest increase in low-density lipoprotein (LDL) cholesterol (9%), a shift in LDL phenotype from dense to large buoyant subfractions (52% of patients), and an increase in total high-density lipoprotein (HDL) cholesterol levels (6%), predominantly in HDL(2) levels (13%), occurred from week 0 to week 8. When atorvastatin was added, there was a further increase in HDL(3) (5%) and expected significant reductions (p <0.0001) in LDL cholesterol (-39%), apolipoprotein B (-35%), and triglyceride levels (-27%). Glycemic control achieved with rosiglitazone alone was not adversely affected by add-on atorvastatin. The combination was well tolerated compared with placebo. To conclude, in addition to the beneficial effects of rosiglitazone on glycemic control, rosiglitazone and atorvastatin in combination achieved 2 goals: the reduction of LDL cholesterol to <100 mg/dl and the removal of small dense LDL in patients with type 2 diabetes mellitus.",2002.0,0,0 1647,12398969,"Comparison of effectiveness and safety of simvastatin in patients <75 versus > or =75 years of age with coronary, cerebral, or peripheral arterial disease.",Jennifer G Robinson; Cynthia Conroy; William J Wickemeyer,,2002.0,0,0 1648,12399758,Optimizing bexarotene therapy for cutaneous T-cell lymphoma.,Rakhshandra Talpur; Staci Ward; Narin Apisarnthanarax; Joan Breuer-Mcham; Madeleine Duvic,"Bexarotene (Targretin oral capsules), the first RXR-selective retinoid ""rexinoid"" approved for all stages of cutaneous T-cell lymphoma (CTCL), had a response rate (RR) of 45% at the optimal dose of 300 mg/m(2) per day in 2 multicenter trials. With hypertriglyceridemia reported at 79%, bexarotene is often administered with lipid-lowering agents (LLAs). Statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) may modulate class II major histocompatibility class expression and T-cell responses. We attempted to optimize the clinical response to bexarotene by controlling dose-limiting hypertriglyceridemia and combining bexarotene with other active agents. We prospectively evaluated 70 patients with CTCL at M. D. Anderson Cancer Center who were treated with oral bexarotene as monotherapy or in combination with other active agents. Fifty-four patients receiving bexarotene monotherapy achieved an overall RR of 48%. Thirteen had stage IA-IIA disease (RR = 53%, 1 complete response [CR]); 41 had stage IIB-IVB disease (RR = 46%, 2 CRs). Forty-two (77%) of these also required one or more LLAs: atorvastatin (n = 29, RR 43%), atorvastatin plus fenofibrate (n = 10, RR 90%), or gemfibrozil (n = 3, RR 33%). Gemfibrozil was discontinued because it increased bexarotene and triglyceride levels. Patients taking 2 LLAs had a significantly higher RR of 90% during monotherapy than those taking one or no LLAs (P <.0001). Forty of 54 patients (74%) received thyroid hormone replacement to normalize thyroxine levels. Four patients receiving monotherapy have complete CRs of >3 years' duration and received maintenance dosing. Sixteen patients with advanced disease treated with bexarotene (225-750 mg/d) in combination with other CTCL therapies achieved an overall RR of 69% (11/16) with concomitant statin therapy. Bexarotene was safely combined with psoralen ultraviolet A (PUVA) plus interferon alfa (IFN-alpha) (n = 2, RR = 50%), with extracorporeal photopheresis (ECP) (n = 8, RR = 75%, 1 CR), with ECP/IFN-alpha (n = 4, RR =50%), with ECP/IFN-alpha/PUVA (n = 1, RR = 100%), and with IFN-alpha/PUVA/topical nitrogen mustard (n = 1, RR = 100%). Two patients receiving IFN-alpha had slight leukopenia, but rhabdomyolysis associated with multiple LLAs did not occur. This single-center study supports the safety and efficacy of bexarotene as both a monotherapy and a combination therapy for CTCL. Long durable CRs may be achieved with oral monotherapy. Use of statins with bexarotene may also increase RRs by permitting higher doses to be administered without interruption, by modulating the immune response, or both. When bexarotene is combined with other active CTCL therapies, higher RRs were achieved in patients with advanced disease, without unacceptable side effects.",2002.0,0,0 1649,12400150,Optimal treatment of hypertension in African Americans. Reaching and maintaining target blood pressure goals.,George L Bakris; Keith C Ferdinand; Janice G Douglas; James R Sowers,"Treatment of hypertension in African Americans has special challenges, including a lack of objective trial data on which to base decisions and differing benefits and responses than with other patients. However, adequate control is possible and should be the goal of treating physicians. This article describes current ""best practice"" guidance on appropriate treatment of high blood pressure in African Americans. Two patient scenarios offer insight into clinical strategies.",2002.0,0,0 1650,12401142,Antioxidants do not prevent heart disease in high-risk individuals.,Kenneth H Johnson,,2002.0,0,0 1651,12401406,Inflammation and immune responses in atherosclerosis.,David R Greaves; Keith M Channon,"Recent studies have highlighted the role of inflammatory mediators and the cells of the innate and adaptive immune response in the initiation, growth and rupture of atherosclerotic plaques. Viewing this form of vascular pathology as a modified form of chronic inflammation suggests new avenues for therapeutic intervention in cardiovascular disease.",2002.0,0,0 1652,12402412,Anti-inflammatory and immunomodulating properties of statins. An additional tool for the therapeutic approach of systemic autoimmune diseases?,Pier Luigi Meroni; Cristina Luzzana; Donatella Ventura,"Cardiovascular diseases secondary to accelerated atherosclerosis are now accepted as a cause of mortality and morbidity in patients suffering from systemic lupus erythematosus and rheumatoid arthritis. More recently, atherosclerosis is emerging as one of the most serious complications in the anti-phospholipid syndrome, although large epidemiological studies, such as those performed in lupus and rheumatoid arthritis patients, have not been performed up to now. Classical risk factors (dislipidemia, hypertension, diabetes, smoking, etc.) and steroid therapy cannot completely explain the high prevalence of cardiovascular complications in systemic autoimmune diseases. Since the modern view defines atherosclerosis as a chronic inflammatory disorder, it has been suggested that systemic inflammation and soluble immune mediators (circulating autoantibodies, immune-complexes, complement activation products) might play a role in accelerating vessel pathology. The main target appears to be the endothelium because of its ability to switch to a pro-adhesive, pro-inflammatory and pro-coagulant surface in response to these mediators. Recent advances in the knowledge of the pharmacology of statins have indicated that these drugs rather than to be simple cholesterol lowering molecules display a pleiotropic effects on several mechanisms involved in the atherosclerotic plaque formation. Their anti-inflammatory activity and particularly their ability to downregulate endothelial cell activation induced by different stimuli strongly suggest their possible use in conditions in which the systemic inflammation and the endothelial activation/damage are thought to represent key pathogenic mechanisms.",2003.0,0,0 1653,12402992,The role of matrix metalloproteinases in vascular disease.,I M Loftus; M M Thompson,"There is growing interest in the role of matrix metalloproteinases in vascular diseases. These conditions are often characterized by excessive tissue remodelling, and increased matrix metalloproteinase activity has been demonstrated in aneurysms, intimal hyperplasia and atherosclerotic plaque disruption. These enzymes represent a potential target for therapeutic intervention to modify vascular pathology. The core of this review is derived from a MEDLINE database literature search. The review found that there is convincing evidence of increased matrix metalloproteinase activity in a spectrum of vascular disease. Evidence for an imbalance promoting increased matrix degradation is less well documented. However, studies of matrix metalloproteinase inhibition in vascular disease models suggest potential therapeutic benefit. In conclusion, in vivo studies of matrix metalloproteinase inhibition are required to further study the potential for reversal or deceleration of the excessive tissue remodelling that accompanies vascular disorders.",2003.0,0,0 1654,12403985,Alzheimer's disease: treatments in discovery and development.,Martin Citron,"Alzheimer's disease is the single biggest unmet medical need in neurology. Current drugs are safe, but of limited benefit to most patients. This review discusses the scientific basis and current status of promising disease-modifying therapies in the discovery and development stages. I describe the major targets of anti-amyloid therapy and the main focus of disease modification approaches. In addition, two new potential treatment approaches supported by retrospective epidemiology are outlined.",2002.0,0,0 1655,12405570,Medium-term follow-up of intermediate coronary stenoses left unrevascularized based on myocardial fractional flow reserve findings.,Murat Ozdemir; Timur Timurkaynak; Mustafa Cemri; Bülent Boyaci; Ridvan Yalçin; Atiye Cengel; Ovsev Dörtlemez; Halis Dörtlemez,"Coronary stenoses of intermediate severity create difficulties in decision making when revascularization is concerned. Myocardial fractional flow reserve (mFFR), an accurate tool to identify physiological significance of individual coronary stenoses, may help solve this problem. Fifty-eight intermediate (30-70%) coronary stenoses in 51 patients (mean age 54.4 +/- 8.9 years, 9 women) were left unrevascularized because of normal (> or = 0.75) mFFR findings and the patients were prospectively followed with regard to the occurrence of death, myocardial infarction and target vessel revascularization. The mean reference vessel diameter, percent stenosis and mFFR of the intermediate lesions were 3.3 +/- 0.3 mm, 46.8 +/- 9.2% and 0.86 +/- 0.05, respectively. Of the 58 intermediate lesions, 20 (34%) were associated with perfusion defects on thallium scan. Significant (> 70%) disease in addition to the one with the intermediate stenosis was present in I coronary artery in 24 (47%), and 2 coronary arteries in 6 (12%) patients and angioplasty of at least one significant stenosis was performed at the initial evaluation in 18 (35%) patients. Follow-up for a mean of 16.6 +/- 6.6 months disclosed no death or myocardial infarction. Target vessel revascularization was performed in 3 (6%) patients at a mean of 4 +/- 2.6 months. A control angiogram, which was performed in 12 of 18 patients who had undergone angioplasty at the initial evaluation revealed restenosis in 3 (25%) patients with no significant angiographic changes in the target intermediate stenoses. Anginal status was found to be significantly improved at follow-up. In this study, we found that intermediate coronary stenoses with an mFFR > or = 0.75 have a favourable medium-term clinical outcome with respect to major cardiac adverse events when left unrevascularized based on mFFR findings.",2003.0,0,0 1656,12405574,Intensive insulin treatment reduces transient ischaemic episodes during acute coronary events in diabetic patients.,Alexander Stefanidis; Andreas Melidonis; Symeon Tournis; Michael Zairis; Stylianos Handanis; Christoforos Olympios; Panayiotis Asimacopoulos; Stefanos Foussas,"This study tested the impact of intensive metabolic treatment with insulin on transient myocardial ischaemia detected with continuous 12-lead ST-segment monitoring during non-ST segment elevation acute coronary syndromes in type 2 diabetic patients. The study included 57 type 2 diabetic patients with non-ST segment elevation acute coronary syndromes.Twenty-eight patients randomized to conventional treatment plus intensive insulin therapy (group A) and twenty-nine to conventional therapy only (group B). Group A patients received insulin by infusion for 48 hours according to a predefined protocol aiming to maintain normoglycaemia. Group B patients received standard coronary care unit treatment. The ST-segment monitoring was performed for 48 hours in the coronary care unit. The two groups were comparable in terms of medical history, clinical and biochemical data. Three patients from both groups were excluded from the analysis because there was objective evidence for evolution in persistent ST-segment elevation acute myocardial infarction. Six patients (24%) from group A vs. twelve from group B (46.2%) had evidence of transient ischaemia (p = 0.098). Group A patients showed significantly lower values in the mean number [group A vs. group B: 0.4 +/- 0.8 vs. 2 +/- 3.1, p < 0.01] and total duration of ST-episodes [group A vs. group B: 2.4 +/- 5.1 vs. 21.2 +/- 31 min, p < 0.01]. Multivariate analysis revealed that the mean plasma glucose during the study period was a powerful predictor of the presence (b:0.377,p < 0.01), the number (b:0.523,p < 0.001) and the total duration (b: 0.686, p < 0.001) of ST-episodes, respectively. CONCLUSIONS; Intensive insulin treatment considerably decreases the number and the total duration of ST-episodes in type 2 diabetic patients suffering from non-ST segment elevation acute coronary syndromes.",2003.0,0,0 1657,12406030,Diabetes in tomorrow's world: dark clouds do have silver linings.,James Shepherd,,2003.0,0,0 1658,12407821,The extent of late in-stent neointima formation is modified by treatment with pravastatin: a preliminary study with intravascular ultrasound.,Francesco Prati; Giorgio Morocutti; Guglielmo Bernardi; Luigi Sommariva; Fabrizio Tomai; Antonio Pagano; Antonio Parma; Alessandro Boccanelli; Paolo Fioretti,"The aim of the present comparative, non-randomized intravascular ultrasound (IVUS) study was to test the effect of pravastatin on late neointima formation in stented de novo lesions. The treatment group consisted of 28 consecutive patients in whom 31 stents were deployed; all patients were prescribed 40 mg daily of pravastatin for a mean follow-up period of 14 +/- 3 months (group 1). The control group consisted of 27 consecutive patients in whom 30 stents were deployed; lipid-lowering treatment was not prescribed; the mean follow-up period for this group of patients was 13 +/- 3 months (group 2). At follow-up IVUS images were acquired at a continuous 0.5 mm/s speed. IVUS measurements of the lumen area, stent area and neointima area were calculated within the stent at 0.5 mm intervals. The stent dimensions and technique of implantation were similar in the two groups. At follow-up the minimal lumen diameter at quantitative coronary angiography was slightly larger in group 1 than in group 2 (2.43 +/- 0.58 vs 2.17 +/- 0.59 mm, p = NS), while the late loss tended to be lower in group 1 than in group 2 (0.28 +/- 0.39 vs 0.63 +/- 0.37 mm, p = NS). At IVUS evaluation, the lumen and stent areas were similar in the two groups whereas the percent neointima area was significantly lower in group 1 than in group 2 (21 +/- 11 vs 29 +/- 11% respectively, p < 0.03). Pravastatin treatment was associated with a significantly reduced late in-stent neointima formation as assessed at IVUS.",2003.0,0,0 1659,12409741,"A randomized, double-blind study of gemfibrozil for the treatment of protease inhibitor-associated hypertriglyceridaemia.",John Miller; Dannae Brown; Janaki Amin; Julia Kent-Hughes; Matthew Law; John Kaldor; David A Cooper; Andrew Carr,"Hypertriglyceridaemia is common in patients with HIV, especially those taking protease inhibitors or with lipodystrophy, frequently observed at levels associated with accelerated cardiac disease. This study aimed to explore the efficacy and safety of gemfibrozil for hypertriglyceridemia in patients with HIV infection. A 16-week, randomized, double-blind, comparative study of low saturated fat diet versus low saturated fat diet with gemfibrozil 600 mg twice daily in patients with triglycerides > or = 3mmol/l receiving protease inhibitor therapy. Following a 4-week period of dietary intervention alone, patients were randomized to gemfibrozil or matching placebo. The primary outcome was the difference in mean change in fasting triglycerides at week 16 between the two groups. 37 men were randomized (17 gemfibrozil, 20 placebo) with median fasting triglycerides 5.6 mmol/l. Mean changes in triglycerides from week 4 to week 16 were -1.22 mmol/l and +0.35 mmol/l for the gemfibrozil and placebo groups respectively (between-group mean difference of 1.57 mmol/l; 95% confidence interval, -6.7 to 3.5; = 0.08). Only one patient treated had triglycerides return to a desirable range (< or = 2.00 mmol/l). No significant changes in the other metabolic parameters were observed. Gemfibrozil was well tolerated, did not appear to induce additional protease inhibitor toxicity, and did not induce changes in CD4 lymphocyte counts or HIV RNA load. Gemfibrozil is safe and demonstrated at most, modest efficacy for hypertriglyceridemia in HIV-infected patients receiving protease inhibitors. Given the level of response, however, it is unclear whether these reductions will confer clinical benefit, at least in the presence of continued protease inhibitor use.",2003.0,0,0 1660,12410084,Lipid-lowering agents and myopathy.,Robert L Wortmann,"Each of the lipid-lowering agents available today can cause myopathy. The severity of the muscle disorder may vary from trivial myalgias or elevations of creatine kinase in asymptomatic individuals to rhabdomyolysis with myoglobinuria, renal failure, and death. Fortunately, significant myopathy occurs at a low rate. However, the large number of individuals taking these medications renders it a significant problem. Although the pathophysiology of the myopathy remains speculative, its occurrence appears to be dose related. Consequently, the total dosage of lipid-lowering drug consumed, the concomitant use of other medications that affect their blood levels, and the individual's specific drug-metabolizing enzyme profile may contribute to this toxicity.",2003.0,0,0 1661,12410168,Statins and omega-3 fatty acids in the treatment of dyslipidemia and coronary heart disease.,A Nordøy,"Dyslipidemia including hypercholesterolemia and hypertriglyceridemia often associated with low levels of HDL-cholesterol is a common and important cluster of risk factors for coronary heart disease. Dyslipidemia is also commonly associated with hypertension, hyperinsulinemia and central obesity in the metabolic syndrome. Lifestyle adjustments including increased physical activity and dietary modifications leading to weight reduction are important first steps in the prevention of coronary heart disease in patients with such abnormalities in lipid metabolism. When these adjustments are insufficient to achieve desirable results, the combined treatment with statins and omega-3 fatty acids is an efficient treatment alternative. Both statins and omega-3 fatty acids have documented their effects against coronary heart disease (CHD) both in primary and secondary prevention trials. The mechanisms involved are only partly explained, however, the synergistic effects of statins and omega-3 fatty acids significantly reduce the risk for CHD in patients with dyslipidemia.",2003.0,0,0 1662,12410906,Use of lipid-lowering drugs in older adults with and without dementia: a community-based epidemiological study.,Eric G Rodriguez; Hiroko H Dodge; Maria A Birzescu; Gary P Stoehr; Mary Ganguli,"To compare the use of lipid-lowering drugs in community-dwelling older adults with and without dementia. Comparison of lipid-lowering drug use by demented cases and nondemented controls based on secondary analysis of data from a longitudinal epidemiologic study. Longitudinal study of a largely rural, low- socioeconomic-status, community-based cohort of older persons residing in the mid-Monongahela Valley of South-west Pennsylvania (the Monongahela Valley Independent Elders Survey). Eight hundred forty-five individuals of mean +/- standard deviation (SD) age of 80.5 +/- 4.6, participating in the fifth biennial wave of data collection. Demographics; medical history; medication regimen (including examination of prescription bottle labels); self-report of most recent visit to primary care physician (PCP); and standardized clinical assessment to determine presence of dementia, including Clinical Dementia Rating (CDR). One hundred seventy participants (20.1% of total subject cohort) had dementia, with a CDR of 0.5 or greater. Mean ages of demented and nondemented individuals were 83.5 +/- 5.1 and 79.8 +/- 4.2, respectively. Similar proportions, 87.7% and 89.5%, of these groups reported PCP visits in the previous year. Of the total sample, 9.4% (3.5% of the demented and 10.8% of the nondemented) were taking lipid-lowering drugs. After adjustment for age, sex, education, visit with PCP within the past year, and potential confounding clinical and lifestyle variables (self-reported heart disease, stroke or transient ischemic attacks, hypertension, smoking, and alcohol consumption), dementia was associated with a lower likelihood of taking a lipid-lowering drug (odds ratio = 0.39, 95% confidence interval = 0.16-0.95). In post hoc subgroup analyses, similar results were found when restricting lipid-lowering drugs to statins alone but were not statistically significant. Drug use was not associated with severity of dementia (CDR = 0.5 vs CDR >or= 1). Demented individuals were less likely than their nondemented counterparts to be taking lipid-lowering drugs. This finding could reflect different prescribing patterns by physicians for demented and nondemented patients or a possible protective effect of these drugs against dementia.",2002.0,0,0 1663,12411646,Impact of infectious burden on progression of carotid atherosclerosis.,Christine Espinola-Klein; Hans-Jürgen Rupprecht; Stefan Blankenberg; Christoph Bickel; Helmuth Kopp; Anja Victor; Gerd Hafner; Wilfried Prellwitz; Wolfgang Schlumberger; Jürgen Meyer,"Recent findings suggest a causative role of infections in the pathogenesis of atherosclerosis. The extent of atherosclerosis and the prognosis of patients with atherosclerosis seem to be increased by the number of infections to which an individual has been exposed. In a prospective study, we evaluated the effect of 8 pathogens and the aggregate pathogen burden on the progression of carotid atherosclerosis. In 504 patients (74.9% men; age, 62.9+/-10 years), we measured intima-media thickness and prevalence of carotid artery stenosis. Follow-up measurements after a mean of 2.5 years were available in 427 patients (85%). Blood samples were taken, and IgG or IgA antibodies to Chlamydia pneumoniae, Helicobacter pylori, Haemophilus influenzae, Mycoplasma pneumoniae, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus types 1 and 2 were measured. Statistical evaluation was performed with logistic regression procedures. Elevated IgA antibodies against C pneumoniae (P<0.04) and IgG antibodies against Epstein-Barr virus (P<0.01) and herpes simplex virus type 2 (P<0.04) were associated with progression of atherosclerosis (increase of intima-media thickness > or =0.1 mm/y or progression of carotid stenosis) after adjustment for age, sex, cardiovascular risk factors, highly sensitive C-reactive protein, and statin intake. Infectious burden, divided into 0 to 3, 4 to 5, and 6 to 8 seropositivities, was significantly associated with progression of atherosclerosis, with odds ratios of 1.8 (95% confidence interval, 1.1 to 2.9) for 4 to 5 and 3.8 (95% CI, 1.6 to 8.8) for 6 to 8 compared with 0 to 3 seropositivities after adjustment. Our results support the hypothesis that the number of infectious pathogens to which an individual has been exposed independently contributes to the progression of carotid atherosclerosis.",2002.0,0,0 1664,12411985,Prevention of heart failure.,David W Baker,"The number of people in the United States with heart failure (HF) is expected to rise dramatically as the population ages unless efforts to prevent HF improve. PubMed/MEDLINE searches were conducted to identify treatment trials of hypertension, hypercholesterolemia, asymptomatic left ventricular systolic dysfunction, and diabetes that reported HF incidence. Treatment of hypertension reduces the incidence of HF by approximately 50%, even among very elderly patients. Diuretics, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors appear more effective than calcium channel blockers and doxazosin. Hydroxy methylglutaryl coenzyme A (HMG CoA) reductase inhibitors reduce the incidence of HF by approximately 20% among patients with hypercholesterolemia and coronary artery disease. ACE inhibitors reduce HF incidence by 37% among patients with reduced systolic function and by 23% among patients with coronary artery disease and normal systolic function. Observational studies have shown lower HF incidence among people with diabetes with better glycemic control. Unfortunately, all of these effective therapies appear to be underused, and control of hypertension is particularly poor. If clinical practice can live up to the potential shown from clinical trials, the suffering and economic toll imposed by HF can be dramatically reduced. Improved control of hypertension, primary prevention of myocardial infarction, and more widespread use of secondary prevention measures are essential.",2003.0,0,0 1665,12412817,"Plasminogen activator inhibitor-1: physiologic role, regulation, and the influence of common pharmacologic agents.",James P Tsikouris; Jose A Suarez; Gary E Meyerrose,"Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of endogenous thrombolysis, thereby promoting thrombosis. PAI-1 is also a primary contributor to the development and recurrence of acute myocardial infarction. The renin angiotensin system, hypertriglyceridemia, hyperglycemia and hyperinsulinemia, and estrogen all influence the fibrinolytic system and PAI-1 in particular. Available data strongly suggest that angiotensin-converting enzyme (ACE) inhibitors and hormone replacement therapy with estrogen beneficially reduce PAI-1 production. Metformin, an agent commonly used for non-insulin-dependent diabetes mellitus (NIDDM), appears to favorably decrease PAI-1 production in NIDDM patients but not nondiabetic patients. Among the cholesterol-lowering statins, clinical literature evaluating pravastatin provides the most compelling data to support this agent's favorable effect on PAI-1. Other available statins either have not displayed an effect on PAI-1 or do not have clear data to conclusively define their effects on the fibrinolytic system.",2003.0,0,0 1666,12414463,Improving the care of patients with non-ST-elevation acute coronary syndromes in the emergency department: the CRUSADE initiative.,James W Hoekstra; Charles V Pollack; Matthew T Roe; Eric D Peterson; Ralph Brindis; Robert A Harrington; Robert H Christenson; Sidney C Smith; E Magnus Ohman; W Brian Gibler,"Although acute coronary syndromes (ACS) represent a well-recognized source of morbidity and mortality for patients with cardiovascular disease, evidence-based therapies shown to improve outcomes for ACS are frequently underused in appropriate patients, especially in the emergency department (ED). Despite dissemination of expert recommendations from the American College of Cardiology/American Heart Association (ACC/AHA) and ED-focused recapitulation of them in the emergency medicine literature, significant barriers continue to limit the adoption of guidelines in clinical practice and appear to hinder the use of beneficial therapies and interventions in the ED. Unique and creative approaches are therefore needed to stimulate better adherence to practice guidelines and improve the quality of care for patients with non-ST-elevation myocardial infarction (NSTE) ACS. The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines) quality improvement and educational initiative provides an innovative and multifaceted approach to the education of emergency physicians and cardiologists in the care of patients with NSTE ACS. The CRUSADE initiative is a multidisciplinary cooperative effort involving over 400 EDs and medical centers. It includes an ACS registry designed to characterize demographic patterns and risk stratification results in patients who meet diagnostic criteria for high-risk NSTE ACS. It also measures the use of ED treatment modalities including aspirin, heparin, beta-blockers, and platelet inhibitors as recommended in the ACC/AHA guidelines. The results of a given institution's treatment patterns will be reported back to the practitioners, with comparisons with national norms. These reports can be used as quality improvement tools to improve care at participating institutions. Beyond a static registry, these reports are coupled with educational efforts by the CRUSADE steering committee, scientific publications of risk stratification practice and success, as well as ED patterns of care, and tailored educational interventions, to reinforce compliance with the ACC/AHA guidelines. This initiative represents a truly innovative approach to improving care for ACS patients in the ED as well as on the cardiology service. This article describes the CRUSADE initiative and its implications for the practicing emergency physician. It is the intent of CRUSADE to improve patient care in the ED by tracking and encouraging compliance with evidence-based guidelines for the evaluation and management of NSTE ACS.",2003.0,0,0 1667,12414837,Clinical review 153: Lipodystrophy in human immunodeficiency virus-infected patients.,Dali Chen; Anoop Misra; Abhimanyu Garg,"Human immunodeficiency virus (HIV) infection is a major global health problem. Recently, combination therapy including HIV-1 protease inhibitors (PIs) has dramatically improved the long-term survival of HIV-infected patients. However, such therapy is associated with a lipodystrophy syndrome characterized by selective loss of sc fat from the face and extremities and, in some patients, accumulation of fat around the neck, dorsocervical region, abdomen, and trunk. Lipodystrophy in HIV-infected patients (LDHIV) is associated with insulin resistance and its metabolic complications such as impaired glucose tolerance, diabetes, hypertriglyceridemia and low serum high density lipoprotein cholesterol levels. PIs appear to be the strongest link to LDHIV; however, fat loss has been reported in some patients taking non-PI antiretroviral drugs. Other factors, such as duration of HIV infection, age, and gender, may also contribute to the risk of development of LDHIV. The molecular basis of LDHIV remains unknown. There is no specific therapy for LDHIV. Avoiding weight gain by reducing energy intake and increasing physical activity may be beneficial in reducing fat accumulation as well as improving metabolic complications. Antihyperglycemic drugs may be used to treat diabetes. Management of dyslipidemia may require lipid-lowering drugs; however, the safety and efficacy of such intervention require further studies. Substitution of PIs with other antiretroviral drugs can mitigate dyslipidemia and glucose intolerance, but whether reversal of lipodystrophy occurs remains unknown. Future research is needed to discover the biochemical and molecular markers of lipodystrophy in HIV patients and develop PIs or other antiretroviral agents that are free of metabolic toxicity.",2002.0,0,0 1668,12416740,Treatment with cerivastatin in primary mixed hyperlipidemia induces changes in platelet aggregation and coagulation system components.,A Ugur Ural; M Ilker Yilmaz; Ferit Avcu; Atilla Yalcin,"Platelet activation, impairment of fibrinolysis, activation of the coagulation pathway, and dyslipidemia are important factors in the pathogenesis and progression of ischemic heart disease, and patients generally need to use an antiplatelet agent. Lipid-lowering cerivastatin, a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, was administered to 20 patients with primary mixed hyperlipidemia for the assessment of the effect of cerivastatin on lipid levels, plasma fibrinogen concentration, factor VII, VIII, and X levels, plasminogen and antiplasmin concentrations, platelet count, and aggregation (adenosine diphosphate [ADP], collagen, and epinephrine induced). Assessments were made immediately after 2 months of a standard lipid-lowering diet, 4 weeks of placebo administration, and 4 weeks of cerivastatin treatment. Cerivastatin achieved significant reductions in triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels. The significant improvement of the lipid profile was associated with platelet aggregation reduction in vitro stimulated by ADP, collagen, and epinephrine (P < .05, P = .05, P < .005, respectively). Significantly lower levels of factor VII and fibrinogen were observed (P = .001, P < .0001) immediately after cerivastatin treatment. No significant differences were detected in factor VIII level, plasminogen and antiplasmin concentrations, and platelet count after cerivastatin treatment. It was concluded that cerivastatin in mixed hyperlipidemia can exert beneficial changes on specific hemostatic variables and platelet aggregation in addition to its positive effects on plasma lipid values.",2002.0,0,0 1669,12417288,Differential hs-CRP reduction in patients with familial hypercholesterolemia treated with aggressive or conventional statin therapy.,Sanne van Wissen; Mieke D Trip; Tineke J Smilde; Jacqueline de Graaf; Anton F H Stalenhoef; John J P Kastelein,"High sensitivity C-reactive protein (hs-CRP) has emerged as the best studied and most promising marker of inflammation in atherosclerotic vascular disease. The ASAP (effects of Atorvastatin vs. Simvastatin on Atherosclerosis Progression) study was a 2-year randomised, double-blind trial with 325 familial hypercholesterolemia patients, treated with torvastatin 80 mg or imvastatin 40 mg. Intima media thickness (IMT) of carotid artery segments and hs-CRP levels were determined at baseline, 1 and 2 years. Baseline median hs-CRP values were 2.1 mg/l (interquartile range (IQR) 0.9-5.2) and 2.0 mg/l (IQR 0.8-3.0) and after 2 years these levels decreased to 1.1 mg/l (IQR 0.6-2.4) and 1.5 mg/l (IQR 0.6-3.0) in the atorvastatin 80 mg and simvastatin 40 mg group, respectively. These changes were significant within as well as between the two groups. No correlations were observed between change in hs-CRP after 2 years and change in lipids. A significant correlation was found in univariate analysis between the decrease of hs-CRP and the reduction of IMT. Our results show that atorvastatin 80 mg reduces hs-CRP levels to a greater extent than simvastatin 40 mg. Furthermore, we show that the extent of hs-CRP reduction is associated with the progression rate of the atherosclerotic process as measured by IMT.",2003.0,0,0 1670,12417534,Chlamydia pneumoniae-atherosclerosis link: a sound concept in search for clinical relevance.,Franz-Josef Neumann,,2002.0,0,0 1671,12417823,Lower is better: The Heart Protection Study.,Ezra A Amsterdam,,2002.0,0,0 1672,12417825,Cardiovascular medications taken by patients aged >or=70 years hospitalized for acute coronary syndromes before hospitalization and at hospital discharge.,Stephen Woodworth; Devraj Nayak; Wilbert S Aronow; Anthony L Pucillo; Srinivas Koneru,"A prospective study was performed in 177 patients, mean age 78+/-6 years, hospitalized with acute coronary syndromes. Obstructive coronary artery disease was documented by coronary angiography in 154 of 177 patients (87%). Coronary revascularization was performed in 96 of 177 patients (54%). Five of 177 patients (3%) died during hospitalization. Compared to use before hospitalization, at hospital discharge the use of aspirin increased from 43% to 84% (p<0.001), the use of clopidogrel increased from 21% to 54% (p<0.001), the use of beta blockers increased from 38% to 76% (p<0.001), the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers increased from 42% to 70% (p<0.001), the use of long-acting nitrates increased from 15% to 31% (p<0.001), and the use of calcium channel blockers decreased from 28% to 23% (p=NS). Dyslipidemia was present in 62% of the 177 patients. The use of statins increased from 34% before hospitalization to 63% at hospital discharge (p<0.001).",2002.0,0,0 1673,12417826,Prevention of sudden death in patients with coronary artery disease: do lipid-lowering drugs play a role?,John De Sutter; Vida Firsovaite; Rene Tavernier,"Ventricular arrhythmias are the most common cause of sudden cardiac death in patients with coronary artery disease. Since treatment of hypercholesterolemia in patients with coronary artery disease reduces the risk of major coronary events by about 30%, one could speculate that this treatment could also result in a reduction of arrhythmic episodes in high-risk patients. In this review, the importance of myocardial ischemia as a trigger for ventricular arrhythmias, as well as the available data that suggest a possible effect of anti-ischemic treatments, including lipid-lowering drugs, on these arrhythmias are presented. Also, possible mechanisms and future research to test the hypothesis that lipid-lowering drugs can reduce life-threatening ventricular arrhythmias are discussed.",2002.0,0,0 1674,12417829,Statins and C-reactive protein: considering a novel marker of cardiovascular risk.,Antonio M Gotto,"Landmark intervention trials have validated the importance of lipid control in reducing the incidence of coronary ischemic events, over a range of baseline lipid levels. With the release of the third iteration of the National Cholesterol Education Programs Adult Treatment Panel guidelines, there is renewed debate about the appropriate use of pharmacologic therapies in individual patients, especially in primary prevention. Markers of low-grade inflammation may capture the inflammatory aspect of atherosclerosis and may prove to be useful clinical predictors of excess coronary risk. C-reactive protein, an acute-phase reactant protein, appears to be one such promising measurement and may have important implications for the optimal targeting of statin therapy.",2002.0,0,0 1675,12418578,Atherosclerosis and cancer: common pathways on the vascular endothelium.,M Morganti; A Carpi; A Nicolini; I Gorini; B Glaviano; M Fini; G Giavaresi; Ch Mittermayer; R Giardino,"This article reviews experimental and clinical data on atherosclerosis and cancer showing common pathogenic mechanisms. It is suggested that common pathways follow dysfunction of the vascular endothelium. The activation of the haemostatic system and the overexpression of cytokines and adhesion molecules by the endothelial cells represent important features of this dysfunction. These mechanisms can be responsible for progression of both diseases and explain the higher incidence of thromboembolic events in cancer patients, the occurrence of similar laboratory findings and the effect of many drugs on the course of the two diseases. Our article confirms that atherosclerosis and cancer share common mechanisms, and we hope it will stimulate further clinical trials on the use of drugs active on the haemostatic system in cancer patients.",2003.0,0,0 1676,12419552,New insights in the transcriptional activity and coregulator molecules in the arterial wall.,Filomena de Nigris; Lilach O Lerman; Claudio Napoli,"A number of vascular diseases are associated with abnormal expression of genes that contribute to their pathophysiological and clinical manifestations, but at the same time offer potential therapeutic targets. One of the promising therapeutic approaches targets the pathophysiological pathways leading to aberrant gene activation, namely transcriptional activity and its molecular modulators (agonists, antagonists, coregulators, and nuclear receptors). The transcription factors can be divided into four classes (I-IV) classified by structural elements, like basic leucine zipper (bZIP) or basic helix-loop-helix (bHLH), which mediate their DNA binding activity but also determine the classes of drugs that can affect their activity. For example, statins modulate activation of the class-I transcription factor sterol responsive element-binding protein (SREBP), whose target genes including hydroxyl-methyl-glutaryl acetyl Coenzyme-A (HMG-CoA) reductase, HMG-CoA synthase, and the low-density lipoprotein receptor, all of which are involved in cholesterol and fatty acid metabolism. Similarly, insulin-like drugs target the nuclear receptor peroxisome-proliferator-activator-receptor (PPAR)-gamma (class-II), several anti-inflammatory drugs inhibit activation of nuclear factor kappa B (NFkappaB) (class-IV), while others (e.g. flavopiridol, rapamycin, and paclitaxel) target regulation of cell-cycle proteins. Increased understanding of the genetic and molecular basis of disease (e.g. transcriptional activity and its coregulation) will potentially enhance future diagnosis, treatment, and prevention of vascular diseases.",2003.0,0,0 1677,12419937,High-density lipoprotein cholesterol and the role of statins.,Pang H Chong; Robert Kezele; Cory Franklin,"Low levels of high-density lipoprotein cholesterol (HDL-C) are currently considered to be a major risk factor for the development of coronary artery disease (CAD). Deficiencies in the HDL metabolic pathway promote atherosclerosis and contribute to CAD. Low HDL-C levels are included in the Framingham 10-year risk assessment for CAD although they are not yet targeted for therapy. Recent clinical trials have shown benefits from raising HDL-C, particularly in patients with lower baseline levels. The statin class of drugs, used primarily to lower the level of low-density lipoprotein-cholesterol, may be able to raise the HDL-C level as well. Statins could potentially affect HDL-C by different modes of action, most importantly by altering reverse cholesterol transport. Among the currently available statins, simvastatin has demonstrated the most consistent ability to raise HDL-C level, but further large-scale studies at an early stage will be needed to prove the antiatherogenic effects of this class of drugs.",2003.0,0,0 1678,12420192,Are we negating the benefits of CABG by forgetting secondary prevention?,P R Belcher; A Gaw; M Cooper; M Brown; D J Wheatley; G M Lindsay,"The objective of the study was to examine medically managed secondary prevention at one year after coronary artery bypass grafting (CABG). In all, 214 consecutive patients undergoing isolated elective CABG seen four weeks preoperatively and one year post-operatively. Preoperative systolic blood pressure averaged 135+/-20 mmHg, which increased to 148+/-25 mmHg (P<0.0001) as did diastolic pressure (81+/-12 to 87+/-13 mmHg; P<0.0001). Anginal symptoms were reported by 45.1% (P<0.0001) although median severity scored lower (4.0 [3.0-5.4] vs 0 [0-2.0]; P<0.0001). Breathlessness decreased from 93% to 64% (P<0.0001) and was scored less severely (4.0 [2.0-5.0] vs 2.0 [0-4.0]; P<0.0001. In all, 88% with postoperative angina reported dyspnoea against 44% of those without (P<0.0001). Calcium antagonist use was more common in patients with angina (27.2% vs 5.1%; P<0.0001), but not nitrates (P=0.8695), diuretics (P=0.4218), digoxin (P=0.2565), beta-blockers (P=0.0820), or ACE inhibitors (P=0.7256). Preoperatively 166 patients (80.2%) took aspirin vs 69.2% afterwards (P=0.0131). Twelve patients (6.5%) received warfarin after operation vs none preoperatively. Two took digoxin (0.97%) preoperatively and 14 (7.7%) postoperatively (P=0.001) for chronic atrial fibrillation. One of these took warfarin. Long-acting nitrate use fell from 63.4% to 15.8% (P <0.0001). Short-acting nitrate use fell similarly (P<0.0001). Preoperatively 37 patients (17.9%) took ACE inhibitors vs 44 postoperatively (24.2%); 39 had not received them before. Preoperatively 48 (23.2%) took diuretics vs 30 (16.5%) postoperatively (P=0.127); 24 had not previously taken diuretics. More patients took HMGCoA inhibitors postoperatively (P=0.0068) and total cholesterol was significantly reduced with a concomitant increase in HDL fraction. Smoking habit was virtually unchanged from 17.8% to 15.1% (P=0.5023). angina was common. Apart from statin prescribing, postoperative secondary prevention measures were poorly applied, less widespread and less effective than preoperatively. The implications are disturbing.",2003.0,0,0 1679,12420194,Effects of atorvastatin on aortic pulse wave velocity in patients with hypertension and hypercholesterolaemia: a preliminary study.,J Raison; A Rudnichi; M E Safar,"As statins may contribute to plaque stabilisation, it is important to evaluate whether these drugs may modify arterial stiffness. In 23 patients, aged 32-70 years, with hypertension and hypercholesterolaemia, a double-blind randomised study vs placebo was performed to evaluate whether atorvastatin was able to modify aortic stiffness, measured from aortic pulse wave velocity (PWV), after a 12-week treatment. The results revealed that atorvastatin did not change blood pressure, significantly lowered (P<0.003; <0.002) plasma total and LDL cholesterol, and increased aortic PWV by +8% (vs -2% under placebo) (P or =18 years) with primary hypercholesterolemia who had not achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel II goals with dietary alteration and statin monotherapy. Patients receiving a stable dose of a statin for > or =6 weeks were randomized to receive concurrent treatment with placebo (n = 390) or ezetimibe (n = 379), 10 mg/day, in addition to continuing their open-label statin for 8 weeks. The primary efficacy variable was the percent change in low-density lipoprotein (LDL) cholesterol from baseline with statin monotherapy to end point after intervention (secondary variables: high-density lipoprotein [HDL] cholesterol and triglycerides). Ongoing statin therapy plus ezetimibe led to changes of -25.1% for LDL cholesterol (HDL cholesterol +2.7%; triglycerides -14.0%) compared with LDL cholesterol -3.7% (p <0.001), HDL cholesterol +1.0% (p <0.05), and triglycerides -2.9% (p <0.001) for placebo added to ongoing statin therapy. Among patients not at LDL cholesterol goal at on-statin baseline, 71.5% receiving statin plus ezetimibe versus 18.9% receiving statin plus placebo reached goal at end point (odds ratio 23.7; p <0.001). The co-administration of statin and ezetimibe was generally well tolerated. Adding ezetimibe to ongoing statin therapy led to substantial additional reduction in LDL cholesterol levels, facilitating attainment of NCEP goals. Ezetimibe offers a new therapeutic option for patients receiving statins who require further reduction in LDL cholesterol.",2002.0,0,0 1684,12423718,Alternative approaches to cholesterol-lowering therapy.,Scott M Grundy,,2002.0,0,0 1685,12424866,Primary prevention of disease of old age.,David R Mehr; Paul E Tatum,"Although increasing disability is a common concomitant of old age, several interventions may prevent or delay disabling diseases. The ""young-old"" differ little from middle-aged people in their potential to benefit from many interventions. As age increases, clinicians need to become increasingly circumspect about interventions with a potential for harm and for benefit. By carefully weighing existing disease burden, the state of our knowledge about prevention, and patient values, however, clinicians may develop a reasonable preventive program in consultation with the patient and, where there is diminished competence, relevant family members. As we gain new knowledge about genetic and other risk factors, we may be able to more accurately and effectively target preventive services to maximize benefits and minimize harms in the population as a whole.",2003.0,0,0 1686,12424868,"Prevention of cardiovascular diseases. Coronary artery disease, congestive heart failure, and stroke.",Barbara J Messinger-Rapport; Dennis Sprecher,"Cardiovascular disease leads to significant morbidity and mortality in the older population. Results of risk reduction can be dramatic in terms of patient survival and quality of life. This article reviews evidence for cardiovascular risk factors and disease prevention in older adults. Interventions which reduce morbidity and mortality from coronary artery disease, heart failure, and cerebrovascular disease in the elderly population are examined. Attention is given to the role of cardiovascular disease in older women and in minorities, subsets not well-represented in many studies.",2003.0,0,0 1687,12424869,Prevention of brain aging and dementia.,Linda J Ball; Stanley J Birge,"The brain is subjected to multiple factors that result in damage to its cellular constituents, the neuron and supporting cells, and the neural networks that form the bases of cognitive ability. Like other systems, the brain has remarkable capacity to repair that damage and to adapt or compensate for the loss of neurons and the disruption of the neural architecture. Brain aging and dementia can be conceptualized as a balance between neuronal injury and repair. This balance can be affected not only by genetic and age-related factors but also by multiple environmental factors. The latter includes many factors, including education, nutrition, exercise, socialization, and stress. As individuals, we have the potential to modify these factors through lifestyle choices. Advances in neuroscience have led to the development of pharmacologic agents that can ameliorate the effects of even genetic (e.g., statins and antihypertensive agents) and age-related (e.g., antioxidants and estrogen replacement) factors. By altering the balance between neuronal injury and repair, we can delay the expression and progression of the neurodegenerative processes of brain aging, AD, and related dementias.",2003.0,0,0 1688,12425182,,,,,0,0 1689,12425372,Ezetimibe in hypercholesterolaemia.,M Farnier,"Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors, compounds that effectively block intestinal absorption of dietary and biliary cholesterol, without affecting absorption of fat soluble vitamins or triglycerides. Ezetimibe underwent glucuronidation to a single metabolite and localised at the intestinal wall, where it prevented luminal cholesterol absorption. Pre-clinical studies demonstrated the lipid-lowering and antiatherosclerotic properties of ezetimibe. The efficacy and safety of ezetimibe monotherapy have been determined in phase II/III studies: in phase II studies, the optimal efficacy was reached with ezetimibe 10 mg per day and the pooled efficacy data have shown that ezetimibe 10 mg has a positive effect on the lipoprotein profile with a significant reduction in LDL-cholesterol of 18.5%, an increase in HDL-cholesterol of 3.5% and a trend towards lowering in triglyceride concentrations (-4.9%). The monotherapy phase III studies have confirmed the efficacy with a decrease in LDL-C of 17.4% and have demonstrated an excellent safety and tolerability profile. The potential for a pharmacokinetic and/or pharmacodynamic interaction between ezetimibe and various statins and the efficacy and safety or the co-administration of ezetimibe and statins have been evaluated in different phase I/II studies: ezetimibe had no significant effect on the pharmacokinetics of simvastatin or atorvastatin. Ezetimibe 10 mg co-administrated with the starting dose of any statin induced a mean 18% additive LDL-C lowering effect. This additive 18% reduction in LDL-C is achieved in one step compared with the three steps necessary with statin monotherapy.",2002.0,0,0 1690,12427413,Comparative beneficial effects of simvastatin and pravastatin on cardiac allograft rejection and survival.,Mandeep R Mehra; Patricia A Uber; Krishnamoorthy Vivekananthan; Sergio Solis; Robert L Scott; Myung H Park; Richard V Milani; Carl J Lavie,"We sought to evaluate the relative effects of low doses of pravastatin (20 mg/day) and simvastatin (10 mg/day) on indices of cardiac allograft rejection. We further examined the relative efficacy and safety of these two drugs on lipid-lowering in heart transplantation. The immunomodulatory effects of hydroxy methyl glutaryl-coenzyme A reductase inhibitors have been increasingly recognized. Previous studies have demonstrated an ameliorative influence of pravastatin on hemodynamically compromising rejection after heart transplantation. A recent observational trial suggested that simvastatin 20 mg/day was associated with trends to lower survival and more adverse effects than pravastatin 40 mg/day. In a 12-month prospective, open-label study, 50 heart transplant recipients received either open-label pravastatin 20 mg daily (n = 24) or simvastatin 10 mg daily (n = 26) within four weeks of transplantation. Indices of allograft rejection including treated rejection, rejection with hemodynamic compromise, noncellular rejection, and mean one-year biopsy score were compared between the two cohorts, as well as with a statin-naive control population (n = 37). Lipid levels, safety, and post-transplant outcomes were also assessed as secondary end points. We found no significant differences in any allograft rejection parameter between the two groups. However, total low-density lipoprotein (LDL), but not high-density lipoprotein cholesterol or triglycerides, were lower in the simvastatin arm (-23% vs. -11%, p = 0.02). No cases of rhabdomyolysis or myositis occurred in either group. Survival at one year was similar in both treatment groups (91% for patients on pravastatin and 92% for patients on simvastatin). Both groups had better survival compared with the statin-naive control group (80%, p = 0.04). Simvastatin (10 mg/day) and pravastatin (20 mg/day) are associated with similar beneficial effects on cardiac allograft rejection and one-year survival. At these doses, simvastatin decreases LDL cholesterol more so than pravastatin with no increase in adverse effects in heart transplantation.",2003.0,0,0 1691,12427649,Low-density lipoprotein level reduction by the 3-hydroxy-3-methylglutaryl coenzyme-A inhibitor simvastatin is accompanied by a related reduction of F2-isoprostane formation in hypercholesterolemic subjects: no further effect of vitamin E.,Raffaele De Caterina; Francesco Cipollone; Francesca Paola Filardo; Marco Zimarino; Walter Bernini; Guido Lazzerini; Tonino Bucciarelli; Angela Falco; Paola Marchesani; Raffaella Muraro; Andrea Mezzetti; Giovanni Ciabattoni,"Both statins and vitamin E, by reducing the rate of lipid peroxidation, may interfere with oxidative stress, but the impact of their combination is unknown. We randomized 43 hypercholesterolemic patients (21 men, 22 women, age 63+/-11 years) to either simvastatin, to achieve >20% reduction of total cholesterol, or simvastatin plus 600 mg/d vitamin E for 2 months. Patients were then crossed over to the alternative treatment. Lipid parameters documented patients' compliance to simvastatin, whereas plasma levels of vitamin E documented compliance and absorption of vitamin E. We assessed urinary excretion of the isoprostane 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) as an in vivo index of oxidative stress at baseline and after each month of therapy. 8-Iso-PGF(2alpha) was significantly reduced by simvastatin, from 361+/-148 pg/mg creatinine (mean+/-SD) at baseline to 239+/-124 pg/mg creatinine after 1 month. The addition of vitamin E did not reduce such levels any further (256+/-125 after 1 month). Linear regression analysis showed a weak inverse relationship of 8-iso-PGF(2alpha) with vitamin E levels but a much stronger relationship with LDL cholesterol (R(2)=0.162; P<0.001). In hypercholesterolemic patients, LDL cholesterol is a major correlate of oxidative stress. Concomitant with LDL cholesterol reduction, simvastatin causes a drastic reduction of oxidative stress to a level that is not further reduced by the addition of vitamin E. Results of clinical trials with vitamin E may have been hampered by inadequate knowledge of the background level of lipid peroxidation, which is a major determinant of vitamin E bioactivity.",2002.0,0,0 1692,12429006,Chlamydia pneumoniae and cardiovascular disease.,Mikkel M Larsen; Birgitte Moern; Andrew Fuller; Paul L Andersen; Lars J Ostergaard,"Chlamydia pneumoniae has been detected in atherosclerotic plaques, while seropositivity to this organism confers a slightly increased risk of coronary events. However, no aetiological link has been established; a major difficulty when investigating this link is the lack of a gold standard for diagnosing chronic vessel infection. The outcomes of case-control studies and prospective trials of macrolides in treatment and prevention of cardiovascular disease have been ambiguous but suggest a short-term preventive effect. Whether this is due to the antimicrobial or anti-inflammatory activity of the macrolides is unknown. Larger and longer prospective trials currently under way may provide better insight into the association of C. pneumoniae with cardiovascular disease. At present, there is no justification for treating cardiovascular disease with antibiotics.",2002.0,0,0 1693,12429870,Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease.,Angelika De Bree; W M Monique Verschuren; Daan Kromhout; Leo A J Kluijtmans; Henk J Blom,"Cardiovascular diseases (CVD), especially coronary heart disease (CHD), are the most important causes of death in industrialized countries. Increased concentrations of total plasma homocysteine (tHcy) have been associated with an increased risk of CHD. Assuming that this relation is causal, a lower tHcy concentration will reduce the occurrence and recurrence of CHD. Therefore, it is important to know which factors determine the tHcy concentration. In the general population, the most important modifiable determinants of tHcy are folate intake and coffee consumption. Smoking and alcohol consumption are also associated with the tHcy concentration, but more research is necessary to elucidate whether these relations are not originating from residual confounding due to other lifestyle factors. The most important nonmodifiable determinant is the 677 C>T polymorphism in the gene that encodes methylenetetrahydrofolate reductase (MTHFR), a regulating enzyme in homocysteine metabolism. Especially subjects with the homozygous form of this polymorphism (i.e., 677TT genotype) and a low folate status have elevated tHcy concentrations. Specific clinical conditions like the use of antiepileptic drugs or methotrexate, renal failure, cancer, rheumatoid arthritis, and hypothyroidism may lead to elevated tHcy concentrations. The available epidemiological evidence indicates that an increased tHcy concentration is not an important risk factor for CHD in healthy subjects. However, prospective studies, which included subjects at high risk of CHD, and secondary prevention trials with intermediary endpoints consistently show that elevations in the tHcy concentration may be an important risk factor in these subjects for a (recurrent) CHD event. The induction of vascular endothelial dysfunction by homocysteine may underlie this increased risk. Ongoing intervention trials will indicate whether homocysteine-lowering through vitamin supplementation, prevents CHD in the treatment groups.",2003.0,0,0 1694,12431639,"Simvastatin effect on NK cells activity in vivo: a double-blind randomized, placebo-controlled study.",A F Santos; E Keitel; A E Bittar; J Neumann; N Fonseca; H Sporleder; R Canabarro; L Kroth; D Saitovitch; V D Garcia,,2003.0,0,0 1695,12433505,C-reactive protein and progressive atherosclerosis.,Elisabetta Rossi,,2002.0,0,0 1696,12433885,Hypertension control at hospital discharge after acute coronary event: influence on cardiovascular prognosis--the PREVENIR study.,J Amar; B Chamontin; J Ferriéres; N Danchin; O Grenier; C Cantet; J-P Cambou,"To assess hypertension control in patients admitted to hospital for an acute coronary event and to investigate the influence on prognosis of controlling hypertension before hospital discharge. Multicentre retrospective cohort study. The medical records were examined of all patients admitted in 77 cardiological centres on January 1998 for myocardial infarction or unstable angina and who survived. Clinical characteristics, blood pressure at hospital discharge, and cardiovascular events during a six month follow up were recorded. Cardiovascular deaths and non-fatal myocardial infarction. Data were available in 1247 patients. At discharge, 411 (32.9%) had uncontrolled hypertension; among these, 276 (22.1%) were uncontrolled on the basis of systolic blood pressure alone. Forty three cardiovascular deaths and 20 non-fatal myocardial infarcts occurred during follow up. In a multivariate analysis, age, left ventricular ejection fraction, previous history of cardiovascular disease, and isolated systolic hypertension (odds ratio 1.9, 95% confidence interval 1.07 to 3.37) were associated with the outcome. 22.1% of patients admitted to hospital for an acute coronary syndrome have uncontrolled isolated systolic hypertension on discharge. This appears to be an independent predictor of cardiovascular outcome.",2002.0,0,0 1697,12434726,Lipid-lowering therapy after coronary artery bypass grafting: time for more aggressive intervention.,B Daniel Lucas,,2003.0,0,0 1698,12436350,"Effects of SREBF-1a and SCAP polymorphisms on plasma levels of lipids, severity, progression and regression of coronary atherosclerosis and response to therapy with fluvastatin.",Lorraine Salek; Silvia Lutucuta; Christie M Ballantyne; Antonio M Gotto; A J Marian,"Sterol regulatory elements binding factor-1a (SREBF-1a) and SREBF cleavage activating protein (SCAP) regulate lipids homeostasis. Polymorphisms in SREBF-1a and SCAP could affect plasma levels of lipids and risk of atherosclerosis. We determined association of SREBF-1a -36del/G and SCAP 2386A/G genotypes with plasma levels of lipids, severity and progression/regression of coronary atherosclerosis, and response to treatment with fluvastatin in a well-characterized Lipoprotein Coronary Atherosclerosis Study population. Plasma lipids and quantitative indices of coronary atherosclerosis were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo in 372 subjects. Fluvastatin reduced plasma levels of total cholesterol by 16%, LDL-C by 25%, and ApoB by 16% and increased plasma levels of HDL-C by 9% and apoA-1 by 7%. Distributions of SREBF-1a SCAP genotypes were 60 GG, 172 del-G and 140 del-del and 88 GG, 188 GA and 96 AA, respectively. There were no significant differences in baseline plasma levels of lipids or indices of severity of atherosclerosis among the genotypes of each gene. There was a strong graded genotype-treatment interaction between SREBF-1a genotypes and change in apoA-I levels in response to fluvastatin (16.5% increase in GG, 10.5% in del/G, and 0.4% in del/del groups). Modest interactions between SREBF-1a genotypes and changes in HDL-C, and apoC-III levels in response to fluvastatin were also present. No genotype-treatment interaction for progression or regression of coronary atherosclerosis was detected. There were no significant interactions between SCAP genotypes and response to therapy. Thus we detected a strong graded interaction between SREBF-1a -36del/G genotypes and response of plasma apoA-I to treatment with fluvastatin.",2003.0,0,0 1699,12436750,Some historical aspects of the development of cardiovascular drugs.,H Scholz,"This is a short historical overview on the development of important cardiovascular drugs. Agents developed during the last 75 years and with relations to German-speaking countries and the German Society of Cardiology (GSC) are primarily discussed. Other compounds, e.g., nitrates, statins or thrombolytics, which have been discovered elsewhere, are not covered in this paper.",2003.0,0,0 1700,12437408,Cost-effectiveness implications of the timing of antiretroviral therapy in HIV-infected adults.,Bruce R Schackman; Kenneth A Freedberg; Milton C Weinstein; Paul E Sax; Elena Losina; Hong Zhang; Sue J Goldie,"The appropriate time to initiate antiretroviral therapy is controversial for human immunodeficiency virus (HIV)-infected patients with CD4 cell counts between 200/microL and 350/microL and low levels of HIV RNA, potentially leading to barriers to treatment access. To examine the effect of cholesterol changes and fat redistribution symptoms on the clinical benefits and cost-effectiveness of early antiretroviral therapy in these patients. We used a state-transition model to compare initiating antiretroviral therapy at CD4 cell counts of 350/microL (early therapy) with initiating therapy at CD4 cell counts of 200/microL (deferred therapy) in patients with HIV RNA levels of 10,000 to 30,000 copies/mL. Data were from randomized clinical trials, cohort studies, and other published literature. If cholesterol changes associated with antiretroviral therapy resulted in a permanent increase in coronary heart disease risk, life expectancy with early therapy was 16.54 years (vs 16.66 years without this risk) and with deferred therapy was 13.73 years (vs 13.80 years without this risk). Early therapy was a more efficient use of resources (ie, dominated) compared with deferred therapy. Early therapy cost $13,000 per quality-adjusted life-year compared with no therapy with or without increased coronary heart disease risk, and $17,000 to $24,000 per quality-adjusted life-year taking into account the quality-of-life reduction in patients with fat distribution symptoms. Early therapy had a higher quality-adjusted life expectancy than deferred therapy as long as this quality-of-life reduction was 70% or less. Changes in cholesterol or quality of life associated with antiretroviral therapy do not justify limiting access to early HIV treatment. The effect of fat redistribution symptoms on quality of life will determine the optimal choice of early vs deferred therapy for an individual patient.",2002.0,0,0 1701,12437496,Fluvastatin.,J M Lawrence; J P D Reckless,"Fluvastatin was the first wholly synthetic statin to the market and is effective in reducing total and low density lipoprotein cholesterol, which translates into reductions in coronary heart disease events. The Lescol Intervention Prevention Study has established the effectiveness of the early use of statins in reducing recurrent events in high-risk patients with coronary heart disease post percutaneous coronary interventions. Fluvastatin is well-tolerated with few side effects. The occurrence of significant abnormalities in liver enzymes is infrequent, and the risk of myositis and rhabdomyolysis seems to be less than with other statins. There have been no reports of fatal rhabdomyolysis to date. The potential for drug interactions with fluvastatin is low. It seems safe in combination with cyclosporin and there have been few reports of rhabdomyolysis when using fluvastatin in combination with other lipid-lowering agents. It is nevertheless important to be vigilant for this potentially important side effect and, as with other statins, inform patients of the potential risk and suggestive symptoms. Fluvastatin provides a useful option in treating hypercholesterolaemia in patients at high risk of coronary heart disease.",2003.0,0,0 1702,12437499,Acyl coenzyme A:cholesterol acyltransferase inhibition: potential atherosclerosis therapy or springboard for other discoveries?,Therese M Heinonen,"Cholesterol is an essential building block without which humans and other animals could not exist. As with most necessities, under certain conditions, excess can sharply tip the scale and lead to an unfavourable outcome. Excess cholesterol is stored as cholesteryl ester through an esterification process regulated in part by acyl coenzyme A:cholesterol acyltransferase (ACAT). ACAT is found in many tissue types which require the storage of cholesterol. Most notably, for cardiovascular disease ACAT activity is significant in intestinal and hepatic tissue and arterial macrophages. Several ACAT inhibitors have been investigated for their potential to favourably alter serum lipoprotein levels by blocking intestinal absorption, hepatic inhibition and/or slowing the progression of atherosclerosis through a non-lipid arterial inhibition. Recent evaluations of ACAT and ACAT inhibitors have provided some insight into the therapeutic potential and risks of ACAT inhibition as a means of treating atherosclerosis.",2003.0,0,0 1703,12437511,Why might statins prevent venous thromboembolism: what needs to be done to know more?,Joel G Ray,Dyslipidaemia may be a risk factor for venous thromboembolism and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may be protective. The current review outlines the cumulative evidence from both the basic and epidemiologic sciences for why this might be so and offers some directions for future research.,2003.0,0,0 1704,12438948,"Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine.",Stuart M Flechner; David Goldfarb; Charles Modlin; Jingyuan Feng; Venkatesh Krishnamurthi; Barbara Mastroianni; Kathy Savas; Daniel J Cook; Andrew C Novick,"Progressive nephrotoxicity caused by calcineurin inhibitor drugs contributes to the long-term decline in renal function in kidney transplant patients. We conducted a randomized, prospective trial of calcineurin inhibitor drug avoidance in 61 adult primary kidney transplant recipients. Each patient received induction therapy with 20 mg basiliximab on days 0 and 4, and maintenance therapy with mycophenolate mofetil 1 g two times per day and steroids. Thirty-one patients received sirolimus, 5 mg daily after a 15-mg loading dose. Doses were then concentration-controlled to keep 24-hr trough levels at 10 to 12 ng/mL for 6 months and 5 to 10 ng/mL thereafter. Thirty patients began cyclosporine therapy at 6 to 8 mg/kg per day in divided doses and were then concentration-controlled to keep 12-hr troughs of 200 to 250 ng/mL. Mean follow-up is 18.1 months (range, 12-26 months). The percentages of 1-year patient survival, graft survival, and biopsy-confirmed acute rejection rates were not significantly different between the sirolimus-treated patients (96.7%, 96.7%, and 6.4%, respectively) and the cyclosporine-treated patients (100%, 95.4%, and 16.6%, respectively). At 6 and 12 months, respectively, the sirolimus-treated patients enjoyed significantly better (P=0.008 and P=0.004) mean serum creatinine levels (1.29 and 1.32 mg/dL) and calculated creatinine clearances (77.8 and 81.1 mL/min) than cyclosporine-treated patients (1.74 and 1.78 mg/dL, and 64.1 and 61.1 mL/min, respectively). Sirolimus-treated recipients have significantly (P=0.001) higher 1-year trough levels of mycophenolic acid (4.16 ng/mL) than cyclosporine-treated patients (1.93 ng/mL). Sirolimus also delays the repopulation of basiliximab-depleted CD25 T cells compared with cyclosporine. Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.",2002.0,0,0 1705,12438974,Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient.,G V Ramesh Prasad; Timothy Wong; Galo Meliton; Salma Bhaloo,"Rhabdomyolysis is a known complication of hepatic 3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitor (statin) therapy for posttransplant hyperlipidemia, and thus monitoring for this effect is indicated. We report a case of an herbal preparation-induced rhabdomyolysis in a stable renal-transplant recipient, attributed to the presence of red yeast rice (Monascus purpureus) within the mixture. The condition resolved when consumption of the product ceased. Rice fermented with red yeast contains several types of mevinic acids, including monacolin K, which is identical to lovastatin. We postulate that the interaction of cyclosporine and these compounds through the cytochrome P450 system resulted in the adverse effect seen in this patient. Transplant recipients must be cautioned against using herbal preparations to lower their lipid levels to prevent such complications from occurring.",2002.0,0,0 1706,12439201,Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel.,Morris Schambelan; Constance A Benson; Andrew Carr; Judith S Currier; Michael P Dubé; John G Gerber; Steven K Grinspoon; Carl Grunfeld; Donald P Kotler; Kathleen Mulligan; William G Powderly; Michael S Saag; International AIDS Society-USA,"Alterations in glucose and lipid metabolism, lactic acidemia, bone disorders, and abnormal body fat distribution have been recognized recently as frequent complications associated with HIV-1 infection and potent antiretroviral therapy, but limited data are available regarding the appropriate management of these disorders. These recommendations were developed to guide physicians actively involved in HIV care in the management of metabolic complications that occur primarily within the context of potent antiretroviral therapy. A 12-member panel representing international expertise in HIV-1 patient care, antiretroviral therapy, and endocrine and metabolic disorders was selected in the spring of 2000 by the International AIDS Society-USA, a not-for-profit physician education organization. Panel members met in closed meetings beginning in May 2000. All work was funded by the International AIDS Society-USA; the panel members are not compensated for their participation. The panel reviewed published results of clinical, epidemiologic, and basic science studies and data and abstracts presented at research conferences, primarily from 1997 to 2002. The panel also considered studies of the pathophysiology and treatment of similar metabolic abnormalities in noninfected persons. Emphasis was placed on results from prospective, randomized, controlled clinical trials when available. For each metabolic complication, 1 or more member(s) reviewed and presented all available evidence to the panel, and then wrote a summary of the evidence and preliminary recommendations. Final recommendations were determined by full group consensus. The summaries were combined into a single working document and all panel members edited and approved all subsequent drafts. Carefully controlled studies to determine the incidence, etiology, risk factors, and most appropriate treatments for metabolic complications in HIV-1 infection are urgently needed. In the absence of these data, and to prevent acute illness and mitigate long-term risks, the panel recommends routine assessment and monitoring of glucose and lipid levels and assessment and monitoring of lactic acidemia and bone abnormalities if clinical signs or symptoms are detected. With the exception of body fat distribution abnormalities, specific treatments for these complications are also recommended. Successful long-term antiretroviral therapy will require diligent monitoring and preemptive treatment of metabolic complications to optimize the risk-benefit ratio of antiretroviral therapies.",2002.0,0,0 1707,12439225,,,,,0,0 1708,12439437,New strategies in managing and preventing atherosclerosis: focus on HDL.,Matthew J Price; Prediman K Shah,"The development of atherosclerosis is a complex process whose central elements include the entrapment of low-density lipoprotein in the vessel wall, its subsequent oxidative modification, and the stimulation of proinflammatory gene expression leading to inflammatory cell recruitment, infiltration, and activation. High-density lipoprotein interacts with this process at multiple points, and these interactions could provide therapeutic targets to prevent, stabilize, or even promote the regression of atherosclerosis. High-density lipoprotein may retard atherosclerotic progression by promoting cholesterol efflux from the arterial wall, thereby reducing plaque lipid content as well as potentially inhibiting nascent fatty streak formation. A growing body of evidence derived from clinical trials supports the contention that the raising of high-density lipoprotein levels may confer significant cardiovascular benefit independently of low-density lipoprotein lowering. An antiatherogenic strategy focusing on high-density lipoprotein and its apolipoproteins represents a new frontier in the management of atherosclerosis.",2003.0,0,0 1709,12439630,Endothelial progenitor cells: regulation and contribution to adult neovascularization.,Dirk H Walter; Stefanie Dimmeler,"Recent studies suggest that circulating progenitor cells contribute to the formation of new blood vessels in adults after tissue ischemia. The infusion of these progenitor cells was used as a therapeutic approach to increase vascularization. In several animal models, progenitor cells improved vascularization and capillary density after peripheral or myocardial ischemia. Moreover, transplantation or progenitor cells increased cardiac function after myocardial ischemia. These studies suggest a potential use of progenitor cells for improvement of therapeutic vasculogenesis in patients with ischemic heart disease. The present article will summarize these findings gained in experimental models. Moreover, novel approaches to increase the function and the number of circulating progenitor cells by pharmacological modulation (cytokines, statins) or gene therapy (VEGF) will be highlighted. Identification of mediators and cellular mechanisms that promote organ-specific recruitment of bone-marrow derived circulating progenitor cells as well as modulation of progenitor cell engraftment will lead to new strategies in order to improve neovascularization and cardiac regeneration in patients with ischemic heart disease.",2003.0,0,0 1710,12439660,The role of serum lipids in exudative diabetic maculopathy: is there a place for lipid lowering therapy?,T A Chowdhury; D Hopkins; P M Dodson; G C Vafidis,"Diabetic maculopathy is a common complication of diabetes mellitus, characterised by macular oedema and frequently accompanied by lipid exudation. It is the major cause of loss of vision from diabetic retinopathy. There is some evidence to implicate serum lipids in exudative maculopathy; cross-sectional studies suggest that higher serum lipid levels are found in patients with macular exudates, and prospective studies have shown an increased risk of exudative maculopathy if baseline cholesterol is higher. The treatment for diabetic maculopathy is laser photocoagulation of the pigment epithelium. With the advent of systemic lipid lowering therapy over the last decade, there may be potential for medical therapy also. There is some anecdotal evidence of the effect of lipid lowering agents (particularly statins) in reducing exudate, and a number of studies have shown that lipid lowering therapy may reduce macular exudates, but numbers in these trials are small. A randomised controlled trial is now required to investigate whether the use of systemic lipid lowering therapy is of benefit in patients with exudative maculopathy, even in the absence of dyslipidaemia.",2003.0,0,0 1711,12439735,Pharmacogenetics research network and knowledge base second scientific meeting.,A F Davis; R M Long,,2003.0,0,0 1712,12440192,,,,,0,0 1713,12441884,HDL and triglyceride as therapeutic targets.,Jean-Charles Fruchart; Patrick Duriez,"Epidemiological studies have shown that plasma HDL-cholesterol is inversely related to coronary artery disease and that there is an inverse relationship between HDL-cholesterol and triglyceride levels, but it is now demonstrated that hypertriglyceridemia is an independent risk factor for coronary heart disease (CHD). The goal of this review is to discuss if triglycerides and HDL-cholesterol could be therapeutic targets to reduce cardiovascular risk. Triglyceride measurement is not informative on the specificity of the triglyceride-rich lipoproteins present in the plasma because some of these are not atherogenic (chylomicrons, large VLDLs) while others are highly atherogenic (small VLDLs, remnants, IDL...). Statins, in addition to reducing LDL-cholesterol, significantly reduced atherogenic remnant lipoprotein cholesterol levels. 4S, CARE+LIPID, and AFCAPS/TexCAPS studies, suggested enhanced therapeutic potential of statins for improving triglyceride and HDL-cholesterol levels in patients with CHD. A fibrate (gemfibrozil) was shown to reduce death from CHD and non-fatal myocardial infarction in secondary prevention of CHD in men with low levels of HDL-cholesterol (VA-HIT); during the treatment these levels predicted the magnitude of reduction in risk for CHD events. ATP III recommendations state, on triglycerides and HDL-cholesterol as targets to reduce cardiovascular risk: (1) that lowering LDL-cholesterol levels is the primary target of therapy, (2) a secondary target is to achieve a triglyceride level < 150 mg/dL and (3) clinical trial data are considered to be insufficient to support recommended a specific HDL-cholesterol goal even if HDL-cholesterol < 40 mg/dL is considered to be a major risk factor of CHD.",2003.0,0,0 1714,12441885,Lipid-lowering therapy in people with type 2 diabetes.,Stephen Colagiuri; James Best,"The risk of cardiovascular disease is markedly increased in people with type 2 diabetes. There is abundant epidemiological and clinical trial evidence that lipid abnormalities play a major role in the pathogenesis of atherosclerotic vascular disease in diabetes. Although the benefits of lipid-lowering therapy are well established in people without diabetes, the evidence in people with diabetes is not as well established. Recent population studies of lipid-lowering therapy and cardiovascular disease outcomes that included people with diabetes and performed a separate subgroup analysis were reviewed. Lipid lowering with statins and fibrates is effective in improving cardiovascular disease outcomes in diabetes, and their effectiveness is similar to that in the non-diabetic population. This effect is well established in secondary prevention and is accumulating for primary prevention. Individuals with diabetes require aggressive management of dyslipidaemia as part of an overall management strategy to reduce the risk of cardiovascular disease. Individuals with a previous cardiovascular disease event should be on lipid-lowering therapy, whereas in those who have not had a previous cardiovascular disease event, the decision to use lipid-lowering therapy should be based on lipid levels and the overall risk of a future event. The results of large studies that are currently in progress specifically in people with diabetes should resolve outstanding questions in relation to lipid-lowering therapy in diabetes.",2003.0,0,0 1715,12441886,Statin use in acute coronary syndromes: cellular mechanisms and clinical evidence.,Robert S Rosenson; Alan S Brown,"Review the cellular mechanisms and clinical evidence for the use of statins in patients with unstable coronary syndromes. Clinical trials of statin therapy in acute coronary syndromes demonstrate a rapid improvement in endothelial function, improved perfusion to ischemic myocardium, and an early reduction in cardiovascular events. The early benefit of statin therapy is related to a combination of molecular mechanisms that involve the oxidized LDL receptor (LOX-1), endothelial localized nitric oxide synthase, inflammatory cytokines, interstitial collagenases, and tissue factor expression. In human atheroma, 3 months' use of statin (pravastatin) therapy reduced the content of oxidized LDL, inflammatory cells (macrophage, T cells) infiltrates, and improved plaque stability by increasing the collagen content of the fibrous cap. The antiatherothrombotic effects of statin therapy appear to have important clinical relevance to patients with impaired myocardial perfusion and acute coronary syndrome.",2003.0,0,0 1716,12441887,Early initiation of statin therapy after a coronary event.,Barry McKeown; Peter L Thompson,"Despite improvements in the early management of acute coronary syndromes, the risk of major cardiovascular complications remains high. Lipid-modifying treatment with statins has the potential to further improve outcomes through improved endothelial function, antithrombotic and antiinflammatory actions. Statins are of proven benefit in patients with stable coronary heart disease. There has been speculation on potential mechanisms of benefit but, until recently, little data on the efficacy and safety of statins in the acute setting. Recent observational studies and randomized trials have addressed some of the questions regarding early initiation of statins in acute coronary syndromes. Recent observational and randomized trials have shown that early commencement of statins in acute coronary syndromes is safe as early as 6 hours after the event and is likely to improve longer-term compliance. The current data are not sufficient to draw conclusions about the efficacy of statins early in the course of acute coronary syndromes. Current management for acute coronary syndromes should include the commencement of statin therapy during initial hospital admission. This recommendation is based on safety and compliance data. More randomized trial evidence is required to determine whether early initiation will produce better outcomes than later initiation after an acute coronary event.",2003.0,0,0 1717,12441889,Role of lipid-modifying therapy in the prevention of initial and recurrent stroke.,Graeme J Hankey,"To establish the role of cholesterol-modifying therapy in stroke prevention. Population-based observational cohort studies show a variable weak positive relationship between increasing plasma total cholesterol concentrations and an increasing risk of ischaemic stroke, which is partly offset by a weaker negative association between decreasing total cholesterol concentrations and an increasing risk of with haemorrhagic stroke. However, randomized controlled trials show unequivocally that lowering plasma total cholesterol by approximately 1.2 mmol/l (and LDL-cholesterol by 1.0 mmol/l) is associated with a reduced relative risk of stroke and other serious vascular events by at least a quarter, and probably a third, without any increase in haemorrhagic stroke, in a wide range of men and women (including individuals with previous stroke). The proportional reduction in stroke risk is consistent, irrespective of the patient's age, baseline plasma cholesterol concentration, and absolute risk of stroke (although perhaps less in very low-risk individuals), but is increased with greater degrees of cholesterol lowering (15% or more), and thus with statin medications, which are more potent than non-statin interventions in lowering cholesterol levels. The absolute reduction in stroke risk achieved by statins is greatest among individuals at highest risk of stroke. Preliminary evidence suggests that lowering total cholesterol levels by diet may be an effective adjunctive therapy to statins, and raising plasma HDL-cholesterol concentrations among patients with coronary heart disease and low HDL-cholesterol levels ( 1 mmol/l) by means of gemfibrozil may also effectively prevent stroke. Statin drugs are effective and safe in preventing initial and recurrent stroke. However, because they are costly, they should probably be restricted to individuals with an annual risk of stroke and other serious vascular events of 3% or greater, and possibly as low as 1.5%, because routine monitoring of plasma cholesterol, and liver and muscle enzyme concentrations is probably no longer necessary.",2003.0,0,0 1718,12441891,The future direction of cholesterol-lowering therapy.,Marc Evans; Aled Roberts; Alan Rees,"Observational studies suggest a continuous positive relationship between vascular risk and cholesterol without any lower threshold level. We review recent and future clinical trials addressing the question of optimal treatment goals for cholesterol reduction and how these relate to present guidelines. With increasing focus on greater cholesterol reduction, new approaches to lipid-lowering therapy are being developed; we discuss some of these agents including the new statin, rosuvastatin and novel cholesterol transport inhibitors such as ezetimibe. The Heart Protection Study demonstrated that LDL cholesterol reduction to levels as low as 1.7 mmol/l was associated with significant clinical benefit in a wide range of high-risk individuals, irrespective of baseline cholesterol levels, with no apparent threshold level for LDL cholesterol with respect to cardiovascular risk. The Heart Protection Study also demonstrated that the benefits of LDL cholesterol reduction extend into peripheral vascular disease and cerebrovascular disease prevention and suggest that the most recent National Cholesterol Education Program Adult Treatment Panel III guidelines, with LDL cholesterol targets of 2.6 mmol/l, may result in undertreatment of a large number of patients. Various large end-point trials, including Treating to New Targets and Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine will attempt to further address the issue of optimal LDL cholesterol reduction. New therapies are being developed to meet the challenge of more intensive cholesterol lowering. Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in LDL cholesterol of 40-69% over its dose range of 5-80 mg. Ezetimibe is a selective cholesterol absorption inhibitor, with a site of action at the intestinal epithelium. Optimum reductions in LDL cholesterol of up to 25 and 60% reduction in chylomicron cholesterol content are seen with a 10-mg dose. Evidence is accumulating supporting the safety and benefits of aggressive cholesterol reduction, with no apparent threshold for LDL cholesterol. New therapies will aid in achieving lower cholesterol levels and the use of combination therapies targeting different aspects of cholesterol metabolism may produce additional benefits. Outcome studies are awaited to further address these issues.",2003.0,0,0 1719,12441896,Atherosclerosis: cell biology and lipoproteins: cholesterol absorption inhibitors: gateway therapy for hypercholesterolaemia.,Andrew J Brown,,2003.0,0,0 1720,12444184,Clinical practice. Transient ischemic attack.,S Claiborne Johnston,,2002.0,0,0 1721,12444536,Lipid lowering: another method of reducing blood pressure?,A S Wierzbicki,"Modern management of cardiovascular risk depends on assessment of cardiovascular risk factors. Hypertension and hyperlipidaemia are synergistic risk factors for cardiovascular events. Both show a degree of cross-correlation through sharing mechanisms of pathogenesis including insulin resistance and endothelial dysfunction. This article reviews the common pathways leading to dyslipidaemia and hypertension and the effects diet and lipid-lowering drug therapies have had on correcting blood pressure in patients with essential hypertension. Both statins and fibrates have shown a capability to lower blood pressure by up to 8/5 and 15/10 mmHg respectively, in some small-scale clinical trials and have effects on arterial wall structure and hence pulse wave velocity. This blood pressure action may account for some of the clinical effects of lipid-lowering drugs on cardiovascular risk. Thus, lipid lowering may provide an additional method of correcting hypertension in some high-risk patients. However, data from large-scale intervention trials are either absent or ambiguous. Definitive large-scale trials to investigate the antihypertensive effects of lipid-lowering drugs are required, although end point studies examining the interaction of lipid-lowering and antihypertensive drugs to determine optimum combinations are already under way.",2003.0,0,0 1722,12445025,"Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers.",Paul D Martin; Patrick D Mitchell; Dennis W Schneck,"To compare the lipid-regulating effects and steady-state pharmacokinetics of rosuvastatin, a new synthetic hydroxy methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, following repeated morning and evening administration in volunteers with fasting serum low-density lipoprotein cholesterol (LDL-C) concentrations < 4.14 mmol l-1. In this open-label two-way crossover trial 24 healthy adult volunteers were randomized to receive rosuvastatin 10 mg orally each morning (07.00 h) or evening (18.00 h) for 14 days. After a 4 week washout period, volunteers received the alternative regimen for 14 days. Rosuvastatin was administered in the absence of food. Reductions from baseline in serum concentrations of LDL-C (-41.3%[morning]vs-44.2%[evening]), total cholesterol (-30.9%vs-31.8%), triglycerides (-17.1%vs-22.7%), and apolipoprotein B (-32.4%vs-35.3%) were similar following morning and evening administration. AUC(0,24 h) for plasma mevalonic acid (MVA), an in vivo marker of HMG-CoA reductase activity, decreased by -29.9% (morning) vs-32.6% (evening). Urinary excretion of MVA declined by -33.6% (morning) vs-29.2% (evening). The steady-state pharmacokinetics of rosuvastatin were very similar following the morning and evening dosing regimens. The Cmax values were 4.58 vs 4.54 ng ml-1, and AUC(0,24 h) values were 40.1 vs 42.7 ng ml-1 h, following morning and evening administration, respectively. There were no serious adverse events during the trial, and rosuvastatin was well tolerated after morning and evening administration. The pharmacodynamic effects and pharmacokinetics of rosuvastatin are not dependent on time of dosing. Morning or evening administration is equally effective in lowering LDL-C.",2003.0,0,0 1723,12446053,"Association of cholesterol levels, hydroxymethylglutaryl coenzyme-A reductase inhibitor treatment, and progression of aortic stenosis in the community.",Michael F Bellamy; Patricia A Pellikka; Kyle W Klarich; A Jamil Tajik; Maurice Enriquez-Sarano,"This study was designed to analyze the association among cholesterol levels, lipid-lowering treatment, and progression of aortic stenosis (AS) in the community. Aortic stenosis is a progressive disease for which there is no known medical treatment to prevent or slow progression. Despite plausible pathologic mechanisms linking hypercholesterolemia to AS progression, clinical studies have been inconsistent and affected by referral bias, and the role of lipid-lowering therapy is uncertain. We determined the association between blood cholesterol levels and progression of native AS (assessed by Doppler echocardiography at baseline and at least six months later; mean interval, 3.7 +/- 2.3 years) in a community-based study of 156 patients (age 77 +/- 12 years; 90 men). Thirty-eight patients received statin treatment during follow-up. In untreated subjects, mean gradient increased from 22 +/- 12 mm Hg to 39 +/- 19 mm Hg, and aortic valve area (AVA) decreased from 1.20 +/- 0.35 cm(2) to 0.91 +/- 0.33 cm(2) (both p < 0.001). The annualized change in AVA was -0.09 +/- 0.17 cm(2)/year (-7% +/- 13%/year). Neither total cholesterol (r = -0.01, p = 0.92) nor low-density lipoprotein cholesterol (r = 0.01; p = 0.88) showed a significant correlation to AS progression. Nevertheless, progression of AS was slower in patients receiving statins compared with untreated patients (decrease in AVA -3 +/- 10% vs. -7 +/- 13% per year, respectively; p = 0.04), even when adjusted for age, gender, cholesterol, and baseline valve area (p = 0.04). The association of statin treatment with slower progression was confirmed when analysis was restricted to patients coming for a systematic follow-up (p=0.02). The odds ratio of AS progression with statin treatment was 0.46 (95% confidence interval, 0.21 to 0.96). In the community, progression of AS shows no trend of association with cholesterol levels. Statin treatment, however, is associated with slower progression, suggesting that the effects of statin treatment on progression of AS should be pursued with appropriate clinical trials.",2003.0,0,0 1724,12446061,"Statin therapy is associated with reduced mortality across all age groups of individuals with significant coronary disease, including very elderly patients.",Chloe A Allen Maycock; Joseph B Muhlestein; Benjamin D Horne; John F Carlquist; Tami L Bair; Robert R Pearson; Qunyu Li; Jeffrey L Anderson; Intermountain Heart Collaborative Study,"This study evaluated the effect of statin therapy on mortality in individuals with significant coronary artery disease (CAD) stratified by age. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) significantly reduce morbidity and mortality in individuals with CAD. Unfortunately, the large statin trials excluded individuals over 80 years old, and it is therefore unknown whether very elderly individuals benefit from statins as do younger individuals. A cohort of 7,220 individuals with angiographically defined significant CAD (> or =70%) was included. Statin prescription was determined at hospital discharge. Patients were followed up for 3.3 +/- 1.8 years (maximum 6.8). Patients were grouped by age (<65, 65 to 79, and > or =80 years) to determine whether statin therapy reduced mortality in an age-dependent manner. Average age was 65 +/- 12 years; 74% were male; and 31% had a postmyocardial infarction status. Overall mortality was 16%. Elderly patients were significantly less likely to receive statins than younger patients (> or =80 years: 19.8%; 65 to 79 years: 21.1%; <65 years: 28.0%; p < 0.001). Mortality was decreased among statin recipients in all age groups: > or =80 years: 29.5% among patients not taking a statin versus 8.5% of those taking a statin (adjusted hazard ratio [HR] 0.50, p = 0.036); 65 to 79 years: 18.7% vs. 6.0% (HR 0.56, p < 0.001); and <65 years: 8.9% vs. 3.1% (HR 0.70, p = 0.097). Statin therapy is associated with reduced mortality in all age groups of individuals with significant CAD, including very elderly individuals. Although older patients were less likely to receive statin therapy, they received a greater absolute risk reduction than younger individuals. More aggressive statin use after CAD diagnosis may be indicated, even in older patients.",2003.0,0,0 1725,12447357,Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics.,Joanne T Brindle; Henrik Antti; Elaine Holmes; George Tranter; Jeremy K Nicholson; Hugh W L Bethell; Sarah Clarke; Peter M Schofield; Elaine McKilligin; David E Mosedale; David J Grainger,"Although a wide range of risk factors for coronary heart disease have been identified from population studies, these measures, singly or in combination, are insufficiently powerful to provide a reliable, noninvasive diagnosis of the presence of coronary heart disease. Here we show that pattern-recognition techniques applied to proton nuclear magnetic resonance (1H-NMR) spectra of human serum can correctly diagnose not only the presence, but also the severity, of coronary heart disease. Application of supervised partial least squares-discriminant analysis to orthogonal signal-corrected data sets allows >90% of subjects with stenosis of all three major coronary vessels to be distinguished from subjects with angiographically normal coronary arteries, with a specificity of >90%. Our studies show for the first time a technique capable of providing an accurate, noninvasive and rapid diagnosis of coronary heart disease that can be used clinically, either in population screening or to allow effective targeting of treatments such as statins.",2003.0,0,0 1726,12450605,Neuroprotective effects of statins may not be related to total and low-density lipoprotein cholesterol lowering.,Sabu J George; Abhay J Dhond; Skip M Alderson; Michael D Ezekowitz,,2003.0,0,0 1727,12451319,,,,,0,0 1728,12451426,The effect of atorvastatin on erythrocyte membranes and serum lipids in patients with type-2 hypercholesterolemia.,M Koter; M Broncel; J Chojnowska-Jezierska; K Klikczynska; I Franiak,". The beneficial effects of statins on clinical events may involve mechanisms that modify endothelial dysfunction, plaque stability, thrombus formation, and inflammatory responses. To determine the effect of atorvastatin on blood rheology in patients with familial hypercholesterolemia (FH), we prospectively studied serum lipid concentration, red cell cholesterol content, lipid peroxidation and erythrocyte membrane fluidity. The aim of this paper was to evaluate the effects of atorvastatin therapy on the erythrocyte membrane structure and the hypolipemic efficacy in patients with FH. MATERIALS, METHODS AND SUBJECTS STUDIED:. The study involved 31 patients with FH and 20 healthy individuals as a control group. The program lasted 20 weeks. For the first 8 weeks, the patients were on a hypolipemic diet only and for the subsequent 12 weeks, alongside the diet they were given 10 mg atorvastatin per day. Laboratory tests were carried out before and after 4 weeks and 12 weeks of the pharmacological treatment. Erythrocyte membrane fluidity was determined using the spin labeled method. The peroxidation of lipids was measured in whole erythrocytes as well as in erythrocyte plasma membranes by means of the thiobarbituric acid technique. . Treatment with atorvastatin reduced serum total cholesterol concentration from 310+/-29 mg/dl in a basal situation to 203+/-34 mg/dl ( P<0.001) at the end of the treatment and low-density lipoprotein (LDL) cholesterol concentration from 225+/-30 mg/dl to 126+/-30 mg/dl ( P<0.001), respectively. The changes observed in the plasma lipids correlate with a significant decrease in erythrocyte membrane cholesterol, from 2.24+/-1.69 to 1.17+/-0.75 mg/mg protein ( P<0.001) after 12 weeks of treatment. The lipid peroxidation in membranes of erythrocytes was lowered from the basal value 0.171+/-0.097 to 0.100+/-0.024 mmol/mg protein ( P<0.05) after 4 weeks of treatment and to 0.057+/-0.020 mmol/mg protein ( P<0.001) after 12 weeks of treatment, and in total erythrocytes from 4.78+/-1.49 to 3.99+/-1.39 mmol/g Hb ( P<0.02) and 2.43+/-0.87 mmol/g Hb ( P<0.001), respectively. The membrane fluidity was estimated by means of parameter S at the depth of the fifth carbon atom. Atorvastatin in hypercholesterolemic erythrocytes enhances the fluidity of the superficial layer from 0.758+/-0.009 up to the values observed in the control group 0.744+/-0.009 ( P<0.001). There is no impact on the microviscosity of the hydrophobic core observed. . Our findings suggest that the atorvastatin therapy reverses the alteration of erythrocyte plasma membrane properties. It may improve blood rheology in patients with FH. This improvement in blood properties may contribute to the well-known beneficial effects of atorvastatin on cardiovascular risk in patients with severe hyperlipidemia and atherosclerotic vascular disease.",2003.0,0,0 1729,12451430,The effect of fluconazole on the pharmacokinetics of rosuvastatin.,K J Cooper; P D Martin; A L Dane; M J Warwick; D W Schneck; M V Cantarini,"To examine the effect of fluconazole, a potent inhibitor of CYP2C9 and CYP2C19, on the pharmacokinetics of rosuvastatin in healthy volunteers. Significantly increased plasma concentrations of fluvastatin have been observed following co-administration with fluconazole. This was a randomised, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers ( n=14) were given fluconazole 200 mg or matching placebo once daily for 11 days; rosuvastatin 80 mg was co-administered on day 8 of dosing. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and active and total 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were measured up to 96 h post-dose. Following co-administration with fluconazole, rosuvastatin geometric least-square mean area under the plasma concentration-time curve (AUC(0-t)) and peak plasma concentration (C(max)) were increased by 14% and 9%, respectively, compared with placebo (90% confidence intervals for the treatment ratios: 0.967 to 1.341 and 0.874 to 1.355, respectively). Individual treatment ratios for AUC(0-t) ranged from 0.59 to 2.23, and for C(max) ranged from 0.52 to 2.28. The limited data available for the N-desmethyl metabolite show that geometric mean C(max) was decreased by approximately 25% compared with placebo. Rosuvastatin accounted for essentially all of the circulating active HMG-CoA reductase inhibitors and most (>90%) of the total inhibitors. Fluconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. Fluconazole produced only small increases in rosuvastatin AUC(0-t) and C(max), which were not considered to be of clinical relevance. The results support previous in-vitro findings that CYP2C9 and CYP2C19 metabolism is not an important clearance mechanism for rosuvastatin.",2003.0,0,0 1730,12453566,The biochemistry and medical significance of the flavonoids.,Bent H Havsteen,"Flavonoids are plant pigments that are synthesised from phenylalanine, generally display marvelous colors known from flower petals, mostly emit brilliant fluorescence when they are excited by UV light, and are ubiquitous to green plant cells. The flavonoids are used by botanists for taxonomical classification. They regulate plant growth by inhibition of the exocytosis of the auxin indolyl acetic acid, as well as by induction of gene expression, and they influence other biological cells in numerous ways. Flavonoids inhibit or kill many bacterial strains, inhibit important viral enzymes, such as reverse transcriptase and protease, and destroy some pathogenic protozoans. Yet, their toxicity to animal cells is low. Flavonoids are major functional components of many herbal and insect preparations for medical use, e.g., propolis (bee's glue) and honey, which have been used since ancient times. The daily intake of flavonoids with normal food, especially fruit and vegetables, is 1-2 g. Modern authorised physicians are increasing their use of pure flavonoids to treat many important common diseases, due to their proven ability to inhibit specific enzymes, to simulate some hormones and neurotransmitters, and to scavenge free radicals.",2003.0,0,0 1731,12454325,Preventing cardiovascular disease in hypertension: effects of lowering blood pressure and cholesterol.,R Green; S Kwok; P N Durrington,"In guidelines for the primary prevention of cardiovascular disease, systolic blood pressure (SBP) or diastolic blood pressure (DBP) is treated with medication at lower levels of risk than those at which statin treatment is recommended for cholesterol lowering. To compare the potential benefits of antihypertensive medication and statin therapy in hypertensive patients, and examine whether this policy is rational. Retrospective cross-sectional survey. We studied 146 men and 150 women aged 56 (54-58) (mean (95% CI)) years and 60 (58-62) years, respectively, who had commenced drug therapy for hypertension within 10 years in five general practices in Greater Manchester. Coronary heart disease (CHD) and stroke risk were calculated, and the potential benefit of blood pressure lowering treatment and statin therapy estimated using the results of published meta-analyses of clinical trials. Blood pressure before treatment was initiated was 176 (173-179)/102 (100-104) mmHg in men and 176 (172-179)/98 (96-100) mmHg in women. Serum cholesterol was 5.7 (5.5-5.9) mmol/l and high density lipoprotein (HDL) cholesterol 1.3 (1.2-1.4) mmol/l in men. The corresponding values in women were 6.3 (6.1-6.5) mmol/l and 1.5 (1.4-1.6) mmol/l. Of the men, 44% (36-52%) smoked and 23% (17-31%) had diabetes mellitus, whereas 27% (20-35%) of the women smoked and 26% (19-34%) had diabetes. These risk factors gave the combined group of men and women a CHD risk of 19.7% (12.0-28.0%) (median (IQR)) and a stroke risk of 8.8% (3.8-13.9%) over the next 10 years. All patients were prescribed antihypertensive medication and 15% subsequently received statin treatment. The 10-year CHD risk would be expected to decrease to 16.5% (10.1-23.5%) on anti-hypertensive therapy. Had statin treatment been given instead, it would have been reduced to 13.2% (8.05-18.7%). For stroke, the 10-year risk on antihypertensive therapy was calculated as 5.5% (2.4-8.6%) and on statin 6.2% (2.7-9.9%). This meant that combined CHD and stroke risk would be reduced from 29.4% (17.5-41.5%) to 22.4% (17.5-41.5%) on antihypertensive therapy and to 20.1% (11.9-28.2%) on statins. The difference between statin and antihypertensive therapy was statistically significant (p<0.0001). Because the object of drug treatment in mild-moderate hypertension is to reduce cardiovascular disease risk and not simply to decrease blood pressure, current recommendations and practice should be revised so that more patients can benefit from evidence-based therapy favouring a more holistic approach, including cholesterol-lowering therapy.",2003.0,0,0 1732,12454344,,,,,0,0 1733,12457780,High-risk elderly patients PROSPER from cholesterol-lowering therapy.,Rory Collins; Jane Armitage,,2002.0,0,0 1734,12457784,Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.,James Shepherd; Gerard J Blauw; Michael B Murphy; Edward L E M Bollen; Brendan M Buckley; Stuart M Cobbe; Ian Ford; Allan Gaw; Michael Hyland; J Wouter Jukema; Adriaan M Kamper; Peter W Macfarlane; A Edo Meinders; John Norrie; Chris J Packard; Ivan J Perry; David J Stott; Brian J Sweeney; Cillian Twomey; Rudi G J Westendorp; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk,"Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006). Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8), but the hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people.",2002.0,1,1 1735,12459073,[Comparative study of the impact of diet versus pravastatin on color vision in Brodman area 19 detected by computerized chromatic analysis (CARDIOCOLOUR Study)].,Antonio Alcalá; Miguel Morell; Francisca Rius,"Hypercholesterolemia causes important neurodegenerative changes in the cerebral cortex, which are manifested by defects in the color perception by the neurons of Brodman area 19. Extensive interventional epidemiological data from both primary and secondary-prevention clinical trials indicate that cardiac ischemic events decrease when total cholesterol or LDL-C is reduced. Our goal was to elucidate the effects of diet compared with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (pravastatin) on color perception using computerized chromatic analysis (CCA) and plasma cholesterol levels. We studied 191 normotensive patients (133 men and 58 women) with pre-study plasma cholesterol levels in excess of 200 mg/dl. Seventy of these patients were treated with the American Heart Association Step II diet for six months. The remaining 121 were treated with pravastatin, 61 patients with 10 mg and 60 patients with 40 mg. They were examined by CCA after excluding any general or ophthalmological pathology. Chromatic vision recovered by 23% with diet, 38% with pravastatin 10 mg and 92% with pravastatin 40 mg. This study confirmed a strong association between therapeutic intervention with either diet or pravastatin and improved color vision.",2003.0,0,0 1736,12460045,Association between vascular access failure and the use of specific drugs: the Dialysis Outcomes and Practice Patterns Study (DOPPS).,Rajiv Saran; Dawn M Dykstra; Robert A Wolfe; Brenda Gillespie; Philip J Held; Eric W Young; Dialysis Outcomes and Practice Patterns Study,"Several drugs have been proposed to improve vascular access patency based on favorable anticoagulant, antiplatelet, or vascular-remodeling properties. However, there is little evidence to guide drug strategies. The association between vascular access patency and the use of specific drugs was studied in a large sample of US hemodialysis patients enrolled in the Dialysis Outcomes and Practice Patterns Study, an international, prospective, observational study. In general, it was assumed that the drugs were prescribed for indications unrelated to vascular access preservation. Primary (unassisted survival) and secondary vascular access patency (assisted survival) were modeled using Cox regression (time to failure) adjusted for age, sex, race, body mass index, incidence to end-stage renal disease, diabetes mellitus, hypertension, valvular disease, chronic obstructive pulmonary disease, aortic aneurysm, deep-vein thrombosis, number of previous permanent accesses, and facility-clustering effects. Fistulae (n = 900) and grafts (n = 1,944) were evaluated separately. Technical failures within the first 30 days of surgical placement were excluded from the analysis. Treatment with calcium channel blockers was associated with improved primary graft patency (relative risk [RR] for failure, 0.86; P = 0.034). Aspirin therapy was associated with better secondary graft patency (RR, 0.70; P < 0.001). Treatment with angiotensin-converting enzyme inhibitors was associated with significantly better secondary fistula patency (RR, 0.56; P = 0.010). Patients administered warfarin showed worse primary graft patency (RR, 1.33; P = 0.037). These findings should help guide clinical trial priorities toward vascular access preservation using one or more of the agents that show significant risk reduction for access failure in this study.",2002.0,0,0 1737,12460866,Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years' follow-up by high-resolution noninvasive magnetic resonance imaging.,Roberto Corti; Valentin Fuster; Zahi A Fayad; Stephen G Worthley; Gerard Helft; Donald Smith; Jesse Weinberger; Jolanda Wentzel; Gabor Mizsei; Michele Mercuri; Juan J Badimon,"Statins are widely used to treat hypercholesterolemia and atherosclerotic disease. Noninvasive MRI allows serial monitoring of atherosclerotic plaque size changes. Our aim was to investigate the effects of lipid lowering with simvastatin on atherosclerotic lesions. A total of 44 aortic and 32 carotid artery plaques were detected in 21 asymptomatic hypercholesterolemic patients at baseline. The effects of statin on these atherosclerotic lesions were evaluated as changes versus baseline in lumen area (LA), vessel wall thickness (VWT), and vessel wall area (VWA) by MRI. Maximal reduction of plasma total and LDL cholesterol by simvastatin (23% and 38% respectively; P<0.01 versus baseline) was achieved after approximately 6 weeks of therapy and maintained thereafter throughout the study. Significant (P<0.01) reductions in maximal VWT and VWA at 12 months (10% and 11% for aortic and 8% and 11% for carotid plaques, respectively), without changes in LA, have been reported. Further decreases in VWT and VWA ranging from 12% to 20% were observed at 18 and 24 months. A slight but significant increase (ranging from 4% to 6%) in LA was seen in both carotid and aortic lesions at these later time points. The present study demonstrates that maintained lipid-lowering therapy with simvastatin is associated with significant regression of established atherosclerotic lesions in humans. Our observations indicate that lipid-lowering therapy is associated with sustained vascular remodeling and emphasize the need for longer-term treatment.",2002.0,0,0 1738,12460867,Oxidized low-density lipoprotein augments and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells.,Uwe Schönbeck; Norbert Gerdes; Nerea Varo; Rebecca S Reynolds; Daniel B Horton; Udo Bavendiek; Linda Robbie; Peter Ganz; Scott Kinlay; Peter Libby,"Although CD40 signaling participates in atherosclerosis, links between lipid risk factors and this inflammatory pathway remain obscure. Cardiovascular risk reduction by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may involve actions beyond lipid lowering, including reduced inflammation. Therefore, this study analyzed whether oxidized low-density lipoprotein (oxLDL) induces CD40/CD40L expression on cells implicated in atherogenesis and whether statins affect their expression in vitro as well as the expression of soluble CD40L (sCD40L) in vivo. Treatment of human vascular endothelial and smooth muscle cells and mononuclear phagocytes with oxLDL augmented the basal expression of CD40 and CD40L mRNA and protein. In contrast, cerivastatin, atorvastatin, or simvastatin concentration-dependently diminished the constitutive as well as oxLDL- or cytokine-induced expression of the receptor/ligand dyad, an effect reversed by mevalonate. Patients treated with statins had diminished sCD40L plasma levels compared with untreated control patients (8.3+/-3.1 ng/mL [n=11] versus 13.1+/-2.5 ng/mL [n=16], P<0.05), supporting the clinical relevance of the in vitro observations. Platelet-enriched plasma of mice deficient in CD40L showed markedly delayed fibrin clot formation, suggesting a role for the ligand in blood coagulation and supporting the hypothesis that statin-mediated reduction in CD40/CD40L expression might limit thrombosis. OxLDL may promote expression of CD40 and CD40L in human atheroma. Statins may limit the expression of the CD40 receptor/ligand dyad in two ways, directly as well as through diminished lipoprotein levels. Thus, reduced CD40 signaling may account for some of the statins' antiinflammatory action.",2002.0,0,0 1739,12460961,Lipid-lowering agents and the risk of hip fracture in a Medicaid population.,W A Ray; J R Daugherty; M R Griffin,"Three recent nested case-control studies conducted in automated databases suggest that users of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have a risk of hip and other osteoporotic fractures half that of non-users of any lipid-lowering drug. However, this comparison may be biased by unmeasured factors associated with treated hyperlipidemias. To compare the risk of hip fracture among users of statins and other lipid-lowering agents, which is less susceptible to bias than the comparisons performed in the previous studies. Retrospective cohort study conducted in the Tennessee Medicaid program between 1 January 1989 through 31 December 1998. New users of all lipid-lowering drugs and randomly selected non-user controls who at baseline were at least 50 years of age and did not have life threatening illness, nursing home residence, or diagnosed dementia or osteoporosis. There were 12506 persons with new use of statins, 4798 with new use of other lipid lowering drugs, and 17280 non-user controls. Fracture of the proximal femur (hip), excluding pathological fractures or those resulting from severe trauma. During 66690 person years of follow up, there were 186 hip fractures (2.8 per 1000). Relative to non-users, the adjusted incidence rate ratios (95% confidence interval) were 0.62 (0.45 to 0.85) for statin users and 0.44 (0.26 to 0.95) for other lipid-lowering drugs. When compared directly with the other drugs, the adjusted incidence rate ratio for statins was 1.42 (0.83-2.43). These data provide evidence that the previously observed protective effect of statins may be explained by unmeasured confounding factors.",2003.0,0,0 1740,12460995,Cyclin-dependent kinases as cellular targets for antiviral drugs.,Luis M Schang,"Cyclin-dependent kinases (cdks) are required for replication of viruses that replicate only in dividing cells, such as adeno- and papillomaviruses. Recently, cdks have been shown to be required also for replication of viruses that can replicate in non-dividing cells, such as HIV-1 and herpes simplex virus types 1 and 2 (HSV-1 and -2). In these experiments, pharmacological cdk inhibitors (PCIs) were shown to have potent antiviral activity in vitro against HIV-1, HSV-1 and -2, human cytomegalovirus, varicella-zoster virus, and to inhibit specific functions of other viruses. Since two PCIs, flavopiridol and roscovitine, are proving to be non-toxic in human clinical trials against cancer, PCIs may be useful as antivirals. As significant advantages, PCIs are active in vitro against many viruses, including drug-resistant strains of HIV-1 and HSV-1, and mutant strains of HIV-1 or HSV-1 resistant to PCIs have not been identified in spite of intense efforts. Furthermore, the antiviral effects of a PCI and a conventional antiviral drug are additive. The aetiopathogenesis of several diseases, such as Kaposi's sarcoma, HPV-induced cervical carcinoma and HIV-associated nephropathy (HIVAN), among others, includes replication or expression of proteins by viruses that require cdks. Thus, PCIs could target both the aetiological agent (the virus) and the pathogenic mechanisms (cell replication). Two important questions regarding the antiviral activities of PCIs are the focus of current research efforts, (i) the identity of the specific cdks that mediate the antiviral activities of PCIs, and (ii) whether PCIs have antiviral activity in vivo at non-toxic doses.",2003.0,0,0 1741,12461482,[Input of coronary artery calcium score assessed by computed tomography in the screening of diabetic coronaropathy].,O Dupuy; L Hauret; L Bonnevie; L Bordier; H Mayaudon; B Bauduceau,"The poor prognosis of coronary artery disease along with the inaccuracy of available testing methods have favoured the development of new screening techniques. One such innovation involves measuring the coronary artery calcium score (CAC). Through computed tomography, this test quantifies the amount of calcium deposited in coronary arteries, itself a reflection of the degree of atherosclerosis. This investigation is a prospective study of 48 diabetic subjects comparing the performance of CAC score with the gold standard testing methods. The results of our study showed that, due to its high negative predictive value, 5 invasive tests were performed needlessly as these subjects had very low CAC scores. At this time, the CAC score is not recommended for every patient but rather on a case-by-case basis. However, it may soon emerge as the next step after the ECG in the evaluation of coronary artery disease. This would alleviate the need for more invasive tests in those patients for whom such investigations are deemed unnecessary. The CAC score, when matched for age, sex and other variables, could also serve as an indication for prescribing medications such as statins, along with other therapeutic interventions. Diabetologists, cardiologists and radiologists must work together in order to gain a better understanding of these new techniques. This may facilitate the emergence of a new approach to the treatment of coronary artery disease.",2003.0,0,0 1742,12462519,,,,,0,0 1743,12463722,Clinical manifestation of atherosclerotic peripheral arterial disease and the role of cilostazol in treatment of intermittent claudication.,John Robert Grouse; Michael C Allan; Marshall B Elam,"Intermittent claudication (IC) is the symptomatic expression of peripheral arterial disease (PAD), which itself is a manifestation of systemic atherosclerosis. Like other forms of atherosclerosis, PAD is associated with elevated rates of cardiovascular and cerebrovascular morbidity and mortality. Until recently, therapeutic options for the treatment of the symptoms of IC have been limited, and the efficacy of available treatment has been questioned. Cilostazol, a selective phosphodiesterase III inhibitor with vasodilator, antiplatelet, and antiproliferative properties, has recently been approved for the treatment of IC symptoms in the United States. Cilostazol significantly improves maximal and pain-free walking distances. Clinical studies have also demonstrated that cilostazol favorably alters plasma lipids (elevates HDL-cholesterol, lowers triglycerides). These properties may contribute to the benefit of this drug in IC and in other diseases secondary to atherosclerosis.",2003.0,0,0 1744,12463730,No effect of rosuvastatin on the pharmacokinetics of digoxin in healthy volunteers.,Paul D Martin; John Kemp; Aaron L Dane; Mike J Warwick; Dennis W Schneck,"The effect of rosuvastatin on the pharmacokinetics of digoxin was assessed in 18 healthy male volunteers in this double-blind, randomized, two-way crossover trial. Volunteers were dosed with rosuvastatin (40 mg once daily) or placebo to steady state before being given a single dose of digoxin 0.5 mg. Blood and urine samples for the measurement of serum and urine digoxin concentrations were collected up to 96 hours following dosing. The effect of rosuvastatin was assessed by constructing 90% confidence intervals (CIs) around the treatment ratios (rosuvastatin + digoxin/placebo + digoxin) for digoxin exposure. The geometric least square mean AUC(0-t) and Cmax of digoxin were only 4% higher when the drug was coadministered with rosuvastatin compared to placebo. The 90% CIs for both treatment ratios (AUC(0-t) = 0.88-1.24; Cmax = 0.89-1.22) fell within the prespecified margin of 0.74 to 1.35; therefore, no significant pharmacokinetic interaction occurred between rosuvastatin and digoxin. The geometric mean amount of digoxin excreted into the urine and its renal clearance were similar with rosuvastatin and placebo. These results demonstrate that rosuvastatin has no effect on the pharmacokinetics of digoxin. Coadministration of rosuvastatin and digoxin was well tolerated.",2003.0,0,0 1745,12466006,Voriconazole: in the treatment of invasive aspergillosis.,Richard B R Muijsers; Karen L Goa; Lesley J Scott,"Voriconazole, a broad-spectrum triazole antifungal agent, inhibits the cytochrome P450-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the fungal membrane and stopping fungal growth. The drug shows excellent in vitro activity against Aspergillus spp., including itraconazole- and amphotericin B-resistant A. fumigatus isolates. At 12 weeks, 52.8% of voriconazole recipients achieved a successful outcome (complete or partial response) versus 31.6% of amphotericin B recipients in a randomised, nonblind trial in 392 patients (aged > or =12 years) with invasive aspergillosis. Patients received intravenous voriconazole (6 mg/kg once every 12 hours on day 1, then 4 mg/kg once every 12 hours for > or =7 days; patients could then be switched to oral voriconazole 200mg once every 12 hours) or intravenous amphotericin B (1 to 1.5 mg/kg/day for > or=14 days). At the investigators' discretion, those who failed to respond to or experienced toxicity with the initial randomised drug could be switched to other licensed antifungal therapy. Voriconazole was generally well tolerated. The most common treatment-related adverse events were transient visual disturbances (approximately 30% of patients) and skin rashes (6%). Voriconazole was generally better tolerated than amphotericin B; voriconazole recipients experienced significantly (p < 0.02 both comparisons) fewer treatment-related adverse events or serious adverse events. The incidence of visual disturbances was significantly (p < 0.001) higher with voriconazole than amphotericin B treatment.",2003.0,0,0 1746,12466341,Effect of fluvastatin slow-release on low density lipoprotein (LDL) subfractions in patients with type 2 diabetes mellitus: baseline LDL profile determines specific mode of action.,Karl Winkler; Claudia Abletshauser; Michael M Hoffmann; Isolde Friedrich; Manfred W Baumstark; Heinrich Wieland; Winfried März,"The objective of this study was to determine the effect of slow-release (XL) fluvastatin on low density lipoprotein (LDL) subfractions in type 2 diabetes. A multicenter, double-blind, randomized, parallel-group comparison of fluvastatin XL 80 mg (n = 42) and placebo (n = 47), each given once-daily for 8 wk, in 89 patients with type 2 diabetes (HbA1c: 7.2 +/- 1.0%, LDL cholesterol (LDL-C): 3.4 +/- 0.7 mmol/liter, high density lipoprotein cholesterol: 1.1 +/- 0.3 mmol/liter, and triglycerides (TG): 2.4 +/- 1.4 mmol/liter). At baseline and on treatment, plasma lipoproteins were isolated and quantified. Eight weeks of fluvastatin treatment decreased total cholesterol (-23.0%, P < 0.001), LDL-C (-29%, P < 0.001) and TG (-18%, P < 0.001), compared with placebo. At baseline, there was a preponderance of dense LDL (dLDL) (apolipoprotein B in LDL-5 plus LDL-6 > 25 mg/dl) in 79% of patients, among whom fluvastatin decreased all LDL subfractions, reductions in dLDL being greatest (-28%, P = 0.001; cholesterol in dLDL -29%). In patients with low baseline dLDL (apolipoprotein B in LDL-5 plus LDL-6 600 had been treated for 6 months and > 200 for 1 year, found reductions of 45 and 42% in low density lipoprotein cholesterol and triglycerides, respectively, at the maximum dose (niacin ER 2000 mg/ lovastatin 40 mg). HDL cholesterol increased by 41%. In addition, the combination decreased lipoprotein (a) by 25% and C-reactive protein by 24%. The niacin ER/lovastatin combination was generally well-tolerated. Flushing was the most common side effect, with approximately 10% of patients intolerant to niacin ER/lovastatin. Hepatotoxicity in this study was 0.5% and myopathy did not occur. Recent studies indicate that niacin can be used safely in diabetic patients who have good glucose control (HbA(1c) < 9%). Once-daily niacin ER/lovastatin exhibits potent synergistic actions on multiple lipid risk factors and represents an effective new agent in the clinical management of dyslipidaemia. Outcome studies are needed to evaluate if combination therapy would result in additive effects on morbidity and mortality.",2003.0,0,0 1756,12473249,Do statins confer early benefit after acute coronary syndromes? The results from FLORIDA.,P D Varosy; D D Waters,,2003.0,0,0 1757,12473253,Statins and stroke: evidence for cholesterol-independent effects.,P Di Napoli; A A Taccardi; M Oliver; R De Caterina,,2003.0,0,0 1758,12473254,Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.,P J Marang-van de Mheen; A H A ten Asbroek; L Bonneux; G J Bonsel; N S Klazinga,"To estimate the cost-effectiveness of the current screening programme on Familial Hypercholesterolaemia (FH) in relatives of diagnosed FH-patients in The Netherlands. Data from 2229 screened FH-relatives, including age, sex, risk factor status and screening outcome, were combined with the Framingham risk function and national disease-specific cost data to arrive at a model-based comparison of survival and costs, with and without the screening programme. Cost-effectiveness ratios were computed for various treatment strategies, with no screening as reference. Costs per life year gained varied between 25.5- and 32-thousand Euros, depending upon the precise treatment strategy after a positive screen. The costs for screening (tracing the FH-positive individuals) were much lower than the follow-up costs (treatment), of which 80% were costs for statins. Consequently, the costs per life year gained of alternative screening programmes are about the same. The cost-effectiveness ratio of FH screening is within the range requiring explicit political consideration in The Netherlands. As the costs of statin treatment are the single most important determinant of costs, policy decisions reduce to decisions on the acceptability of statin treatment for this risk group. Pending major changes in statin price, clear guidelines should be developed on how screen positive individuals should be treated, since not all of them have an elevated cholesterol level.",2003.0,0,0 1759,12473255,Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial.,A H Liem; A J van Boven; N J G M Veeger; A J Withagen; R M Robles de Medina; J G P Tijssen; D J van Veldhuisen; FLuvastatin On Risk Diminishment after Acute myocardial infarction study group,"Residual ischaemia following acute myocardial infarction (AMI) is related to an adverse outcome, although the effect of early initiation of statin therapy is unknown. A randomized, placebo-controlled, double-blind, parallel study was performed, which compared fluvastatin 80 mg daily with placebo in patients with an AMI and total cholesterol of <6.5 mmol.l(-1). Ischaemia was measured by ambulatory electrocardiographic (AECG) monitoring over 48-h at baseline, after 6 weeks and at 12 months. Five hundred and forty patients were included (83% male, age 61+/-11 years); 43% had an anterior AMI and 50% were treated with fibrinolytics in the acute phase. After 12 months, the total cholesterol (TC) level was reduced by 13% and LDL-C (low-density-lipoprotein cholesterol) by 21% (from 3.5 mmol.l(-1) to 2.7 mmol.l(-1)) in the fluvastatin treatment group. Both TC and LDL increased by 9% in the placebo group (P<0.001 between groups). At baseline, ischaemia on AECG was present in only 11% of patients, and absent in 77%; in the remaining 11%, recordings were technically inadequate. After 6 weeks, 32/48 (67%), and 12 months 35/46 (76%) of the patients with ischaemia on the baseline AECG, no longer showed signs of ischaemia. Nevertheless, ischaemia at baseline was predictive for the occurrence of any major clinical event (RR=2.35; 95% CI 1.39-3.2;P <0.001). Fluvastatin treatment did not affect ischaemia on AECG, nor the occurrence of any major clinical events as compared to placebo. Post-hoc analysis in patients with the most pronounced ischaemia at baseline showed a trend for a beneficial effect of fluvastatin on major clinical events (P=0.084). Residual ischaemia after AMI is observed less frequently in the present study, than in earlier studies, although it is predictive for future cardiovascular events. As a result, the present study was underpowered, and no effect of fluvastatin on AECG ischaemia, or major clinical events in the first year after AMI, could be detected. The present data do not confirm other reports which support widespread use of statin treatment early after AMI.",2003.0,1,1 1760,12473258,The endothelial nitric oxide synthase (Glu298Asp and -786T>C) gene polymorphisms are associated with coronary in-stent restenosis.,A H Gomma; M A Elrayess; C J Knight; E Hawe; K M Fox; S E Humphries,"Coronary stent deployment is a major advance in percutaneous treatment of ischaemic heart disease, but 10-40% of patients still develop angiographic restenosis by 6 months due to neointimal hyperplasia. Patient-specific factors, including genetic factors, can contribute to this process. We have conducted a prospective study to examine the involvement of genetic risk factors (eNOS, ACE, MMP-3, IL-6, and PECAM-1) in restenosis following coronary stent deployment. A total of 226 patients who underwent elective and successful coronary artery stenting to de novo lesions in native coronary arteries were studied. Two hundred and five (90.7%) patients were restudied by coronary angiogram at 6 months and the stented lesions were assessed using an automated quantitative angiography system. Genotype was determined by polymerase chain reaction (PCR) and restriction enzyme digestion. Restenosis rate, defined as >or=50% diameter stenosis, was 29.3%. The overall genotype frequency distributions were in Hardy-Weinberg equilibrium for all variants. Carriers of the 298Asp allele of the eNOS Glu298Asp polymorphism showed a higher frequency of restenosis with an odds ratio of 1.88 (95%CI: 1.01-3.51, P=0.043) compared to 298Glu homozygotes. Carriers of the -786C allele of the eNOS -786T>C polymorphism also showed a higher frequency of restenosis with odds ratio of 2.06 (95%CI: 1.08-3.94, P=0.028). These effects were essentially additive and were independent of other classical risk factors. Other studied genes did not show significant association with coronary in-stent restenosis. In patients with coronary artery disease, the possession of the 298Asp and -786C variants of the eNOS gene are a risk factor for coronary in-stent restenosis, demonstrating the importance of the nitric oxide system in restenosis.",2003.0,0,0 1761,12473877,Risk factors for non-haemorrhagic stroke in patients with coronary heart disease and the effect of lipid-modifying therapy with pravastatin.,Malcolm J West; Harvey D White; R John Simes; Adrienne Kirby; John D Watson; Neil E Anderson; Graeme J Hankey; Susan Wonders; David Hunt; Andrew M Tonkin,"To determine the relative importance of recognised risk factors for non-haemorrhagic stroke, including serum cholesterol and the effect of cholesterol-lowering therapy, on the occurrence of non-haemorrhagic stroke in patients enrolled in the LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease) study. The LIPID study was a placebo-controlled, double-blind trial of the efficacy on coronary heart disease mortality of pravastatin therapy over 6 years in 9014 patients with previous acute coronary syndromes and baseline total cholesterol of 4-7 mmol/l. Following identification of patients who had suffered non-haemorrhagic stroke, a pre-specified secondary end point, multivariate Cox regression was used to determine risk in the total population. Time-to-event analysis was used to determine the effect of pravastatin therapy on the rate of non-haemorrhagic stroke. There were 388 non-haemorrhagic strokes in 350 patients. Factors conferring risk of future non-haemorrhagic stroke were age, atrial fibrillation, prior stroke, diabetes, hypertension, systolic blood pressure, cigarette smoking, body mass index, male sex and creatinine clearance. Baseline lipids did not predict non-haemorrhagic stroke. Treatment with pravastatin reduced non-haemorrhagic stroke by 23% (P = 0.016) when considered alone, and 21% (P = 0.024) after adjustment for other risk factors. The study confirmed the variety of risk factors for non-haemorrhagic stroke. From the risk predictors, a simple prognostic index was created for non-haemorrhagic stroke to identify a group of patients at high risk. Treatment with pravastatin resulted in significant additional benefit after allowance for risk factors.",2003.0,0,0 1762,12475448,A long-term perspective on the protective effects of an early invasive strategy in unstable coronary artery disease: two-year follow-up of the FRISC-II invasive study.,Bo Lagerqvist; Steen Husted; Fredrik Kontny; Ulf Näslund; Elisabeth Ståhle; Eva Swahn; Lars Wallentin; Fast Revascularization during InStability in Coronary artery disease-II Investigators,"We sought to report the first and repeat events and to separate spontaneous and procedure-related events over two years in the Fast Revascularization during InStability in Coronary artery disease (FRISC-II) invasive trial. The FRISC-II invasive trial compared the long-term effects of an early invasive versus noninvasive strategy, in terms of death and myocardial infarction (MI) and the need for repeat hospital admissions and late revascularization procedures in patients with coronary artery disease (UCAD). In the FRISC-II trial, 2,457 patients with UCAD were randomized to an early invasive or noninvasive strategy. At 24 month follow-up, there were reductions in mortality (n = 45 [3.7%] vs. 67 [5.4%]; risk ratio 0.68 [95% confidence interval (CI) 0.47 to 0.98]; p = 0.038), MI (n = 111 [9.2%] vs. 156 [12.7%]; risk ratio 0.72 [95% CI 0.57 to 0.91]; p = 0.005), and the composite end point of death or MI (n = 146 [12.1%] vs. 200 [16.3%]; risk ratio 0.74 [95% CI 0.61 to 0.90]; p = 0.003) in the invasive compared with the noninvasive group. Procedure-related MIs were two to three times more common, but spontaneous ones were three times less common in the invasive than in the noninvasive group. After the first year, there was no difference in mortality (n = 20 [1.7%]) between the two groups and fewer MIs in the invasive group (p = 0.031). In UCAD, the early invasive approach leads to a sustained reduction in mortality, cardiac morbidity, and the need for repeat hospital admissions and late revascularization procedures. Although the benefits are greatest during the first months, during the second year, cardiac morbidity is lower and the need for hospital care is less in the invasive group.",2003.0,0,0 1763,12475449,"Cardioprotective effects of an early invasive strategy for non-ST-segment elevation acute coronary syndromes: are we all becoming ""interventional"" cardiologists?",Ravi K Yarlagadda; William E Boden,,2003.0,0,0 1764,12478088,Bcl-2 expression is moderately correlated with long-term variability of CD4 T-cell increase under successful highly active antiretroviral therapy.,Maria Cristina Uccelli; Carlo Torti; Eugenia Quiros-Roldan; Carmine Tinelli; Andrea Patroni; Francesco Castelli; Giampiero Carosi; Paolo Airò,,2003.0,0,0 1765,12478495,"Pharmaceutical initiatives to combat atherosclerosis--what to do with the good, the bad, and the ugly lipoproteins.",Russell H Samson,"The patient with peripheral arterial disease (PAD) poses a special problem. Not only are vascular surgeons interested in preventing the limb complications of PAD, but also the associated cardiac and neurological events that contribute greatly to the overall morbidity and mortality of their patients. Therefore, the control of atherosclerotic risk factors must be considered as important a therapeutic goal as surgical and endovascular control of limb ischemia. To accomplish this, the ""complete"" vascular surgeon must understand the common lipid abnormalities, their diagnosis, and treatment. The scientific literature on this subject is truly overwhelming in volume and scope, yet an overly simple ""cook book"" approach is not adequate or appropriate. This report summarizes current knowledge on this topic, providing sufficient essential detail for the reader to understand why, when, and how to administer which lipid-controlling agents to patients with PAD.",2003.0,0,0 1766,12478816,Variations in lipoprotein levels after myocardial infarction and unstable angina: the LATIN trial.,Claudio Fresco; Aldo P Maggioni; Stefano Signorini; Piera A Merlini; Paolo Mocarelli; Gianna Fabbri; Donata Lucci; Marco Tubaro; Marinella Gattone; Carlo Schweiger; LATIN Investigators,"The aim of this study was to prospectively evaluate the magnitude of the variations in lipid levels in a large population of patients admitted for acute myocardial infarction (MI) and unstable angina (UA). Clinical data and blood samples were prospectively collected from consecutive patients with MI and UA. The study population consisted of patients with symptoms lasting < or = 12 hours (for MI) or with the last episode of rest pain within 12 hours and associated with ECG changes (for UA). The exclusion criteria were recent hospitalization for any reason or current treatment with lipid-lowering drugs. Blood samples were obtained at admission, the following morning, at discharge and after 3 months. Samples were centrifuged immediately and 4 aliquots of serum were stored at -20 degrees C. The measurements were performed centrally. We enrolled 1864 patients (1275 with MI and 589 with UA). Serum levels of total and LDL-cholesterol decreased significantly after admission, both in MI and UA patients. After 3 months, serum levels of total cholesterol returned to baseline, while those of LDL-cholesterol were still significantly lower. Between admission and the following morning, total and LDL-cholesterol decreased significantly by 7 and 10% respectively for MI and by 5 and 6% for UA. Lipid measurements not performed at admission accounted for a significant decrease in the number of patients identifiable as hyperlipidemic and suitable for lipid-lowering treatment (18% of MI patients and 11% of UA patients). Serum cholesterol concentrations drop significantly during hospitalization for an acute coronary syndrome after a few hours from admission to the coronary care unit. Lipid profile assessment should be scheduled at admission in order to correctly identify hyperlipidemic patients.",2003.0,0,0 1767,12479491,"Whom should we profile? Examining diabetes care practice variation among primary care providers, provider groups, and health care facilities.",Sarah L Krein; Timothy P Hofer; Eve A Kerr; Rodney A Hayward,"To evaluate the amount of variation in diabetes practice patterns at the primary care provider (PCP), provider group, and facility level, and to examine the reliability of diabetes care profiles constructed using electronic databases. Clinical and administrative data obtained from the electronic information systems at all facilities in a Department of Veterans Affairs' (VA) integrated service network for a study period of October 1997 through September 1998. This is a cohort study. The key variables of interest are different types of diabetes quality indicators, including measures of technical process, intermediate outcomes, and resource use. A coordinated registry of patients with diabetes was constructed by integrating laboratory, pharmacy, utilization, and primary care provider data extracted from the local clinical information system used at all VA medical centers. The study sample consisted of 12,110 patients with diabetes, 258 PCPs, 42 provider groups, and 13 facilities. There were large differences in the amount of practice variation across levels of care and for different types of diabetes care indicators. The greatest amount of variance tended to be attributable to the facility level. For process measures, such as whether a hemoglobin A1c was measured, the facility and PCP effects were generally comparable. However, for three resource use measures the facility effect was at least six times the size of the PCP effect, and for inter-mediate outcome indicators, such as hyperlipidemia, facility effects ranged from two to sixty times the size of the PCP level effect. A somewhat larger PCP effect was found (5 percent of the variation) when we examined a ""linked"" process-outcome measure linking hyperlipidemia and treatment with statins). When the PCP effect is small (i.e., 2 percent), a panel of two hundred diabetes patients is needed to construct profiles with 80 percent reliability. little of the variation in many currently measured diabetes care practices is attributable to PCPs and, unless panel sizes are large, PCP profiling will be inaccurate. If profiling is to improve quality, it may be best to focus on examining facility-level performance variations and on developing indicators that promote specific, high-priority clinical actions.",2002.0,0,0 1768,12479764,"Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).",ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial,"Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease (CHD) reduce CHD events. However, many of these studies were too small to assess all-cause mortality or outcomes in important subgroups. To determine whether pravastatin compared with usual care reduces all-cause mortality in older, moderately hypercholesterolemic, hypertensive participants with at least 1 additional CHD risk factor. Multicenter (513 primarily community-based North American clinical centers), randomized, nonblinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Ambulatory persons (n = 10 355), aged 55 years or older, with low-density lipoprotein cholesterol (LDL-C) of 120 to 189 mg/dL (100 to 129 mg/dL if known CHD) and triglycerides lower than 350 mg/dL, were randomized to pravastatin (n = 5170) or to usual care (n = 5185). Baseline mean total cholesterol was 224 mg/dL; LDL-C, 146 mg/dL; high-density lipoprotein cholesterol, 48 mg/dL; and triglycerides, 152 mg/dL. Mean age was 66 years, 49% were women, 38% black and 23% Hispanic, 14% had a history of CHD, and 35% had type 2 diabetes. Pravastatin, 40 mg/d, vs usual care. The primary outcome was all-cause mortality, with follow-up for up to 8 years. Secondary outcomes included nonfatal myocardial infarction or fatal CHD (CHD events) combined, cause-specific mortality, and cancer. Mean follow-up was 4.8 years. During the trial, 32% of usual care participants with and 29% without CHD started taking lipid-lowering drugs. At year 4, total cholesterol levels were reduced by 17% with pravastatin vs 8% with usual care; among the random sample who had LDL-C levels assessed, levels were reduced by 28% with pravastatin vs 11% with usual care. All-cause mortality was similar for the 2 groups (relative risk [RR], 0.99; 95% confidence interval [CI], 0.89-1.11; P =.88), with 6-year mortality rates of 14.9% for pravastatin vs 15.3% with usual care. CHD event rates were not significantly different between the groups (RR, 0.91; 95% CI, 0.79-1.04; P =.16), with 6-year CHD event rates of 9.3% for pravastatin and 10.4% for usual care. Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol (9.6%) and LDL-C (16.7%) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention.",2002.0,1,1 1769,12479771,The ALLHAT lipid lowering trial--less is less.,Richard C Pasternak,,2002.0,0,0 1770,12480041,Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque.,Paul A Tunick; Ambika C Nayar; Gregory M Goodkin; Sunil Mirchandani; Steven Francescone; Barry P Rosenzweig; Robin S Freedberg; Edward S Katz; Robert M Applebaum; Itzhak Kronzon; NYU Atheroma Group,"Severe aortic plaques seen on transesophageal echocardiography (TEE) are a high-risk cause of stroke and peripheral embolization. Evidence to guide therapy is lacking. Retrospective information was obtained regarding the occurrence of embolic events (stroke, transient ischemic attacks, or peripheral emboli) in 519 patients with severe thoracic aortic plaque seen on TEE since 1988. Treatment with statins, warfarin, or antiplatelet medications was noted. Treatment was not randomized. In a matched-paired analysis, each patient taking each class of therapy was matched for age, gender, previous embolic event, hypertension, diabetes, congestive failure, and atrial fibrillation to someone not taking that medication. Multivariate analysis was also performed. An embolic event occurred in 111 patients (21%). Multivariate analysis showed that statin use was independently protective against recurrent events (p = 0.0001). Matched analysis also showed a protective effect of statins (p = 0.0004; absolute risk reduction 17%, relative risk reduction 59%, number needed to treat [n = 6]). No protective effect was found for warfarin or antiplatelet drugs. The odds ratio for embolic events was 0.3 (95% confidence interval [CI] 0.2 to 0.6) for statin therapy, 0.7 (95% CI 0.4 to 1.2) for warfarin, and 1.4 (95% CI 0.8 to 2.4) for antiplatelet agents. Thus, there is a protective effect of statin therapy, and no significant benefit of warfarin or antiplatelet drugs on the incidence of stroke and other embolic events in patients with severe thoracic aortic plaque on TEE.",2003.0,0,0 1771,12480043,Justifying lipid-lowering therapy in persons >/=65 years of age.,John C LaRosa,,2003.0,0,0 1772,12480044,Atherosclerosis of the thoracic aorta: from risk stratification to treatment.,Ariel Cohen; Pierre Amarenco,,2003.0,0,0 1773,12480052,Effects of gemfibrozil conversion to fenofibrate on lipids in patients on statin therapy.,John C Corbelli; Michael F Bullano; Vincent J Willey; Mark J Cziraky; Mary E Corbelli; William Waugh,,2003.0,0,0 1774,12481201,Update on fenofibrate.,David R P Guay,"Fenofibrate is a fibric acid derivative that has been marketed since the mid-1970's (1998 in the United States). Its active metabolite, fenofibric acid, is responsible for the primary pharmacodynamic effects of the drug: reductions in total plasma cholesterol, low density lipoprotein cholesterol, triglycerides, and very low-density lipoprotein concentrations and increases in high-density lipoprotein cholesterol and apolipoproteins AI and AII concentrations. These effects are mediated by activation of peroxisome proliferator-activated receptor-alpha (PPAR(alpha)). The drug has broad spectrum utility, with documented efficacy in Fredrickson types IIa, IIb, III, IV, and V hyperlipidemias. Fenofibrate is well tolerated, with digestive and musculoskeletal side effects similar to those of other fibrates. Results of the initial cardiovascular morbidity/mortality outcomes study with fenofibrate (known as DAIS [Diabetes Atherosclerosis Intervention Study]) were encouraging vis-à-vis slowing of atherosclerotic progression in the coronary vasculature of type II diabetics. The results of other ongoing outcome trials are eagerly awaited. These results will help to establish the overall place of fenofibrate in the hypolipidemic armamentarium.",2003.0,0,0 1775,12481202,Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor.,Anders G Olsson; Fergus McTaggart; Ali Raza,"Rosuvastatin, a new statin, has been shown to possess a number of advantageous pharmacological properties, including enhanced HMG-CoA reductase binding characteristics, relative hydrophilicity, and selective uptake into/activity in hepatic cells. Cytochrome p450 (CYP) metabolism of rosuvastatin appears to be minimal and is principally mediated by the 2C9 enzyme, with little involvement of 3A4; this finding is consistent with the absence of clinically significant pharmacokinetic drug-drug interactions between rosuvastatin and other drugs known to inhibit CYP enzymes. Dose-ranging studies in hypercholesterolemic patients demonstrated dose-dependent effects in reducing low-density lipoprotein cholesterol (LDL-C) (up to 63%), total cholesterol, and apolipoprotein (apo) B across a 1- to 40-mg dose range and a significant 8.4% additional reduction in LDL-C, compared with atorvastatin, across the dose ranges of the two agents. Rosuvastatin has also been shown to be highly effective in reducing LDL-C, increasing high-density lipoprotein cholesterol (HDL-C), and producing favorable modifications of other elements of the atherogenic lipid profile in a wide range of dyslipidemic patients. In patients with mild to moderate hypercholesterolemia, rosuvastatin has been shown to produce large decreases in LDL-C at starting doses, thus reducing the need for subsequent dose titration, and to allow greater percentages of patients to attain lipid goals, compared with available statins. The substantial LDL-C reductions and improvements in other lipid measures with rosuvastatin treatment should facilitate achievement of lipid goals and reduce the requirement for combination therapy in patients with severe hypercholesterolemia. In addition, rosuvastatin's effects in reducing triglycerides, triglyceride-containing lipoproteins, non-HDL-C, and LDL-C and increasing HDL-C in patients with mixed dyslipidemia or elevated triglycerides should be of considerable value in enabling achievement of LDL-C and non-HDL-C goals in the numerous patients with combined dyslipidemias or metabolic syndrome who require lipid-lowering therapy. Rosuvastatin is well tolerated alone, and in combination with fenofibrate, extended-release niacin, and cholestyramine, and has a safety profile similar to that of currently marketed statins. A large, long-term clinical trials program is under way to investigate the effects of rosuvastatin on atherosclerosis and cardiovascular morbidity and mortality.",2003.0,0,0 1776,12481542,Bone growth stimulators. New tools for treating bone loss and mending fractures.,James F Whitfield; Paul Morley; Gordon E Willick,"In the new millennium, humans will be traveling to Mars and eventually beyond with skeletons that respond to microgravity by self-destructing. Meanwhile in Earth's aging populations growing numbers of men and many more women are suffering from crippling bone loss. During the first decade after menopause all women suffer an accelerating loss of bone, which in some of them is severe enough to result in ""spontaneous"" crushing of vertebrae and fracturing of hips by ordinary body movements. This is osteoporosis, which all too often requires prolonged and expensive care, the physical and mental stress of which may even kill the patient. Osteoporosis in postmenopausal women is caused by the loss of estrogen. The slower development of osteoporosis in aging men is also due at least in part to a loss of the estrogen made in ever smaller amounts in bone cells from the declining level of circulating testosterone and is needed for bone maintenance as it is in women. The loss of estrogen increases the generation, longevity, and activity of bone-resorbing osteoclasts. The destructive osteoclast surge can be blocked by estrogens and selective estrogen receptor modulators (SERMs) as well as antiosteoclast agents such as bisphosphonates and calcitonin. But these agents stimulate only a limited amount of bone growth as the unaffected osteoblasts fill in the holes that were dug by the now suppressed osteoclasts. They do not stimulate osteoblasts to make bone--they are antiresorptives not bone anabolic agents. (However, certain estrogen analogs and bisphosphates may stimulate bone growth to some extent by lengthening osteoblast working lives.) To grow new bone and restore bone strength lost in space and on Earth we must know what controls bone growth and destruction. Here we discuss the newest bone controllers and how they might operate. These include leptin from adipocytes and osteoblasts and the statins that are widely used to reduce blood cholesterol and cardiovascular damage. But the main focus of this article is necessarily the currently most promising of the anabolic agents, the potent parathyroid hormone (PTH) and certain of its 31- to 38-aminoacid fragments, which are either in or about to be in clinical trial or in the case of Lilly's Forteo [hPTH-(1-34)] tentatively approved by the Food and Drug Administration for treating osteoporosis and mending fractures.",2003.0,0,0 1777,12482559,Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus.,M A van de Ree; M V Huisman; H M G Princen; A E Meinders; C Kluft; DALI-Study Group,"Statins are known to reduce CRP concentrations, but whether high doses are more effective is not known. In a prospective double-blind multicenter study in 186 DM2 patients without manifest coronary artery disease and with dyslipidemia, the effect of a 30-week treatment with 10 and 80 mg atorvastatin or placebo on the reduction of hs-CRP levels was measured. Median CRP levels increased with 6.6% in the placebo group and were reduced by 15 and 47%, respectively, with atorvastatin 10 and 80 mg (P<0.001; significantly different from 10 mg atorvastatin and from placebo (P<0.001). Variation in IL-6 and plasma lipids associated for 21 and 8%, respectively, with variation in CRP levels (P<0.001 and P=0.01). Of patients with a baseline CRP level above an arbitrary threshold of 3.0 mg/l, 56% in the 80 mg atorvastatin group reached a level of less than 3.0 mg/l, versus 23% randomized to 10 mg atorvastatin (P<0.01) and 17% in the placebo group (P<0.005). In DM2 patients high dose atorvastatin induced a strong reduction in CRP levels. The decrease in CRP was mainly independent of effects on lipid lowering and changes in IL-6 levels. The pleiotropic effect of high-dose atorvastatin on inflammation could add to its cardioprotective effect in high-risk patients.",2003.0,0,0 1778,12482568,Atorvastatin reduces expression of leukocyte adhesion molecules in patients with hypercholesterolemia.,Tomás Stulc; Michal Vrablík; Zdislava Kasalová; Richard Ceska; Iuri Marinov,,2003.0,0,0 1779,12483466,Endothelial nitric oxide synthase genotype modulates the improvement of coronary blood flow by pravastatin: a placebo-controlled PET study.,Tarja A Kunnas; Terho Lehtimäki; Reijo Laaksonen; Erkki Ilveskoski; Tuula Janatuinen; Risto Vesalainen; Pirjo Nuutila; Pekka J Karhunen; Juhani Knuuti; Seppo T Nikkari,"The objective was to study whether coronary blood flow or its response to pravastatin are affected by genetic variation in the endothelial nitric oxide synthase (eNOS) gene. Vascular endothelial nitric oxide maintains endothelium-dependent vasodilatation and also mediates antithrombotic actions. Its formation is catalyzed by eNOS, a constitutive enzyme, which has a polymorphic site in intron 4 (4a/b). Some clinical studies have suggested an association of the rare a-allele of eNOS with coronary artery disease and myocardial infarction. We carried out a double-blind placebo-controlled study involving 43 men (aged 35+/-4 years), who were randomized to receive either 40 mg/day pravastatin ( n=21) or placebo ( n=22) for 6 months. Myocardial blood flow was measured by positron emission tomography (PET) using (15)O-labeled water. PET was performed at rest and after stimulation by adenosine infusion. PET and lipid analyses were carried out at baseline and after 6 months. eNOS genotyping was done by PCR. At baseline there were no differences in basal or adenosine-stimulated coronary blood flow between subjects with either eNOS bb or ba genotypes. At the end of the study genotypes reacted differently between pravastatin and placebo groups with respect to the change in adenosine-stimulated flow (ANCOVA P=0.008). More specifically, after pravastatin treatment the adenosine-stimulated flow increased by 54.5% in men with the eNOS ba genotype, whereas in the men with the bb genotype no significant change in flow was observed ( P=0.002 for ba versus bb). In the placebo group there were no significant changes in blood flow from the baseline values ( P=0.916 for ba versus bb). After pravastatin treatment both genotype groups showed a similar decrease in serum total cholesterol and low-density lipoprotein cholesterol ( P<0.00001 for both). Our results suggest that adenosine-stimulated myocardial perfusion improves after treatment with pravastatin in subjects with the eNOS ba genotype but not in those with the bb genotype. This effect is not dependent on the decrease of serum cholesterol.",2003.0,0,0 1780,12483541,Microcirculation as a target for the anti-inflammatory properties of statins.,Rosario Scalia; Timothy J Stalker,"Statins are inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, a ubiquitous enzyme critical for the biosynthesis of cholesterol. Because of their cholesterol-lowering properties, statins are extensively used in medical practice, and large clinical trials have shown that statins effectively reduce cardiovascular related morbidity and mortality. In the past 5 years, an important, new concept suggesting that the cardioprotective effects of statins are not necessarily related to cholesterol-lowering actions has emerged. Indeed, in vivo findings have clearly shown that statins exert anti-inflammatory and immunomodulatory effects and that they modulate vascular remodeling under normocholesterolemic conditions. These pleiotropic properties of statins affect important molecules in vascular biology and help preserve endothelial function in acute and chronic inflammatory states of the cardiovascular system, including coronary and cerebral artery diseases, diabetes, and atherosclerosis. Emerging evidence indicates that the microcirculation is a crucial target for the pleiotropic actions of statins because of its important role in regulating blood flow, leukocyte-endothelium interactions, and vascular remodeling. Accordingly, this review focuses on the role that the microcirculation plays in the vascular protective action of statins.",2003.0,0,0 1781,12485557,"Clinical inquiries. Do antioxidants (vitamins C, E) improve outcomes in patients with coronary artery disease?",O Josh Bloom; Todd McDiarmid; Caryn Scoville,,2003.0,0,0 1782,12485562,Influenza vaccine does not produce myopathy in patients taking statins.,Bibiana Chazan; Rachel Weiss; Hava Tabenkin; Miguel Mines; Raul Raz,,2003.0,0,0 1783,12486428,"Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in patients with hypercholesterolemia: a randomized, double-blind, 52-week trial.",W Virgil Brown; Harold E Bays; David R Hassman; James McKenney; Rohini Chitra; Howard Hutchinson; Elinor Miller; Rosuvastatin Study Group,"The primary objective of this trial was to compare the efficacy of rosuvastatin with that of pravastatin and simvastatin for lowering low-density lipoprotein cholesterol (LDL-C) levels. In this randomized, double-blind, multicenter trial, lipid levels were measured in 477 patients (baseline LDL-C > or =160 and <250 mg/dL) who received fixed doses of 5 mg of rosuvastatin, 10 mg of rosuvastatin, 20 mg of pravastatin, or 20 mg of simvastatin for 12 weeks. For an additional 40 weeks, individual daily doses were sequentially doubled to a maximum of 80 mg of rosuvastatin, 40 mg of pravastatin, and 80 mg of simvastatin, according to investigator discretion and if National Cholesterol Education Program Adult Treatment Panel II (ATP II) LDL-C goals were not achieved. At 12 weeks, percent LDL-C reductions after both 5-mg and 10-mg rosuvastatin treatment, which were 39.1% and 47.4%, respectively, were significantly different (P <.05) from LDL-C reductions after 20-mg pravastatin (26.5%) and 20-mg simvastatin (34.6%) treatment. After 52 weeks, more rosuvastatin-treated patients remained at their starting dose than did simvastatin or pravastatin patients. After dose titration, 88% and 87.5% of the rosuvastatin 5-mg and 10-mg groups, respectively, achieved their ATP II LDL-C goals, compared with 60% for pravastatin and 72.5% for simvastatin. All study treatments were well tolerated. Rosuvastatin reduced LDL-C levels more than pravastatin or simvastatin in patients with hypercholesterolemia in a 52-week dose-titration study.",2003.0,1,1 1784,12486429,,,,,1,1 1785,12487148,Structural biology and function of solute transporters: implications for identifying and designing substrates.,Eric Y Zhang; Gregory T Knipp; Sean Ekins; Peter W Swaan,"Solute carrier (SLC) proteins have critical physiological roles in nutrient transport and may be utilized as a mechanism to increase drug absorption. However, we have little understanding of these proteins at the molecular level due to the absence of high-resolution crystal structures. Numerous efforts have been made in characterizing the peptide transporter (PepT1) and the apical sodium dependent bile acid transporter (ASBT) that are important for both their native transporter function as well as targets to increase absorption and act as therapeutic targets. In vitro and computational approaches have been applied to gain some insight into these transporters with some success. This represents an opportunity for optimizing molecules as substrates for the solute transporters and providing a further screening system for drug discovery. Clearly the future growth in knowledge of SLC function will be led by integrated in vitro and in silico approaches.",2003.0,0,0 1786,12488647,Pravastatin promotes coronary collateral circulation in patients with coronary artery disease.,Hiroaki Nishikawa; Shin-ichiro Miura; Bo Zhang; Hideki Shimomura; Hidekazu Arai; Yoshihiro Tsuchiya; Keijiro Saku,"Previous studies suggested that hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) promotes collateral circulation in ischemic limbs of rabbits. The present study was designed to determine the association between treatment with pravastatin and the development of coronary collateral circulation as assessed by the Rentrop Score in patients with coronary artery disease (CAD) in a case-control study. The study included patients who had one (1-V), two (2-V) or three (3-V) significantly stenosed vessels. Patients who did and did not receive pravastatin were defined as case participants (n = 42) and control participants (n = 100), respectively. The case participants included a higher percentage of 3-V patients with a Rentrop Score 1 compared to the control participants but there was no difference among 1-V and 2-V patients, suggesting that pravastatin was associated with coronary collateral circulation independent of the number of stenosed vessels. Patients with 3-V disease who were treated with pravastatin were most likely [odds ratio (confidence interval), 17.4 (4.4-115)] to develop collateral circulation, as assessed by multiple logistic regression analysis. Treatment with pravastatin was associated with the development of collateral circulation in patients with CAD, suggesting that such action constitutes part of the pleiotropic effects of statin.",2003.0,0,0 1787,12489273,"Chemoprevention of colorectal cancer: problems, progress, and prospects.",Jaye L Viner; Asad Umar; Ernest T Hawk,"Chemoprevention holds great promise as a complement to traditional CRC screening and treatment. Effective chemopreventive agents might improve patient outcomes by reducing the number of missed lesions, the morbidity associated with their identification and treatment, and their malignant potential. In addition, chemoprevention may reduce neoplastic potential simultaneously in several organs and improve clinical outcomes for persons at risk for cancers at multiple sites (e.g., colorectal and extracolonic cancers in HNPCC cohorts). Complex molecular circuits underlie the disease mosaic that is associated with aging. Several of these diseases share common mechanisms against which preventive interventions appear to be effective, such as NSAIDs for colorectal neoplasia and neurodegenerative disease, and statins for cardiovascular disease and colorectal neoplasia. Understanding these mechanisms and effects could raise prevention science to an entirely new level. The number of trials that are investigating chemopreventives against CR neoplasia is relatively small; if these agents live up to a fraction of their promise, the public health impact may be great (see Table 6).",2003.0,0,0 1788,12490687,Herbal remedies.,Peter A G M De Smet,,2002.0,0,0 1789,12492223,Spirulina-associated hepatotoxicity.,Motoh Iwasa; Mika Yamamoto; Yuji Tanaka; Masahiko Kaito; Yukihiko Adachi,,2003.0,0,0 1790,12492458,Treatment with atorvastatin alters the ratio of interleukin-12/interleukin-10 gene expression [corrected].,R P Naoumova; D D Patel; F H O'Neill; G R Thompson; B L Knight,"Statins have been shown to have pleiotropic effects extending beyond their ability to lower cholesterol. Seventeen patients with heterozygous familial hypercholesterolaemia participated in a single-blind placebo controlled study. The patients underwent three treatment regimens: placebo (4 weeks), atorvastatin 10 mg day(-1) (4 weeks) and atorvastatin 40 mg day(-1) (12 weeks). Following each treatment period, serum lipids and plasma mevalonic acid were measured, mononuclear leukocytes were isolated and total RNA was prepared. The content of mRNA for IL-12p35 and IL-10 was assayed, blinded, by real-time quantitative polymerase chain reactions. Treatment of the subjects with atorvastatin decreased the abundance of IL-12p35 mRNA in mononuclear cells, but did not alter that of IL-10, so that the ratio of the IL-12p35 to IL-10 mRNA content was significantly reduced (P < 0.0026). The IL-12p35/IL-10 ratio correlated significantly with plasma mevalonic acid concentrations but not with serum LDL concentrations. This study provides evidence that atorvastatin exerts an immunomodulatory effect in vivo, characterized by a decrease in the ratio of IL-12 mRNA to IL-10 mRNA in leukocytes. The immunomodulatory effect of statins, in addition to their cholesterol-lowering properties, may contribute to the rapid cardiovascular benefit observed during treatment with statins and reduced the rate of rejection in patients with solid organ transplantation.",2003.0,0,0 1791,12493130,,,,,0,0 1792,12493414,Sirolimus rescue treatment in calcineurin-inhibitor nephrotoxicity after kidney transplantation.,J Wyzgal; L Paczek; G Senatorski; J Zygier; W Rowiński; J Szmidt; A Perkowska,,2003.0,0,0 1793,12493534,Stress proteins and glial functions: possible therapeutic targets for neurodegenerative disorders.,Yoshihisa Kitamura; Yasuyuki Nomura,"Recent findings suggest that unfolded or misfolded proteins participate in the pathology of several neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Usually, several stress proteins and glial cells act as intracellular molecular chaperones and show chaperoning neuronal function, respectively. In the brains of patients with neurodegenerative disorders, however, stress proteins are expressed and frequently associated with protein aggregates, and glial cells are activated around degenerative regions. In addition, several stress proteins and glial cells may also regulate neuronal cell death and loss. Therefore, some types of stress proteins and glial cells are considered to be neuroprotective targets. We summarize the current findings regarding the neuroprotective effects of stress proteins and glial cells, and discuss the possibility of using this knowledge to develop new therapeutic strategies to treat neurodegeneration.",2003.0,0,0 1794,12494951,Causal structures for evaluating statin class effects.,John D Seeger,,2003.0,0,0 1795,12495163,Comparison of gemfibrozil and fenofibrate in patients with dyslipidemic coronary heart disease.,Kathleen A Packard; James M Backes; Thomas L Lenz; Richard L Wurdeman; Christopher Destache; Daniel E Hilleman,"To compare the lipid-lowering effects of gemfibrozil and fenofibrate in patients with dyslipidemic coronary heart disease. Open label, fixed-dosage, retrospective-prospective, one-way crossover from gemfibrozil to fenofibrate. University-affiliated outpatient clinics. Eighty patients with coronary heart disease with a baseline low-density lipoprotein cholesterol (LDL) level above 130 mg/dl or a triglyceride level of 200 mg/dl or higher who had been receiving gemfibrozil 600 mg twice/day. Thirty-nine (49%) patients had received concomitant therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) for a minimum of 9 months. All patients received gemfibrozil 600 mg twice/day for at least 3 months before being switched to fenofibrate 201 mg/day. Patients receiving concomitant statin therapy before crossover continued the statin at the same dosage after crossover. Before crossover, a fasting lipid profile was determined and patients were queried about the side effects of lipid-lowering therapy. A repeat fasting lipid profile was obtained 12 weeks after the crossover. Patients were stratified into those receiving versus those not receiving concomitant statin therapy. In both of these groups, fenofibrate was associated with significantly greater reductions in total cholesterol, LDL, and triglycerides than gemfibrozil (all p < 0.001). In addition, fenofibrate was associated with a significantly greater increase in high-density lipoprotein cholesterol (HDL) than gemfibrozil (p < 0.001). No patients reported new-onset adverse effects after the crossover. Compared with gemfibrozil, fenofibrate produced significantly greater reductions in total cholesterol, LDL, and triglycerides and significantly greater increases in HDL. These changes were evident in patients receiving and not receiving concomitant statin therapy.",2003.0,0,0 1796,12495166,Implications of amyloid precursor protein and subsequent beta-amyloid production to the pharmacotherapy of Alzheimer's disease.,Carlos H Rojas-Fernandez; Ming Chen; Hugo L Fernandez,"Alzheimer's disease is the most common type of dementia in older people. It is highly prevalent, affecting 35-45% of those aged 85 years or older. This disease has devastating consequences to patients, their families, caregivers, and the health care system. Much has been learned about its pathobiology, which has led to the beta-amyloid (Abeta) hypothesis. This hypothesis continues to be the predominant postulate of the pathobiology of Alzheimer's disease. Under this hypothesis, abnormal accumulation of Abeta is followed by a cascade of neurotoxic effects, which eventually result in neurodegeneration and development of Alzheimer's disease. This is thought to be the result of altered processing of the amyloid precursor protein (APP), preferentially by beta- and gamma-secretase enzymes rather than nonamyloidogenic processing by alpha-secretase. The growing body of knowledge regarding the processing of APP to various forms of Abeta has resulted in new approaches to the investigation of putative anti-Alzheimer's disease compounds, including immune-based therapies and various agents that can positively affect APP processing.",2003.0,0,0 1797,12495278,Factors affecting outcome after percutaneous renal artery stent insertion.,Vlado Perkovi; Ken R Thomson; Gavin J Becker,"Renal artery stenosis is increasingly being treated with the percutaneous insertion of stents. Little data are available to help select patients most likely to derive benefit from the procedure. Data were gathered on all patients treated with renal artery stent insertion at the Royal Melbourne Hospital prior to 1998, and who were followed-up for at least 6 months or until death. Multivariate regression analysis was used to identify factors associated with patient survival and renal survival (survival free of dialysis). Adequate data were available on 148 of 198 patients treated during this time (75%). A baseline creatinine over 0.15 mmol/L and age over 70 were strongly associated with worse patient survival (Likelihood ratio(LR) 9.96, p < 0.0001 and 3.4, p = 0.001 respectively) and renal survival (LR 7.8, p < 0.001 and 2.7, p < 0.01 respectively). The presence of diabetes was also associated with worse overall survival (LR 2.2, p < 0.05) but not renal survival, while the presence of another nephropathic disorder was associated with worse renal survival (LR 2.8, p < 0.01) but not overall survival. The use of ACE inhibitors after the stenting procedure was associated with a significantly better renal survival (LR 0.46, p < 0.05). Patients with baseline renal impairment, older age, diabetes or another coexistent renal disease have poor outcomes after renal artery stent insertion. A relatively conservative approach to revascularisation may be preferable in these patient groups. The use of ACE inhibitors after stent insertion is associated with a reduced likelihood of death or dialysis.",2003.0,0,0 1798,12495286,Neuromuscular toxicity in nephrotic patients treated with fluvastatin.,Sanaa Gazarin; Hassan Abd-El-Hady; Osama Gheith; Mahmoud Rasem; Mohamed Saad; Kefaya El-Sayed; Mohamed Sobh; Galal Amer,"Nephrotic dyslipidemia is a risk factor for the development of systemic atherosclerosis, and may aggravate glomerulosclerosis and enhance progression of glomerular disease. The greatest and most consistent reductions in LDL-cholesterol are achieved with HMG-CoA reductase inhibitors but their efficacy and safety in long-term therapy need to be evaluated. In this study, we gave fluvastatin to 21 nephrotic patients and followed then up clinically, neurophysiologically and by laboratory tests. There was an improvement in the lipogram, with reductions of triglycerides (TG) (33%) and LDL (35%) at three months. There was no clinical manifestation of myopathy and CPK was normal. Electromyographic data showed significant decreases in the amplitude and duration of motor unit action potentials in the proximal muscles with statin therapy, but these changes did not amount to classic myopathy. We conclude that fluvastatin is a safe drug for long-term use in dyslipidemic nephrotic patients. However, we suggest further studies to verify whether the early electromyography (EMG) changes observed in this study may progress or not on its longer term use.",2003.0,0,0 1799,12498006,Pleiotropic effects of HMG-CoA reductase inhibitors.,Thomas M A Bocan,"HMG-CoA reductase, in addition to being the rate-limiting enzyme in the cholesterol biosynthetic pathway, is involved in the regulation of receptors for low-density lipoprotein (LDL)-cholesterol. Clinical studies in men and women demonstrate that inhibitors of HMG-CoA reductase (statins), by reducing plasma cholesterol, may limit the development of atherosclerosis and reduce the risk of mortality and ischemic events. Preclinical evidence suggests that under controlled conditions of plasma cholesterol lowering, statins may have ancillary properties or pleiotropic effects, which may directly limit atherosclerosis progression. In this review, pleiotropic effects have been defined as 'ancillary properties of statins, which result in hepatic and/or vascular changes that may or may not be a consequence of inhibition of HMG-CoA reductase.' Beyond the LDL lowering activity of statins, improvements have been noted in endothelial dysfunction through direct stimulation of expression of such vasodilators as nitric oxide and/or reduction in vasoconstrictors. Factors associated with atherogenesis, such as monocyte adhesion to endothelial cells, macrophage production of proinflammatory molecules and matrix metalloproteases, smooth muscle cell proliferation and migration and macrophage-induced oxidation of LDL particles have also been reduced by various statins. It is unclear whether the observed pleiotropic effects are independent of LDL-cholesterol lowering or inhibition of HMG-CoA reductase, and whether they are clinically relevant; however, one can conclude that the pleiotropic effects appear to be a class effect of statins and can be attenuated by addition of the post-reductase product, mevalonate.",2003.0,0,0 1800,12498007,Combination therapy with statins.,Helena Gylling; Tatu A Miettinen,"Statins effectively inhibit cholesterol synthesis and are currently the most commonly used drugs for the treatment of hypercholesterolemia. However, patients with familial hypercholesterolemia and those unwilling to take, or who cannot tolerate statins, and patients with combined hyperlipidemia require a combination treatment. Statins combined with cholesterol malabsorption, caused, e.g., by plant stanol esters or ezetimibe (Schering-Plough Corp/Merck & Co Inc), or with bile acid malabsorption, caused by bile acid binding resins or guar gum, inhibit compensatory increases in cholesterol synthesis and effectively lower LDL cholesterol levels. Combination therapy of statins with fibrates should be controlled by lipidology experts. Recent information on indications and advantages of combining statins with n-3 fatty acids, hormone replacement therapy, or niacin, will also be discussed.",2003.0,0,0 1801,12498009,Avasimibe Pfizer.,John R Burnett; Murray W Huff,Avasimibe (also known as CI-1011 or PD-148515) is a selective acyl-coenzyme A:cholesterol O-acyltransferase (ACAT) inhibitory lipid-regulating agent under development by Pfizer (formerly Parke-Davis) for the potential treatment of hyperlipidemia and atherosclerosis. The compound is currently undergoing phase III clinical trials [371470].,2003.0,0,0 1802,12498010,Pitavastatin Nissan/Kowa Yakuhin/Novartis/Sankyo.,Nicholas A Flores,"Pitavastatin (nisvastatin) is an HMG CoA reductase inhibitor being developed jointly by Nissan, Kowa Kogyo, Novartis and Sankyo for the potential treatment of atherosclerosis and hyperlipidemia.",2003.0,0,0 1803,12499611,Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia.,Masunori Matsuzaki; Toru Kita; Hiroshi Mabuchi; Yuji Matsuzawa; Noriaki Nakaya; Shinichi Oikawa; Yasushi Saito; Jun Sasaki; Kazuaki Shimamoto; Hiroshige Itakura; J-LIT Study Group. Japan Lipid Intervention Trial,"Hyperlipidemia is a well-established risk factor for primary coronary heart disease (CHD). Although simvastatin is known to lower serum lipid concentrations, the protective effect of such lipid-lowering therapy against primary CHD has not been established in Japanese patients with hypercholesterolemia. The Japan Lipid Intervention Trial was a 6-year, nationwide cohort study of 47,294 patients treated with open-labeled simvastatin (5-10 mg/day) and monitored by physicians under standard clinical conditions. The aim of the study was to determine the relationship between the occurrence of CHD and the serum lipid concentrations during low-dose simvastatin treatment. Simvastatin reduced serum concentrations of total cholesterol (TC), low-density lipoprotein- cholesterol (LDL-C) and triglyceride (TG), by 18.4%, 26.8% and 16.1% on average, respectively, during the treatment period. The risk of coronary events was higher when the average TC concentration was > or =240 mg/dl and the average LDL-C concentration was > or =160 mg/dl. The incidence of coronary events increased in the patients with TG concentration > or =300 mg/dl compared with patients with TG concentration <150 mg/dl. The high-density lipoprotein cholesterol (HDL-C) inversely correlated with the risk of coronary events. The J-curve association was observed between average TC or LDL-C concentrations and total mortality. Malignancy was the most prevalent cause of death. The health of patients should be monitored closely when there is a remarkable decrease in TC and LDL-C concentrations with low-dose statin. A reasonable strategy to prevent coronary events in Japanese hypercholesterolemic patients without prior CHD under low-dose statin treatment might be regulating the serum lipid concentrations to at least <240 mg/dl for TC, <160 mg/dl for LDL-C, <300 mg/dl for TG, and >40 mg/dl for HDL-C.",2003.0,0,0 1804,12499612,Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia and coronary heart disease: secondary prevention cohort study of the Japan Lipid Intervention Trial (J-LIT).,Hiroshi Mabuchi; Toru Kita; Masunori Matsuzaki; Yuji Matsuzawa; Noriaki Nakaya; Shinichi Oikawa; Yasushi Saito; Jun Sasaki; Kazuaki Shimamoto; Hiroshige Itakura; J-LIT Study Group. Japan Lipid Intervention Trial,"Hyperlipidemia is primarily implicated in the progression of coronary heart disease (CHD) and its treatment is essential for patients with a history of CHD. Statins such as simvastatin, the lipid-lowering agents, are well-known for their ability to normalize patient's serum lipid levels. The Japan Lipid Intervention Trial study of simvastatin is the first nationwide investigation of the relationship between serum lipid levels and the development of CHD in Japanese patients with hypercholesterolemia. Of 5,127 patients, exclusively with a history of documented CHD at enrollment, 4,673 were treated with open-labeled simvastatin at an initial dose of 5-10 mg/day and were monitored for 6 years. The risk of coronary events tended to be higher in patients with a serum total cholesterol (TC) > or =240 mg/dl compared with total cholesterol <240 mg/dl. The concentration of low-density lipoprotein cholesterol (LDL-C) positively correlated and that of high-density lipoprotein cholesterol (HDL-C) inversely correlated with the risk of CHD. Each 10 mg/dl decrease in LDL-C and each 10 mg/dl increase in HDL-C concentration reduced the risk of CHD by 8.0% (95% confidence interval 3.8-12.0) and 28.3% (95% CI 13.9-40.3), respectively. A reasonable therapeutic strategy to reduce CHD progression in patients with prior CHD under low-dose statin treatment might be regulating the serum LDL-C concentration to at least <120 mg/dl and HDL-C >40 mg/dl, respectively.",2003.0,0,0 1805,12500022,Comparison of micronized fenofibrate and pravastatin in patients with primary hyperlipidemia.,Jean Ducobu; Luc VanHaelst; Herve Salomon,"Micronized fenofibrate lowers total cholesterol and low-density lipoprotein cholesterol to a similar extent as statins but raises high-density lipoprotein cholesterol and lowers triglycerides to a greater extent. The comparative lipid-modifying efficacy of micronized fenofibrate and pravastatin has not been evaluated in dyslipidemic patients. This prospective, multicenter, randomized trial compared the efficacy of 3 months' treatment with micronized fenofibrate (200 mg once daily) or pravastatin (20 mg once daily) in hypercholesterolemic type IIa and mixed dyslipidemic type IIb patients. Two hundred sixty-five male and female patients (18-75 years) were recruited from 28 European centers, and 151 were analyzed. Micronized fenofibrate was at least as effective as pravastatin in reducing levels of low-density lipoprotein cholesterol and total cholesterol in primary dyslipidemia but was significantly more effective than pravastatin in raising high-density lipoprotein cholesterol (respectively, 13.2% vs. 5.6%; p = 0.0084) and lowering triglycerides (-38.7% vs. -11.8%; p = 0.0001). In type IIa dyslipidemia, micronized fenofibrate was as effective as pravastatin in raising high-density lipoprotein cholesterol (+8.6% vs. +8.0%) but was fivefold more effective in lowering triglycerides (-34.3% vs. -7.2%; p = 0.0001). In type IIb dyslipidemic patients with low baseline high-density lipoprotein cholesterol levels, micronized fenofibrate was 10-fold and nearly 3-fold superior to pravastatin in raising high-density lipoprotein cholesterol and lowering triglycerides, respectively. Micronized fenofibrate may be considered an effective first-line therapy for patients with primary hyperlipidemia, particularly those with type IIb mixed dyslipidemia or type 2 diabetes.",2003.0,0,0 1806,12500883,Enhancing the quality of care for patients with coronary heart disease: the design and baseline results of the hastening the effective application of research through technology (HEART) trial.,David C Goff; Lin Gu; Larry K Cantley; Deborah G Parker; Stuart J Cohen,"Effective therapies exist for reducing mortality in persons with coronary heart disease (CHD), but they remain underused. To report the design and baseline results of a quality improvement project designed to increase the use of hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, beta-adrenergic blocking agents, and angiotensin-converting enzyme (ACE) inhibitors in patients with CHD in a network-model managed care setting. Patients with CHD were identified by searching a claims database. Use of therapies was assessed by linkage with a pharmacy benefits database. A survey was mailed to primary care physicians to collect information related to attitudes and behavioral intentions regarding aggressive management of CHD. An intervention, consisting of a guideline summary, performance feedback, and medical chart reminders, was evaluated in a randomized, practice-based trial. Among 1189 patients with CHD, the median prevalence of receipt of HMG-CoA reductase inhibitors, beta-adrenergic blocking agents, and ACE inhibitors across practices at baseline (the first 3 months of 1999) was 50.0%, 35.0%, and 18.8%, respectively. Reported barriers included a perception that aggressive management of CHD is thought to be unimportant by support staff yet to require significant staff time. Aggressive management of CHD was perceived to incur non-reimbursable costs, to be unimportant in their patient population, to require a great deal of patient education and self-management, and to be limited because many patients do not adhere to therapy. Opportunities exist for enhancing the quality of care provided to patients with CHD. Our experience to date supports the logistical feasibility of implementing network-level quality enhancement efforts in managed care networks.",2003.0,0,0 1807,12501010,"Cerivastatin, a HMG-CoA reductase inhibitor, reduces plasminogen activator inhibitor-1 (PAI-1) expression in endothelial cells by down-regulation of cellular signaling and the inhibition of PAI-1 promoter activity.",Maria Swiatkowska; Zofia Pawlowska; Janusz Szemraj; Józef Drzewoski; Cezary Watala; Czeslaw S Cierniewski,"Statins, which competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity and reduce mevalonate synthesis, are believed to exert a plethora of pleiotropic effects. In this report, molecular mechanisms of the inhibitory effect on plasminogen activator inhibitor type 1 (PAI-1) expression produced by cerivastatin (CRV), the most active compound in this class, were studied using monocultures of human endothelial cell line (EA.hy 926). CRV similar to another statin, lovastatin (LOV), significantly inhibited PAI-1 expression and its release from endothelial cells, nonstimulated and stimulated with TNF-alpha. The inhibitory effect of CRV could be detected at the level of PAI-1 promoter in EA.hy 926 cells transfected with plasmid p800 LUC containing PAI-1 promoter fragment (+71 to -800), as well as at the level of PAI-1 mRNA. The PAI-1 promoter activity was markedly suppressed in the nonstimulated cells and almost completely inhibited in TNF-alpha-stimulated cells. In addition, CRV at low doses (IC(50) of 4 - 6 microM) significantly inhibited mitogen-activated protein kinases (MAPKs) phosphorylation. The majority of inhibitory effects occurred at significantly lower concentrations for CRV compared to LOV. The mechanism by which CRV inhibits PAI-1 expression appears to be directly associated with geranylgeranylation of some cell proteins, since the inhibitory effect on PAI-1 expression can be reversed by geranylgeranyl-pyrophosphate but not by farnesyl-pyrophosphate.",2003.0,0,0 1808,12502921,Statin therapy in the elderly-the evidence mounts.,Gary E Sander; Thomas D Giles,,2003.0,0,0 1809,12503944,Niacin-ER and lovastatin treatment of hypercholesterolemia and mixed dyslipidemia.,Barbara T Yim; Pang H Chong,"To review the currently available information on the once-daily combination of niacin extended-release (ER)/lovastatin in the treatment of patients with hypercholesterolemia and mixed dyslipidemia at high risk for cardiovascular events. MEDLINE (1966-July 2002) was searched for primary and review articles. Data from the manufacturer were also included. All articles and product labeling deemed relevant to the combination of niacin and statins (i.e., lovastatin) were included for review. English-language studies selected for inclusion were limited to those with human subjects. The Food and Drug Administration approved a new fixed-dose combination of niacin-ER/lovastatin, which is administered once daily. The efficacy and safety of the combined agent have been proven to be similar to either component used alone or in combination for management of hyperlipidemia and mixed dyslipidemia. Elevated low-density lipoprotein cholesterol (LDL-C) is independently associated with a higher risk for cardiovascular events. Lowering of elevated LDL-C concentrations with statin monotherapy may be insufficient in patients at high risk for cardiovascular events. In fact, consideration of elevated triglycerides (TGs) and/or low concentrations of high-density lipoprotein cholesterol (HDL-C) in patients with elevated LDL-C places them at greater risk. The addition of niacin may enhance or improve the lipid profile of those who require a further decrease of TGs and/or increase of HDL-C even after stable statin therapy. Niacin-ER offers efficacy similar to that of immediate-release niacin, but minimal myopathy and hepatotoxicity (compared with sustained-release niacin). Although no clinical outcomes are available, current evidence shows that the combination product offers adequate lowering of LDL-C and TGs and increasing HDL-C. The data suggest that therapy with the niacin-ER and lovastatin combination product is safe and does not increase the incidence of adverse effects.",2003.0,0,0 1810,12504665,Verapamil is associated with an increased risk of cancer in the elderly: the Rotterdam study.,A B Beiderbeck-Noll; M C J M Sturkenboom; P D van der Linden; R M C Herings; A Hofman; J W W Coebergh; H G M Leufkens; B H Ch Stricker,"The association between the use of calcium channel blockers (CCB) and cancer has received ample attention, but is still controversial. In this study, we have tested the hypothesis that the observed association between CCB and cancer in earlier studies could be explained by residual confounding or by misclassification of exposure because of the use of cross-sectional data on drug use. Data from the Rotterdam Study, a prospective population-based cohort study in the municipal area Ommoord, were used. The study population consisted of a cohort of 3204 participants aged 71 years or older who were followed from a baseline interview in the period 1991-1993 for the occurrence of incident cancer. Data on drug use were gathered at baseline and through the seven community pharmacies which served the Ommoord region during the study period between 1 January 1991 and 1 January 1999. Incident cancer events were gathered from a nationwide registry of hospitalisation data and from a specialised cancer centre in the Rotterdam region. We performed three analyses. First, we followed the method, and adjusted for the same risk factors, as in the earlier studies. In the second analysis, we included all risk factors that were univariately associated with cancer in the Rotterdam Study. In the third analysis, we included exposure to CCBs as time-varying co-variates, while adjusting for potential confounders. The relative risk (RR) of cancer associated with CCB was 1.4 (95% Confidence Interval (CI): 0.9-2.0) in the first analysis and lowered to 1.2 (95% CI: 0.8-1.8) upon adjustment for the different co-variates in the second. In both analyses, however, verapamil was significantly associated with cancer with RRs of 2.1 (95% CI: 1.1-4.0) and 2.0 (1.01-3.9), respectively, whereas no associations were found with the other CCB in this study, i.e. diltiazem and nifedipine. A significantly increased risk of cancer was found for intermediate daily doses of verapamil and diltiazem. Intake of other antihypertensives such as beta-blocking agents, diuretics and ACE-inhibitors was not associated with cancer. In the third analysis with exposure to CCB as time-varying co-variates, the risk increase was non-significant for use of 2 years or less, 1.0 (95% CI: 0.7-1.5), and for use for a cumulative period of more than 2 years, 1.3 (95% CI: 0.8-2.0). However, in all models the hazard ratio was statistically significantly increased for verapamil, but not for diltiazem and nifedipine. On the basis of these analyses, we found no increase in cancer in users of diltiazem and nifedipine, nor in users of other antihypertensives. In line with earlier studies, however, we found an increased risk of cancer in users of verapamil. At variance with the conclusions from several other studies, we think that it is too early to conclude that CCB are not associated with cancer.",2003.0,0,0 1811,12505111,Statins do not meet expectations for lowering low-density lipoprotein cholesterol levels when used in clinical practice.,Joseph P Frolkis; Gregory L Pearce; Vijay Nambi; Stephen Minor; Dennis L Sprecher,"Statins have become a mainstay in the treatment of hyperlipidemia, based on their potency and favorable side-effect profile. Drug choice is presumed to be guided by the estimated degree of low-density lipoprotein (LDL) cholesterol lowering required in a particular patient and the projected efficacy of any drug-dose combination, as contained in the package inserts for each medication. We investigated whether these expectations were met in a clinical practice. Data were analyzed for 367 hyperlipidemic patients in a preventive cardiology practice who were not taking statins at entry, who were given a standard statin dose at their first visit, and who had at least one follow-up visit on the same drug/dose. Expected LDL cholesterol reductions were calculated for each patient based on guidelines in the package inserts for each drug. The mean (+/-SD) observed LDL cholesterol reduction of 26% +/- 20% was significantly less than expected (34% +/- 7%, P < 0.001). The ratio of observed to expected reduction was not different for the three statins used (atorvastatin, 0.79 +/- 0.48; simvastatin, 0.88 +/- 0.61; pravastatin, 0.75 +/- 0.69; P = 0.39). The use of statins in a clinical practice led to observed reductions in LDL cholesterol level that were significantly less than those projected by package insert guidelines. We believe this gap reflects the reduced patient compliance frequently observed in clinical practice settings, rather than any inherent difference in statin responsiveness of a practice versus a trial population. Physicians should be aware of this disparity when using statins in the clinical setting.",2003.0,0,0 1812,12505120,Adherence to statin therapy: why aren't we doing better?,Frank M Sacks,,2003.0,0,0 1813,12505222,Early statin therapy restores endothelial function in children with familial hypercholesterolemia.,Saskia de Jongh; Marc R Lilien; Jos op't Roodt; Erik S G Stroes; Henk D Bakker; John J P Kastelein,"This study was designed to determine whether simvastatin improves endothelial function in children with familial hypercholesterolemia (FH). Endothelial function measured by flow-mediated dilation of the brachial artery (FMD) is used as a surrogate marker of cardiovascular disease (CVD). Adult studies have shown that statins reverse endothelial dysfunction and therefore reduce the risk for future CVD. The study included 50 children with FH (9 to 18 years) and 19 healthy, non-FH controls. Children with FH were randomized to receive simvastatin or placebo for 28 weeks. The FMD was performed at baseline and at 28 weeks of treatment. At baseline, FMD was impaired in children with FH versus non-FH controls (p < 0.024). In the simvastatin FH group, FMD improved significantly, whereas the FMD remained unaltered in the placebo FH group throughout the study period (absolute increase 3.9% +/- 4.3% vs. 1.2% +/- 3.9%, p < 0.05). In the simvastatin FH group, FMD increased to a level similar to the non-FH controls (15.6% +/- 6.8% vs. 15.5% +/- 5.4%, p = 0.958). Upon treatment, the simvastatin FH group showed significant absolute reductions of total cholesterol (TC) (-2.16 +/- 1.04 mmol/l, 30.1%) and low-density lipoprotein cholesterol (LDL-C) (-2.13 +/- 0.99 mmol/l, 39.8%). The absolute change of FMD after 28 weeks of therapy was inversely correlated to changes of TC (r = -0.31, p < 0.05) and LDL-C (r = -0.31, p < 0.05). Our data show significant improvement of endothelial dysfunction towards normal levels after short-term simvastatin therapy in children with FH. These results emphasize the relevance of statin therapy in patients with FH at an early stage, when the atherosclerotic process is still reversible.",2003.0,0,0 1814,12505223,Shifting the diagnosis and treatment of atherosclerosis to children and young adults: a new paradigm for the 21st century.,Sotirios Tsimikas; Joseph L Witztum,,2003.0,0,0 1815,12505224,Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia.,Michael H Davidson; Thomas McGarry; Robert Bettis; Lorenzo Melani; Leslie J Lipka; Alexandre P LeBeaut; Ramachandran Suresh; Steven Sun; Enrico P Veltri,"The purpose of this study was to assess the efficacy and safety of ezetimibe administered with simvastatin in patients with primary hypercholesterolemia. Despite the availability of statins, many patients do not achieve lipid targets. Combination therapy with lipid-lowering agents that act via a complementary pathway may allow additional patients to achieve recommended cholesterol goals. After dietary stabilization, a 2- to 12-week washout period, and a 4-week, single-blind, placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =145 mg/dl to < or =250 mg/dl and triglycerides (TG) < or =350 mg/dl were randomized to one of the following 10 groups administered daily for 12 consecutive weeks: ezetimibe 10 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg plus simvastatin 10, 20, 40, or 80 mg; or placebo. The primary efficacy variable was percentage reduction from baseline to end point in direct LDL-C for the pooled ezetimibe plus simvastatin groups versus pooled simvastatin groups. Ezetimibe plus simvastatin significantly improved LDL-C (p < 0.01), high-density lipoprotein cholesterol (HDL-C) (p = 0.03), and TG (p < 0.01) compared with simvastatin alone. Ezetimibe plus simvastatin (pooled doses) provided an incremental 13.8% LDL-C reduction, 2.4% HDL-C increase, and 7.5% TG reduction compared with pooled simvastatin alone. Coadministration of ezetimibe and simvastatin provided LDL-C reductions of 44% to 57%, TG reductions of 20% to 28%, and HDL-C increases of 8% to 11%, depending on the simvastatin dose. Ezetimibe 10 mg plus simvastatin 10 mg and simvastatin 80 mg alone each provided a 44% LDL-C reduction. The coadministration of ezetimibe with simvastatin was well tolerated, with a safety profile similar to those of simvastatin and of placebo. When coadministered with simvastatin, ezetimibe provided significant incremental reductions in LDL-C and TG, as well as increases in HDL-C. Coadministration of ezetimibe with simvastatin was well tolerated and comparable to statin alone.",2003.0,0,0 1816,12505225,Low-density lipoprotein lowering therapy: an analysis of the options.,Frank M Sacks,,2003.0,0,0 1817,12505250,Measuring the cost-effectiveness of lipid-lowering drugs in the elderly: the outcomes research and economic analysis components of the PROSPER trial.,Jerry Avorn; Josh Benner; Ian Ford; David A Ganz; Allan Gaw; Robert J Glynn; Joseph Jackson; A Margot Lagaay; Sebastian Schneeweiss; Thomas Walley; Philip S Wang; Outcomes Research Working Group and the PROSPER Study Group,"Little information exists to quantify the functional status and economic consequences of lipid-lowering therapy in elderly patients. We describe the design of the cost-effectiveness component of the first large, randomized, placebo-controlled trial of lipid-lowering therapy in subjects aged 70 years or older. The PROspective Study of Pravastatin in the Elderly at Risk has randomized 5804 men and women 70-82 years old, with existing vascular disease or related risk factors, to receive 40 mg/d of pravastatin or placebo. The cost-effectiveness study will be based on within-trial observations of differences between the two study arms in rates of myocardial infarction, stroke and related vascular disease outcomes (including vascular dementia). In addition to comparing within-trial clinical outcomes, we will model the projected changes in life expectancy and cardiovascular outcome rates that would be seen with lifelong use of the drug, based on the risk reduction rates seen in the trial as well as baseline observational data from the three countries where the trial is being conducted (Scotland, Ireland and the Netherlands). A state transition (Markov) model will be constructed to estimate the likely states of health, functional status and health care resource utilization (including lipid-lowering drug costs) in a cohort of elderly patients with versus without pravastatin therapy over a series of 1-year cycles until death. In addition, a standard measure of utility (the Health Utilities Index) will be administered to all study subjects to permit calculation of quality-adjusted life-years gained with this regimen. This approach will make it possible to go beyond the calculation of a single endpoint for each subject, and to translate the trial findings into definitions of effectiveness and outcomes that will be relevant to the ongoing debate concerning how best to relate the benefits of such medications to their costs.",2003.0,0,0 1818,12505562,"Efficacy and safety of minimal dose (< or =1,000 units) unfractionated heparin with abciximab in percutaneous coronary intervention.",Scott J Denardo; Keith E Davis; Philip R Reid; James E Tcheng,"Abciximab decreases adverse cardiac ischemic events, and in some subgroups, decreases the need for revascularization after percutaneous coronary intervention (PCI). However, abciximab may cause bleeding complications and thrombocytopenia after PCI. We hypothesized that the efficacy and safety of PCI would be maintained, if not improved, when performed using abciximab accompanied by only minimal doses (< or =1,000 U) of unfractionated heparin. In this prospectively designed observational study, we assessed 500 consecutive patients who underwent PCI, consisting of either stent deployment or high-speed rotational atherectomy, and who received abciximab accompanied by only a minimal dose of unfractionated heparin, as directed by a novel dosing strategy: (1) if the patient was previously receiving an infusion of heparin, then it was terminated upon arrival to the cardiac catheterization laboratory, and no further heparin was administered; or (2) if the patient was not receiving an infusion of heparin, then a single bolus infusion of 1,000 U was administered after establishment of vascular access. The median activated clotting time for the patients during PCI was 168 seconds (25% quartiles, 153 to 185). The technical success rate was 99.8%. There were no major adverse clinical events during the 24 hours after PCI. The incidence of non-Q-wave myocardial infarction was 1.6%. The incidences of major and minor bleeding complications were 0.2% and 3.6%, respectively, and the incidence of thrombocytopenia was 2.2%. During the 30 days after PCI, there was 1 major adverse clinical event (0.2%). During the 1 year after PCI, among the remaining patients, there were 92 adverse events (18.4%). We conclude that, in the context of historical data, the efficacy and safety of PCI using either stent deployment or high-speed rotational atherectomy is maintained, if not improved, when performed using abciximab accompanied by only minimal doses of unfractionated heparin.",2003.0,0,0 1819,12505564,Long-term (three-year) outcomes after stenting of unprotected left main coronary artery stenosis in patients with normal left ventricular function.,Seung-Jung Park; Seong-Wook Park; Myeong-K i Hong; Cheol Whan Lee; Jae-Hwan Lee; Jae-Joong Kim; Yang Soo Jang; Eak-Kyun Shin; Yoshinori Yoshida; Takashi Tamura; Takeshi Kimura; Masakiyo Nobuyoshi,"The purpose of this study was to analyze long-term follow-up information from patients treated with stenting for unprotected left main coronary artery (LMCA) stenosis. Stenting of unprotected LMCA stenosis is often performed in selected patients, but the long-term safety of this therapy is not yet established. Between January 1995 and September 2000, 270 consecutive patients with unprotected LMCA stenosis and normal left ventricular function who underwent treatment at 4 clinical centers were included in this study. Data were forwarded to the coordinating center using a standard case report form. The procedural success rate was 98.9%. There were no deaths, 3 stent thromboses, and 3 Q-wave myocardial infarctions during the hospitalization. Angiographic follow-up was performed in 237 patients (follow-up rate 87.8%), and the restenosis rate was 21.1%. The reference size was an independent predictor of binary restenosis (odds ratio 0.543, 95% confidence interval 0.308 to 0.957, p = 0.03). During the follow-up period (32.3 +/- 18.5 months), there were 20 deaths (8 cardiac, 12 noncardiac) and 5 nonfatal myocardial infarctions. Target and new lesion revascularizations were required in 45 (16.7%) and 31 (11.5%) patients, respectively. The cumulative probabilities free from major adverse cardiac events were 81.9 +/- 2.4%, 78.4 +/- 2.6%, and 77.7 +/- 2.7%, respectively, at 1, 2, and 3 years. Combined coronary artery disease and postprocedural minimal luminal diameter were the significant predictors of major adverse cardiac events. Thus, the long-term prognosis of patients after stenting of unprotected LMCA stenosis was favorable in selected patients with normal left ventricular function.",2003.0,0,0 1820,12505568,Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease.,Dennis W Schneck; Robert H Knopp; Christie M Ballantyne; Ruth McPherson; Rohini R Chitra; Steven G Simonson,"The lipid-lowering effects of rosuvastatin and atorvastatin were determined across their dose ranges in a 6-week, randomized, double-blind trial. Three hundred seventy-four hypercholesterolemic patients with fasting low-density lipoprotein (LDL) cholesterol > or =160 but <250 mg/dl (> or =4.14 but <6.47 mmol/L) and fasting triglycerides <400 mg/dl (<4.52 mmol/L) and without active arterial disease within 3 months of entry received once-daily rosuvastatin (5, 10, 20, 40, or 80 mg [n = 209]) or atorvastatin (10, 20, 40, or 80 mg [n = 165]). The percentage decrease in plasma LDL cholesterol versus dose was log-linear for each drug, ranging from -46.6% to -61.9% for rosuvastatin 10 and 80 mg, compared with -38.2% to -53.5% for atorvastatin 10 and 80 mg. The dose curve for rosuvastatin yielded an 8.4% greater decrease in LDL cholesterol compared with atorvastatin at any given dose (p <0.001). Similarly greater decreases were observed for rosuvastatin across the dose range in total cholesterol (-4.9%), non-high-density lipoprotein (non-HDL) cholesterol (-7.0%), apolipoprotein B (-6.3%), and related ratios versus atorvastatin (all p <0.001). Because dose responses for HDL cholesterol, triglycerides, and apolipoprotein A-I were non-log-linear and nonparallel between the 2 drugs, percentage changes from baseline were compared at each dose. Significantly greater increases for rosuvastatin compared with atorvastatin were observed for HDL cholesterol at 40 and 80 mg, and for apolipoprotein A-I at 80 mg. Significantly greater triglyceride decreases were seen at 80 mg with atorvastatin over rosuvastatin. Both rosuvastatin and atorvastatin were well tolerated over 6 weeks.",2003.0,1,1 1821,12505569,Comparison of the effects of atorvastatin versus simvastatin on subclinical atherosclerosis in primary preventionas determined by electronbeam tomography.,Harvey S Hecht; S Mitchell Harman,"This study was designed to evaluate the effects of lipid-lowering therapy by atorvastatin versus simvastatin on calcified plaque progression, as determined by serial electron beam tomography (EBT), in primary prevention patients. In this observational study, serial EBT was performed before and after 1.2 years of atorvastatin (n = 103) and simavastatin therapy (n = 46); approximately 50% of each group was on niacin as well, in similar doses. There were no differences in demographic parameters between the groups. Total, low-density lipoprotein (LDL), and non-high-density lipoprotein (HDL) cholesterol were significantly higher in the atorvastatin group before treatment. Before treatment, EBT calcium score and volume scores were 469 and 378, respectively, in the atorvastatin patients, and 388 and 307, respectively, in the simvastatin patients (p = NS, atorvastatin vs simvastatin). After treatment, there were no differences in any lipid or EBT values between the groups. Post-treatment total cholesterol and LDL cholesterol were 156 and 79 mg/dl, respectively, in the atorvastatin cohort and 154 and 76 mg/dl, respectively, in the simvastatin group (p = NS). Calcium score and volume progressed 10.8%/year and 8.5%/year, respectively, in the atorvastatin group, and 7.5%/year and 7.8%/year in the simvastatin group (p = NS, atorvastatin vs simvastatin). We conclude that aggressive treatment with atorvastatin and simvastatin in the primary prevention population, to similar lipid levels, is associated with equal progression of EBT-determined calcified plaque. This suggests that these hydroxymethylglutaryl coenzyme A reductase inhibitors exhibit a ""class effect"" with respect to progression of subclinical atherosclerosis.",2003.0,0,0 1822,12506780,Idiopathic inflammatory myopathy: management and prognosis.,Chester V Oddis,"We are entering an exciting era in our understanding and management of the connective tissue diseases and, in particular, inflammatory myopathy. There is an established array of immunosuppressive regimens available to clinicians; rehabilitative and physical therapeutic interventions are evolving to provide many nonpharmacologic options to complement current therapy. Our ability to quantify [table: see text] the disease burden, using newly developed tools to distinguish myositis disease activity from disease damage, will allow us to measure with greater sensitivity the effects of treatment interventions. These measures, together with the development of international consensus regarding the standardization of many clinical trial design parameters, will enhance our capacity to conduct well-designed, prospective, multicenter studies of established and newly developed therapies. The explosion of immunopathogenetic information, in conjunction with novel biologic agents (Table 4), will afford investigators a treatment menu with multiple therapeutic options. The continuing challenge for the practitioner is the development of a logical, well-studied, multifaceted, and multidisciplinary holistic approach that optimizes the risk: benefit ratio for each individual patient and uses a rational combination of immunomodulatory agents in conjunction with ancillary measures.",2003.0,0,0 1823,12507200,Epidemiology and prevention of colorectal cancer.,Ernest T Hawk; Paul J Limburg; Jaye L Viner,"CRC, the second-leading cause of cancer death in the United States, is a highly preventable disease. Ironically, available and effective screening technologies are not consistently applied, even as new ones are developed. This discordance between preventive opportunity and practice conveys a sobering message regarding nontechnologic issues that must be addressed if the promise of CRC prevention is to be realized. Our response to this message will determine the public health impact of cancer prevention. In the 1980s, cancer chemoprevention was regarded as scientific speculation. Within the last decade, however, cancer has been recognized as a late, nonobligate stage of carcinogenesis, a chronic process that provides time and targets for preventive intervention. Further advances are emerging out of rigorous clinical testing, which remains the limiting factor in transforming ingenious concepts into useful tools for the prevention of CRC. The challenges and rewards of participation in chemoprevention research--both as patients and health care providers-have never been greater.",2003.0,0,0 1824,12507668,Is atherosclerotic vascular disease related to a high-fat diet?,William S Weintraub,,2003.0,0,0 1825,12508907,Toxic multinodular goiter in the elderly.,P Vitti; T Rago; M Tonacchera; A Pinchera,"Toxic nodular goiter (TNG) is the most frequent cause of thyrotoxicosis in the elderly, specially in iodine deficient areas. Epidemiological studies have shown that in iodine deficient areas (Jutland) the incidence of hyperthyroidism is significantly higher with respect to areas with normal iodine intake (Iceland) and it is due to TNG. A careful epidemiological study recently carried out in Pescopagano, in southern Italy, an area characterized by a mild to moderate iodine deficiency, indicates that, in its natural history, nodular goiter contributes to the development of functional autonomy and eventually hyperthyroidism. Somatic activating mutations of the TSH receptor are involved in the pathogenesis of TNG. It is supposed that the prolonged iodine deficiency associated with chronic TSH stimulation increases the replication of follicular thyroid cells, and favor the appearance and expression of mutations of the TSH receptor gene. The clinical signs are usually more subtle than those observed in Graves' disease: a long phase of subclinical hyperthyroidism (normal circulating thyroid hormones and undetectable TSH levels) can precede the appearance of the symptoms. Cardiac symptoms are most frequent, (arrhythmia and atrial fibrillation). Thyroid scintigraphy in toxic multinodular goiter shows an uneven distribution of the radionuclide with multiple hyperfunctioning nodules and cold nodules. Thyroid US shows goiter with inhomogeneous solid nodules often with ill-defined borders. The treatment with antithyroid drug does not allow a permanent remission of hyperthyroidism, but its use is indicated to achieve euthyroidism before the definitive treatment. The definitive treatment is radioiodine or thyroidectomy.",2003.0,0,0 1826,12509366,,,,,0,0 1827,12509760,A guide to drug discovery: Target selection in drug discovery.,Jonathan Knowles; Gianni Gromo,"Target selection in drug discovery--defined here as the decision to focus on finding an agent with a particular biological action that is anticipated to have therapeutic utility--is influenced by a complex balance of scientific, medical and strategic considerations. In this article, we provide an introduction to the key issues in target selection and discuss the rationale for decision making.",2003.0,0,0 1828,12510011,Does simvastatin affect mood and steroid hormone levels in hypercholesterolemic men? A randomized double-blind trial.,Markku T Hyyppä; Erkki Kronholm; Arja Virtanen; Aila Leino; Antti Jula,"Epidemiological and clinical studies have suggested that powerful cholesterol lowering may have adverse effects on mood and psychological well-being. Inhibition of cholesterol biosynthesis by simvastatin (a hydroxymethyl glutaryl coenzyme A reductase inhibitor) may also reduce steroid hormone biosynthesis. To explore if mood changes are related with steroid hormone levels, we designed a randomized double-blind placebo-controlled crossover trial. The separate and combined effects of a Mediterranean-type diet intervention and treatment with simvastatin 20 mg/day PO for 12 weeks were studied in 120 hypercholesterolemic but otherwise healthy middle-aged men. Psychological functioning was assessed with questionnaires, and steroid hormone levels in blood were assayed radioimmunologically before and after the treatments. Simvastatin resulted in a statistically significant increase of depression and somatization without changes in the anxiety, hostility or aggression scores. Mood changes seemed to be unrelated with the statistically significant but clinically insignificant decline in serum testosterone levels and unrelated with the increase in serum dehydroepiandrosterone levels.",2003.0,0,0 1829,12510391,Pharmacoeconomic evaluation of anti-hyperlipidemic agent fenofibrate.,Toru Hayakawa; Koichi Shimoyama; Shigeru Sekiya; Masatomo Sekiguchi; Nobuo Inotsume,"We evaluated the economic efficiency as well as the clinical effectiveness on serum lipid levels of a change in drug therapy from bezafibrate or a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor to fenofibrate. Subjects were 26 outpatients suffering from type IIb or type IV hyperlipidemia who visited our hospital between October 2000 and January 2001. Medication doses, and serum lipid levels were recorded prior to the change to fenofibrate and at 6 months after the change. Medical costs were also calculated at the same time points. A significant reduction in medical costs of 14.9% was observed following the change to fenofibrate. Serum lipid levels were not significantly different, although an increase in low density lipoprotein-cholesterol (LDL-cholesterol) was observed in patients changing from the HMG-CoA reductase inhibitor. The actual drug costs were reduced by 21.8% in the bezafibrate to fenofibrate group and by 23.7% in the HMG-CoA reductase inhibitor to fenofibrate group. Although the drug costs of changing to fenofibrate decreased significantly, other costs remained almost unchanged.",2003.0,0,0 1830,12510951,Matching the standards of clinical trial evidence with application in practice.,N Sharpe,"A high standard of proof of efficacy and safety is required in clinical trials. This standard requires careful translation into practice, combining an evidence-based approach with clinical experience and judgment to maximise patient benefits and minimise harms. The tendency to extend application of new treatments to patient groups other than those for whom reliable data exist should be avoided. Equally, extrapolation of the data to agents of the same class untested for particular indications should not occur. If the considerable potential benefits of modern cardiovascular therapeutics are to be maximised and harms avoided, clinicians should observe these principles carefully as new treatments become accessible and are applied.",2003.0,0,0 1831,12511114,Simvastatin reduced mortality and vascular events in high-risk patients.,C R Kumana; B M Cheung; I J Lauder,,2003.0,0,0 1832,12511759,Determination of lipid profiles and use of statins in patients with ischemic stroke or transient ischemic attack.,Wolfgang Lalouschek; Wilfried Lang; Stefan Greisenegger; Marcus Müllner; Vienna Stroke Study Group,"Statins reduce the risk of myocardial infarction and stroke in patients with vascular disease. Inappropriate serum lipid determination and underuse of statins have been documented in patients with coronary artery disease. Evaluation of hyperlipidemia and treatment with statins in patients with recent ischemic cerebrovascular events have not yet been investigated. We determined the frequency of total cholesterol (TC) and low-density lipoprotein cholesterol measurements and the use of statins in a multicenter prospective cohort study of 1743 patients with acute ischemic stroke or transient ischemic attack (TIA). Using multivariate logistic regression analysis, we determined the influence of several clinical variables on lipid measurements and the prescription of statins at hospital discharge. TC was measured in 90% and low-density lipoprotein cholesterol was measured in 48% of the patients. Differences between the centers accounted for most of the observed variability in a multivariate model. Statin prescription also varied widely between the centers. The prescription of a statin at discharge was most strongly associated with statin intake before the event and with increasing TC levels; elderly patients received statins less often. Coronary artery disease, peripheral artery disease, and other manifestations of atherosclerosis were not independently associated with the use of statins; 68% of the patients with manifest atherosclerosis and TC levels >200 mg/dL were discharged without a statin. The determination of serum lipid profiles varies widely between different centers. Statins are highly underused in patients with recent ischemic stroke or TIA, particularly in those in whom statins are indicated according to existing recommendations (eg, patients with additional coronary artery disease and hypercholesterolemia). Currently, international guidelines concerning the use of statins are not adequately implemented in clinical practice in patients with stroke or TIA.",2003.0,0,0 1833,12514649,Hierarchical modeling: its time has come.,Elizabeth DeLong,,2003.0,0,0 1834,12514650,Adherence to practice guidelines: the role of specialty society guidelines.,Lucian L Leape; Joel S Weissman; Eric C Schneider; Robert N Piana; Constantine Gatsonis; Arnold M Epstein,"Physician adherence to guidelines is often poor, but the reasons have not been completely studied. We investigated whether physician adherence to guidelines for percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) varied by source, development methods, or the extent of their evidence-base. We assessed adherence to guidelines developed by the American College of Cardiology/American Heart Association (ACC/AHA) for PTCA (1988 and 1993) and for CABG (1990) and guidelines developed by RAND for PTCA and CABG in 1990. We randomly sampled patients on Medicare who were undergoing coronary angiography in 5 states in 1991 and 1992, extracting clinical and laboratory data from medical records and using computer programs to classify the appropriateness of each procedure. A total of 543 PTCA and 676 CABG procedures were studied. By use of the 1988 ACC/AHA guidelines, 30% of PTCAs were rated class III (inappropriate), whereas 24% were class III by use of the 1993 guidelines. Only 1.5% of CABG procedures were class III with ACC/AHA guidelines. By use of RAND guidelines, 12% of PTCA and 9% of CABG procedures were classified as inappropriate. Adherence to guidelines is higher when the recommendations are supported by evidence from randomized clinical trials (CABG). The credibility of the source and familiarity with the guidelines do not ensure compliance. When evidence is lacking, as with PTCA at the time of this study, guideline recommendations may lag behind appropriate changes in clinical practice. More frequent revisions coupled with on-line access have the potential to make guidelines more useful.",2003.0,0,0 1835,12514651,Comparing hierarchical modeling with traditional logistic regression analysis among patients hospitalized with acute myocardial infarction: should we be analyzing cardiovascular outcomes data differently?,Peter C Austin; Jack V Tu; David A Alter,"Data in health research are frequently structured hierarchically. For example, data may consist of patients treated by physicians who in turn practice in hospitals. Traditional statistical techniques ignore the possible correlation of outcomes within a given practice or hospital. Furthermore, imputing characteristics measured at higher levels of the hierarchy to the patient-level artificially inflates the amount of available information on the effect of higher-level characteristics on outcomes. Conventional logistic regression models and multilevel logistic regression models were fit to a cross-sectional cohort of patients hospitalized with a diagnosis of acute myocardial infarction. The statistical significance of the effect of patient, physician, and hospital characteristics on patient outcomes was compared between the 2 modeling strategies. The 2 analytic strategies agreed well on the effect of patient characteristics on outcomes. According to the traditional analysis, teaching status was statistically significantly associated with 5 of the 9 outcomes, whereas the multilevel models did not find a statistically significant association between teaching status and any patient outcomes. Similarly, the traditional and multilevel models disagreed on the statistical significance of the effect of being treated at a revascularization hospital and 3 patient outcomes. In comparing the resultant models, we see that false inferences can be drawn by ignoring the structure of the data. Conventional logistic regression tended to increase the statistical significance for the effects of variables measured at the hospital-level compared to the level of significance indicated by the multilevel model.",2003.0,0,0 1836,12515734,Diets and clinical coronary events: the truth is out there.,William S Yancy; Eric C Westman; Patricia A French; Robert M Califf,,2003.0,0,0 1837,12515739,Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction.,Wei C Lau; Lucy A Waskell; Paul B Watkins; Charlene J Neer; Kevin Horowitz; Amy S Hopp; Alan R Tait; David G M Carville; Kirk E Guyer; Eric R Bates,"We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4. Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34+/-23, 58+/-15 (P=0.027), 74+/-10 (P=0.002), and 89+/-7 (P=0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55+/-12 versus 42+/-12% platelet aggregation; P=0.002), as did troleandomycin (78+/-18 versus 45+/-18% platelet aggregation; P<0.0003), whereas rifampin enhanced platelet aggregation inhibition (33+/-18 versus 56+/-20% platelet aggregation, P=0.001). CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel.",2003.0,0,0 1838,12515749,Simvastatin initiated early after heart transplantation: 8-year prospective experience.,Klaus Wenke; Bruno Meiser; Joachim Thiery; Dorothea Nagel; Wolfgang von Scheidt; Karl Krobot; Gerhard Steinbeck; Dietrich Seidel; Bruno Reichart,"Randomized clinical trials have demonstrated that the use of statins in heart transplant patients lowers cholesterol levels and significantly reduces mortality and the development of transplant vasculopathy. The aim of the present study was to test these effects and the safety of statin therapy over an 8-year period. In 1991, a prospective, randomized, unmasked study was initiated to compare the efficacy of simvastatin, started on the fourth postoperative day (n=35), with that of dietary therapy alone (n=37). Because of significantly improved survival and a lower incidence of transplant vasculopathy, most patients in both groups received statins as open-label prescriptions after 4 years. After 8 years, the Kaplan-Meier survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P<0.006 by log rank; hazard ratio, 0.24; 95% CI, 0.08 to 0.71). Deaths in the simvastatin and control groups were due to transplant vasculopathy (1 versus 4; P<0.2), severe transplant rejection (1 versus 5; P<0.1), malignancies (0 versus 3; P<0.1), and other causes (2 versus 3; P<0.7). The incidence of transplant vasculopathy confirmed by angiography was 24.4% in the simvastatin group versus 54.7% in the control group (P<0.02 by log rank). There was no difference in organ function between the 2 groups. No severe adverse effects of the therapy were observed up to the end of the 8-year observation period. Simvastatin therapy initiated early after heart transplantation leads to significantly better 8-year survival rates and a significantly lower incidence of transplant vasculopathy without impairment of organ function or severe adverse effects.",2003.0,0,0 1839,12517257,Developing pharmaceutical treatments for peripheral artery disease.,Daniel A Duprez; Marc L De Buyzere; Alan T Hirsch,"Peripheral artery disease (PAD) is a debilitating atherosclerotic disease of the lower limbs and is associated with an increased risk of cardiovascular morbidity and mortality. Treatment goals should be aimed at providing symptom relief (claudication) and reducing the risk of systemic cardiovascular morbidity and mortality. In the development of pharmaceutical treatment for PAD, aggressive non-pharmacological intervention and pharmacological treatment of the risk factors associated with PAD should be given. Antiplatelet therapy, aspirin, should be given to every PAD patient if there are no contraindications. Should symptoms worsen or intolerance to aspirin develop, ticlopidine or clopidogrel would be the alternative. Several pharmacological agents have been developed to improve the functional state of the claudicant and to relieve the symptoms. Many studied drugs have shown either no, small or potential benefit. With future development of new drugs for PAD, there is an absolute need for very strict, well-designed protocols in order to evaluate the claudication distance and progression of the disease, as well as the reduction in cardiovascular morbidity and mortality.",2003.0,0,0 1840,12517273,Recent developments in antiangiogenic therapy.,Keith Dredge; Angus G Dalgleish; J Blake Marriott,"The use of antiangiogenic therapy is gaining momentum as a novel treatment for a number of conditions, ranging from cancer to psoriasis. This has stemmed from research in the early 1970s showing that the formation of new blood vessels by pre-existing endothelial cells is essential in tumour growth and progression. However, although antiangiogenic therapy was hailed as a new avenue of treatment for cancer, initial clinical data have been disappointing. This has led to the reassessment of antiangiogenic therapy for cancer, and new strategies have been proposed to increase the efficacy of these agents in this setting. Angiogenesis has also been implicated in other conditions that are notoriously difficult to treat, such as arteriosclerosis, arthritis, psoriasis and diabetic retinopathy. Increased understanding of the angiogenic process, the diversity of its inducers and mediators, appropriate drug schedules and the use of these agents with other modalities may lead to radically new treatment regimens for many of these conditions. The role of angiogenesis in different pathological settings, and emerging antiangiogenic agents currently in preclinical and clinical studies are discussed in this review. However, while potential benefits are profound, limitations of antiangiogenic therapy have also been identified, suggesting that there is also a need for caution in applying these compounds to the clinical setting.",2003.0,0,0 1841,12517361,"Cholesterol-lowering medication, cholesterol level, and reproductive hormones in women: the Women's Ischemia Syndrome Evaluation (WISE).",C Noel Bairey Merz; Marian B Olson; B Delia Johnson; Vera Bittner; T Keta Hodgson; Sarah L Berga; Glenn D Braunstein; Carl J Pepine; Steven E Reis; George Sopko; Sheryl F Kelsey; Women's Ischemia Syndrome Evaluation,"Reproductive hormones such as estrogen, progesterone, and testosterone are synthesized from a common cholesterol precursor pathway. We hypothesized that use of statins and the resultant lower blood lipoprotein levels would be associated with lower reproductive hormone levels in women. We also sought to evaluate this association, independent of statin use, particularly among premenopausal women of childbearing age. We enrolled 453 (114 pre-, 30 peri-, and 309 postmenopausal) women with coronary risk factors (mean [+/- SD] age, 58 +/- 13 years) who were undergoing coronary angiography for suspected ischemia at four academic medical centers. Blood lipoprotein levels (total cholesterol, triglycerides, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein cholesterol) and serum reproductive hormone levels (estradiol, bioavailable estradiol, estrone, progesterone) were measured. Use of statins was associated with lower lipoprotein levels, but not lower reproductive hormone levels, in all women. Mean estradiol levels were not significantly lower among premenopausal women with very low LDL cholesterol levels compared with women with higher LDL cholesterol levels (estradiol: 71 +/- 52 pg/mL vs. 88 +/- 67 pg/mL, P = 0.32). Among women undergoing coronary angiography for suspected myocardial ischemia, the use of statins, or lower cholesterol levels, are not associated with significantly lower levels of reproductive hormones.",2003.0,0,0 1842,12519819,Pharmacologic approaches to the prevention of type 2 diabetes in high risk pediatric patients.,Michael Freemark,,2003.0,0,0 1843,12520824,Update in the management of stroke.,N Venketasubramanian; H M Chang; B P L Chan,"Recent advances have improved the outlook for patients with stroke, Singapore's fourth leading cause of death. Stroke unit care reduces death, dependency and institutionalisation, independent of age, gender and stroke severity. Neuroimaging is essential prior to initiation of specific therapies. While computed tomography (CT) Head remains the most widely used modality, magnetic resonance imaging (MRI), particularly diffusion weighted imaging (DWI) has enhanced the positive diagnosis of ischaemic stroke. General medical measures include close monitoring, adequate oxygenation, avoidance of excessive blood pressure lowering, reduction of hyperthermia, control of hyperglycaemia, adequate nutrition, prevention of complications and early rehabilitation. Despite the risk of fatal intracranial haemorrhage, thrombolysis may improve outcomes in appropriately selected patients with ischaemic stroke. No safe and effective neuroprotectant has been found. While suboccipital craniectomy is established for large cerebellar infarcts and haemorrhage, surgical evacuation of supratentorial haemorrhage has not been shown to be beneficial. Hemicraniectomy reduces mortality after massive hemispheric ischemic stroke. Early and sustained antiplatelet use after atherothrombotic stroke reduces stroke recurrence. Stroke recurrence is also reduced by sustained warfarin use for cardioembolic stroke, carotid endarterectomy for severe symptomatic internal carotid artery stenosis, blood pressure lowering starting after the acute phase of stroke and lipid lowering. On-going clinical trails are likely to provide better treatments in the near future.",2003.0,0,0 1844,12521635,Role of C-reactive protein in the assessment of cardiovascular risk.,Ishwarlal Jialal; Sridevi Devaraj,,2003.0,0,0 1845,12522461,Lipid lowering in hypertension and heart protection: observations from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) and the Heart Protection Study.,S Nadar; H S Lim; D G Beevers; G Y H Lip,,2003.0,0,0 1846,12523463,Meta-analysis of interventions to improve drug adherence in patients with hyperlipidemia.,Andrew M Peterson; Liza Takiya; Rebecca Finley,"To examine the results of meta-analyses addressing the net effect of tools and methods to enhance drug adherence in patients with hyperlipidemia. We searched MEDLINE, International Pharmaceutical Abstracts (IPA), PsychLit, Educational Resource Information Clearinghouse (ERIC), and Excerpta Medica Database (EMBASE) databases (1996-2000) for randomized controlled trials of interventions to improve patients' adherence to drug regimens for hyperlipidemia. All trials selected had at least 10 subjects/group. Effect sizes, represented as the correlation coefficient, were calculated from Cohen's d and d'. Analysis of variance and the Q test were performed to evaluate statistical significance and heterogeneity. Of the 484 articles evaluated, only four met the criteria for inclusion. Multiple interventions or study samples were identified in two articles. Each intervention was counted as a separate study, yielding seven cohorts with a total of 3077 subjects. Behavioral interventions accounted for five cohorts (2915 subjects). No cohorts received solely educational interventions. Two cohorts, with a total of 162 subjects, received a combination of behavioral and educational interventions. Homogeneity of groupings and effect sizes were calculated for the overall grouping as well as for each type of intervention. Overall, the effect size for the data was 0.14 (95% confidence interval [CI] 0.10-0.17) and the data were homogenous (Q = 7.36, df = 4, p = 0.29). The effect size for the behavioral interventions was 0.14 (95% CI 0.11-0.18, Q = 5.25, df = 4, p = 0.26). For interventions that combined behavioral and educational components, the effect size was 0.03 (CI -0.13-0.18, Q = 0.204, df = 1, p = 0.65). The interventions evaluated had little impact on drug adherence. More studies are needed to assess how to improve drug adherence in patients with hyperlipidemia.",2003.0,0,0 1847,12523682,Lower plasma noradrenaline and blood viscosity on carvedilol vs atenolol in men with recent myocardial infarction.,Gisli Jonsson; Eigil Fossum; Sverre E Kjeldsen; Aud Høieggen; Ingrid Os; Ivar Eide; Arne Westheim,"The Carvedilol Acute Myocardial Infarction Study (CAMIS) investigates cardiac remodeling in patients (n = 250) randomized to carvedilol vs atenolol and treated for 12 months after acute myocardial infarction. In a sub-study, we compared sympathetic, hemorrheological and vascular effects in small but particularly well-matched groups of participants who had been on reasonably equipotent but unchanged doses of carvedilol (n = 10) or atenolol (n = 10) for at least 4 weeks. Blood pressures (p < 0.05), plasma adrenaline (p = 0.034), plasma vasopressin (p = 0.022) and whole blood viscosity at shear rate 0.5 cp (p = 0.050), 1.1 cp (p = 0.023), 5.8 cp (p = 0.049) and 201 cp (p = 0.060) taken in the laboratory at baseline before 2 h of using the hyperinsulinemic, isoglycemic glucose clamp were lower on carvedilol. Plasma noradrenaline was lower on carvedilol at baseline and throughout the clamp (p < 0.0005). Forearm vascular resistance as measured by plethysmography during the clamp tended to be lower on carvedilol (p = 0.074). No significant difference was found between the groups in glucose disposal rate measured by clamp, maximal forearm blood flow and minimal forearm vascular resistance after 10 min of ischemia, or in ambulatory blood pressure and heart rate taken a few days later. Thus, potential benefits of carvedilol vs atenolol were seen in these post-infarction patients in a laboratory setting. These findings suggest that the inhibitory effects on the sympathetic nervous system and related blood viscosity are stronger with carvedilol than with atenolol.",2003.0,0,0 1848,12525719,"Awareness, treatment, and control of vascular risk factors in African Americans with stroke.",S Ruland; R Raman; S Chaturvedi; S Leurgans; P B Gorelick; AAASPS Investigators. African American Antiplatelet Stroke Prevention Study,"To investigate control of risk factors in African American patients with previous stroke. The baseline history, physical examination, and laboratory data for 1,086 subjects enrolled in the African American Antiplatelet Stroke Prevention Study from 1995 to 1999 were studied. The level of awareness, pharmacologic treatment, and control of diabetes mellitus (casual plasma glucose level > or =200 mg/dL), hypertension (blood pressure > or =140/90 mm Hg), and hypercholesterolemia (serum total cholesterol level > or =240 mg/dL) were determined. Forty percent of subjects reported a history of diabetes mellitus or use of diabetic medication, and 2% of the remaining subjects had a serum glucose level of > or =200 mg/dL. Of those subjects known to be diabetic, 33% had a serum glucose level of > or =200 mg/dL. A history of hypertension or use of antihypertensive medication was reported in 87% of subjects, and 48% of the remaining subjects were found to have a blood pressure of > or =140/90 mm Hg on exam. Of those subjects known to be hypertensive by history, 73% were on antihypertensive medication, but only 30% of the treated subjects had a blood pressure under 140/90 mm Hg. A history of hypercholesterolemia or use of a lipid-lowering agent was reported in 40% of subjects, and 24% of the remaining subjects had a cholesterol level of > or =240 mg/dL. Use of a lipid-lowering agent was reported in 43% of subjects known to be hypercholesterolemic, and 38% of the hypercholesterolemic subjects had a cholesterol level of > or =240 mg/dL. Inadequate rates of awareness and control of cardiovascular disease and stroke risk factors are seen in a clinical trial of African American stroke patients and are comparable with those of previously published reports.",2003.0,0,0 1849,12528318,,,,,0,0 1850,12529091,Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency.,Marcello Tonelli; Lemuel Moyé; Frank M Sacks; Bryce Kiberd; Gary Curhan; Cholesterol and Recurrent Events (CARE) Trial Investigators,"Cardiovascular disease is a common cause of morbidity and death in persons with renal insufficiency. Although 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitors (statins) are effective for secondary prevention of cardiovascular events in the general population, they have not been specifically studied in chronic renal insufficiency. To determine whether pravastatin is effective and safe for secondary prevention of cardiovascular events in persons with chronic renal insufficiency. Post hoc subgroup analysis of a randomized, double-blind, placebo-controlled trial. The Cholesterol and Recurrent Events (CARE) study, a randomized trial of pravastatin versus placebo in 4159 participants with previous myocardial infarction and total plasma cholesterol levels less than 6.21 mmol/L (<240 mg/dL). 1711 participants with chronic renal insufficiency defined by creatinine clearance less than or equal to 75 mL/min, using the Cockcroft-Gault equation. The primary outcome was death from coronary disease or symptomatic nonfatal myocardial infarction. After a median follow-up of 58.9 months, the incidence of the primary end point was lower in participants receiving pravastatin than in those receiving placebo (adjusted hazard ratio, 0.72 [95% CI, 0.55 to 0.95]; P = 0.02). Pravastatin was associated with lower adjusted hazard ratios for major coronary events (0.72 [CI, 0.59 to 0.88]; P = 0.001) and coronary revascularization (0.65 [CI, 0.50 to 0.83]; P = 0.001), but not total mortality (0.81 [CI, 0.61 to 1.08]; P = 0.14) or stroke (0.62 [CI, 0.39 to 1.00]; P = 0.051). Tests for interaction suggested that the observed benefit was independent of the presence and severity of renal insufficiency. Incidence of side effects was similar in persons receiving pravastatin and those receiving placebo. These data suggest that pravastatin is effective and appears safe for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Since statins may be underused in this setting, physicians should consider prescribing them for patients with chronic renal insufficiency and known coronary disease.",2003.0,0,0 1851,12529900,Preventive health care for older patients.,Susan Mockus Parks; Christine Hsieh,"This chapter addresses key components of screening and preventive care for the older population. The older population is heterogeneous, ranging from the competent, active, well individual to the frail, demented individual. Certain preventive measures are important for all individuals such as counseling on exercise and screening for high blood pressure. However, universal cancer, cholesterol, or dementia screening may not be cost effective and beneficial in all older adults. These preventive measures should be guided by the individuals' circumstances including their life expectancy, co-morbid illnesses, functional capacity, and quality of life. Clinicians may be able to individualize preventive medicine decisions by stratifying their patients into well and frail using the guidelines we have provided. The goal of prevention and screening in older patients is to improve function and quality of life. Primary care physicians should facilitate discussion of preventive measures with their older patients as part of their ongoing health care.",2003.0,0,0 1852,12532169,Statins in acute coronary syndromes.,Sean C Reinhardt; Carl J Vaughan,"The development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) has been a very significant development in the management of coronary artery disease. Large prospective clinical trials have provided unequivocal evidence that cholesterol lowering therapy with statins reduces all-cause mortality in patients with coronary artery disease. There is now accumulating data indicating that statin treatment should be initiated early after an acute coronary syndrome. This body of evidence is based on large databases in which investigators compared outcomes among patients taking statins with those patients who were not prescribed cholesterol lowering therapy. Prospective, randomized, clinical trials also indicate that early statin therapy reduces recurrent ischemia. Finally, studies examining long-term compliance with statin therapy suggest increased adherence to therapy when statins are prescribed during the initial hospitalization for an acute coronary syndrome. In tandem with these clinical observations, there is a large body of scientific data that highlights many important cellular and molecular mechanisms through which statins may confer early benefit. These effects involve relatively rapid improvement in endothelial function, antiischemic, antithrombotic and antiinflammatory actions of statins.",2003.0,0,0 1853,12534315,Comparison of the efficacy and tolerability of policosanol with atorvastatin in elderly patients with type II hypercholesterolaemia.,Gladys Castaño; Rosa Mas; Lilia Fernández; José Illnait; Meylin Mesa; Estrella Alvarez; Magnolia Lezcay,"Hypercholesterolaemia is a risk factor for coronary heart disease (CHD). Clinical studies have shown that lowering elevated serum total cholesterol (TC) levels, and particularly low density lipoprotein-cholesterol (LDL-C) levels, reduces the frequency of coronary morbidity and deaths, whereas high serum levels of high density lipoprotein-cholesterol (HDL-C) protect against CHD. Policosanol is a cholesterol-lowering drug purified from sugar cane wax with a therapeutic dosage range from 5-20 mg/day. Atorvastatin is an HMG-CoA reductase inhibitor which across its dosage range (10-80 mg/day) has shown significantly greater lipid-lowering effects than all previously marketed statins. This study was undertaken to compare the efficacy and tolerability of policosanol with atorvastatin in older patients with type II hypercholesterolaemia. This randomised, single-blind, parallel-group study was conducted in older patients (60-80 years) with type II hypercholesterolaemia. After 4 weeks on a cholesterol-lowering diet, 75 patients were randomised to policosanol or atorvastatin 10mg tablets taken once daily with the evening meal for 8 weeks. An interim and final check-up were performed at 4 and 8 weeks, respectively, after treatment was initiated. At 4 (p < 0.0001) and 8 (p < 0.00001) weeks, policosanol 10 mg/day significantly lowered serum LDL-C levels by 17.5 and 23.1%, respectively compared with baseline; corresponding values for atorvastatin were 28.4 and 29.8%. At study completion, policosanol significantly (p < 0.0001) reduced serum TC (16.4%), LDL-C/HDL-C ratio (25.5%) and TC/HDL-C ratio (19.3%), as well as (p < 0.001) triglyceride levels (15.4%). Atorvastatin significantly (p < 0.0001) decreased serum TC (22.6%), LDL-C/HDL-C (26.2%) and TC/HDL-C (19.8%) ratios, as well as (p < 0.001) triglyceride levels (15.5%). Atorvastatin was significantly more effective than policosanol in reducing LDL-C and TC, but similar in reducing both atherogenic ratios and triglyceride levels. Policosanol, but not atorvastatin, significantly (p < 0.05) increased serum HDL-C levels by 5.3%. Both treatments were well tolerated. At study completion, atorvastatin mildly, but significantly (p < 0.05) increased creatine phosphokinase (CPK) and creatinine, whereas policosanol significantly reduced AST and glucose (p < 0.01) and CPK (p < 0.05) levels. All individual values, however, remained within normal limits. Three atorvastatin but no policosanol patients withdrew from the study because of adverse events: muscle cramps (1 patient), gastritis (1 patient) and uncontrolled hypertension, abdominal pain and myalgia (1 patient). Overall, no policosanol and seven atorvastatin patients (18.9%) reported a total of nine mild or moderate adverse events during the study (p < 0.01). This study shows that policosanol (10 mg/day) administered for 8 weeks was less effective than atorvastatin (10 mg/day) in reducing serum LDL-C and TC levels in older patients with type II hypercholesterolaemia. Policosanol, but not atorvastatin, however, significantly increased serum HDL-C levels, whereas both drugs similarly reduced atherogenic ratios and serum triglycerides. Policosanol was better tolerated than atorvastatin as revealed by patient withdrawal analysis and overall frequency of adverse events. Nevertheless, further studies must be conducted in larger sample sizes and using dose-titration methods to achieve target lipid levels in order to reach wider conclusions.",2003.0,0,0 1854,12534325,Fenofibrate-induced hyperhomocysteinaemia: clinical implications and management.,Jutta Dierkes; Sabine Westphal; Claus Luley,"Fenofibrate is among the drugs of choice for treatment of hypertriglyceridaemia and low levels of high-density lipoprotein (HDL)-cholesterol, both recognised as risk factors for cardiovascular disease. Recently, a number of studies have shown an elevation of homocysteine levels with fenofibrate or bezafibrate therapy. Homocysteine is an atherogenic amino acid derived from the methionine cycle. At present, the underlying mechanism for this elevation has not been elucidated. While deterioration of vitamin status does not seem to be involved, impairment of renal function or changes in creatine metabolism are regarded as probable mechanisms. In patients not receiving lipid-lowering drugs, vitamin supplementation with folic acid and vitamin B12 effectively reduces the plasma homocysteine level. Two studies have shown that addition of folic acid or a vitamin combination to fenofibrate prevented most of the homocysteine increase associated with fenofibrate. Although the consequence of increasing homocysteine levels for cardiovascular risk has not been proven at present, it has to be considered that fenofibrate will be given for long-term treatment. Therefore, addition of folic acid and vitamin B12 to fenofibrate can be recommended to prevent the increase of homocysteine associated with fenofibrate, or treatment could be changed to gemfibrozil, which does not increase plasma homocysteine levels.",2003.0,0,0 1855,12534331,Treatment of lupus nephritis.,Fayez F Hejaili; Louise M Moist; William F Clark,"Renal involvement in systemic lupus erythematosus (SLE) is a serious complication of the disease. However, the prognosis of patients with lupus nephritis is continually improving with 10-year survival rates now greater than 75%. This improvement reflects earlier diagnosis due to more sensitive and specific diagnostic tests, better clinical appreciation of the natural history, and improved treatment of SLE and its manifestations. This review of the treatment of lupus nephritis has graded the level of evidence of specific treatment using the guidelines of the US Preventive Service Task Force. Although many new treatments have been advocated, the best evidence for treating proliferative lupus nephritis relies on a strategy combining specific treatment of the SLE as well as generalised treatment of the associated comorbidities. This strategy involves a combination of corticosteroids and cytotoxic agents plus or minus the adjunctive use of antimalarials, coordinated aggressive management of hypertension, proteinuria, infections, dyslipidaemia, thrombotic coagulopathy and potential renal replacement therapies.",2003.0,0,0 1856,12534449,Time-dependent effect of statins on platelet function in hypercholesterolaemia.,L Puccetti; A L Pasqui; M Pastorelli; G Bova; M Cercignani; A Palazzuoli; P Angori; A Auteri; F Bruni,"Reduction of platelet activity induced by statins has been described as a positive effect exerted by such molecules on vascular thrombotic events. However, the relations among cholesterol (LDL-C) reduction, the timing of the antiplatelet effect, the involved mechanisms and the doses of each statin able to reduce platelet function are not actually well known. The aim of our study was to evaluate the impact of simvastatin (20 mg day-1), atorvastatin (10 mg day-1), fluvastatin (40 mg day-1) and pravastatin (40 mg day-1) on platelet function in hypercholesterolaemic subjects with relation to (LDL-C), oxidized-LDL (ox-LDL) and antiport mechanism modifications. Sixteen subjects were assigned to each treatment (40 males, 24 females, mean age 48.7 +/- 13.4, LDL-C 5.13 +/- 0,23 mmol L-1) and evaluated for platelet surface P-selectin (P-sel), lipid profile, ox-LDL, platelet-associated ox-LDL (Pox-LDL), platelet cholesterol content, antiport mechanisms, and intracellular and systemic NO synthase every 7 days for one month. Our data show a strong relation between enhanced P-sel and Pox-LDL (r = 0.68, P < 0.01). Simvastatin, atorvastatin, fluvastatin and pravastatin reduce platelet activity after 1, 2, 3 and 4 weeks of treatment, respectively (P < 0.001, P < 0.001, P < 0.01, P < 0.05). Pox-LDL are modulated early by simvastatin, atorvastatin and fluvastatin Pox-LDL (r = 0.66, 0.65 and 0.52; P < 0.001, 0.001 and 0.01, respectively) whereas LDL-C and ox-LDL reductions associated to modifications of antiport activity act later. Moreover, they are the most relevant finding in pravastatin-related subjects. Our data suggest a different impact of several statins on platelet function, which is initially related to interference with Pox-LDL rather than LDL-C reduction.",2003.0,0,0 1857,12534645,Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects.,Kelvin J Cooper; Paul D Martin; Aaron L Dane; Mike J Warwick; Ali Raza; Dennis W Schneck,"To examine in vivo the effect of ketoconazole on the pharmacokinetics of rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n = 14) received ketoconazole 200 mg or placebo twice daily for 7 days, and rosuvastatin 80 mg was coadministered on day 4 of dosing. Plasma concentrations of rosuvastatin, and active and total HMG-CoA reductase inhibitors were measured up to 96 h postdose. Following coadministration with ketoconazole, rosuvastatin geometric least square mean AUC(0,t) and Cmax were unchanged compared with placebo (treatment ratios (90% confidence intervals): 1.016 (0.839, 1.230), 0.954 (0.722, 1.260), respectively). Rosuvastatin accounted for essentially all of the circulating active HMG-CoA reductase inhibitors and most (> 85%) of the total inhibitors. Ketoconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. Ketoconazole did not produce any change in rosuvastatin pharmacokinetics in healthy subjects. The data suggest that neither cytochrome P450 3A4 nor P-gp-mediated transport contributes to the elimination of rosuvastatin.",2003.0,0,0 1858,12535740,Increased levels of asymmetric dimethylarginine in populations at risk for atherosclerotic disease. Effects of pravastatin.,Hilde M Eid; J Eritsland; Jakob Larsen; Harald Arnesen; Ingebjørg Seljeflot,"The aim of the present study was to investigate plasma levels of asymmetric dimethylarginine (ADMA), an important endogenous inhibitor of nitric oxide synthase, in populations at high risk for atherosclerosis as compared to healthy controls, and furthermore to evaluate the effect of cholesterol lowering therapy in individuals with hypercholesterolemia. The present study consisted of 32 men with untreated hypercholesterolemia (HC group), 38 individuals with well-controlled insulin-dependent diabetes mellitus (DM group) and 20 healthy individuals (controls). The HC subjects were randomly allocated into a double blinded, placebo-controlled cross-over designed study with 8 weeks treatment with pravastatin (40 mg/day) or matching placebo. ADMA levels were statistically significantly higher in DM and HC individuals as compared to controls (P<0.001 for both), and the L-arginine/ADMA ratios were significantly lower in both groups (P<0.001 and P<0.005, respectively). Significant reductions in total cholesterol (TC) and LDL-C levels on pravastatin were obtained (P<0.001 for both), whereas no changes were observed in the levels of ADMA or the L-arginine/ADMA ratios. Statistically significant correlations between ADMA and TC and LDL-C were found (r=0.41, P<0.001 for both). In conclusion, significantly elevated ADMA levels and reduced L-arginine/ADMA ratios were found in individuals with diabetes type-1 as well as in hypercholesterolemia. Treatment with pravastatin 40 mg/day for 8 weeks had no effect on the levels of ADMA in hypercholesterolemic men.",2003.0,0,0 1859,12535744,Atorvastatin enhances the plasma clearance of chylomicron-like emulsions in subjects with atherogenic dyslipidemia: relevance to the in vivo metabolism of triglyceride-rich lipoproteins.,Andrei C Sposito; Raul D Santos; Rosangela F Amâncio; Jose A F Ramires; M John Chapman; Raul C Maranhão,"Delayed chylomicron clearance is a characteristic of patients with coronary artery disease. In vivo study of the clearance of labeled chylomicron-like emulsions constitutes a valid model system for evaluation of chylomicron catabolism. The effects of atorvastatin at low (10 mg) and high (40 mg) dose upon the intravascular metabolism and plasma kinetics of chylomicron-like emulsions were evaluated in fasting hyperlipidemic subjects (n=45). Subjects were randomized to a 6-week treatment period with placebo (n=15), low dose or high dose atorvastatin (10 mg/day, n=17 and 40 mg/day, n=13). The chylomicron-like emulsion, double-labeled with 14C-Cholesteryl oleate (14C-CE) and 3H-triolein (3H-TG), was injected in a bolus after a 12-h fast, and blood samples were collected up to 60 min. Plasma decay curves were determined for labeled emulsion CE and TG and residence times (RT) calculated by the occupancy principle. The 14C-CE RT was decreased by 50% after low dose atorvastatin and by 73% after atorvastatin at high dose in comparison to placebo (P<0.05). The 3H-TG RT was significantly reduced (-55%) after high dose atorvastatin, but in contrast was not significantly reduced after placebo or low dose statin. By compartmental analysis, both doses of atorvastatin led to marked elevation in the slow removal component of emulsion remnant particles (10 mg/day=107%; 40 mg/day=195%, P=0.01). Equally, the rapid removal component was increased (+99%) at high dose (P=0.015). Recirculation of 3H-fatty acids was significantly reduced at both statin doses (43 and 83%, respectively) in comparison to placebo (P=0.01). In conclusion, atorvastatin treatment accelerates the plasma clearance of chylomicron-like emulsions and reduces recirculation of fatty acids in subjects with atherogenic hyperlipidemia. Such effect might implicate in reduction of cardiovascular risk.",2003.0,0,0 1860,12535759,Does pravastatin affect circulating levels of soluble TNF receptor 2 in hypercholesterolemic patients?,Hitoshi Ando; Toshinari Takamura; Ken-ichi Kobayashi; Hirofumi Misu; Kenso Osawa,,2003.0,0,0 1861,12535822,Raised serum levels of soluble CD40 ligand in patients with familial hypercholesterolemia: downregulatory effect of statin therapy.,Anne G Semb; Sanne van Wissen; Thor Ueland; Tineke Smilde; Torgun Waehre; Mieke D Tripp; Stig S Frøland; John J P Kastelein; Lars Gullestad; Terje R Pedersen; Pål Aukrust; Anton F H Stalenhoef,"In the present study, we investigated the effects of statins on serum levels of soluble CD40 ligand (sCD40L) in patients with familial hypercholesterolemia (FH). Atherosclerotic disease seems to involve inflammatory and immunologic mechanisms, and sCD40L has recently been identified as one of the key players in the atherosclerotic process. HMG-Co A reductase inhibitors, statins, have been recognized as immunomodulators and reduce cardiovascular events and mortality, but the effects of statins on sCD40L has not been clarified. In a randomized, double-blind, clinical trial, as part of the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trial, 110 patients with FH were given atorvastatin 80 mg/daily (n = 57) or simvastatin 40 mg/daily (n = 53) for two years. Our main findings were: 1) at baseline patients with FH had significantly higher (approximately 27-fold) serum levels of sCD40L than healthy controls; 2) statin therapy markedly decreased serum levels of sCD40L (approximately 40% reduction); 3) this decrease in sCD40L was found during both ""aggressive"" (i.e., atorvastatin) and ""conventional"" (i.e., simvastatin) statin therapy and was not correlated with the degree of reduction in cholesterol levels. Our findings may suggest enhanced CD40L-CD40 interaction in FH and that this inflammatory response may be downregulated by statins.",2003.0,0,0 1862,12537169,Echinacea.,Benjamin Kligler,"Echinacea is the name of a genus of native North American plants, commonly known as the purple coneflower. The most widely used herbal product in the United States is a liquid extract made from the root of Echinacea purpurea. Because the active component of the plant has not been identified, commercial echinacea products are not typically standardized to any particular component. The research literature on echinacea is difficult to evaluate because of the heterogeneity of the products used in various studies. The herb has been recommended as a prophylactic treatment for upper respiratory infection and is widely used for this indication. However, based on the current literature, it appears that prophylactic echinacea does not have a significant impact on the frequency, severity, or duration of upper respiratory infection. The data regarding treatment of upper respiratory infection appear to support a modest positive effect. No significant herb-drug interactions with echinacea have been reported; adverse effects reported generally have been uncommon and minor, including abdominal upset, nausea, and dizziness.",2003.0,0,0 1863,12538418,Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure.,Justin A Ezekowitz; Finlay A McAlister; Paul W Armstrong,"Although previous work has suggested that anemia is associated with an increased mortality in selected patients with congestive heart failure (CHF), little is known about the prevalence and predictors of anemia, or whether anemia is an independent prognostic factor in unselected, community-based patients with CHF. We analyzed a population-based cohort of patients with new-onset CHF from a database of patients discharged from 138 acute-care hospitals in Alberta, Canada, between April 1993 and March 2001. Logistic regression, Kaplan-Meier survival analyses, and Cox proportional hazards model were used. Among the 12 065 patients with CHF (median age 78 years), 17% had anemia, 58% of whom had anemia of chronic disease. After adjustment for clinical and demographic variables, patients with anemia were more likely to be older (odds ratio [OR] 1.01 per year) and female (OR 1.2 [95% confidence interval 1.1 to 1.3]) and to have a history of chronic renal insufficiency (OR=3.2 [95% confidence interval 2.8 to 3.6]), or hypertension (OR 1.3 [95% confidence interval 1.2 to 1.5]). Hazard ratios for mortality, adjusting for covariates, were 1.34 (1.24 to 1.46) in anemic patients, and 1.36 (1.23 to 1.50) in those patients with anemia of chronic disease. In this large cohort of community-dwelling patients with CHF, anemia is common and an independent prognostic factor for mortality. Further research into the mechanisms of anemia in CHF and randomized controlled trials to test whether correction of anemia improves prognosis in CHF are needed.",2003.0,0,0 1864,12538423,C-reactive protein and ischemia in users and nonusers of beta-blockers and statins: data from the Heart and Soul Study.,Mary S Beattie; Michael G Shlipak; Haiying Liu; Warren S Browner; Nelson B Schiller; Mary A Whooley,"Elevated levels of C-reactive protein (CRP) are associated with an increased risk of coronary events, but whether inflammation is associated with inducible ischemia in patients with stable coronary disease is unknown. We recruited patients with known coronary disease from 2 VA Medical Centers and 1 University-based medical center for the Heart and Soul Study. We measured CRP levels in 118 participants who had exercise-induced ischemia and in 111 who did not have inducible ischemia, as determined by stress echocardiography. We used logistic regression to examine the risk of exercise-induced ischemia associated with elevated CRP. We found that 75% (39/52) of participants in the highest CRP category (>0.38 mg/dL) had inducible ischemia, compared with 45% (79/177) in the lower 4 categories combined (adjusted odds ratio 4.2; 95% confidence interval 1.6 to 11; P=0.004). However, this association differed in users and nonusers of beta-blockers and statins. Among 89 participants who did not use beta-blockers, 93% in the highest CRP category had exercise-induced ischemia, compared with 42% in the lower 4 categories (P=0.03). Among 67 participants who did not use statins, 94% in the highest CRP category had exercise-induced ischemia, compared with 44% in the lower 4 categories (P=0.009). We did not observe a significant association between CRP and ischemia among participants who were treated with either of these medications. Elevated CRP levels are associated with inducible ischemia in patients with stable coronary disease, particularly among those not treated with beta-blockers or statins.",2003.0,0,0 1865,12538425,Statin therapy interacts with cytomegalovirus seropositivity and high C-reactive protein in reducing mortality among patients with angiographically significant coronary disease.,Benjamin D Horne; Joseph B Muhlestein; John F Carlquist; Tami L Bair; Troy E Madsen; Noal I Hart; Jeffrey L Anderson; Intermountain Heart Collaborative (IHC) Study Group,"Seropositivity to cytomegalovirus (CMV) and elevated C-reactive protein (CRP) may jointly predict increased mortality rates in patients with coronary artery disease (CAD). Therapy with statins reduces lipid levels but may also have other beneficial (eg, antiinflammatory) effects. This study prospectively evaluated the effect of statins on CMV-and CRP-associated death among patients with significant, angiographically defined CAD. We monitored 2315 patients with angiographically significant CAD (stenosis > or =70%) for an average of 2.4 years (maximum, 5.8 years). Anti-CMV IgG antibody levels and CRP concentrations were measured at baseline, and statin prescription was recorded. As previously reported, mortality rate was higher for CMV seropositivity (+) with high CRP (hazard ratio [HR], 2.0) and lower for statins (HR, 0.50). Compared with CMV(-)/low CRP (mortality rate, 5% with statin versus 4% without statin), the protective effect of statin therapy was markedly greater for CMV(+)/low CRP (mortality rate, 2% versus 7%; HR, 0.44; 95% CI, 0.16 to 1.3), CMV negative (-)/high CRP (mortality rate, 1% versus 8%; HR, 0.16), and CMV(+)/high CRP (mortality rate, 6% versus 17%; HR, 0.42; 95% CI, 0.25 to 0.70). After adjustment, interactions were found for statin therapy with CMV(+)/low CRP (P for interaction=0.065), CMV(-)/high CRP (P for interaction=0.051), and CMV(+)/high CRP (P for interaction=0.024). The survival benefit of statins interacted with CMV seropositivity and high CRP to significantly reduce mortality rates among patients with CAD. This finding supports the hypothesis that statins have beneficial, ""lipid-independent,"" antiinflammatory effects. The mechanism of statin benefit associated with CMV seropositivity remains to be determined.",2003.0,0,0 1866,12538446,The statins as anticancer agents.,Kelvin K W Chan; Amit M Oza; Lillian L Siu,"3-Hydroxy-3-methylgutaryl CoA reductase inhibitors, commonly referred to as the statins, have proven therapeutic and preventative effects in cardiovascular diseases. Recently, there are emerging interests in their use as anticancer agents based on preclinical evidence of their antiproliferative, proapoptotic, anti-invasive, and radiosensitizing properties. Inhibition of 3-hydroxy-3-methylgutaryl CoA reductase by the statins interferes with the rate-limiting step of the mevalonate pathway, leading to reduced levels of mevalonate and its downstream products, many of which play important roles in critical cellular functions such as membrane integrity, cell signaling, protein synthesis, and cell cycle progression. Perturbations of these processes in neoplastic cells by the statins may therefore result in control of tumor initiation, growth, and metastasis. The statins have demonstrated growth inhibitory activity in cancer cell lines and preclinical tumor models in animals. Phase I trials of statins in humans have demonstrated myotoxicity as their main dose-limiting toxicity, and Phase II trials in various tumor types are ongoing to evaluate their efficacy. Potential future directions in the development of the statins as anticancer agents include combinations with chemotherapeutic or other molecular-targeted agents, combinations with radiotherapy, maintenance therapy in minimal disease status, and as chemopreventive therapy.",2003.0,0,0 1867,12539808,"Effects of simvastatin, an HMG-CoA reductase inhibitor, in patients with hypertriglyceridemia.",Jonathan Isaacsohn; Donald Hunninghake; Helmut Schrott; Carlos A Dujovne; Robert Knopp; Stuart R Weiss; Harold Bays; John R Crouse; Michael H Davidson; Leonard M Keilson; James McKenney; Stanley G Korenman; Adrian S Dobs; Evan Stein; Ronald M Krauss; Darbie Maccubbin; Meehyung Cho; Diane J Plotkin; Yale B Mitchel,"Patients with elevated levels of serum triglycerides (TG) often have other associated lipid abnormalities (e.g., low levels of high-density lipoprotein cholesterol [HDL-C]) and are at increased risk of developing coronary heart disease. Although the therapeutic benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in hypercholesterolemic patients have been well established, less is known about the effects of statins in patient populations with hypertriglyceridemia. The purpose of this study was to evaluate the lipoprotein-altering efficacy of simvastatin in hypertriglyceridemic patients. This was a multicenter, randomized, double-blind, placebo-controlled study. In all, 195 patients with fasting serum triglyceride levels between 300 and 900 mg/dl received once daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. Compared with placebo, simvastatin treatment across all doses resulted in significant reductions (p < 0.05 - < 0.001) in serum levels of triglycerides (-20 to -31% decrease) and TG-rich lipoprotein particles. Significant (p < 0.001) reductions were also seen in low-density lipoprotein cholesterol (-25 to -35%) and non-HDL-C (-26 to -40%). Levels of HDL-C were increased (7-11%) in the simvastatin groups compared with placebo (p < 0.05 - < 0.001). The results of this study demonstrate the beneficial effects of simvastatin in patients with hypertriglyceridemia.",2003.0,0,0 1868,12539990,Management of hyperlipidemia in the elderly population: an evidence-based approach.,Deep Dalal; Joseph A Robbins,"Coronary heart disease (CHD) is the leading cause of morbidity and mortality in patients more than 65 years old. Within this population, elevated cholesterol levels are prevalent and associated with increased risk of CHD. Despite increasing emphasis on lipid-lowering treatment in the elderly population, questions remain regarding secondary and primary prevention of CHD. According to current clinical trial evidence, lipid-lowering therapy, specifically with HMG-CoA-reductase inhibitors, can reduce CHD morbidity and mortality without increased adverse effects in the elderly population. Lipid-lowering treatment should be considered for patients aged 65 to 75 years with a history of CHD or who are at moderate to high risk for CHD. Estrogen replacement therapy (ERT), which has also been shown to lower cholesterol levels, raises special considerations for postmenopausal women. However, recent findings suggest that postmenopausal women with a history of CHD should not be given estrogen solely for secondary prevention of CHD events.",2003.0,0,0 1869,12540794,Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival.,Josep M Llovet; Jordi Bruix,"There is no standard treatment for patients with unresectable hepatocellular carcinoma (HCC). Survival benefits derived from medical interventions are controversial. The aim of this systematic review was to assess the evidence of the impact of medical treatments on survival. Randomized controlled trials (RCTs) that were published as full papers assessing survival for primary treatments of HCC were included. MEDLINE, the Cochrane Library, CANCERLIT, and a manual search from 1978 to May 2002 were used. The primary end point was survival, and the secondary end point was response to treatment. Estimates of effect were calculated according to the random effects model. Sensitivity analysis included methodological quality. We identified 61 randomized trials, but only 14 met the criteria to perform a meta-analysis assessing arterial embolization (7 trials, 545 patients) or tamoxifen (7 trials, 898 patients). Arterial embolization improved 2-year survival compared with control (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32-0.89; P =.017). Sensitivity analysis showed a significant benefit of chemoembolization with cisplatin or doxorubicin (OR, 0.42; 95% CI, 0.20-0.88) but none with embolization alone (OR, 0.59; 95% CI, 0.29-1.20). Overall, treatment induced objective responses in 35% of patients (range, 16%-61%). Tamoxifen showed no antitumoral effect and no survival benefits (OR, 0.64; 95% CI, 0.36-1.13; P =.13), and only low-quality scale trials suggested 1-year improvement in survival. In conclusion, chemoembolization improves survival of patients with unresectable HCC and may become the standard treatment. Treatment with tamoxifen does not modify the survival of patients with advanced disease.",2003.0,0,0 1870,12542719,Researching new treatments for obesity: from neuroscience to inflammation.,Richard Donnelly,,2003.0,0,0 1871,12543298,Clopidogrel-associated angioedema.,Tanja C Fischer; Margitta Worm; David A Groneberg,,2003.0,0,0 1872,12544413,Metabolic complications of antiretroviral therapy in children.,Ethan G Leonard; Grace A McComsey,"Survival in HIV-infected children has greatly improved with the introduction of highly active antiretroviral therapy. Children are more vulnerable than adults to metabolic side effects of therapy because of its potential impact on growth and the children's likely greater cumulative exposure. This review summarizes the epidemiology and management of lipodystrophy, dyslipidemia, insulin resistance, hyperlactatemia, osteopenia and growth failure in HIV-infected children.",2003.0,0,0 1873,12545342,Fluvastin therapy affects TAFI concentration in kidney transplant recipients.,Jolanta Malyszko; Jacek S Malyszko; Michal Mysliwiec,"Thrombin activatable fibrinolysis inhibitor (TAFI) is a glycoprotein, linking coagulation and fibrinolysis. Recently, attention has been drawn to the beneficial effects of statins on haemostasis in kidney patients prone to dyslipidaemia and with a high risk of cardiovascular death. The purpose of this study was to assess whether fluvastatin affects TAFI concentration in renal transplant recipients. We evaluated thrombin-antithrombin (TAT) complexes, prothrombin fragments 1+2, thrombomodulin, plasmin-antiplasmin (PAP) complexes, TAFI, P-selectin, and lipoprotein (a), 1, 2, and 3 months before and after fluvastatin treatment and in normolipaemic kidney transplant recipients and healthy volunteers. Cholesterol and LDL fell significantly as soon as 1 month after treatment had begun and remained lowered during the therapy. TAFI and prothrombin fragments 1+2 decreased significantly after 3 months of fluvastatin administration, whereas P-selectin decreased significantly after 2 months and remained significantly lower after 3 months of this therapy. We can conclude that fluvastatin is an effective hypolipaemic agent that favourably affects haemostasis.",2003.0,0,0 1874,12546641,Levels of adhesion molecules do not decrease after 3 months of statin therapy in moderate hypercholesterolaemia.,Bernd Jilma; Christian Joukhadar; Ulla Derhaschnig; Fausi Rassoul; Volker Richter; Michael Wolzt; Guido T Dorner; Vanessa Petternel; Oswald F Wagner,"Studies in animals and humans indicate a pivotal role for adhesion molecules (AMs) in the pathogenesis of atherosclerosis. Whereas an association between hypercholesterolaemia and AM expression has been suggested, it is unclear whether lowering cholesterol decreases AM expression and release. We compared the effects of a 3-month treatment with standard doses of three different statins (atorvastatin, simvastatin and pravastatin) on plasma levels of circulating AM (cAM) in 75 hypercholesterolaemic patients in a randomized clinical trial. Plasma levels of circulating (c)E-selectin, circulating intercellular adhesion molecule-1 (cICAM-1) and circulating vascular cell adhesion molecule-1 (cVCAM-1) were measured before and after 3 months of therapy. None of the statins lowered plasma cAM levels and pooled analyses of all patients showed a 1.7% [95% confidence interval (CI), -1.4-4.9%] increase in cE-selectin, a 2.1% (95% CI, -0.2-4.4%) increase in cICAM-1, and a 2.7% (95% CI, -0.6-6.1%) increase in cVCAM-1 levels. cAM levels did not decrease, even in patients with a >50% decrease ( n =19) in low-density lipoprotein cholesterol levels. This study provides strong evidence that 3 months of therapy with three different statins does not decrease cAM levels, despite normalization of cholesterol levels, and a minor decrease in C-reactive protein levels in patients with moderate hypercholesterolaemia.",2003.0,0,0 1875,12546864,,,,,0,0 1876,12547874,Atorvastatin dose-dependently decreases hepatic lipase activity in type 2 diabetes: effect of sex and the LIPC promoter variant.,Ingrid I L Berk-Planken; Nicoline Hoogerbrugge; Ronald P Stolk; Aart H Bootsma; Hans Jansen; DALI Study Group,"Hepatic lipase (HL) is involved in the metabolism of several lipoproteins and may contribute to the atherogenic lipid profile in type 2 diabetes. Little is known about the effect of cholesterol synthesis inhibitors on HL activity in relation to sex and the hepatic lipase gene, the LIPC promoter variant in type 2 diabetes. Therefore, we studied the effect of atorvastatin 10 mg (A10) and 80 mg (A80) on HL activity in 198 patients with type 2 diabetes. Patients (aged 45-75 years, without manifest coronary artery disease, total cholesterol 4.0-8.0 mmol/l, and fasting triglycerides [TG] 1.5-6.0 mmol/l) were included in a double-blind, randomized, placebo-controlled trial for 30 weeks (Diabetes Atorvastatin Lipid Intervention study). HL activity at baseline was significantly higher in our population compared with an age-matched control group without type 2 diabetes (406 +/- 150 vs. 357 +/- 118 units/l). HL activity in men versus women (443 +/- 158 vs. 358 +/- 127 units/l), in carriers of the LIPC C/C allele versus carriers of the T/T allele (444 +/- 142 vs. 227 +/- 96 units/l), and in Caucasians versus blacks (415 +/- 150 vs. 260 +/- 127 units/l) all differed significantly (P < 0.001). Atorvastatin dose-dependently decreased HL (A10, -11%; A80, -22%; both P < 0.001). Neither sex nor the LIPC C-->T variation influenced the effect of atorvastatin on HL activity. Sex, LIPC promoter variant, and ethnicity significantly contribute to the baseline variance in HL activity. Atorvastatin treatment in diabetic dyslipidemia results in a significant dose-dependent decrease in HL activity, regardless of sex or the LIPC promoter variant.",2003.0,0,0 1877,12548082,Effect of high-dose statin treatment on plasma concentrations of endogenous nitric oxide synthase inhibitors.,Hannu Päivä; Juha Laakso; Terho Lehtimäki; Marja Isomustajärvi; Inkeri Ruokonen; Reijo Laaksonen,"Asymmetric dimethylarginine (ADMA) and monomethylarginine (LMMA) are endogenous inhibitors of nitric oxide synthase. A high level of ADMA in plasma has shown to be a significant risk factor for acute coronary syndromes and elevated plasma ADMA levels are prevalent in patients with hypercholesterolemia. It was therefore hypothesized that lowering plasma cholesterol levels with statin treatment would also lower ADMA concentrations. This double-blind study addressed the effect of high-dose statin treatment on plasma levels of ADMA and LMMA. Forty-eight subjects with mild hypercholesterolemia were randomly assigned to receive simvastatin 80 mg/d, atorvastatin 40 mg/d, or placebo for 8 weeks. Both statins decreased low-density lipoprotein cholesterol effectively (simvastatin 54% and atorvastatin 49%). However, concentrations of arginine derivatives remained unchanged during statin treatment and did not correlate with cholesterol levels. This study indicates that statin treatment has no clear influence on plasma ADMA or LMMA concentrations.",2003.0,0,0 1878,12549983,hsCRP and HDL effects of statins trial (CHEST): rapid effect of statin therapy on C-reactive protein and high-density lipoprotein levels A clinical investigation.,Benjamin J Ansell; Karol E Watson; Robert E Weiss; Gregg C Fonarow,"Inflammation contributes to the pathogenesis of coronary heart disease and elevated serum levels of C-reactive protein (CRP) are independently associated with increased coronary risk. This study assessed whether there were differences in the effects on CRP and high-density lipoprotein (HDL) cholesterol levels among patients treated with three common statins. In a prospective, observational study, 80 dyslipidemic adults without evidence of cardiovascular disease were treated with 10 mg atorvastatin (A), 20 mg simvastatin (S), or 40 mg pravastatin (P) daily. CRP and lipid profiles were assayed before and after 12 weeks of therapy; in 21 patients, CRP levels were also measured after 1 and 4 weeks. The three treatment groups experienced comparable reductions in CRP (A: 33%, S: 42%, and P: 30%) and statistically insignificant changes in HDL cholesterol levels. CRP began to decrease after 1 week of treatment, and decreased further at 4 and 12 weeks of therapy. The change in the log-transformed CRP concentration correlated with the change in the log-transformed LDL cholesterol concentration. Subjects had similar baseline CRP levels, lipid profiles, and coronary risk factors. The authors conclude that at doses achieving similar reductions in LDL cholesterol, the three statins were associated with comparable decreases in CRP without significant changes in HDL cholesterol levels. The correlation between the reductions in CRP and LDL cholesterol differs from the findings of other published studies, and should prompt further investigation of the mechanism by which statins reduce CRP.",2003.0,0,0 1879,12549990,Rosuvastatin: a new HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia.,Angela Cheng-Lai,"Because of their excellent tolerability and their positive impact on lipid parameters, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have become the drugs of first choice for many patients with dyslipidemia. Rosuvastatin is an investigational statin in the U.S. with a number of favorable characteristics, which include low lipophilicity, high hepatocyte selectivity, minimal metabolism, and a low propensity for cytochrome P450 drug interactions. Rosuvastatin has been studied at doses ranging from 1 to 80 mg. In comparative clinical trials, rosuvastatin given at 5 to 10 mg/day reduced low-density lipoprotein cholesterol to a significantly greater extent than atorvastatin 10 mg/day, pravastatin 20 mg/day, and simvastatin 20 mg/day. In addition, rosuvastatin exhibited beneficial effects on other lipid parameters such as high-density lipoprotein cholesterol and triglycerides. Rosuvastatin's safety profile was demonstrated to be similar to those of other statins. Given its favorable pharmacokinetic and pharmacodynamic characteristics, rosuvastatin is likely to become a valuable addition to the statin drug class. The author reviews the pharmacologic and pharmacokinetic properties of this new statin.",2003.0,0,0 1880,12551853,Clinical application of C-reactive protein for cardiovascular disease detection and prevention.,Paul M Ridker,,2003.0,0,0 1881,12551863,,,,,0,0 1882,12551866,Effect of nifedipine and cerivastatin on coronary endothelial function in patients with coronary artery disease: the ENCORE I Study (Evaluation of Nifedipine and Cerivastatin On Recovery of coronary Endothelial function).,ENCORE Investigators,"Endothelial dysfunction is an important feature of atherosclerosis. Inhibition of the HMG-CoA pathway and of calcium channels improves endothelial function experimentally and in the forearm circulation. Thus, we investigated the effects of a statin and/or a calcium antagonist on coronary endothelial function in patients with coronary artery disease (CAD). In 343 patients undergoing percutaneous coronary intervention in 29 centers, acetylcholine (10(-6) to 10(-4) mol/L) was infused in a coronary segment without angiographically significant CAD. Changes in coronary diameter were measured by quantitative angiography. Endothelium-independent responses were assessed by intracoronary adenosine (1.2 mg/mL) and nitroglycerin (250 microg). Thereafter, patients were randomized in a double-blind manner to placebo, cerivastatin 0.4 mg/d, nifedipine 30 to 60 mg/d, or their combination. Studies were repeated at 6 months. In the most constricted segment, nifedipine but not cerivastatin reduced vasoconstriction to acetylcholine (18.8% versus placebo 10.0%; P<0.05). Patients not taking ACE inhibitors showed a smaller improvement in the placebo group (6.0%), but nifedipine still had an effect (17.0%; P<0.05 versus placebo). Analysis of all evaluable coronary segments revealed an 11% reduction of acetylcholine-induced vasoconstriction in patients receiving nifedipine and cerivastatin (P<0.05 versus placebo). Cerivastatin lowered LDL cholesterol by 35% (P<0.001). The ENCORE I trial demonstrates that multicenter studies on coronary endothelial function are feasible. After 6 months' treatment, nifedipine improved coronary endothelial function in the most constricted segment. The combination of nifedipine and cerivastatin tended to improve endothelial function; however, this only reached significance in an analysis of all coronary segments.",2003.0,0,0 1883,12551869,Alcohol consumption and plasma concentration of C-reactive protein.,Michelle A Albert; Robert J Glynn; Paul M Ridker,"Moderate alcohol intake has been associated with lower cardiovascular mortality. However, data evaluating the relationship between C-reactive protein (CRP), a predictor of cardiovascular risk, and alcohol consumption are sparse. The relationship between alcohol consumption and CRP was evaluated in a cross-sectional survey and over time among 1732 men and 1101 women participating in the Pravastatin Inflammation/CRP Evaluation Study. CRP levels were lower in those with moderate alcohol intake versus light or occasional intake: in 5 categories of alcohol intake (no alcohol or <1 drink monthly, 1 to 3 drinks monthly, 1 to 4 drinks weekly, 5 to 7 drinks weekly, and > or =2 drinks daily), median CRP levels were 2.60 mg/L (interquartile range (IQR), 1.20 to 5.30 mg/L), 2.20 mg/L (IQR, 1.00 to 4.40 mg/L), 1.70 mg/L (IQR, 0.80 to 3.80 mg/L), 1.60 mg/L (IQR, 0.80 to 3.30 mg/L), and 1.80 mg/L (IQR, 0.80 to 2.90 mg/L), respectively. This relationship was present among men, women not taking hormone replacement therapy, nonsmokers, and those individuals with and without a history of cardiovascular disease (all P<0.001). In multivariate analysis, the relationship between alcohol consumption and CRP remained significant after controlling for multiple traditional cardiovascular risk factors. Alcohol consumption did not significantly affect the change in CRP or lipid levels associated with statin use. Moderate alcohol consumption was associated with lower CRP concentrations than no or occasional alcohol intake, an effect that was independent of alcohol-related effects on lipids. Alcohol may attenuate cardiovascular mortality in part through an anti-inflammatory mechanism.",2003.0,0,0 1884,12553491,Optimal treatment and current situation in reperfusion after thrombolysis for acute myocardial infarction.,Kent Dauterman; Eric Topol,"Acute myocardial infarction is the leading cause of death in the industrialized world and the paramount goal is establishing early, complete, and sustained reperfusion at the myocardial tissue level. For hospitals without the capacity to perform emergent percutaneous coronary intervention, fibrinolytic therapy plays a critical role although it is limited by a 67% success rate. Despite promising pilot studies, reduced-dose fibrinolytic therapy with glycoprotein IIb/IIIa therapy (GUSTO-V) and full-dose fibrinolytic therapy with enoxaparin (ASSENT-3) or bivalirudin (HERO-2) provide only marginally improved clinical outcomes. Adjunctive in-hospital and secondary preventive measures should include an aspirin, a beta-blocker, an ACE inhibitor, and a statin, based on the Heart Protection Study, unless contraindicated. Patients should be risk stratified, participate in a cardiac rehabilitation program, cease smoking tobacco, and have an intracardiac defibrillator (ICD) implanted if their LV systolic function is < or = 30% at one month based on the MADIT-2 trial.",2003.0,0,0 1885,12553742,Treating to goal: new strategies for initiating and optimizing lipid-lowering therapy in patients with atherosclerosis.,Gregg C Fonarow; National Cholesterol Education Program (NCEP),"Abstract: The National Cholesterol Education Program (NCEP) guidelines prepared by the Adult Treatment Panel (ATP) provide clinicians with recommendations for the clinical management of abnormal blood cholesterol to reduce the risk of cardiovascular events. The recently updated NCEP guidelines have included a number of key amendments such as the recognition of low high-density lipoprotein cholesterol (HDL-C) as a risk factor for cardiovascular disease, while maintaining the focus of treatment on lowering low-density lipoprotein cholesterol (LDL-C) levels. Several agents can be used to modify the lipid profile in-line with the NCEP ATP-III recommendations, but hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) remain the most effective and best-tolerated drugs for lowering LDL-C. The optimal time to initiate drug therapy had been in question, although recent studies suggest in-hospital initiation following admission with cardiovascular disease reduces the risk of recurrent events and improves long-term patient compliance. Inpatient physicians and nurses therefore play a pivotal role in influencing not only short-term management needs, but also the long-term recovery of their patients. This role should not be underestimated, as recent surveys have highlighted a significant problem of undertreatment in patients with documented atherosclerosis with regards to lipid-lowering and other cardioprotective therapy. Although reversing patient undertreatment will require clinicians to address a variety of issues, systematic in-hospital initiation of currently available lipid-lowering therapies in patients with atherosclerotic vascular disease is likely to have major benefits, reducing the occurrence of cardiovascular events and saving lives. Several statins, cholesterol absorption inhibitors, novel metabolic inhibitors, and combinations of agents are currently in clinical development and it is hoped that these will also assist clinicians in the important task of getting patients to recommended LDL-C and HDL-C levels.",2003.0,0,0 1886,12556541,Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.,Peter Gaede; Pernille Vedel; Nicolai Larsen; Gunnar V H Jensen; Hans-Henrik Parving; Oluf Pedersen,"Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria. The primary end point of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin. The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79). A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent.",2003.0,0,0 1887,12556656,"Meta-analysis, meta-regression, and meta-physics.",John B Kostis,,2003.0,0,0 1888,12556657,Benefits of antihypertensive pharmacologic therapy and blood pressure reduction in outcome trials.,Ji-Guang Wang; Jan A Staessen,"In a quantitative overview of published trials, we investigated whether pharmacologic properties of antihypertensive drugs, as opposed to reduction in blood pressure, explain cardiovascular outcomes in hypertensive or high-risk patients. We used meta-regression to investigate the association between the odds ratios of outcome (experimental vs. reference treatment) and the corresponding blood pressure differences between study groups. Thus, we correlated odds ratios with between-group differences in systolic pressure. We then compared odds ratios of benefit observed in recent trials with those predicted by meta-regression on the basis of the differences in systolic pressure between randomized groups. Among nine actively-controlled trials in hypertension, significant differences in systolic pressure (follow-up minus baseline) between randomized groups (experimental minus reference) were observed in the ALLHAT, CAPPP, MIDAS, and NORDIL trials. Furthermore, the differences in achieved systolic and/or diastolic pressure between study groups were also significant in the hypertension trials and studies in high-risk patients, which involved untreated control patients. The differences between the observed odds ratios and those predicted by meta-regression did not reach statistical significance except for NORDIL and the single-drug therapy subgroup of the PROGRESS trial. In NORDIL, the risk of stroke was lower on diltiazem than on the older drug classes despite a 3.1 mm Hg higher systolic pressure on the calcium channel blocker. In PROGRESS, perindopril alone reduced blood pressure by 5/3 mm Hg, but did not affect the incidence of all cardiovascular events or the recurrence of stroke. In conclusion, the finding that in the reviewed trials blood pressure reduction largely accounted for outcome emphasizes the desirability of tight blood pressure control. The hypothesis that blood pressure-lowering medications might influence cardiovascular prognosis over and beyond their antihypertensive effect remains to a large extent unproved.",2003.0,0,0 1889,12558496,Correlates of endothelial function and their relationship with inflammation in patients with familial hypercholesterolaemia.,Paul L van Haelst; Jasper J van Doormaal; Folkert W Asselbergs; Arie M van Roon; Nic J G M Veeger; Maureen M Henneman; Andries J Smit; Jan Willem Cohen Tervaert; Johan F May; Rijk O B Gans,"Atherosclerosis is characterized by a low-grade systemic inflammatory response and endothelial dysfunction. The aim of the present study was to investigate a possible relationship between systemic markers of inflammation, serum markers of endothelial activation and endothelium-dependent vasodilatation in a group of high-risk patients, and to evaluate the effects of intervention with high doses of simvastatin on these parameters. In patients with heterozygous familial hypercholesterolaemia, without atherosclerotic events, flow-mediated vasodilatation (FMD) of the brachial artery was measured after a wash-out period for lipid-lowering drugs (baseline) and after 6 weeks of treatment with simvastatin 80 mg daily. Levels of C-reactive protein (CRP), soluble intercellular cell-adhesion molecule (s-ICAM) and soluble E-selectin (s-E-selectin) were determined at baseline and again after 6 weeks and 12 months of therapy. A total of 35 subjects participated in the study (mean age 42 years; 60% male). When divided into tertiles according to FMD (<3.9%, 3.9-9.0% and >9.0%), no differences in levels of CRP, s-ICAM-1 and/or s-E-selectin were detected between the groups. Moreover, no changes in FMD, levels of CRP or levels of s-ICAM-1 and/or s-E-selectin were found during treatment with simvastatin. We conclude that endothelial function, as reflected by FMD, does not seem to be related to markers of inflammation in familial hypercholesterolaemia subjects at high risk of, but without clinically overt signs of, atherosclerosis. Moreover, aggressive lipid-lowering therapy with simvastatin does not result in improved endothelial function or in a reduction of markers of inflammation in these patients.",2003.0,0,0 1890,12559221,"Clinical trials update from the American Heart Association meeting: PROSPER, DIAL, home care monitoring trials, immune modulation therapy, COMPANION and anaemia in heart failure.",A P Coletta; N Nikitin; A L Clark; J G F Cleland,"This article continues a series of reports on research developments of particular interest to those involved in the management of patients with heart failure. Summaries of the following trials, reported at the 75th Scientific Sessions of the American Heart Association held in Chicago, Illinois between 17th and 20th November 2002 are included: PROSPER; DIAL; home care monitoring trials; immune modulation therapy; COMPANION; and anaemia in heart failure.",2003.0,0,0 1891,12562305,Antifungal pharmacotherapy for invasive mould infections.,Jason C Gallagher; Elizabeth S Dodds Ashley; Richard H Drew; John R Perfect,"The incidence of invasive mould infections is increasing and is associated with significant morbidity and mortality. Among the most prevalent of these infections are those caused by Aspergillus and Fusarium species. Invasive disease caused by moulds frequently presents as a pulmonary infection, but haematogenous infection can occur. Some moulds cause cutaneous disease through either direct inoculation of the skin or secondary spread to the skin after dissemination from another body site. Early diagnosis can often be difficult and, unfortunately, diagnosis occurs late in the course of illness in many cases. Treatment options have historically been limited by the need for intravenous administration (amphotericin B), significant toxicities (amphotericin B), lack of reliable in vitro activity (e.g., amphotericin B in Fusarium and Scedosporium apiospermum infections) and relative lack of clinical experience with newer agents. The recent approval of voriconazole (Vfend, Pfizer) introduces a treatment option that demonstrates both in vitro and in vivo activity against a variety of moulds. With the recent development of the new echinocandin class of antifungal agents and newer broad-spectrum azole antifungal agents with in vitro mould activity, there is a renewed emphasis on fungal treatment strategies. Antimould therapy presents challenges in adverse effect avoidance and management, drug interactions and pharmacoeconomic considerations. Furthermore, combination therapy is being explored with these various new antifungal agents. The administration of an optimal fungicidal therapy early in the course of the illness and control of the underlying disease are vital to prevent complications and mortality from these tenacious mycoses.",2003.0,0,0 1892,12562722,A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution.,Melissa D Johnson; Carol D Hamilton; Richard H Drew; Linda L Sanders; Gennethel J Pennick; John R Perfect,"To determine the effect of omeprazole on peak serum concentrations (C(max)) of itraconazole oral solution (IOS), we carried out a randomized, open-label, prospective, crossover study. Fifteen healthy, non-pregnant adults received a single dose of IOS 400 mg on two occasions, at least 7 days apart, with omeprazole 40 mg nightly for 7 days before either IOS dose 1 or 2. C(max), time to C(max) (T(max)) and AUC(0-8) were determined for itraconazole and its active metabolite, hydroxyitraconazole, for each dose and compared. Omeprazole did not significantly affect the C(max), T(max) or AUC(0-8) of itraconazole or hydroxyitraconazole when administered as IOS.",2003.0,0,0 1893,12563563,Developments in restenosis.,Philip Chan,"Restenosis is a major complication leading to the failure of vascular procedures, including surgery, angioplasty and stenting. Major efforts including over 100 clinical trials have been made to overcome this complication, with little success to date. Issues relating to trial rationale, design, measurement and biology are addressed in this review.",2003.0,0,0 1894,12563570,Mortality benefit of angiotensin-converting enzyme inhibitors after cardiac events in patients with end-stage renal disease.,Peter A McCullough; Keisha R Sandberg; Jerry Yee; Michael P Hudson,"HYPOTHESIS/INTRODUCTION: The risks and benefits of angiotensin-converting enzyme (ACE) inhibitors in patients with end-stage renal disease (ESRD) after cardiac events are unknown. We sought to determine the independent effect of ACE inhibitors (ACE-I) on long-term mortality in ESRD patients after cardiac events. We analysed a prospective coronary care unit registry and identified 527 ESRD patients, 368 with complete data on medications prescribed, over eight years at a single, tertiary centre. The overall mean age was 64.4+13.8 years with 54.9% men, and 59.2% African-American. A total of 143/386 (37.0%) were prescribed ACE-I during the hospital stay for cardiac reasons, including congestive heart failure (CHF) 52.8% and acute coronary syndromes (ACS) 47.2%. There were no significant differences in the rates of hypotension or arrhythmias in those who were treated with ACE-I versus those who were not. Survival analysis over three years, adjusted for known confounders, demonstrated a 37% reduction in all-cause mortality in those who received ACE-I, (p=0.0145). In the setting of coronary care unit admission for CHF and ACS, ESRD patients selected for ACE-I, did not have increased rates of adverse haemodynamic or arrhythmic complications. The use of ACE-I conferred an independent mortality reduction over long-term follow-up.",2003.0,0,0 1895,12564455,"Re: Gómez-Gerique, et al. Effect of atorvastatin and bezafibrate on plasma levels of C-reactive protein in combined (mixed) hyperlipidemia. Atherosclerosis 2002;162:245-51.",Patrick M Moriarty; James M Backes,,2003.0,0,0 1896,12565097,Comparison of effectiveness of statin monotherapy versus statin and niacin combination therapy in primary prevention and effects on calcified plaque burden.,Harvey S Hecht; S Mitchell Harman,,2003.0,0,0 1897,12567159,Beneficial effect of donepezil augmentation for the management of comorbid schizophrenia and dementia.,Rafael Stryjer; Rael D Strous; Faina Bar; Edith Werber; Ginette Shaked; Yosef Buhiri; Moshe Kotler; Abraham Weizman; Jose M Rabey,"Comorbid schizophrenia and dementia is a common clinical phenomenon; however, management of the coexisting illnesses remains incomplete. Donepezil, a cholinesterase inhibitor, may be beneficial for the management of symptoms of Alzheimer's disease, a disease in which cholinergic pathways in the cerebral cortex and basal forebrain are well known to be compromised. Furthermore, impaired cognition in elderly schizophrenic patients has been observed to be more than two thirds; however, there are no published controlled studies reporting the use of cholinesterase inhibitors in the management of schizophrenia in patients with associated dementia. In this study, six patients with chronic schizophrenia and comorbid dementia were administered donepezil, 5 mg, in single-blind fashion as augmentation to their standard antipsychotic medication for a 4-week period. Patients were evaluated with the Mini Mental State Examination (MMSE); Alzheimer's Disease Assessment Scale, Cognitive subscale; Positive and Negative Symptom Scale (PANSS); and the Clinical Global Impression (CGI) scales. A significant improvement was noted in MMSE scores (P < 0.01) and for CGI scores (P < 0.01). In addition, three patients demonstrated improvement on the PANSS. Donepezil appears to be an effective treatment for the management of symptoms of dementia accompanying patients with comorbid schizophrenia and dementia. Since cholinergic dysfunction may be present in some patients with schizophrenia, the authors' findings further demonstrate the possibility that this disorder may be managed with cholinergic medications as augmenting agents, at least in this specific subpopulation of patients with comorbid dementia. To confirm the findings of this preliminary trial, further investigation is mandated with a larger sample of subjects in the context of a double-blind medication trial.",2003.0,0,0 1898,12568290,,,,,0,0 1899,12569241,All hats off to ALLHAT: a massive study with clear messages.,John Chalmers,,2003.0,0,0 1900,12570713,Prospects for pharmacologic inhibition of hepatic glucose production.,R Kurukulasuriya; J T Link; D J Madar; Z Pei; J J Rohde; S J Richards; A J Souers; B G Szczepankiewicz,"Type 2 diabetes is a widespread disease where effective pharmacologic therapies can have a profound beneficial public health impact. Increased hepatic glucose production (HGP) is observed in diabetics and its moderation by currently available agents provides therapeutic benefits. This review describes the challenges associated with the discovery of small molecules that inhibit HGP. Gluconeogenesis, glycogenolysis, liver architecture, and hepatocyte composition are described to provide background information on hepatic function. Current methods of target validation for drug discovery, HGP measurement, diabetes animal models, as well as current drug therapies are covered. In the accompanying review article the new drug targets being probed to produce the next generation of therapies are described. Significant pharmaceutical and academic efforts to pharmacologically inhibit HGP has the opportunity to provide new therapeutics for type 2 diabetics.",2003.0,0,0 1901,12570936,Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction.,Katsuomi Iwakura; Hiroshi Ito; Masashi Ikushima; Shigeo Kawano; Atsushi Okamura; Katsuaki Asano; Tadashi Kuroda; Koji Tanaka; Tohru Masuyama; Masatsugu Hori; Kenshi Fujii,"We investigated the association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction (AMI). Hyperglycemia is associated with increased risks of heart failure, cardiogenic shock, and death after AMI, but its underlying mechanism remains unknown. A total of 146 consecutive patients with a first AMI were studied by intracoronary myocardial contrast echocardiography (MCE) after successful reperfusion within 24 h after symptom onset. Two-dimensional echocardiography was recorded on day 1 and three months later to determine the change in the wall motion score (DeltaWMS; sum of 16 segmental scores; dyskinesia = 4 to normokinesia = 0). The no-reflow phenomenon was found on MCE in 49 (33.6%) of 146 patients; their glucose level on hospital admission was significantly higher than that of patients who did not exhibit this phenomenon (209 +/- 79 vs. 159 +/- 56 mg/dl; p < 0.0001). There was no difference in glycosylated hemoglobin or in the incidence of diabetes mellitus between the two subsets. The no-reflow phenomenon was more often observed in the 75 patients with hyperglycemia (>/=160 mg/dl) than in those without hyperglycemia (52.0% vs. 14.1%; p < 0.0001). Patients with hyperglycemia had a higher peak creatine kinase level (2,497 +/- 1,603 vs. 1,804 +/- 1,300 IU/l; p = 0.005) and a lower DeltaWMS (3.7 +/- 4.8 vs. 5.7 +/- 4.3; p = 0.01) than did those without hyperglycemia. The blood glucose level was an independent prognostic factor for no reflow, along with age, gender, absence of pre-infarction angina, complete occlusion of the culprit lesion, and anterior AMI. Hyperglycemia might be associated with impaired microvascular function after AMI, resulting in a larger infarct size and worse functional recovery.",2003.0,0,0 1902,12570960,ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina).,Raymond J Gibbons; Jonathan Abrams; Kanu Chatterjee; Jennifer Daley; Prakash C Deedwania; John S Douglas; T Bruce Ferguson; Stephan D Fihn; Theodore D Fraker; Julius M Gardin; Robert A O'Rourke; Richard C Pasternak; Sankey V Williams; American College of Cardiology; American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina),,2003.0,0,0 1903,12571693,CCORT/CCS quality indicators for acute myocardial infarction care.,Chau T T Tran; Douglas S Lee; Virginia F Flintoft; Lyall Higginson; F Curry Grant; Jack V Tu; Jafna Cox; Doug Holder; Cynthia Jackevicius; Louise Pilote; Paul Tanser; Christopher Thompson; Edward Tsoi; Wayne Warnica; Andreas Wielgosz; Canadian Cardiovascular Outcomes Research Team/Canadian Cardiovascular Society; Acute Myocardial Infarction Quality Indicator Panel,"Although quality indicators for the care of acute myocardial infarction (AMI) patients have been described for other countries, there are none specifically designed for the Canadian health care system. The authors' goal was to develop a set of Canadian quality indicators for AMI care. A literature review identified existing quality indicators for AMI care. A list of potential indicators was assessed by a nine-member panel of clinicians from a variety of disciplines using a modified-Delphi panel process. After an initial round of rating the potential indicators, a series of indicators was identified for a second round of discussion at a national meeting. Further refinement of indicators occurred following a teleconference and review by external reviewers. To identify an AMI cohort, case definition criteria were developed, using a hospital discharge diagnosis for AMI of International Classification of Diseases-Ninth revision (ICD-9) code 410.x. Thirty-seven indicators for AMI care were established. Pharmacological process of care indicators included administration of acetylsalicylic acid, beta-blockers, angiotensin-converting enzyme inhibitors, thrombolytics and statins. Mortality and readmissions for AMI, unstable angina and congestive heart failure were recommended as outcome indicators. Nonpharmacological indicators included median length of stay in the emergency department, and median waiting times for cardiac catheterization, percutaneous coronary intervention and/or coronary artery bypass graft surgery. A set of Canadian quality indicators for the care of AMI patients has been established. It is anticipated that these indicators will be useful to clinicians and researchers who want to measure and improve the quality of AMI patient care in Canada.",2003.0,0,0 1904,12572539,Fresh from the pipeline. Ezetimibe.,John Earl; Peter Kirkpatrick,,2003.0,0,0 1905,12572627,Palm technology moves resident data recording into new dimension.,Marc S Rosenthal; Robert W Wolford,,2003.0,0,0 1906,12572632,Use of osteopathic manipulative treatment by Ohio osteopathic physicians in various specialties.,Donald G Spaeth; Alfred M Pheley,"The authors mailed a survey designed to determine the use of osteopathic manipulative treatment (OMT) to the 2,318 active osteopathic physicians registered with the Ohio Osteopathic Association; 871 responses were received, for a response rate of 38%. Approximately 75% of the respondents had not or had rarely used OMT: 44% of these respondents did not use any OMT and 31% reported treating fewer than 10 patients with OMT during the week before the survey. Approximately 25% of the surveyed osteopathic physicians treated more than 10 patients with OMT, and about 6% of these treated more than 30 patients with OMT. Respondents represented 40 specialty disciplines. All of the osteopathic physicians in 17 specialties reported no OMT use, osteopathic physicians in 9 specialties reported using OMT for fewer than 10 patients during the previous week, and osteopathic physicians in 9 specialties reported using OMT for more than 10 patients during the previous week. Of the somatic dysfunctions listed in the survey, low back disorders were treated with OMT most often. Few osteopathic specialists used OMT for patients with asthma or chronic obstructive pulmonary disease. The data suggest that a great opportunity exists to increase the use of OMT by osteopathic physicians, especially those who are specialists.",2003.0,0,0 1907,12573191,Benefits of simvastin in cholesterol lowering.,John A Farmer,,2003.0,0,0 1908,12573192,Benefits of atorvastatin in cholesterol lowering.,John A Farmer,,2003.0,0,0 1909,12573193,Statins and myotoxicity.,John A Farmer,"The significant age-adjusted decline in cardiovascular mortality that has occurred over the past three decades is multifactorial. However, the advent of statin therapy has markedly facilitated the optimization of dyslipidemia in patients at risk for coronary events. Statin therapy has proven to be effective in reducing morbidity and mortality in large-scale primary and secondary prevention trials. As with all therapies, the administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co A) reductase inhibitors is not without clinical risks. Myopathy, albeit uncommon, was one of the earliest clinical problems associated with statin therapy. Recent data from the large-scale statin mega-trials have clarified the quantitative clinical risk-benefit relationship of reductase inhibitors relative to the induction of muscle toxicity. Histopathologic studies have clarified the potential role of statins in the syndrome of myalgias and normal creatine kinase levels. However, the precise mechanism of statin-associated muscle toxicity remains unclear and is potentially related to genetically mediated muscle enzyme defects, drug interactions, intracellular depletion of metabolic intermediates, and intrinsic properties of the statins per se.",2003.0,0,0 1910,12574532,Ever decreasing circles: advances in antiplatelet therapy and anticoagulation.,J Kennedy; A M Buchan,,2003.0,0,0 1911,12574533,Statins in threatened stroke.,Markku Kaste,,2003.0,0,0 1912,12574539,Prevention and health services delivery.,Larry B Goldstein,,2003.0,0,0 1913,12576762,[Effect of high doses of atorvastatin on the endothelial function of the coronary arteries].,Audrius Simaitis; Aleksandras Laucevicius,"The aim of this study is to investigate the role of high doses of atorvastatin (80 mg per day) in the treatment of endothelium dysfunction of the coronary arteries. Intracoronary acethylcholine test was performed for 28 (16 in treatment group and 12 in control group) patients who had normal coronary angiogram or minimal lesions (stenosis <50%) and symptomatic coronary heart disease. Acetylcholine was given into left coronary artery in three stages (2 min each) at estimated intracoronary concentrations 10(-6) mol/l, 3.3x10(-6) mol/l,and 10(-5) mol/l. Treatment group patients were given atorvastatin 80 mg per day. Intracoronary acetylcholine test was repeated after six months. The target segment was the segment that exhibited the maximal constrictive response at baseline in a given patient. Total cholesterol was reduced by 40.6+/-11.2% (p<0.001), low density lipoproteins cholesterol by 55.4+/-14% (p<0.001), triglycerides by 29.6% (p<0.05) and high density lipoproteins cholesterol was increased by 24.7% (p<0.05) in atorvastatin group after 6 months of therapy. No significant lipid changes were observed in the control group. Sixteen target segments in the treatment group and 12 segments in the control group were selected for primary efficacy parameter. The vasoconstrictor reaction to acetylcholine was similar at baseline in both groups: -16.8%+/-11.6% of diameter in atorvastatin group and -14.2%+/-13.7% in control group (p=0.58) at dose 10(-6) mol/l, -43.5%+/-21.2% in atorvastatin group and -41.2%+/-22.4% in control group (p=0.79) at dose 3.3x10(-6) mol/l, -64.5%+/-12.4% in atorvastatin group and -57.4%+/-15.6% in control group (p=0.35) at dose 10(-5) mol/l. Treatment with high doses of atorvastatin markedly decreased acetylcholine - induced vasoconstriction: -6.5%+/-14.5% of diameter in atorvastatin group versus -18.3%+/-14.0% in control group (p=0.04) at dose 10(-6) mol/l, -19.7%+/-22.8% in atorvastatin group versus -40.0%+/-25.0% in control group (p=0.034) at dose 3.3x10(-6) mol/l, -29.9%+/-21.3% in atorvastatin group (6 segments) versus -48.7%+/-19.0% in control group (3 segments, p=0.24) at dose 10(-5) mol/l. Treatment with high doses of atorvastatin significantly improves endothelium-mediated response to acetylcholine in the coronary arteries of the patients with minimal lesions.",2003.0,0,0 1914,12578509,"Trends in treatment and outcomes for acute stroke patients in Ontario, 1992-1998.",Jack V Tu; Yanyan Gong,"Several interventions have been shown to be of benefit to patients with stroke (hereafter referred to as stroke patients) in clinical trials, but the net effect of these interventions in the general stroke population has not been established. The purpose of this study was to evaluate temporal trends in the characteristics, treatments, and outcomes of acute stroke patients in the province of Ontario. We conducted a population-based retrospective cohort study using linked administrative databases of all 91 419 patients discharged with a most-responsible diagnosis of acute stroke from acute care hospitals in Ontario from April 1, 1992, to March 31, 1999 (fiscal years 1992-1998). The average age and proportion of stroke patients with co-existing diseases increased over time. The proportion of elderly patients 65 years and older who received warfarin sodium (Coumadin) and statins increased during the study period (14.6% to 19.6% [P =.001] and 2.7% to 15.0% [P<.001], respectively). Declines in the median length of stay (11 to 8 days [P<.001]) and risk-adjusted in-hospital mortality (21.9% to 18.9% [P<.001]) were significant, but the 30-day mortality rates for acute stroke stayed relatively constant (19.7% to 19.0% [P =.18]). We found a moderate decline in risk-adjusted 1-year mortality (34.1% to 32.0% [P<.001]) and stroke readmission rates (12.1% to 9.9% [P =.001]). Improvements in the outcomes of stroke patients have occurred in Ontario during the 1990s, despite an increasing proportion of elderly stroke patients with multiple comorbidities. Increasing use of secondary prevention medications may explain this trend.",2003.0,0,0 1915,12578514,The importance of indirect costs in primary cardiovascular disease prevention: can we save lives and money with statins?,Steven A Grover; Vivian Ho; Frédéric Lavoie; Louis Coupal; Hanna Zowall; Louise Pilote,"The losses in productivity due to cardiovascular disease (CVD) are substantial but rarely considered in health economic analyses. We compared the cost-effectiveness of lipid level modification in the primary prevention of CVD with and without these indirect costs. We used the Cardiovascular Life Expectancy Model to estimate the long-term benefits and cost-effectiveness of lipid level modification with atorvastatin calcium, including 28% and 38% reductions in total cholesterol and low-density lipoprotein cholesterol levels, respectively, and a 5.5% increase in high-density lipoprotein cholesterol level. The direct costs included all medical care costs associated with CVD. The indirect costs represented the loss of employment income and the decreased value of housekeeping services after different manifestations of CVD. All costs were expressed in 2000 Canadian dollars. When only direct medical care costs were considered, the incremental cost-effectiveness ratios for lifelong therapy with atorvastatin calcium, 10 mg/d, were generally positive, ranging from a few thousand to nearly $20 000 per year of life saved. When the societal point of view was adopted and indirect costs were included, the total costs were generally negative, representing substantial cost savings (up to $50 000) and increased life expectancy for most groups of individuals. Lipid therapy with statins can reduce CVD morbidity and mortality as demonstrated in a number of clinical trials. Adding the indirect CVD costs associated with productivity losses at work and home can result in forecasted cost savings to society as a whole such that lipid therapy could potentially save lives and money.",2003.0,0,0 1916,12578881,Statin use and leg functioning in patients with and without lower-extremity peripheral arterial disease.,Mary McGrae McDermott; Jack M Guralnik; Philip Greenland; William H Pearce; Michael H Criqui; Kiang Liu; Lloyd Taylor; Cheeling Chan; Leena Sharma; Joseph R Schneider; Paul M Ridker; David Green; Maureen Quann,"We determined whether statin use (versus nonuse) is associated with superior lower-extremity functioning independently of cholesterol levels and other confounders in patients with and without peripheral arterial disease. Participants included 392 men and women with an ankle brachial index (ABI) <0.90 and 249 with ABI 0.90 to 1.50. Functional outcomes included 6-minute walk distance and 4-meter walking velocity. A summary performance score combined performance in walking speed, standing balance, and time for 5 repeated chair rises into an ordinal score ranging from 0 to 12 (12=best). Adjusting for age, sex, ABI, comorbidities, education level, medical insurance status, cholesterol, and other confounders, participants taking statins had better 6-minute walk performance (1276 versus 1218 feet, P=0.045), faster walking velocity (0.93 versus 0.89 m/s, P=0.006), and a higher summary performance score (10.2 versus 9.4, P<0.001) than participants not taking statins. Positive associations were attenuated slightly after additional adjustment for C-reactive protein level but remained statistically significant for walking velocity and the summary performance score. We did not find significant associations between lower-extremity functioning and aspirin, ACE inhibitors, vasodilators, or beta-blockers. Statin use is associated with superior leg functioning compared with no statin use, independent of cholesterol levels and other potential confounders. These data suggest that non-cholesterol-lowering properties of statins may favorably influence functioning in persons with and without peripheral arterial disease.",2003.0,0,0 1917,12580184,Slowing Parkinson's disease progression: recent dopamine agonist trials.,J Eric Ahlskog,"In recent clinical trials, chronic treatment of patients with PD with pramipexole or ropinirole was associated with a slower decline of imaged striatal dopaminergic signal, compared to levodopa monotherapy. Although this could reflect slowed progression of PD, equally plausible is a pharmacologic effect on proteins that interact with the imaging radioligands. To date, there is no compelling evidence favoring dopamine agonists over levodopa; either is an appropriate choice for initial treatment of PD.",2003.0,0,0 1918,12580993,Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients.,Steffen Bauer; Elke Störmer; Andreas Johne; Hagen Krüger; Klemens Budde; Hans-Hellmut Neumayer; Ivar Roots; Ingrid Mai,"This study investigated the effects of St John's wort extract (SJW) on the pharmacokinetics and metabolism of the immunosuppressant cyclosporin A (CSA). In an open-label study, 11 renal transplant patients received 600 mg SJW extract daily for 14 days in addition to their regular regimen of CSA. Blood concentrations of CSA and its metabolites AM1, AM1C, AM9, AM19, and AM4N were measured by HPLC. After 2 weeks of SJW coadministration, dose-corrected AUC0-12, Cmax and Ctrough values for CSA decreased significantly by 46%[geometric mean ratio baseline/SJW (95% CI): 1.83 (1.63-2.05)], 42%[1.72 (1.42-2.08)], and 41%[1.70 (1.17-2.47)], respectively. CSA doses were increased from a median of 2.7 mg day(-1) kg(-1) at baseline to 4.2 mg day(-1) kg(-1) at day 15, with the first dose adjustment required only 3 days after initiation of SJW treatment. Additionally, the metabolite pattern of CSA was substantially altered during SJW treatment. Whereas dose-corrected AUC values for AM1, AM1c and AM4N significantly decreased by 59%, 61%, and 23% compared with baseline, AUC values for AM9 and AM19 were unchanged. Following the increase in CSA dose, observed AUC and Cmax values for AM9, AM19, and AM4N increased by 20-51% and 43-90%, respectively. Administration of SJW extract to patients receiving CSA treatment resulted in a rapid and significant reduction of plasma CSA concentrations. Additionally, the substantial alterations in CSA metabolite kinetics observed may affect the toxicity profile of the drug.",2003.0,0,0 1919,12580994,Low-dose atorvastatin therapy does not augment endothelial function in active hypercholesterolaemic males.,Melinda M Parnell; Jaye P F Chin-Dusting; Jennifer Starr; David M Kaye,"As statin therapy has been demonstrated to augment endothelial function in sedentary hypercholesterolaemia (HC), we aimed to investigate the effects of atorvastatin therapy on endothelial function in physically active, HC men. Eleven physically active, HC males were recruited. Endothelial function [forearm blood flow response to brachial artery infusion of acetylcholine (Ach)] was assessed twice in each subject following atorvastatin or no therapy in a randomized crossover design. In addition, endothelial function was compared with an active, normolipidaemic control group (C). Atorvastatin therapy reduced total and LDL cholesterol, but had no effect on basal blood flow or endothelial function (peak ACh mean difference +/- standard error 0.75 +/- 1.75 ml min(-1) per 100 ml tissue) [95% confidence interval (CI) -3.1, 4.6]. In addition, there was no difference in endothelial function between the HC and C groups (-1.14 +/- 2.60 ml min(-1) per 100 ml tissue; CI -6.53, 4.25). Statin therapy in HC patients with normal endothelial function does not augment endothelial function.",2003.0,0,0 1920,12581326,Atorvastatin treatment for hyperlipidemia in pediatric renal transplant recipients.,Elizabeth Argent; Gad Kainer; Maggie Aitken; Andrew R Rosenberg; Fiona E Mackie,"The objective of this prospective study was to determine the prevalence of hyperlipidemia in our pediatric renal transplant patients and to treat those with persistently elevated cholesterol and/or low-density lipoprotein (LDL) levels. All patients with a functioning renal allograft for greater than 6 months were studied (n = 18). Patients with cholesterol and/or LDL levels greater than the 95th percentile (n = 9) were commenced on an HMG-CoA reductase inhibitor, Atorvastatin and monitoring was performed for efficacy and adverse effects. Total serum cholesterol was elevated in 11 of 18 (61%) and triglyceride (TG) was elevated in 12 of 18 (67%) patients. Atorvastatin treatment was effective with a mean percentage reduction of total cholesterol of 41 +/- 10% (p < 0.01 vs. before treatment), LDL 57 +/- 7% (p < 0.01 vs. before treatment) and TG 44 +/-25% (p = 0.05 vs. before treatment). No adverse effects on allograft function or cyclosporin levels were experienced. Hyperlipidemia is a common problem and Atorvastatin is a safe and effective treatment in pediatric renal transplant recipients.",2003.0,0,0 1921,12581545,"Prospective, noninterventional, uncontrolled, open-chart, pharmacoepidemiologic study of prescribing patterns for lipid-lowering drugs at a tertiary care teaching hospital in North India.",Pankaj Goyal; Geeta Sharma; Baljinderpal S Bal; Jatinder Singh; Jagjit Singh; Gurpreet Kaur Randhawa; Shaloo Pandhi; Rohit Sharma,"The guidelines for management of dyslipidemia released by the US National Cholesterol Education Program (NCEP) have been questioned for their relevance in the South Asian Indian populations because these populations are reported to have significantly different lipoprotein parameters and atherogenic risk factors than Western populations. The aim of this study was to determine current prescribing patterns for lipid-lowering drugs (LLDs) adopted by physicians in North India. This prospective, noninterventional, uncontrolled, open-chart, pharmacoepidemiologic study was conducted from June 2000 to August 2000 at a tertiary care hospital in North India and included 200 dyslipidemic patients. The pattern of prescribing LLDs was recorded, along with the serum levels of lipid parameters-total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and lipoprotein(a) (Lp[a])-at the time of initiating LLD therapy and compared with the 1993 NCEP-II therapeutic guidelines for dyslipidemia management. The mean (SD) levels of lipid parameters in the study population were as follows: TC, 223.2 (21.5) mg/dL; TG, 258.4 (61.3) mg/dL; LDL-C, 131.6 (26.5) mg/dL; HDL-C, 39.8 (8.9) mg/dL; and Lp(a), 44.8 (26.8) mg/dL. The LLDs prescribed were fibrates (53.5%) and statins (46.5%). Forty percent of patients prescribed LLDs did not meet the NCEP-II criteria for initiation of LLD therapy. Considerable differences in prescribing patterns of LLDs were observed compared with the then-prevalent NCEP-II guidelines. However, due to the abnormally high serum Lp(a) levels present in the average dyslipidemia profile in South Asian Indian populations, this pattern was in accordance with the specific recommendations made for these populations, as well as with the 2001 NCEP-III guidelines.",2003.0,0,0 1922,12582448,"Imatinib mesylate (Gleevec, Glivec): a new therapy for chronic myeloid leukemia and other malignancies.",Juan Carlos Hernández-Boluda; Francisco Cervantes,"Imatinib mesylate (STI571, Gleevec, Glivec, a selective inhibitor of the BCR-ABL tyrosine kinase causative of chronic myeloid leukemia (CML), represents the paradigm of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a targeted molecular therapy. Phase II clinical trials have shown marked therapeutic activity of imatinib in all evolutive phases of CML, but notably in the chronic phase, where it induces complete hematological responses in almost 100% of patients resistant or intolerant to interferon, with a major cytogenetic response rate of 60%, including 41% complete cytogenetic responses. The preliminary results of an ongoing phase III multicenter randomized study comparing imatinib with interferon plus cytarabine as first-line treatment for CML favor imatinib in terms of efficacy and safety. If confirmed with longer follow-up,these results would establish imatinib as the choice therapy for the majority of CML patients, with allogeneic transplantation being restricted as initial therapy only to younger patients with a family donor. Longer follow-up will answer some questions, such as those on long-term safety, durability of the responses, whether these will translate into a survival prolongation and the possibility of molecular responses. In addition, further information on the mechanisms involved in the primary and acquired resistance to imatinib is needed. Besides the Bcr-Abl protein, the drug is also active against other tyrosine kinases, such as Abl, the stem-cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this sense, it must be pointed out that imatinib has shown a remarkable activity in gastrointestinal stromal tumors.",2003.0,0,0 1923,12582450,Therapeutic approaches to the treatment of Alzheimer's disease.,Kiyofumi Yamada; Nabeshima Toshitaka,"Alzheimer's disease is the most common cause of progressive decline of cognitive function in aged humans and is characterized by the presence of numerous senile plaques and neurofibrillary tangles accompanied by neuronal loss. The only treatment currently available for the disease is pharmacotherapy with acetylcholinesterase inhibitors, a palliative strategy aimed at the temporary improvement of cognitive function. Other strategies with disease-modifying potential may include the use of antiinflammatory drugs, estrogen replacement therapy and antioxidants. Recent progress in understanding the molecular and cellular pathophysiology of Alzheimer's disease has suggested possible pharmacological interventions that could modify the development and progress of the disease (disease-modifying therapy), such as treatment with secretase inhibitors, transition metal chelators, HMG-CoA reductase inhibitors and amyloid-b immunization. Inhibitors of tau hyperphosphorylation may also modulate the development and progress of the disease.",2003.0,0,0 1924,12584671,"Effects of the vasopeptidase inhibitor, omapatrilat, in 723 patients with coronary heart disease.",Bruce Neal; Stephen MacMahon; Takayoshi Ohkubo; Alan Brnabic; Andrew Tonkin; Pacific Study Group,"Among individuals with a history of myocardial infarction (MI), higher levels of blood pressure (BP) are associated with increased long-term risks of death from coronary heart disease. Treatment with a BP-lowering regimen, based on omapatrilat may result in greater clinical benefits than treatment with a regimen based on a regular angiotensin-converting enzyme (ACE) inhibitor because of more favourable effects on the renin-angiotensin-aldosterone system. Seven hundred and twenty-three clinically stable patients with a history of MI or unstable angina, and a mean entry BP of 134/77 mmHg, were randomised to six months treatment with omapatrilat 40 mg, omapatrilat 20 mg, or matching placebo. After six months, mean BP levels (systolic/diastolic) in the omapatrilat 40 mg group were reduced by 4.3/2.9 mmHg (95% confidence interval 1.3 to 7.2/1.2 to 4.6). Mean BP levels in the omapatrilat 20 mg group were reduced by 4.6/1.0 mmHg (1.6 to 7.6/ 0.7 to 2.6) in comparison with the placebo group. Both doses of omapatrilat also produced significant decreases in plasma ACE activity and significant increases in levels of plasma renin activity, atrial natriuretic peptide, endothelin and homocysteine (p<0.05 for all). Premature discontinuations were more frequent with omapatrilat than with placebo (p<0.001 for 20 mg and 40 mg). Omapatrilat produced changes in BP, neurohormone and biochemical parameters that were similar for the two doses. The long-term clinical implications of the observed effects are uncertain and a large-scale randomised trial would be required to reliably establish the effects of omapatrilat on the risks of major vascular disease events among patients with coronary heart disease.",2003.0,0,0 1925,12586255,Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia.,Boris Kerzner; John Corbelli; Stephan Sharp; Leslie J Lipka; Lorenzo Melani; Alexandre LeBeaut; Ramachandran Suresh; Pabak Mukhopadhyay; Enrico P Veltri; Ezetimibe Study Group,"This multicenter, randomized, double-blind, placebo-controlled clinical study assessed the efficacy and safety of ezetimibe administered with lovastatin in primary hypercholesterolemia. After dietary stabilization, a 2- to 12-week washout period, and a 4-week single-blind placebo lead-in period, 548 patients with low-density lipoprotein (LDL) cholesterol > or =145 mg/dl (3.75 mmol/L) and < or =250 mg/dl (6.47 mmol/L) and triglycerides < or =350 mg/dl (3.99 mmol/L) were randomized to one of the following, administered daily for 12 weeks: ezetimibe 10 mg; lovastatin 10, 20, or 40 mg; ezetimibe 10 mg plus lovastatin 10, 20, or 40 mg; or placebo. The primary efficacy variable was percentage decrease in direct LDL cholesterol from baseline to end point for pooled ezetimibe plus lovastatin versus pooled lovastatin alone. Ezetimibe plus lovastatin significantly improved concentrations of LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides compared with lovastatin alone (p <0.01). The coadministration of ezetimibe provided an incremental 14% LDL cholesterol decrease, a 5% HDL cholesterol increase, and a 10% decrease in triglycerides compared with pooled lovastatin alone. Ezetimibe plus lovastatin provided mean LDL cholesterol decreases of 33% to 45%, median triglyceride decreases of 19% to 27%, and mean HDL cholesterol increases of 8% to 9%, depending on the statin dose. The coadministration of ezetimibe 10 mg plus the starting dose of lovastatin (10 mg) provided comparable efficacy to high-dose lovastatin (40 mg) across the lipid profile (LDL cholesterol, HDL cholesterol, and triglycerides). Ezetimibe plus lovastatin was well tolerated, with a safety profile similar to both lovastatin alone and placebo. The coadministration of ezetimibe and lovastatin may offer a new treatment option in lipid management of patients with hypercholesterolemia.",2003.0,0,0 1926,12586267,Effects of combined low-density lipoprotein apheresis and aggressive statin therapy on coronary calcified plaque as measured by computed tomography.,Udo Hoffmann; Kurt Derfler; Martin Haas; Alfred Stadler; Thomas Joseph Brady; Karam Kostner,,2003.0,0,0 1927,12588540,Physical activity in relation to indices of endothelial function and angiogenesis factors in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).,D C Felmeden; C G C Spencer; A D Blann; D G Beevers; G Y H Lip,"Hypertension is an important risk factor for cardiovascular disease. The latest guidelines recommend regular physical exercise as initial step or adjunct in the treatment of hypertension. We investigated the association between physical activity and the degree of hypertension, as well as the relation to indices of endothelial damage/dysfunction and angiogenesis. We studied 234 patients with hypertension (198 males; mean age 64 years; mean blood pressure 166/90 mmHg), who were compared with 60 age and sex-matched healthy normotensive controls. We assessed the patient's physical activity using the validated Baecke physical activity questionnaire and measured flow-mediated dilatation (FMD) of the brachial artery and von Willebrand factor (vWf) as indices of endothelial damage/dysfunction, whilst angiogenesis was assessed by measurement of plasma vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1) both by ELISA. When hypertensive patients were compared with the controls, there was no statistically significant difference in total physical activity score using the Baecke questionnaire although plasma VEGF and vWf levels were higher, but sFlt-1 levels and FMD lower (all P < 0.001). Patients with high physical activity were younger, and had lower mean diastolic blood pressure and 10-year Framingham stroke risk, when compared with those with low physical activity; but indices of endothelial damage/dysfunction and angiogenesis were not significantly different. Physical activity scores in hypertensive patients are not significantly different from healthy normotensive controls, and there appears to be no relation to the abnormal processes of endothelial damage/dysfunction and angiogenesis seen in hypertensives.",2003.0,0,0 1928,12588574,Physical performance measures in the clinical setting.,Stephanie Studenski; Subashan Perera; Dennis Wallace; Julie M Chandler; Pamela W Duncan; Earl Rooney; Michael Fox; Jack M Guralnik,"To assess the ability of gait speed alone and a three-item lower extremity performance battery to predict 12-month rates of hospitalization, decline in health, and decline in function in primary care settings serving older adults. Prospective cohort study. Primary care programs of a Medicare health maintenance organization (HMO) and Veterans Affairs (VA) system. Four hundred eighty-seven persons aged 65 and older. Lower extremity performance Established Population for Epidemiologic Studies of the Elderly (EPESE) battery including gait speed, chair stands, and tandem balance tests; demographics; health care use; health status; functional status; probability of repeated admission scale (Pra); and primary physician's hospitalization risk estimate. Veterans had poorer health and higher use than HMO members. Gait speed alone and the EPESE battery predicted hospitalization; 41% (21/51) of slow walkers (gait speed <0.6 m/s) were hospitalized at least once, compared with 26% (70/266) of intermediate walkers (0.6-1.0 m/s) and 11% (15/136) of fast walkers (>1.0 m/s) (P <.0001). The relationship was stronger in the HMO than in the VA. Both performance measures remained independent predictors after accounting for Pra. The EPESE battery was superior to gait speed when both Pra and primary physician's risk estimate were included. Both performance measures predicted decline in function and health status in both health systems. Performance measures, alone or in combination with self-report measures, were more able to predict outcomes than self-report alone. Gait speed and a physical performance battery are brief, quantitative estimates of future risk for hospitalization and decline in health and function in clinical populations of older adults. Physical performance measures might serve as easily accessible ""vital signs"" to screen older adults in clinical settings.",2003.0,0,0 1929,12590226,Optimal management of nonalcoholic fatty liver/steatohepatitis.,Herbert L Bonkovsky,,2003.0,0,0 1930,12590901,Statin effects beyond lipid lowering--are they clinically relevant?,P O Bonetti; L O Lerman; C Napoli; A Lerman,,2003.0,0,0 1931,12591845,"Women, older persons, and ethnic minorities: factors associated with their inclusion in randomised trials of statins 1990 to 2001.",C Bartlett; P Davey; P Dieppe; L Doyal; S Ebrahim; M Egger,,2003.0,0,0 1932,12592082,Bexarotene is a new treatment option for lymphomatoid papulosis.,Richard A Krathen; Staci Ward; Madeleine Duvic,"Lymphomatoid papulosis (LyP) is a clonal T cell proliferation with large cell histology, a chronic course, and an increased risk of lymphoma. Bexarotene (Targretin) is an RXR-selective retinoid (rexinoid) approved for the cutaneous manifestations of cutaneous T cell lymphoma. To determine whether bexarotene is effective in treating LyP. Ten patients with chronic and symptomatic LyP were prospectively treated with oral (n = 3) or topical gel (n = 7) formulations of bexarotene. A favorable response to bexarotene treatment with decreased numbers or duration of lesions was seen in all with objective responses in 8 patients. Bexarotene may be an effective palliative treatment for LyP, warranting further controlled studies.",2003.0,0,0 1933,12593493,Effects of policosanol and lovastatin in patients with intermittent claudication: a double-blind comparative pilot study.,Gladys Castaño; Rosa Más; Lilia Fernández; Rafael Gámez; José Illnait,"Policosanol is a cholesterol-lowering drug with concomitant antiplatelet effects. The present study was undertaken to compare the effects of policosanol and lovastatin on patients with moderately severe intermittent claudication. The study had a 4-week baseline step, followed by a 20-week double blinded, randomized treatment period. Twenty-eight patients who met study entry criteria were randomized to policosanol 10 mg or lovastatin 20 mg tablets once daily. Walking distances in a treadmill (constant speed 3.2 km/hr, slope 10 degrees, temperature 25 degrees C) were assessed before and after 20 weeks of treatment. Both groups were similar at randomization. Compared with baseline, policosanol increased significantly (p < 0.01) the initial claudication distance (ICD) from 160.39 +/- 15.82 m to 211.31 +/- 21.48 m (+33.7%) and the absolute claudication distance (ACD) (p < 0.001) from 236.39 +/- 25.44 m to 288.09 +/- 28.47 m (+24.3%); meanwhile both variables remained unchanged after lovastatin therapy. Changes in ICD and ACD were significantly larger in the policosanol than in the lovastatin group (p < 0.01). Policosanol, but not lovastatin, significantly increased (p < 0.05) the ankle/arm index, although between-group differences were not significant. The frequency of patients reporting improvement on quality of life domains was greater in the policosanol than in the lovastatin group. Policosanol significantly (p < 0.001) lowered total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) by 17.5% and 31.0%, respectively, and meanwhile increased (p < 0.01) high-density lipoprotein-cholesterol (HDL-C) levels by 31.5%. Lovastatin reduced (p < 0.01) TC (18.0%), LDL-C (22.6%), and (p < 0.05) triglycerides (9.8%). In addition, policosanol, but not lovastatin, moderately, but significantly, reduced (p < 0.05) fibrinogen levels, so that final values and percent changes in both groups were different (p < 0.01). Treatments were well tolerated. Only 1 lovastatin patient withdrew from the study because of a nonfatal myocardial infarction. Five lovastatin patients, but none from the policosanol group, experienced 6 adverse events (AE) (p < 0.01). The present results indicate that policosanol, but not lovastatin, is a suitable alternative to manage patients with intermittent claudication because of pleiotropic properties beyond its cholesterol-lowering effects.",2003.0,0,0 1934,12594645,,,,,0,0 1935,12595055,What's new in vascular surgery.,William H Pearce,,2003.0,0,0 1936,12595916,Pharmacology of the ACAT inhibitor avasimibe (CI-1011).,Gemma Llaverías; Juan C Laguna; Marta Alegret,"Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL. The concentration-dependent reduction in cellular cholesteryl ester content in these cells was not accompanied by an increase in intracellular free cholesterol, which is in agreement with a good safety profile for avasimibe. In the liver, avasimibe caused a significant reduction in the secretion of apo B and apo B-containing lipoproteins into plasma. Avasimibe induced cholesterol 7alpha-hydroxylase and increased bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in cholesterol-fed as well as in non-cholesterol-fed animals. In these models, plasma cholesterol levels were reduced, mainly due to the decrease in the non-HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50-500 mg/day, significantly reduced plasma total triglyceride and VLDL-cholesterol. Although total cholesterol, LDL-cholesterol, and HDL-cholesterol were unchanged, it must be stressed that animal data suggest that avasimibe may have direct antiatherosclerotic activity in addition to its cholesterol-lowering effect. Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces matrix metalloproteinase expression and activity. Moreover, avasimibe and statins have been shown to have synergistic effects, and the combination therapy may not only inhibit atherosclerotic lesion progression but also induce lesion regression, independently of changes in plasma cholesterol.",2003.0,0,0 1937,12596356,Personalized medicine.,Kewal K Jain,"Personalized medicine simply means the prescription of specific therapeutics best suited for an individual based on pharmacogenetic and pharmacogenomic information. The basis of personalized medicine are reviewed. Several technologies are used including single nucleotide polymorphism genotyping. haplotyping, gene expression studies by biochip/microarrays and proteomics. Molecular diagnostics will play an important role in the development of personalized medicine, in which therapy and diagnosis will be integrated. There are several examples of the personalized medical approach, which include genotype-based selection of patients for effective cancer therapy, to spare those who would not respond or would suffer undesirable side effects. Personalized therapy is financially feasible, as it will reduce the costs of drug development by shortening the drug development cycle. The introduction of pharmacogenomics into clinical trials is reducing the chances of failed clinical trials and increasing the prospects of safer and more effective therapies for specific groups of patients. Several advantages, as well as challenges to the development of personalized medicine are examined. Personalized medicine is anticipated to be an acceptable part of medical practice by the year 2010.",2003.0,0,0 1938,12597264,Outcome measurement: evaluating evidence for managing patients with acute coronary syndromes.,Christi Deaton; William S Weintraub,"Evidence-based practice has been proposed as a means to improve the quality of care and decrease unwarranted variability in practice, but evaluating clinical trial data as evidence for practice is made more difficult because practice changes rapidly. This article reviews current clinical trial data on the management of patients with acute coronary syndromes, but the same principles can be used when evaluating alternative medicines. Current evidence supports risk stratification, early treatment with glycoprotein IIb/IIIa inhibitors, and an early invasive strategy in patients who are at intermediate to high risk. In addition, cholesterol-lowering statins should be initiated early in the patient's hospitalization.",2003.0,0,0 1939,12598136,Parsing an enigma: the pharmacodynamics of aspirin resistance.,Garret A FitzGerald,,2003.0,0,0 1940,12598874,Steps taken toward improving dementia treatment during 2002.,Carol A Miller,,2003.0,0,0 1941,12600918,Reduced connexin43 expression inhibits atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice.,Brenda R Kwak; Niels Veillard; Graziano Pelli; Flore Mulhaupt; Richard W James; Marc Chanson; François Mach,"Gap junctions allow the direct exchange of ions and small molecules between cells in contact, thus coordinating physiological processes such as cell growth and differentiation. We have recently demonstrated increased expression of the gap junction protein connexin43 (Cx43) in specific subsets of cells in atherosclerotic lesions. Because the development of atherosclerosis depends critically on paracrine cell-to-cell interactions, we hypothesized that direct intercellular communication via gap junctions may be another factor controlling atherogenesis. The role of Cx43 in atherogenesis was examined by use of both a genetic and a pharmacological approach. First, atherosclerosis-susceptible LDL receptor-deficient (LDLR-/-) mice with normal (Cx43+/+) or reduced (Cx43+/-) levels of Cx43 were fed a cholesterol-rich diet for 14 weeks. The progression of atherosclerosis was reduced by 50% (P<0.01) in the thoracoabdominal aorta and in the aortic roots of Cx43+/-LDLR-/- mice compared with Cx43+/+LDLR-/- controls. Atheroma in Cx43+/-LDLR-/- mice contained fewer inflammatory cells and exhibited thicker fibrous caps with more collagen and smooth muscle cells. Next, we observed that HMG-CoA reductase inhibitors, or ""statins,"" lipid-lowering drugs well known for their pleiotropic antiatherogenic effects, reduced Cx43 expression in primary human vascular cells in vitro. Atheroma of LDLR-/- mice treated orally with pravastatin contained fewer inflammatory cells and exhibited thicker fibrous caps than controls. This was associated with reduced Cx43 expression in lesions of statin-treated mice. These data indicate a critical role for Cx43-mediated gap junctional communication in atherosclerotic plaque formation.",2003.0,0,0 1942,12602373,Telithromycin: new preparation. A needless addition to the other macrolides.,,"(1) Macrolides are an alternative to beta-lactam agents for treating uncomplicated community-acquired pneumonia, acute exacerbations of chronic bronchitis, sinusitis and throat infections. The choice of macrolides is based mainly on the risk of interactions, which is lowest with spiramycin. (2) Telithromycin is a macrolide antibiotic derived from erythromycin. It was first marketed in France in 2002, for the above indications. (3) Telithromycin is no more effective than the antibiotics with which it has been compared, namely amoxicillin and clarithromycin in non life-threatening pneumonia; amoxicillin-clavulanate and cefuroxime axetil in acute exacerbations of chronic bronchitis and acute sinusitis; and clarithromycin and phenoxymethylpenicillin (penicillin V) in pharyngotonsillitis. (4) In clinical trials, telithromycin was not more effective than comparator antibiotics on infections thought to be due to pneumococcal strains resistant to penicillin and/or erythromycin. Cases of erythromycin cross-resistance have been observed. (5) The adverse effects of telithromycin are the same as those of other macrolides, mainly gastrointestinal disturbances, headache, dizziness, and hepatotoxicity. Telithromycin also carries a risk of torsades de pointes, and seems to cause more visual problems than other macrolides. (6) Telithromycin inhibits cytochrome P450 isoenzymes, so there is a high risk of drug interactions. (7) In practice, spiramycin remains the standard option when a macrolide is indicated for the treatment of common ENT and pulmonary infections.",2003.0,0,0 1943,12602538,Atorvastatin improves metabolic control and endothelial function in type 2 diabetic patients: a placebo-controlled study.,E Dalla Nora; A Passaro; P F Zamboni; F Calzoni; R Fellin; A Solini,"Several pieces of evidence support a role of inflammatory processes in the pathogenesis of atherosclerosis; it is also known that endothelial dysfunction is the initial lesion of the atherosclerotic process. Among other markers of endothelial dysfunction, some adhesion molecules seem to play an interesting role. The aim of the present study was to evaluate the effect of atorvastatin vs placebo on some indexes of leukocytes adhesion in a group of Type 2 diabetic patients. Twenty-five Type 2 diabetic patients free from microangiopathic complications and with LDL-cholesterol lower than 180 mg/dl were randomized to receive either atorvastatin (T2DA) or placebo (T2Dp) for twelve months. BMI, fasting plasma glucose, glycated hemoglobin (HbA1c), albumin excretion rate (AER), lipid profile, and serum concentrations of vascular cell adhesion molecule-1 (VCAM1), E-selectin and cadherin-5 were measured at baseline and at the end of the follow-up. At T0 E-selectin was 16 +/- 6 ng/ml in T2DA and 17 +/- 13 in T2Dp; VCAM1 was 413 +/- 112 ng/ml in T2DA and 411 +/- 112 in T2Dp. At T12 VCAM1 and E-selectin did not vary in T2Dp, while a significant reduction was observed in T2DA (VCAM1 275 +/- 104 ng/ml and E-selectin 8 +/- 3 ng/ml; p < 0.001 and p < 0.01, respectively). T2DA also showed a reduction of total and LDL cholesterol and an improved glycemic control respect to T2Dp. Hypolipidemic therapy was the strongest independent predictor of the cytokines variations along the time. These results confirm the role of statins in modulating endothelial function also in Type 2 diabetes, outlining a therapeutic role of these molecules probably independent from the hypolipidemic effect.",2003.0,0,0 1944,12603176,"Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin.",Jasper Dingemanse; Dieter Schaarschmidt; Paul L M van Giersbergen,"In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP) 2C9 and 3A4. To investigate in vivo the mutual pharmacokinetic interactions between bosentan and simvastatin, a CYP3A4 substrate. Nine healthy male subjects were treated in a three-period randomised crossover study with: (A) bosentan 125 mg twice daily for 5.5 days; (B) simvastatin 40 mg once daily for 6 days; and (C) bosentan 125 mg twice daily and simvastatin 40 mg once daily for 5.5 and 6 days, respectively. Plasma concentration-time profiles of bosentan and its metabolites (treatments A and C) and simvastatin and beta-hydroxyacid simvastatin (treatments B and C) were determined on day 6. Steady-state conditions for bosentan and its metabolites were attained on day 4 of treatment. The pharmacokinetic parameters of bosentan and its metabolites were not influenced by concomitant treatment with simvastatin: areas under the plasma concentration-time curve over one administration interval of 12 hours (AUC(tau)) [geometric mean and 95% CI] were 4586 (3719-5656) and 4928 (3945-6156) micro g * h/L. In contrast, bosentan significantly reduced exposure to simvastatin and beta-hydroxyacid simvastatin by 34 and 46%, respectively. AUC(tau) values for simvastatin were 30.5 (23.1-40.2) and 20.0 (15.9-25.1) micro g * h/L and for beta-hydroxyacid simvastatin 43.0 (32.1-57.8) and 23.4 (16.7-32.6) micro g * h/L in treatments B and C, respectively. Concomitant treatment with bosentan reduces the exposure to simvastatin and beta-hydroxyacid simvastatin by approximately 40%, indicating that in vivo bosentan is also a mild inducer of CYP3A4.",2003.0,0,0 1945,12603188,Behavioural and psychological symptoms of dementia: a seven-tiered model of service delivery.,Henry Brodaty; Brian M Draper; Lee-Fay Low,"People with dementia usually experience behavioural and psychological symptoms of dementia (BPSD) during the course of their illness. Currently, in Australia, there is a lack of comprehensive planning for managing and preventing BPSD, and the resources required for optimal care are inadequate and unevenly distributed. We propose a seven-tiered model of service delivery based on severity and prevalence of BPSD, ranging from no dementia through tiers of increasingly severe behavioural disturbance to the propensity for extreme violence in a small number of individuals. Each tier is associated with a different model of intervention. People with dementia may move up or down between tiers depending on their condition, their care and the intervention provided. Lower-level interventions may prevent the need for the more intensive interventions needed when disturbance becomes more severe.",2003.0,0,0 1946,12603254,"Treatment of mild cognitive impairment: rationale, present and future strategies.",Vesna Jelic; Bengt Winblad,"Mild cognitive impairment (MCI) is a condition with a high conversion rate to Alzheimer's disease (AD), which justifies early diagnostic and therapeutic interventions. At the moment, treatment strategies for AD could be extrapolated to interventional strategies in MCI. This article reviews currently available symptomatic treatments with acetylcholinesterase inhibitors, putative treatments such as antiglutamatergic drugs, nootropics, antioxidants, anti-inflammatory drugs and still controversial estrogen replacement therapy, and visionary treatments targeting neuropathological substrates of the disease, such as amyloid production and aggregation, phosphorylation of tau, formation of neurofibrillary tangles and apoptosis. Findings from epidemiological studies have expanded our knowledge on risk as well as possible neuroprotective factors and given means to develop preventive strategies with antihyperlipidaemic drugs such as statins. A wide range of suggested treatments and their possible combinations necessitate their efficacy assessment in well-designed randomized clinical trials where the crucial prerequisites are selection of the treatment population and definitions of outcome measures. Prevention and disease-modifying strategies are raising ethical questions because interventions are focused on non-diseased elderly at risk, which means that emphasis should be not only on efficacy but also on long-term safety.",2003.0,0,0 1947,12605558,,,,,0,0 1948,12605562,Novel antibacterial agents for the treatment of serious Gram-positive infections.,Darren Abbanat; Mark Macielag; Karen Bush,"With the continuing development of clinical drug resistance among bacteria and the advent of resistance to the recently released agents quinupristin-dalfopristin and linezolid, the need for new, effective agents to treat multi-drug-resistant Gram-positive infections remains important. This review focuses on agents presently in clinical development for the treatment of serious multidrug-resistant staphylococcal, enterococcal and pneumococcal infections, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae. Agents to be discussed that affect the prokaryotic cell wall include the antimethicillin-resistant S. aureus cephalosporins BAL9141 and RWJ-54428, the glycopeptides oritavancin and dalbavancin and the lipopeptide daptomycin. Topoisomerase inhibitors include the fluoroquinolones gemifloxacin, sitafloxacin and garenoxacin. Protein synthesis inhibitors are represented by the ketolides telithromycin and cethromycin, the oxazolidinones and the glycylcycline tigecycline. Although each of these compounds has demonstrated antibacterial activity against antibiotic-resistant pathogens, their final regulatory approval will depend on an acceptable clinical safety profile.",2003.0,0,0 1949,12605563,The role of pharmacological enhancement in protease inhibitor-based highly active antiretroviral therapy.,Stephen L Becker,"Having changed the landscape in the treatment of HIV infection, the functional efficacy of current protease inhibitors (PIs) remains limited by their pharmacokinetic and pharmacodynamic profiles. Complex metabolism by the cytochrome P450 system (particularly the 3A4 isoenzyme), action of membrane drug transporter elements (such as P-glycoprotein and multi-drug resistance-associated proteins) and activation of the nuclear receptor steroid xenobiotic receptor may alter exposures and compromise the antiretroviral activity of these drugs. These factors, as well as inadequate adherence, can facilitate the emergence of PI resistance and lead to regimen failure. Coadministration of ritonavir can enhance exposures of a primary PI by inhibiting CYP3A4 metabolism, P-glycoprotein activity and multi-drug resistance protein-1-mediated efflux. Adding ritonavir, however, is not without cost. Dyslipidaemia (possibly increasing the risk of cardiovascular events), gastrointestinal intolerance, multiple drug-to-drug interactions and activation of steroid xenobiotic receptor can all result and must be balanced against the pharmacokinetic improvement rendered by the addition of ritonavir. Understanding the pharmacological origins for the variations in exposures of PIs, both between and within patients, is important for the successful use of these agents.",2003.0,0,0 1950,12605567,The potential of nitric oxide therapeutics in stroke.,M R Willmot; P M W Bath,"The therapeutic modulation of the nitric oxide (NO) system has generated considerable interest as a new way for managing many disease processes. In stroke, a useful strategy is to increase NO availability and thereby exploit its beneficial antiplatelet, antiatherosclerotic, haemodynamic and neuroprotective properties. Pharmacologically, this can be achieved by providing NO substrate, using NO donors or by upregulating nitric oxide synthase. Alternatively, one can reduce NO availability by inhibiting NO synthase and thereby limiting its pro-inflammatory and neurotoxic properties. This article reviews developments in NO-related therapeutics for treatment of stroke, with a particular emphasis on compounds that are in the clinical research and development pipeline. Although the routine use of NO therapeutics for the prevention or treatment of stroke cannot currently be recommended, we are evidently at an exciting stage in their pharmacological development. Definitive randomised controlled trials in stroke patients are required as a matter of urgency.",2003.0,0,0 1951,12605568,Treatment of scleroderma: an update.,Sangeeta D Sule; Fredrick M Wigley,"The goal of this article is to update the reader and focus on novel therapies and clinical trials published since our last review [6]. Evidence suggests that drug intervention should target one or all of three biological processes: vascular disease, autoimmunity and tissue fibrosis. Efforts should be made to classify the subtype of scleroderma, to determine the activity of the disease process and the degree of specific organ involvement before specific treatment decisions are made. Cyclophosphamide in fibrosing alveolitis, intravenous prostaglandins and other vasodilators for the vascular disease, endothelin-1 inhibition in pulmonary hypertension and immunosuppressive therapy for early inflammatory disease, all appear to have benefit. Several agents used in vitro and in animal models of fibrosis also show promise including anti-transforming growth factor-beta, the statins and anti-integrins. More experience in well-designed clinical trials is needed to define the role of these agents in treating scleroderma.",2003.0,0,0 1952,12605572,Expanding indications of statins; implications of the Heart Protection Study.,Amar M Salam,"The Heart Protection Study is the largest trial of statin therapy conducted to date. It provides important new information on the use of statins in women, the elderly, diabetics and people with low baseline cholesterol pretreatment and those with prior occlusive non-coronary vascular disease. In this report, the paper is discussed with the significance of the results outlined in view of existing evidence from previously published trials. In addition, ongoing trials and future directions are explored.",2003.0,0,0 1953,12605757,[Analysis of differences in flow-mediated dilation in relation to the treatment of coronary patients].,Enrique Novo García; Javier Balaguer; Eulalia Jiménez; Alberto García Lledó; Manuela Caballero; Manuel Chaparro,"Flow-mediated dilation (FMD) is thought to be related to the development of coronary disease. We were interested in knowing the degree of FMD in a large sample of coronary patients in relation to the therapy they were given in clinical practice. We studied 1,081 coronary patients (age 68 +/- 12 years, 73% male) in which FMD was evaluated in the brachial artery. The patients were classified into 5 treatment groups (416 who receive 2 or more treatments were excluded): group A: 81 controls treated with aspirin, group B: 198 treated with ACE inhibitors, group C: 106 with calcium antagonists, group D: 145 with beta-blockers, and group E: 135 with lipid lowering medication (93% statins). ANOVA was used to analyze the differences between groups. With regard to the number of risk factors present in each group, the patients treated with ACE inhibitors (2.44 +/- 0.79 vs 2.14 +/- 0.89; p < 0.05) and statins (3.45 +/- 0.70 vs 2.14 +/- 0.89; p < 0.05) had more risk factors than GrA and higher levels of LDL-cholesterol (ACE inhibitors 145.0 +/- 33.5 vs 128.5 +/- 32.2 and statins 157.8 +/- 45.3 vs 128.5 +/- 32.2; p < 0.05). GrB had a higher glycemia than controls (123.4 +/- 32.2 vs 114.7 +/- 33.7; p < 0.05). The control group was younger than the therapeutic groups (p < 0.05). Compared with the control group, FMD was significantly higher only in the group treated with ACE inhibitors (3.42 +/- 6.01 vs 0.82 +/- 6.04; p < 0.05). Multivariate logistical regression showed that treatment with ACE inhibitors and statins (p < 0.05) were independent predictors of FMD > 4%. Treatment with ACE inhibitors or statins was predictive of the normalization of FMD in coronary patients in clinical practice.",2003.0,0,0 1954,12606523,Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome.,Gerald F Watts; P Hugh R Barrett; Juying Ji; Adrian P Serone; Dick C Chan; Kevin D Croft; Franziska Loehrer; Anthony G Johnson,"The metabolic syndrome is characterized by insulin resistance and abnormal apolipoprotein AI (apoAI) and apolipoprotein B-100 (apoB) metabolism that may collectively accelerate atherosclerosis. The effects of atorvastatin (40 mg/day) and micronised fenofibrate (200 mg/day) on the kinetics of apoAI and apoB were investigated in a controlled cross-over trial of 11 dyslipidemic men with the metabolic syndrome. ApoAI and apoB kinetics were studied following intravenous d(3)-leucine administration using gas-chromatography mass spectrometry with data analyzed by compartmental modeling. Compared with placebo, atorvastatin significantly decreased (P < 0.001) plasma concentrations of cholesterol, triglyceride, LDL cholesterol, VLDL apoB, intermediate-density lipoprotein (IDL) apoB, and LDL apoB. Fenofibrate significantly decreased (P < 0.001) plasma triglyceride and VLDL apoB and elevated HDL(2) cholesterol (P < 0.001), HDL(3) cholesterol (P < 0.01), apoAI (P = 0.01), and apoAII (P < 0.001) concentrations, but it did not significantly alter LDL cholesterol. Atorvastatin significantly increased (P < 0.002) the fractional catabolic rate (FCR) of VLDL apoB, IDL apoB, and LDL apoB but did not affect the production of apoB in any lipoprotein fraction or in the turnover of apoAI. Fenofibrate significantly increased (P < 0.01) the FCR of VLDL, IDL, and LDL apoB but did not affect the production of VLDL apoB. Relative to placebo and atorvastatin, fenofibrate significantly increased the production (P < 0.001) and FCR (P = 0.016) of apoAI. Both agents significantly lowered plasma triglycerides and apoCIII concentrations, but only atorvastatin significantly lowered (P < 0.001) plasma cholesteryl ester transfer protein activity. Neither treatment altered insulin resistance. In conclusion, these differential effects of atorvastatin and fenofibrate on apoAI and apoB kinetics support the use of combination therapy for optimally regulating dyslipoproteinemia in the metabolic syndrome.",2003.0,0,0 1955,12606925,Modifying cardiovascular risk in diabetes mellitus.,Weidong Gu; Paul S Pagel; David C Warltier; Judy R Kersten,,2003.0,0,0 1956,12609587,Macrolides in dermatology.,Noah S Scheinfeld; William D Tutrone; Omar Torres; Jeffrey M Weinberg,,2003.0,0,0 1957,12610743,Pharmacokinetics and pharmacodynamics of rosuvastatin in subjects with hepatic impairment.,S G Simonson; P D Martin; P Mitchell; D W Schneck; K C Lasseter; M J Warwick,"To assess the effect of chronic hepatic impairment on rosuvastatin disposition, pharmacodynamic activity and tolerability. This was an open-label, non-randomised, parallel-group trial. Six subjects were enrolled in each of three hepatic-function strata: Child-Pugh class A (CP-A, mild impairment), Child-Pugh class B (CP-B, moderate impairment) and normal hepatic function; the latter two strata were age, weight, race, sex and smoking history matched. All subjects were given rosuvastatin 10 mg for 14 days. In subjects with CP-A, and in four of six subjects with CP-B, rosuvastatin steady-state AUC(0-24) and C(max) were similar to subjects with normal hepatic function (geometric mean values 60.7 ng h/ml and 6.02 ng/ml, respectively). Two of six subjects with CP-B who had the highest CP scores (i.e. the highest degrees of hepatic impairment) had the highest AUC(0-24) (128 ng h/ml and 242 ng h/ml) and C(max) (23.4 ng/ml and 96.7 ng/ml) values. Low-density lipoprotein cholesterol (LDL-C) was decreased in all strata, but the response was more variable in the CP-B group. Rosuvastatin was well tolerated, and the safety profile was similar in subjects with hepatic impairment and normal hepatic function. In most subjects with mild-to-moderate hepatic impairment, the steady-state pharmacokinetics of rosuvastatin were similar to subjects with normal hepatic function (more extensive hepatic impairment may increase systemic exposure to rosuvastatin), and most had LDL-C reductions similar to subjects with normal hepatic function.",2003.0,0,0 1958,12611741,"Interventions for mild cognitive impairment and Alzheimer disease: new strategies, new hope.",P Murali Doraiswamy,,2003.0,0,0 1959,12611742,Drug development and Alzheimer disease.,Allen D Roses; Menelas N Pangalos,,2003.0,0,0 1960,12612852,[Prevention of dementias: state of the art].,Isabella Heuser,"Dementias of late life constitute a major public health challenge. Alzheimer disease (AD) is the most common form. Epidemiological studies suggest that the use of nonsteroidal anti-inflammatory drugs, wine and coffee consumption and regular physical activity may delay onset of AD or reduce rate of progression. Preclinical research in animals and epidemiological studies in humans have shown that estrogen substitution strategies and lipid lowering statins may be beneficial. Thus, despite the lack of prospective studies and, therefore, consensus, different pharmacological strategies for persons at high risk for Alzheimer's disease are discussed.",2003.0,0,0 1961,12612871,Undertreatment of hyperlipidemia in patients with coronary artery disease and heart failure.,Carla A Sueta; Mark W Massing; Mridul Chowdhury; David P Biggs; Ross J Simpson,"Coronary artery disease patients with heart failure (CAD+HF) are at high risk for cardiovascular events. We examined the frequency of lipid assessment and prescription of lipid-lowering agents in outpatients with combined CAD+HF compared with patients with CAD alone. We analyzed an administrative data set from the Quality Assurance Program II, a Merck & Co., Inc., sponsored national retrospective chart audit of 41,487 CAD patients seen at 296 ambulatory medical practices. About 34% of these patients had CAD+HF. Documentation of low-density lipoprotein (LDL) cholesterol was significantly lower in patients with CAD+HF (53%) compared with those with CAD alone (69%). Lipid-lowering drugs were prescribed in only 36% of patients with CAD+HF, compared with 52% of patients with CAD alone. Lipid levels alone did not justify this disparity. Patients with documented LDL cholesterol values were 4 times more likely to receive a prescription for a lipid-lowering medication than those without recorded values. Other predictors of lipid-lowering prescription included: younger age, history of myocardial infarction, revascularization, care by a cardiologist, and geographic region. Patients with CAD, HF, and advanced age simultaneously experience among the highest risk and the lowest lipid-lowering treatment rates. Strategies to increase LDL testing and aggressively treat patients with heart failure and CAD are warranted.",2003.0,0,0 1962,12612979,"A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease.",Stefano Bianchi; Roberto Bigazzi; Alberto Caiazza; Vito M Campese,"Chronic kidney diseases, particularly if presenting with significant proteinuria, are commonly associated with substantial alteration of serum lipid levels. Experimental evidence suggests that lipid abnormalities may contribute to the progression of kidney disease. However, studies in humans on the subject are scarce. In a prospective, controlled open-label study, the authors have evaluated the effects of one-year treatment with atorvastatin, a 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, versus no treatment on proteinuria and progression of kidney disease in 56 patients with chronic kidney disease. Before randomization, all patients had already been treated for one year with angiotensin-converting enzyme (ACE) inhibitors or angiotensin AT1 receptor antagonists (ARBs) and other antihypertensive drugs. By the end of one-year treatment, urine protein excretion decreased from 2.2 +/- 0.1 to 1.2 +/- 1.0 g every 24 hours (P < 0.01) in patients treated with atorvastatin in addition to ACE inhibitor and ARBs. By contrast, urinary protein excretion decreased only from 2.0 +/- 0.1 to 1.8 +/- 0.1 g every 24 hours (P value not significant) in patients who did not receive atorvastatin in addition to ACE inhibitor or ARBs. During this time, creatinine clearance decreased only slightly and not significantly (from 51 +/- 1.8 to 49.8 +/- 1.7) in patients treated with atorvastatin. By contrast, during the same period of observation, creatinine clearance decreased from 50 +/- 1.9 to 44.2 +/- 1.6 mL/min (P < 0.01) in patients who did not receive atorvastatin. This study has shown that treatment with atorvastatin in addition to a regimen with ACE inhibitors or ARBs may reduce proteinuria and the rate of progression of kidney disease in patients with chronic kidney disease, proteinuria, and hypercholesterolemia. The benefits appear to occur in addition to those of treatment with ACE inhibitor and ARBs.",2003.0,0,0 1963,12613230,Statin fails to meet expectations.,Kate Traynor,,2003.0,0,0 1964,12614193,ACE inhibitors or AT-1 antagonists - which is OPTIMAAL after acute myocardial infarction?,Sheila A Doggrell,"OPTIMAAL (Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan) is the first major study to compare an angiotensin II Type 1 antagonist losartan (Cozaar trade mark, Merck) with an ACE inhibitor captonpril (Capoten trade mark, Elan) after myocardial infarction in patients with left ventricular dysfunction. Patients were assigned to a target dose of losartan 50 mg/day and captopril 50 mg t.i.d., as tolerated. The primary end point was all-cause mortality and there were 499 (18%) and 447 (16%) deaths in the losartan and captopril group, respectively (p = 0.07). However, there were significantly more cardiovascular deaths with losartan (420, 15%) than with captopril (363, 13%; p = 0.03). Losartan was better tolerated than captopril with fewer patients discontinuing medication (17 versus 23% for losartan and captopril, respectively). In conclusion, if tolerated, captopril should remain the preferred treatment for patients after complicated acute myocardial infarction.",2003.0,0,0 1965,12615272,Effect of atorvastatin (80 mg) and simvastatin (40 mg) on plasma fibrinogen levels and on carotid intima media thickness in patients with familial hypercholesterolemia.,Mieke D Trip; Sanne van Wissen; Tineke J Smilde; Barbara A Hutten; Anton F H Stalenhoef; John J P Kastelein,,2003.0,0,0 1966,12615276,Monitoring of hepatic function during amiodarone therapy.,P Timothy Pollak; Yong Dong You,,2003.0,0,0 1967,12615850,Drugs of the 21st century: telithromycin (HMR 3647)--the first ketolide.,Grit Ackermann; Arne C Rodloff,Telithromycin (HMR 3647) is the first ketolide introduced into clinical practice. Ketolides are semisynthetic derivates of erythromycin A that carry novel biological properties on the erythronolide A ring. This new class of antimicrobials was designed to overcome current resistance mechanisms against erythromycin A within Gram-positive cocci. Ketolides do not induce macrolide-lincosamide-streptogramin B (MLS(B)) resistance and are active against erythromycin resistance methylase gene (erm)-carrying Gram-positive cocci. This review summarizes published data on telithromycin and intends to define the challenge that a new antimicrobial brings to medical practice.,2003.0,0,0 1968,12615984,"Identifying acute myocardial infarction: effects on treatment and mortality, and implications for National Service Framework audit.",R J Sapsford; R A Lawrance; M F Dorsch; R Das; B M Jackson; C Morrell; M B Robinson; A S Hall; Evaluation of Methods and Management of Acute Coronary Events Study Group,"The National Service Framework (NSF) for Coronary Heart Disease requires annual clinical audit of the care of patients with myocardial infarction, with little guidance on how to achieve these standards and monitor practice. To assess which method of identification of acute myocardial infarction (AMI) cases is most suitable for NSF audit, and to determine the effect of the definition of AMI on the assessment of quality of care. Observational study. Over a 3-month period, 2153 consecutive patients from 20 hospitals across the Yorkshire region, with confirmed AMI, were identified from coronary care registers, biochemistry records and hospital coding systems. The sensitivity and positive predictive value of AMI patient identification using clinical coding, biochemistry and coronary care registers were compared to a 'gold standard' (the combination of all three methods). Of 3685 possible cases of AMI singled out by one or more methods, 2153 patients were identified as having a final diagnosis of AMI. Hospital coding revealed 1668 (77.5%) cases, with a demographic profile similar to that of the total cohort. Secondary preventative measures required for inclusion in NSF were also of broadly similar distribution. The sensitivities and positive predictive values for patient identification were substantially less in the cohorts identified through biochemistry and coronary care unit register. Patients fulfilling WHO criteria (n=1391) had a 30-day mortality of 15.9%, vs. 24.2% for the total cohort. Hospital coding misses a substantial proportion (22.5%) of AMI cases, but without any apparent systematic bias, and thus provides a suitably representative and robust basis for NSF-related audit. Better still would be the routine use of multiple methods of case identification.",2003.0,0,0 1969,12618273,Effects of atorvastatin on electrophoretic characteristics of LDL particles among subjects with heterozygous familial hypercholesterolemia.,Mathieu Larivière; Benoít Lamarche; Matteo Pirro; Jean-Charles Hogue; Jean Bergeron; Claude Gagné; Patrick Couture,"The effects of the HMG CoA reductase inhibitor atorvastatin on electrophoretic characteristics of LDL particles were evaluated in 46 patients (28 males and 18 females) with heterozygous familial hypercholesterolemia (FH) aged 20-61 carrying either a negative or a defective LDL receptor gene mutation. Following a 6 week drug-free baseline period, FH heterozygotes were treated with atorvastatin (median dose: 20 mg/day, range 10-80 mg/day)) for 6 months to maintain their plasma LDL-cholesterol concentrations between 4.0 and 5.0 mmol/l. Atorvastatin treatment significantly reduced plasma total cholesterol, LDL-cholesterol and triglyceride levels and increased plasma HDL-cholesterol. Furthermore, atorvastatin treatment significantly increased LDL peak particle diameter (LDL-PPD) by 0.5% (from 255.0+/-6.2 to 256.4+/-5.5 A, P=0.004) and reduced the absolute concentration of cholesterol among small (<255 A) and large (>260 A) LDL particles by 35% (P<0.001). Changes in LDL-PPD and plasma triglyceride levels were inversely correlated (R=-0.34; P=0.02). Stepwise multiple linear regression analyses showed that 41.6% of the variation in the LDL-PPD response to atorvastatin was attributable to the initial LDL-PPD (14.4%, P=0.003), the apo E polymorphism (12.4%, P=0.02), the nature of the LDL receptor gene mutation (9.6%, P=0.01) and change in triglyceride levels (5.2%, P=0.04). Moreover, the reduction in the cholesterol content of LDL <255 A was directly correlated with the daily dosage of atorvastatin (P=0.05). Results of the present study showed that atorvastatin alters significantly LDL heterogeneity in patients at high risk of coronary heart disease (CHD) such as FH heterozygotes. These results also suggest that genetic and metabolic factors may be important determinants of atorvastatin-induced changes of LDL particle size and distribution among FH heterozygotes.",2003.0,0,0 1970,12618561,Lipoatrophic diabetes and other related syndromes.,Elif Arioglu Oral,,2003.0,0,0 1971,12618643,Effect of tiered prescription copayments on the use of preferred brand medications.,Thomas S Rector; Michael D Finch; Patricia M Danzon; Mark V Pauly; Bharati S Manda,"Health plans are increasingly using more open drug formularies that offer differential prescription copayments as an incentive to enrollees to use brands that plans prefer. How much this financial incentive affects use of preferred brands has not been widely reported. The aim of this study was to estimate the effect of tiered copayments on the choice between preferred and nonpreferred brand medications. Longitudinal logistic regression analyses of pharmacy claims from 1998 and 1999 comparing concurrent groups that were or were not exposed to tiered copayments. Enrollees in four independent physician practice association model health plans who had pharmacy claims for angiotensin converting enzyme inhibitors (ACEI), proton pump inhibitors (PPI), or hydroxymethylglutaryl coenzyme A reductase inhibitors (STATINS). Change in the percentage of prescription claims that were for preferred brands. Regression adjusted estimates of the average net increase in the percentage use of preferred brands of ACEI, PPI and STATIN from first quarter 1998 to third quarter 1999 attributed to tiered prescription copayments were 13.3 (P = 0.001), 8.9 (P = 0.03), and 6.0 (P <0.001) percentage points, respectively. Tiered prescription copayments were associated with a significant shift from nonpreferred to preferred brand medications. This type of financial incentive can help purchasers providing open access drug benefits by steering use of medications toward lower cost brands. The clinical effects of changes in medication use brought about differential copayments warrant further investigation.",2003.0,0,0 1972,12620535,Potential public health implications of the hypocholesterolemic effects of soy protein.,Mark J Messina,,2003.0,0,0 1973,12624557,A prospective study in primary care in patients without vascular disease comparing levels of coronary risk factors in those recommended for lipid-lowering drugs based on either absolute risk or absolute risk reduction.,Sud Ramachandran; Peter Croft; Richard H Neary,"In the United Kingdom, the current recommendation is that lipid-lowering drugs should be prescribed for primary prevention only to subjects with an absolute coronary risk (AR) greater than 15% in 5 years (i.e., myocardial infarction or angina). However, to achieve greater benefit it may be preferable to direct treatment to those patients showing the greatest absolute risk reduction (ARR). The aim of this study was to compare the characteristics of subjects eligible for lipid-lowering drugs based on the AR criteria or on an ARR of >4.45%. A prospective study was carried out over 29 months in primary care in a part of the United Kingdom with a prevalence of coronary disease nearly 20% above the national average. Risk factors were recorded in men and women aged 30-75 years who were being considered by their primary care physician for lipid-lowering drug therapy. Of the 2351 patients included in the study, 2139 (91%) and 101 (4.3%) were, respectively, below and above the criteria for treatment by both AR and ARR criteria. In 111 (4.7%) subjects, treatment was recommended based on only one of the criteria-82 on AR and 29 on ARR. Comparing these two groups, those treated on AR only were older (mean age 68.1 years [SD, 4.1] vs. 49.1 years [SD, 4.6]; p<0.0001) and had a lower total cholesterol (260 vs. 288 mg/dL; p=0.015); higher high-density lipoprotein cholesterol (50 vs. 43 mg/dL; p=0.003), lower low-density lipoprotein cholesterol (160 vs. 184 mg/dL; p=0.03), a lower total to high-density lipoprotein cholesterol ratio (5.4 vs. 7.1; p<0.0001), and lower triglycerides (258 vs. 435 mg/dL; p=0.007). The AR group also had a higher mean systolic blood pressure (170.9 vs. 158.9 mm Hg; p=0.013), presumably an attribute of their greater age. Although the AR and ARR groups did not show a difference in the proportion of males or diabetics, there was a significantly greater proportion of smokers in the latter group (72% vs. 35%; p=0.001). In conclusion, treatment recommendations based on AR alone would result in nontreatment of young subjects with significant hyperlipidemia and at high relative risk of coronary disease, whereas lipid-lowering drugs would be given preferentially to patients whose main coronary heart disease risk factors are age and hypertension but not hyperlipidemia. By contrast, treatment recommendations based on ARR ensure that lipid-lowering drugs are directed to patients who will derive the most benefit. Furthermore, delaying treatment in younger subjects at high relative risk but not high AR results in their accumulating significant coronary risk in the years before their AR exceeds an arbitrary threshold before lipid-lowering drugs are prescribed.",2003.0,0,0 1974,12624559,The intestinal absorption of biliary and dietary cholesterol as a drug target for lowering the plasma cholesterol level.,Stephen D Turley; John M Dietschy,"Elevated plasma low-density lipoprotein cholesterol levels constitute a major risk factor for coronary heart disease. The plasma low-density lipoprotein cholesterol concentration is dictated partly by the efficiency of intestinal cholesterol absorption. The efficacy of treatments designed to block cholesterol absorption is partially offset to the extent that the liver compensates for the interruption to the enterohepatic movement of cholesterol by increasing the rate at which it synthesizes cholesterol. Currently, the most widely-used treatment for hypercholesterolemia is based on a class of agents (statins) that partially inhibit cholesterol synthesis within the body. Recent clinical trials with a unique, potent, and selective cholesterol absorption inhibitor (ezetimibe) used in combination with lower doses of various statins showed an additive reduction in plasma low-density lipoprotein cholesterol levels which equaled the reduction achieved with maximal doses of statins given alone. Combination therapy using a statin and this novel cholesterol absorption inhibitor represents an efficacious new approach to the treatment of hypercholesterolemia in the general population.",2003.0,0,0 1975,12624564,ALLHAT and AFFIRM.,Philip R Liebson,,2003.0,0,0 1976,12625030,Amyloid inhibitors and Alzheimer's disease.,Weiming Xia,"Neuritic plaques composed of amyloid beta-protein (A beta) are an early and invariant neuropathological feature of Alzheimer's disease (AD). The current preclinical search for drugs is mainly focused on decreasing A beta production by inhibiting beta- or gamma-secretase, blocking the formation of these plaques by preventing A beta protofibril and fibril formation, and alleviating the toxic effects of neuritic plaque deposition. Increasing numbers of drugs currently used as therapies for other diseases are now entering clinical trials for AD, but the molecular targets of these drugs and their relevance to A beta toxicity needs to be thoroughly addressed. This knowledge will allow us to fully understand the A beta-related pathways in AD pathogenesis and explore novel therapeutic interventions.",2003.0,0,0 1977,12625594,Matrix metalloproteinases and coronary artery diseases.,Uichi Ikeda; Kazuyuki Shimada,"Matrix metalloproteinases (MMPs) play an important role in cardiovascular remodeling by degrading the extracellular matrix. Enhanced MMP expression has been detected in the atherosclerotic plaque, and activation of MMPs appears to be involved in the vulnerability of the plaque. Circulating MMP levels are elevated in patients with acute myocardial infarction and unstable angina. Increased MMP expression is also observed after coronary angioplasty, which is related to late loss index after the procedure. These observations suggest that MMP expression may be not only related to instability of the plaque, but also to the formation of restenotic lesions. The development of therapeutic drugs targeted specifically against MMPs may be useful in the prevention of atherosclerotic lesion development, plaque rupture, and restenosis.",2003.0,0,0 1978,12626213,Differing effects of low-dose estrogen-progestin therapy and pravastatin in postmenopausal hypercholesterolemic women.,S R Davis; R Goldstat; A Newman; K Berry; H G Burger; I Meredith; K Koch,"Most studies examining the potential cardioprotective effects of postmenopausal estrogen have been undertaken in healthy women, with doses that may not be appropriate for long-term intervention. New low-dose estrogen-progestin regimens alleviate postmenopausal symptoms with a favorable side-effect profile; however, little is known of the impact of such regimens in women at increased risk of cardiovascular disease. Hence, we have evaluated the effects of low-dose oral estrogen-progestin therapy on serum lipoprotein lipids, brachial artery reactivity and fibrinogen in hypercholesterolemic postmenopausal women in direct comparison with the effects of pravastatin, a lipid-lowering agent known to reduce cardiovascular events in women. In a randomized, double-blind, double-dummy, parallel trial, we studied the effects of continuous combined estrogen-progestin therapy (1 mg 17beta-estradiol with 500 micro g norethisterone acetate daily) or pravastatin (20 mg daily) in 72 postmenopausal women with fasting serum low-density lipoprotein (LDL) cholesterol levels greater than 124 mg/dl after an 8-week run-in diet, over a 24-week period. The primary end-point was percentage change in LDL cholesterol from baseline. The intention-to-treat population comprised 65 women, mean age 59 +/- 6.3 years, and 29 in each group completed the trial. Diet alone reduced LDL cholesterol significantly in both treatment groups, in association with a reduction in weight during this period. Compared with respective baseline values, pravastatin decreased LDL cholesterol and total cholesterol to a greater extent than hormone therapy (p = 0.0001 and 0.003 for difference between treatments, respectively). High-density lipoprotein (HDL) cholesterol levels decreased with hormone therapy, but did not change with pravastatin (p = 0.01). Lipoprotein(a) decreased significantly with hormone therapy only (-14%, 95% confidence interval (CI) -21 to -6%, p = 0.01 for difference between groups). Brachial artery flow-mediated dilatation (FMD) was impaired at baseline, and this increased with hormone therapy (absolute mean change in artery diameter as percentage units 2.07, 95% CI 0.57-3.57, p = 0.009) versus no change with pravastatin (0.19, 95% CI -1.1 to 1.5, p = 0.78), with a near-significant difference between the two groups (p = 0.058). A significant correlation between improved brachial artery FMD and reduction in LDL cholesterol was not observed. Fibrinogen decreased significantly in both treatment groups with no difference between treatments. In postmenopausal hypercholesterolemic women, pravastatin and hormone therapy exhibited divergent effects. The former lowered total and LDL cholesterol more effectively, whereas hormone therapy lowered lipoprotein(a) significantly and improved brachial artery endothelium-dependent dilatation, independent of the reduction in LDL cholesterol. The modest increase in brachial artery FMD seen is consistent with hypercholesterolemia compromising endothelial integrity, and suggests that the important effect of estrogen on the endothelial microenvironment may be attenuated in women with endothelial dysfunction.",2003.0,0,0 1979,12627404,Identifying effective and/or safe doses by stepwise confidence intervals for ratios.,Frank Bretz; Ludwig A Hothorn; Jason C Hsu,"Typical randomized clinical dose-finding studies consist of the comparison of several doses of a drug versus a placebo. Interest lies in estimating relevant doses among those under investigation for efficacy and safety variables, such as the minimum effective dose or the maximum safe dose (or estimating both doses simultaneously). Step-down procedures have been proposed for comparing the standardized differences of the dose groups against placebo. In this paper we consider the ratio of population means and propose stepwise confidence intervals for these ratios. These confidence intervals do not require multiplicity adjustments and yield the same decisions as the associated test procedures. In addition, several power concepts are investigated within the present framework. The results allow sample size determination in the design phase of a study for the probability of estimating correctly the dose of interest. Auxiliary results of a numerical study show the range of application of these methods.",2003.0,0,0 1980,12628031,Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects.,Kirsten B Holven; Tor S Haugstad; Torbjørn Holm; Pål Aukrust; Leiv Ose; Marit S Nenseter,"Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, has been suggested to be a novel risk factor for endothelial dysfunction. It has previously been reported that hyperhomocysteinaemia may be associated with impaired endothelium-dependent vasodilation and reduced plasma level of NO-derived endproducts (NOx). In the present study, plasma levels of arginine and ADMA were measured in twenty-one healthy control subjects, and in twenty-one hyperhomocysteinaemic subjects before and after 6 weeks and 12 months of folic acid supplementation, and compared with previously measured plasma NOx values in the hyperhomocysteinaemic subjects. Compared with control subjects, hyperhomocysteinaemic subjects had higher plasma levels of arginine and ADMA. More importantly, folic acid therapy significantly reduced plasma levels of arginine and ADMA. Furthermore, plasma levels of arginine and ADMA were positively correlated with plasma homocysteine levels and negatively correlated with plasma folate, as well as negatively correlated with plasma NOx. Our results suggest that ADMA may be a mediator of the atherogenic effects of homocysteine.",2003.0,0,0 1981,12628358,Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection.,Oliver Neuhaus; Juan J Archelos; Hans-Peter Hartung,"Multiple sclerosis (MS) is the most common disabling neurological disease of young adulthood. Following advances in the understanding of the immunological mechanisms that underlie the pathogenesis of MS, a growing arsenal of immunomodulatory agents is available. Two classes of immunomodulators are approved for long-term treatment of MS, the efficacy of several promising new concepts is being tested in clinical trials and classical immunosuppressive agents used in MS treatment have been shown to exert specific, immunomodulatory effects. Furthermore, two recent observations have changed our basic understanding of the pathogenesis of MS. First, immune cells in MS lesions have neuroprotective activity, which indicates a beneficial role of neuroinflammation. Second, there is evidence that axonal loss, rather than demyelination, underlies the progression of MS and, hence, constitutes a therapeutic target.",2003.0,0,0 1982,12630585,Chlamydia pneumoniae and coronary artery disease: the antibiotic trials.,John P Higgins,"Parallel with the mounting evidence that atherosclerosis has a major inflammatory component, provoking agents that may initiate and drive this process have been sought. Infectious agents such as Chlamydia pneumoniae have been alleged to be activators of inflammation that may contribute to atherosclerosis and thus coronary artery disease (CAD) and its associated complications. A logical pneumoniae extension of this theory whether treating C pneumoniae infection with antibiotics and/or modulating inflammatory processes can affect CAD and its sequelae. This article discusses the potential role of C pneumoniae in atherosclerosis, its detection, and the rationale for antibiotics. Additionally, it summarizes the current randomized clinical trials of antichlamydial antibiotics in patients with CAD and draws conclusions based on the results.",2003.0,0,0 1983,12633795,"Comparison of once-daily, niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]).",Harold E Bays; Carlos A Dujovne; Mark E McGovern; T Eric White; Moti L Kashyap; A Gene Hutcheson; John R Crouse; ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation,"This study compared the relative efficacy of a once-daily niacin extended-release (ER)/lovastatin fixed-dose combination with standard doses of atorvastatin or simvastatin, with a special emphasis on relative starting doses. Subjects (n = 315) with elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol blood levels (defined as LDL cholesterol blood levels > or =160 mg/dl without coronary artery disease, or > or =130 mg/dl if coronary artery disease was present, and HDL cholesterol <45 mg/dl in men and <50 mg/dl in women) were randomized to atorvastatin, simvastatin, or niacin ER/lovastatin for 16 weeks. The primary efficacy variables were the mean percent change in LDL cholesterol and HDL cholesterol levels from baseline. After 8 weeks, the starting dose niacin ER/lovastatin 1,000/40 mg and the 10-mg starting dose atorvastatin both lowered mean LDL cholesterol by 38%. After 12 weeks, niacin ER/lovastatin 1,000/40 mg lowered LDL cholesterol by 42% versus 34% with the 20-mg starting dose of simvastatin (p <0.001). Niacin ER/lovastatin increased HDL cholesterol significantly more than atorvastatin or simvastatin at all compared doses (p <0.001). Niacin ER/lovastatin also provided significant improvements in triglycerides, lipoprotein(a), apolipoprotein A-1, apolipoprotein B, and HDL subfractions. A total of 6% of study subjects receiving niacin ER/lovastatin withdrew because of flushing. No significant differences were seen among study groups in discontinuance due to elevated liver enzymes. No drug-induced myopathy was observed. Niacin ER/lovastatin was comparable to atorvastatin 10 mg and more effective than simvastatin 20 mg in reducing LDL cholesterol, was more effective in increasing HDL cholesterol than either atorvastatin or simvastatin, and provided greater global improvements in non-HDL cholesterol, triglycerides, and lipoprotein(a).",2003.0,0,1 1984,12634877,"Should patients with chronic heart failure be treated with ""statins""?",Emma Ashton; Danny Liew; Henry Krum,"There are a number of theoretical reasons as to why 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) should be prescribed to patients with chronic heart failure (CHF). These agents are proven to prevent coronary heart disease, the major etiological factor in the development of CHF. Potential additional effects of these agents include inhibition of proinflammatory cytokine activity and other potential beneficial effects on cardiac remodeling. However, there are also possible adverse effects of this strategy, supported by the overriding observation that low plasma lipid levels portend a poorer prognosis in patients with established CHF. Potential mechanisms by which statins may directly confer adverse effects include a reduction in levels of the antioxidant ubiquinone and an increase in blood endotoxin levels, both of which may contribute to CHF disease progression. Given these uncertainties, an answer to the question of whether or not therapy for CHF should include statins requires a definitive clinical trial. The importance of such a trial is further highlighted by the already commonplace usage of statins amongst patients with CHF.",2003.0,0,0 1985,12634978,Beyond lipid-lowering: effects of statins on endothelial nitric oxide.,Ulrich Laufs,"Endothelial dysfunction is now recognised as an important process in the pathogenesis of atherosclerosis. Nitric oxide (NO) release by the endothelium regulates blood flow, inflammation and platelet aggregation, and consequently its disruption during endothelial dysfunction can decrease plaque stability and encourage the formation of atherosclerotic lesions and thrombi. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) are often utilised in the prevention of coronary heart disease due to their efficacy at lowering lipid levels. However, statins may also prevent atherosclerotic disease by non-lipid or pleiotropic effects, for example, improving endothelial function by promoting the production of NO. There are various mechanisms whereby statins may alter NO release, such as inhibiting the production of mevalonate and important isoprenoid intermediates, thereby preventing the isoprenylation of the small GTPase Rho, which negatively regulates the expression of endothelial nitric oxide synthase (eNOS). Furthermore, statins may also increase eNOS activity via post-translational activation of the phosphatidylinositol 3-kinase/protein kinase Akt (PI3 K/Akt) pathway and/or through an interaction with the molecular chaperone heat-shock protein 90 (HSP90). Data suggest that statins may vary in their efficacy for enhancing the release of NO, and the mechanisms dictating these differences are not yet clear. By increasing NO production, statins may interfere with atherosclerotic lesion development, stabilise plaque, inhibit platelet aggregation, improve blood flow and protect against ischaemia. Therefore, the ability of statins to improve endothelial function through the release of NO may partially account for their beneficial effects at reducing the incidence of cardiovascular events.",2003.0,0,0 1986,12635468,Simvastatin and pravastatin equally improve flow-mediated dilation in males with hypercholesterolemia.,Miran Sebestjen; Marko Boh; Irena Keber,"Both simvastatin and pravastatin have been shown to improve endothelial function in patients with hypercholesterolemia. To our knowledge there has been no comparative study of these two HMG-CoA reductase inhibitors on endothelial dysfunction measured by flow-mediated dilation of the brachial artery in patients with hypercholesterolemia. Fourteen middle-aged males with hypercholesterolemia (means +/- SD: total cholesterol 7.03 +/- 0.88 mmol/l, LDL cholesterol 5.02 +/- 0.63 mmol/l, HDL cholesterol 1.3 +/- 0.38 mmol/l and triglycerides 1.47 +/- 0.26 mmol/l) were randomised, after a 6 weeks' run-in phase with AHA step I diet treatment, to 12 weeks' treatment either with simvastatin or pravastatin. Both statins were given in a daily dose of 10 mg for 6 weeks, which was increased to 20 mg daily in patients who did not achieve an LDL-cholesterol goal of < 3.4 mmol/l. Endothelial dysfunction was measured as flow-mediated brachial artery dilation (FMD) using high resolution ultrasound. There were no significant differences between the drugs in reduction of total cholesterol, LDL cholesterol and triglycerides, or elevation of HDL cholesterol. FMD increased in the simvastatin group from 6.8 +/- 3.2 to 12.3 +/- 2.9% (p < 0.03) and in the pravastatin group from 6.3 +/- 4.8 to 13.3 +/- 4.7% (p = 0.001). The improvement in FMD was the same in both groups (p = 0.64) and did not correlate with changes of the lipid parameters measured. Both simvastatin and pravastatin reduce endothelial dysfunction to the same degree in patients with hypercholesterolemia, independently of changes in lipid parameters.",2003.0,0,0 1987,12635864,Simvastatin and markers of endothelial function in patients undergoing continuous ambulatory peritoneal dialysis.,J Malyszko; J S Malyszko; T Hryszko; S Brzosko; M Mysliwiec,"Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are prone to dyslipidemia and have a high risk of cardiovascular death. The aim of this study was to assess the effects of a 6-month treatment with simvastatin (10 mg at bedtime) on markers of endothelial cell injury in 12 hypercholesterolemic CAPD patients. Cholesterol and low-density lipoprotein cholesterol fell significantly after 1 month of therapy. Simvastatin treatment significantly decreased concentrations of vascular cell adhesion molecule and intracellular adhesion molecule after 3 and 6 months of the therapy, respectively. Thrombomodulin decreased significantly after 6 months of the treatment, whereas von Willebrand's factor, P-selectin and E-selectin remained unaltered during simvastatin therapy. Simvastatin, an effective hypolipemic agent, favorably affects endothelial function and may potentially slow the progression of atherosclerosis and confer protection from thrombotic complications in patients with hypercholesterolemia undergoing CAPD.",2003.0,0,0 1988,12636343,Fungal nail infection: assessing the new treatment options.,Georgeanne Botek,"Onychomycosis can be improved or eradicated with appropriate treatment. Newer oral antifungal drugs are highly effective and have few adverse effects, although care in prescribing is needed because of potential drug interactions and hepatobiliary dysfunction.",2003.0,0,0 1989,12637115,"A 52-week, multicenter, randomized, parallel-group, double-blind, double-dummy study to assess the efficacy of atorvastatin and simvastatin in reaching low-density lipoprotein cholesterol and triglyceride targets: the treat-to-target (3T) study.",Anders G Olsson; Mats Eriksson; Owe Johnson; Thomas Kjellström; Jan Lanke; Mogens Lytken Larsen; Terje Pedersen; Matti J Tikkanen; Olov Wiklund; 3T Study Investigators,"Guidelines for the prevention of coronary heart disease call for low-density lipoprotein cholesterol (LDL-C) reduction as the primary target of treatment and reduction of triglycerides (TG) as an additional target. The purpose of this study was to investigate the ability of atorvastatin and simvastatin to reduce LDL-C and TG concentrations and to meet 3 target lipid levels: LDL-C or=4.0 mmol/L (>or=155 mg/dL), were randomized in a 1:1 ratio to receive once-daily oral treatment with 20 mg atorvastatin or 20 mg simvastatin. Fasting (12-hour) blood samples for the estimation of lipid levels and clinical laboratory values were collected after 4, 8, 12, 26, and 52 weeks. The dose was doubled after 12 weeks if the target National Cholesterol Education Program level of LDL-C (0) and no effect (RRR<0) of LLT on stroke incidence, with a cutoff for benefit of 232 mg/dL (6.0 mmol/L). Lipid-lowering therapy reduces stroke incidence in coronary patients, especially when total cholesterol level is lowered to less than 232 mg/dL (6.0 mmol/L), which explains the best results being obtained with statins.",2003.0,0,1 1994,12639883,Lipid lowering to delay the progression of coronary artery disease.,Michael D Feher,,2003.0,0,0 1995,12640189,Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature.,Anoop Misra; Abhimanyu Garg,"We present clinical descriptions, metabolic features, and patterns of body fat loss of 16 patients with acquired generalized lipodystrophy (AGL) seen by us over the last 10 years. In addition, we review 63 cases of AGL reported in the literature. Based on these data, we propose new diagnostic criteria for AGL, the essential criterion being selective loss of body fat from large regions of the body occurring after birth. We also propose a subclassification of AGL into 3 varieties, type 1, the panniculitis variety; type 2, the autoimmune disease variety; and type 3, the idiopathic variety, which affect nearly 25%, 25%, and 50% of patients, respectively. Most of the patients presented in childhood and adolescence. Females were affected approximately 3 times more than males. Subcutaneous fat loss was severe and usually affected the face, trunk, abdomen, and extremities. In some patients, fat loss also involved the palms and soles and intraabdominal region; however, the bone marrow and retroorbital fat were preserved in all patients. Clinically, patients may have voracious appetite, fatigue, and acanthosis nigricans. Hepatomegaly was common, mostly due to hepatic steatosis. Most AGL patients had fasting and/or postprandial hyperinsulinemia, diabetes mellitus, hypertriglyceridemia, and low serum levels of high-density lipoprotein cholesterol, leptin, and adiponectin. Diabetes mellitus and hypertriglyceridemia were less prevalent in the panniculitis variety compared with the idiopathic and autoimmune varieties. The management of AGL includes cosmetic surgery for loss of fat. Severe hypertriglyceridemia should be treated with a very low-fat diet and omega-3 polyunsaturated fatty acid supplementation from fish oils. Management of diabetes is difficult and may necessitate insulin therapy in large doses. Insulin sensitizers such as metformin and thiazolidinediones have been used, although their long-term efficacy and safety remain unknown. Subcutaneous administration of recombinant leptin in AGL patients with hypoleptinemia effectively improves hyperglycemia, hypertriglyceridemia, and hepatic steatosis. Leptin therapy, however, remains investigational. Fibrates alone or in combination with statins may be used to treat hypertriglyceridemia.",2003.0,0,0 1996,12640509,Comparison of the effect of two HMG CoA reductase inhibitors on LDL susceptibility to oxidation.,Vera Lúcia Portal; Emílio H Moriguchi; José Luiz da Costa Vieira; Sadi Schio; Eduardo T Mastalir; Fabiana Buffé; Eleni Borges Bortolini; Ricardo Santalucia Brüch; Rubem Rodrigues,"To study the differences between fluvastatin and pravastatin regarding LDL susceptibility to oxidation, plasma levels of total cholesterol (TC), HDL-C, LDL-C and triglycerides (TG) in hypercholesterolemic patients with established coronary heart disease (CHD). A double-blind randomized parallel study was conducted that included 41 hypercholesterolemic outpatients with CHD treated at the Instituto de Cardiologia do Rio Grande do Sul. The inclusion criteria were LDL-C above 100 mg/dL and triglycerides below 400 mg/dL based on 2 measures. After 4 weeks on a low cholesterol diet, those patients that fullfilled the inclusion criteria were randomized into 2 groups: the fluvastatin group (fluvastatin 40 mg/day) and the pravastatin group (pravastatin 20 mg/day), for 24 weeks of treatment. LDL susceptibility to oxidation was analyzed with copper-induced production of conjugated dienes (Cu2+) and water-soluble free radical initiator azo-bis (2'-2'amidinopropanil) HCl (AAPH). Spectroscopy nuclear magnetic resonance was used for determination of lipids. After 24 weeks of drug therapy, fluvastatin and pravastatin significantly reduced LDL susceptibility to oxidation as demonstrated by the reduced rate of oxidation (azo and Cu) and by prolonged azo-induced lag time (azo lag). The TC, LDL-C, and TG reduced significantly and HDL-C increased significantly. No differences between the drugs were observed. In hypercholesterolemic patients with CHD, both fluvastatin and pravastatin reduced LDL susceptibility to oxidation.",2003.0,0,0 1997,12641482,Statin therapy in the elderly: does it make good clinical and economic sense?,Moira M B Mungall; Allan Gaw; James Shepherd,"HMG-CoA reductase inhibitors (statins) have been established as the dominant treatment for coronary heart disease (CHD). This dominance is based on an impressive body of clinical trial evidence showing significant benefits in primary prevention of cardiovascular events in individuals at risk for CHD and in secondary prevention of such events in patients with CHD and high or normal plasma cholesterol levels. There is, however, significant room for improvement in the treatment of CHD with respect both to drug efficacy and to the disparity between evidence-based medicine and actual clinical practice particularly in relation to treatment strategies for the elderly. Current statins fall short of requirements for 'ideal' lipid-lowering treatment in several respects; 'super' statins and other agents currently in development may satisfy more of these requirements. Moreover, available therapies are not applied optimally, because of physician nonacceptance and/or patient noncompliance; thus, the majority of patients with CHD or its risk factors still have cholesterol levels that exceed guideline targets. There is also evidence that older patients with CHD, or at high risk of CHD, are undertreated - possibly because of concerns regarding the increased likelihood of adverse events or drug interactions or doubts regarding the cost effectiveness of statin therapy in this population. This group is of particular clinical relevance, since it is showing a proportionate rapid expansion in most national populations. To address their potential healthcare needs, the ongoing Pravastatin in the Elderly at Risk (PROSPER) study is assessing the effects of pravastatin in elderly patients (5804 men and women aged 70-82 years) who either have pre-existing vascular disease or are at significant risk for developing it, with the central hypothesis that statin therapy (pravastatin 40 mg/day) will diminish the risk of subsequent major vascular events compared with placebo. After a 3.2-year treatment period, a primary assessment will be made of the influence of statin treatment on major cardiovascular events (a combination of CHD death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Optimal deployment of the currently available agents and of newer agents (no matter how well they satisfy requirements for ideal treatment) ultimately depends on the establishment of an evidence base and may require far-reaching educational programmes that change the way risk factor management is viewed by caregivers and patients alike.",2003.0,0,0 1998,12642064,Acute myocardial infarction.,Eric Boersma; Nestor Mercado; Don Poldermans; Martin Gardien; Jeroen Vos; Maarten L Simoons,"Acute myocardial infarction is a common disease with serious consequences in mortality, morbidity, and cost to the society. Coronary atherosclerosis plays a pivotal part as the underlying substrate in many patients. In addition, a new definition of myocardial infarction has recently been introduced that has major implications from the epidemiological, societal, and patient points of view. The advent of coronary-care units and the results of randomised clinical trials on reperfusion therapy, lytic or percutaneous coronary intervention, and chronic medical treatment with various pharmacological agents have substantially changed the therapeutic approach, decreased in-hospital mortality, and improved the long-term outlook in survivors of the acute phase. New treatments will continue to emerge, but the greatest challenge will be to effectively implement preventive actions in all high-risk individuals and to expand delivery of acute treatment in a timely fashion for all eligible patients.",2003.0,0,0 1999,12643070,[Secondary prevention after ischemic stroke].,R W Baumgartner; D Georgiadis,"This paper reviews secondary prevention of stroke by the therapy of vascular risk factors, anticoagulation, surgical and endovascular procedures. Two recently published studies, the PROtection aGainst REcurrent Stroke Study (PROGRESS) and the Heart Protection Study (HPS) demonstrated for the first time the efficacy of antihypertensive and lipid lowering by statins in stroke secondary prevention. PROGRESS has shown that the combination of perindoprile and indapamide reduced the occurrence of ischemic and hemorrhagic strokes in hyper- and normotensive patients by 40%, whereas HPS demonstrated a 20% reduction of ischemic strokes in cases with normal or elevated serum cholesterol. Symptomatic carotid stenoses with a distal degree of > or = 70% should undergo endarterectomy; in the presence of a distal degree of stenosis of 50-69% an individual treatment decision is performed; carotid surgery is not indicated in < 50% stenoses. Patients with a cardiac source of embolism (except those with cardiac myxoma or bacterial endocarditis) should be anticoagulated with a target INR of 2.5 (range 2-3). Patients who have no indication for vascular surgery or anticoagulation will be treated with platelet inhibitors. Aspirin 100 mg/d or the combination aspirin-dipyridamole are the treatment of choice. If cerebral ischemia reoccurs with aspirin or in case of aspirin intolerance clopidogrel will be administered. Patients with cerebral ischemia occurring while they are treated with clopidogrel may receive an oral anticoagulation with a target INR of 2.0 (range 1.5-2.5).",2003.0,0,0 2000,12643184,Heart protection study: LDL lowering therapy and cardiovascular outcomes in patients with low cholesterol levels or diabetes.,Mrinalini Kulkarni; Peter D Reaven,,2003.0,0,0 2001,12644139,Conversion to sirolimus after kidney and liver transplantation: indications and outcomes.,L Wramner; G Norden; G Herlenius; S Friman; M Olausson; L Bäckman,,2003.0,0,0 2002,12644150,Sirolimus in patients after liver transplantation.,D Kniepeiss; F Iberer; B Grasser; S Schaffellner; K H Tscheliessnigg,,2003.0,0,0 2003,12646936,New targets for therapy in acute myeloid leukemia.,F R Appelbaum,,2003.0,0,0 2004,12648032,,,,,0,0 2005,12652161,"Nitric oxide, atherosclerosis and the clinical relevance of endothelial dysfunction.",Todd J Anderson,"The endothelium plays a key role in vascular homeostasis through the release of a variety of autocrine and paracrine substances, the best characterized being nitric oxide. A healthy endothelium acts to prevent atherosclerosis development and its complications through a complex and favorable effect on vasomotion, platelet and leukocyte adhesion and plaque stabilization. The assessment of endothelial function in humans has generally involved the description of vasomotor responses, but more widely includes physiological, biochemical and genetic markers that characterize the interaction of the endothelium with platelets, leukocytes and the coagulation system. Stable markers of inflammation such as high sensitivity C-reactive protein are indirect and potentially useful measures of endothelial function for example. Attenuation of the effect of nitric oxide accounts for the majority of what is described as endothelial dysfunction. This occurs in response to atherosclerosis or its risk factors. Much remains to be learned about the molecular and genetic pathophysiological mechanisms of endothelial cell abnormalities. However, pharmacological intervention with a growing list of medications can favorably modify endothelial function, paralleling beneficial effects on cardiovascular morbidity and mortality. In addition, several small studies have provided tantalizing evidence that measures of endothelial health might provide prognostic information about an individual patient's risk of subsequent events. As such, the sum of this evidence makes the clinical assessment of endothelial function an attractive surrogate marker of atherosclerosis disease activity. The review will focus on the role of nitric oxide in atherosclerosis and the clinical relevance of these findings.",2003.0,0,0 2006,12652162,Acute and chronic endothelial dysfunction: implications for the development of heart failure.,Axel Linke; Fabio Recchia; Xiaoping Zhang; Thomas H Hintze,"Heart failure has been characterized by a reduction in cardiac contractile function resulting in reduced cardiac output. The clinical symptoms including mild tachycardia, reduced arterial pressure, increased venous or filling pressure and exercise intolerance have conceptually, to a large degree, been attributed to cardiac myocyte dysfunction. More recently, a vascular component has been recognized to contribute to heart failure. Among the most studied vascular mechanisms that might contribute to the development of heart failure has been the reduced production of nitric oxide or the reduced bioactivity of NO associated with both basic models of heart failure and disease in patients. The still evolving concept that heart failure is a cytokine activated state has, in addition, focused attention on the possibility that the cytokine driven isoform of NO synthase (NOS), iNOS, may produce sufficient quantities of NO to actually suppress cardiac myocyte function contributing to the reduced inotropic state in the failing heart. Thus, our view of the role of NO in the development of heart failure has evolved from simply a reduction in production of NO in blood vessels, to altered substrate availability (i.e. L-arginine), to increased scavenging of NO by superoxide anion, to increased production of NO from iNOS. As these concepts develop, our approach to the therapeutics of heart failure has also progressed with the recognition of the need to develop treatments directed towards addressing one or more of these etiologies. This review will focus on these aspects of the involvement of NO in the development of heart failure and some of the treatments that have developed from our understanding of the basic biology of NO to address these pathohysiologic states.",2003.0,0,0 2007,12652163,Statins and the role of nitric oxide in chronic heart failure.,Stephan von Haehling; Stefan D Anker; Eberhard Bassenge,"Endothelial dysfunction plays an important role in a number of cardiovascular diseases. An important pathogenetic factor for the development of endothelial dysfunction is lack of nitric oxide (NO), which is a potent endothelium-derived vasodilating substance. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), originally designed to lower plasma cholesterol levels, seem to ameliorate endothelial dysfunction by a mechanism so far only partly understood. However, statins increase nitric oxide synthase activity. It has been speculated that this and other ""side effects"" of statin treatment are due to inhibition of Rho, an intracellular signalling protein that initiates Rho kinase transcription. Moreover, statins possess anti-inflammatory characteristics. Some statins have proven to lower plasma levels of C-reactive protein, which is induced by pro-inflammatory cytokines. Other statins have been demonstrated to directly inhibit pro-inflammatory cytokine induction. Finally, some data suggest that statins might be able to counterbalance an increased production of oxygen free radicals. Since chronic heart failure is accompanied not only by endothelial dysfunction, but also by pro-inflammatory cytokine activation and enhanced formation of oxygen free radicals, it is tempting to speculate that statins might be an ideal candidate to treat certain features of this disease. The doses needed to achieve the desired effects might be much lower than those needed to treat hypercholesterolemia.",2003.0,0,0 2008,12655157,"Sustained reduction of serum cholesterol in low-dose 6-year simvastatin treatment with minimum side effects in 51,321 Japanese hypercholesterolemic patients.",Yuji Matsuzawa; Toru Kita; Hiroshi Mabuchi; Masunori Matsuzaki; Noriaki Nakaya; Shinichi Oikawa; Yasushi Saito; Jun Sasaki; Kazuaki Shimamoto; Hiroshige Itakura; J-LIT Study Group,"The Japan Lipid Intervention Trial (J-LIT) study, a nationwide cohort study utilizing the clinical practice of general physicians, was designed to clarify the relationship between the incidence of coronary heart disease and serum lipid concentrations during simvastatin therapy, as well as the safety of the therapy, in a large number of Japanese hypercholesterolemic patients. All the enrolled patients were treated with simvastatin. The current study analyzed the lipid lowering effect and safety of the low-dose simvastatin therapy used in the J-LIT study. Open-labeled simvastatin was given to 51,321 patients at an initial dose of mostly 5 mg/day. After 6 months of the treatment, the average serum total cholesterol (TC) and low density lipoprotein-cholesterol concentrations in all the patients followed up were reduced by 18.3% and 26.0%, respectively, and that of high density lipoprotein-cholesterol increased 2.3% on average. These concentrations were well maintained throughout the 6-year treatment period. A minority of patients (1.4%) unexpectedly had a remarkable reduction in TC concentration by more than 40%. Hyper-responders, even to low-dose statin, were found for the first time in this large-scale and long-term investigation. Overall adverse drug reactions occurred in 3.3% of subjects during the 6-year treatment, the major events being hepatic and musculoskeletal disorders, of which the incidence was less than 1%. Low-dose simvastatin therapy of 5 mg/day effectively controlled the serum TC concentration by reducing it by approximately 20% on average in hypercholesterolemic Japanese patients, a reduction that corresponds to the effect of simvastatin 20 mg/day in Western studies. In addition, the low incidence of drug-related adverse events in this study may be also related to the low dosage of simvastatin.",2003.0,0,0 2009,12655280,Antibodies to oxidized low-density lipoprotein in patients following coronary artery revascularization.,Edgar R Miller; Thomas P Erlinger; Roger S Blumenthal; Simeon Margolis; Jerilyn K Allen,"Measurement of antibodies to oxidized low-density lipoprotein (AB-oxLDL) has been proposed as a way of identifying individuals at risk for cardiovascular disease beyond the determination of LDL cholesterol (LDL-c) alone. While this hypothesis is appealing, evidence that AB-oxLDL is a risk factor independent of LDL-c levels remains to be established. We conducted a cross-sectional study of 158 hypercholesterolemic adults who underwent coronary revascularization. Patients were randomized in a clinical trial to a nurse case management (NURS) or an enhanced usual care (EUC) group. The goal in the NURS group was to achieve an LDL-c <85 mg/dl with pharmacotherapy and lifestyle advice. Six months after revascularization, serum and urine were collected to determine lipids, AB-oxLDL, urinary isoprostanes (an in-vivo marker of oxidative damage), oxygen-radical-absorbing capacity (ORAC) of serum, serum carotenoids, alpha-tocopherol and C-reactive protein (CRP). After 6 months of intervention, the NURS group had a mean (+/-SD) LDL-c of 84 (18) mg/dl compared with 105 (25) mg/dl in the EUC group (P < 0.001). In addition, AB-oxLDL was lower (median +/- 95% confidence interval, -202 milliunits (mU)/ml, -372 to -32, P = 0.02) in the NURS group (488 mU/ml, 399, 588) than in the EUC group (690 mU/ml, 544, 847). The difference in AB-oxLDL between groups persisted after adjustment for LDL-c (-316 mU/ml, -519 to -112, P = 0.005). Further adjustment for ORAC and alpha-tocopherol did not diminish the group effect. The groups did not differ significantly in serum antioxidants, urinary isoprostane excretion or CRP. In additional analyses, change in LDL-c from baseline was not associated with AB-oxLDL at 6 months. Our results demonstrate lower AB-oxLDL in patients who achieve greater lipid reduction. However, AB-oxLDL appears to be independent of achieved LDL-c, ORAC levels or serum antioxidant levels. These results support the hypothesis that AB-oxLDL is independent of LDL-c level. Further prospective studies are needed to determine the prognostic value of AB-oxLDL.",2003.0,0,0 2010,12656644,Pharmacological treatment of patients with peripheral arterial disease.,Chin K Kim; Carsten M Schmalfuss; Richard S Schofield; David S Sheps,"Atherosclerosis is a disease process that affects the coronary, cerebral and peripheral arterial circulation. While great emphasis has been placed on the aggressive pharmacological management of coronary artery disease, less attention has been paid to the pharmacological management of peripheral vascular disease, despite its significant morbidity and mortality. The purpose of medical management in peripheral arterial disease is to relieve symptoms of claudication and to prevent thrombotic vascular events. These goals are best achieved through aggressive risk factor modification and pharmacotherapy. Risk factor modification includes smoking cessation, adequate control of blood pressure and cholesterol, as well as aggressive glycaemic control in patients with diabetes mellitus. Antiplatelet therapy and relief of claudication is also achieved through pharmacotherapy. With aggressive risk factor modification and adequate pharmacotherapy, patients with peripheral arterial disease can have an improved quality of life as well as prolonged survival.",2003.0,0,0 2011,12656649,Lovastatin extended release: a review of its use in the management of hypercholesterolaemia.,Monique P Curran; Karen L Goa,"Lovastatin extended release (ER) provides a new form of delivery for lovastatin, an HMG-CoA reductase inhibitor. Lovastatin ER delivers the drug in a more sustained fashion, as shown by a smoother plasma concentration-time profile, a lower maximum plasma concentration and a prolonged half-life compared with that of lovastatin immediate release (IR). At dosages of 10-60 mg/day, lovastatin ER significantly reduced levels of total cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides, and increased levels of high density lipoprotein-cholesterol, in patients with primary hypercholesterolaemia in a randomised, double-blind study of 12 weeks' duration. These effects were maintained in a 6-month extension study in which patients received lovastatin 40 or 60 mg/day. In a randomised 4-week study in 24 patients with primary hypercholesterolaemia, the reduction in plasma LDL-cholesterol levels was significantly greater with lovastatin ER 40 mg/day than with the IR formulation administered at the same dosage. Lovastatin ER was well tolerated in all studies and adverse events were usually mild to moderate and transient. The tolerability profile of lovastatin ER was similar to that of lovastatin IR. There were no reports of clinically relevant elevations in liver transaminases or creatine phosphokinase attributed to the drug in recipients of lovastatin ER. The ER formulation of lovastatin provides smooth and sustained delivery of this established and well-tolerated agent over the dosage interval, significantly reducing LDL-cholesterol in patients with primary hypercholesterolaemia. If, as expected, the beneficial changes in lipid levels are maintained during long-term treatment and further clinical experience confirms the greater efficacy of the lovastatin ER formulation than the IR formulation, then lovastatin ER is likely to supplant lovastatin IR and provide a useful option in the management of patients with dyslipidaemia and prevention of coronary heart disease.",2003.0,0,0 2012,12657430,Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer's disease.,Judes Poirier,"There is much evidence suggesting that there is a strong relationship between the deterioration of brain lipid homeostasis, vascular changes and the pathogenesis of Alzheimer's disease (AD). These associations include: (1). recognition that a key cholesterol transporter, apolipoprotein E type 4, acts a major genetic risk factor for both familial and sporadic AD; (2). epidemiological studies linking cardiovascular risk factors, such as hypertension and high plasma cholesterol, to dementia; (3). the discovery that small strokes can precipitate clinical dementia in cognitively normal elderly subjects; (4). the modulation of degradation of the amyloid precursor protein by cholesterol administration in cell culture and in animal models of beta-amyloid overproduction; and (5). the beneficial effect of cholesterol-lowering drugs, such as Probucol and statins, in combating common AD. The recent finding that there is a genetic association between the HMGR gene locus and sporadic AD further suggests that brain cholesterol metabolism is central to AD pathophysiology, and a potential therapeutic target for disease stabilization and primary disease prevention.",2003.0,0,0 2013,12659359,Treatment of patients with lipid disorders in the primary care setting: new treatment guidelines and their implications.,Joseph M Keenan,"Coronary heart disease (CHD) remains a major cause of morbidity and mortality throughout North America. The role played by lipid abnormalities is now well established, and primary care physicians can play a major role in reversing the increasing prevalence of CHD by following the recommended guidelines of the National Cholesterol Expert Panel (NCEP ATP-III). While many physicians are aware of the importance of lowering lipid levels, a large number of patients still fail to reach their treatment goals. It is therefore important to identify patients at risk of developing coronary events due to abnormal lipid profiles and to quickly implement effective prevention programs. Although diet and other lifestyle modifications should form the basis of lipid management, the addition of lipid-modifying drugs is often necessary. Several lipid-modifying agents are available, but the proven efficacy and good tolerability of statins has increasingly made them the drugs of choice.",2003.0,0,0 2014,12659599,Hemostatic effects of atorvastatin versus simvastatin.,Gurhan Kadikoylu; Vahit Yukselen; Irfan Yavasoglu; Zahit Bolaman,"To compare the effects of simvastatin and atorvastatin on hemostatic parameters. Sixty-one patients with primary hypercholesterolemia without coronary heart disease were treated with atorvastatin 10-20 mg/d or simvastatin 10-20 mg/d. At baseline, 4, 12, and 24 weeks, lipid levels such as low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), triglycerides (TGs), and hemostatic parameters such as platelet counts, partial thromboplastin time (PTT) prothrombin time (PT), and fibrinogen levels were measured. At 12 weeks, the doses of the statins were increased to 20 mg/d in 10 of 35 (28.5%) patients treated with atorvastatin and 18 of 26 (69.2%) patients treated with simvastatin when the target level of LDL-C (130 mg/dL) was not reached. Mean doses were atorvastatin 12.8 mg/d and simvastatin 16.9 mg/d. After 24 weeks, 5 patients (14.3%) in the atorvastatin group and 4 patients (15.3%) in the simvastatin group had not reached the goal. In patients with diabetes, target level (LDL-C <100 mg/dL) was not reached in 35.7% of patients in the atorvastatin group and 44.4% of patients in the simvastatin group. Both simvastatin and atorvastatin were effective in lowering TC and LDL-C levels (p < 0.001). Atorvastatin lowered TGs significantly (p < 0.01). Neither atorvastatin nor simvastatin significantly reduced VLDL-C levels. HDL-C levels increased with atorvastatin, but there was no significant difference between the 2 groups. Platelet counts decreased with both statins nonsignificantly. Moreover, fibrinogen levels decreased with simvastatin and atorvastatin, but these reductions were significant only for simvastatin (p < 0.05). We detected prolongation of the PT with both drugs (p < 0.05); however, prolongation of the PTT was significant only with simvastatin (p < 0.001). Effectiveness of both statins on lipid and hemostatic parameters was dose related. Adverse effects were seen in 5 patients (14.2%) treated with atorvastatin and 3 patients (11.5%) treated with simvastatin. Elevations in serum transaminase levels >3 times the upper limit of normal and in creatine phosphokinase >5 times the upper limit of normal were not observed in any group. Atorvastatin was more effective than simvastatin on lipid parameters, although statistically insignificantly, while simvastatin produced more significant changes than atorvastatin on hemostatic parameters. The mean dose of simvastatin was greater than that of atorvastatin. Both statins had increased effects on lipid and hemostatic parameters when doses were increased. Atorvastatin and simvastatin were well tolerated. Different effects of statins on lipid levels and on coagulation parameters should be considered in patients with hypercholesterolemia and tendency to coagulation, especially in preventing thrombotic events. Further studies in larger trials are needed to confirm these observations.",2003.0,1,1 2015,12659977,Endothelium and the lipid metabolism: the current understanding.,Sandeep T Laroia; Apar Kishor Ganti; Archana T Laroia; Ketki K Tendulkar,"The endothelium is a dynamic organ and responds to various physical and humoral conditions. The endothelium secretes several biologically active substances, both vasoconstrictors and vasodilators, which control these processes. Endothelial function is most commonly assessed as the vasodilatory response to stimuli. Several endothelium-dependent agonists have been identified, each of which acts through a membrane receptor. Nitric oxide which is continuously synthesized by the endothelium has a wide range of biological properties that maintain vascular homeostasis. It is a potent vasodilator and inhibitor of platelet aggregation and thus has an important protective role. Endothelial dysfunction in hypercholesterolemic patients is in large part due to a reduced bioavailability of NO. Traditional coronary risk factors, especially hypercholesterolemia, produce endothelial dysfunction even in patients with normal blood vessels. The underlying mechanisms involve a local inflammatory response, release of cytokines and growth factors, activation of oxidation-sensitive mechanisms in the arterial wall, modulation of intracellular signaling pathways, increased oxidation of low-density lipoprotein cholesterol, and quenching of nitric oxide. Clinical studies have shown a significant improvement in endothelial dysfunction following lowering of serum cholesterol levels, infusion of nitric oxide donors like L-arginine and exercise training. Clinical trials are underway examining the role of endothelin-1 receptor antagonists like bosentan in the prevention of graft atherosclerosis.",2003.0,0,0 2016,12659988,Effects of statin on plaque stability and thrombogenicity in hypercholesterolemic patients with coronary artery disease.,Ji Won Son; Kwang Kon Koh; Jeong Yeal Ahn; Dong Kyu Jin; Gi Soo Park; Dae Sung Kim; Eak Kyun Shin,"Plaque stability and thrombogenicity contribute to development and clinical expression of atherosclerosis. Experimental studies have shown that lipoproteins or mevalonate regulate matrix metalloproteinase (MMP)-9, tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1) expression, providing nonlipid mechanism. We administered simvastatin 20 mg daily during 14 weeks to 32 hypercholesterolemic patients with coronary artery disease. Compared with pretreatment values, simvastatin significantly lowered lipoprotein levels (all P<0.01). Compared with pretreatment values, simvastatin significantly lowered plasma levels of MMP-9, TF, and PAI-1 (P=0.009, P=0.032, and P=0.007, respectively). There were significant inverse correlations between pretreatment MMP-9, TF activity or PAI-1 antigen and the degree of change in those levels after simvastatin (r=-0.793, P<0.001; r=-0.482, P=0.005 and r=-0.590, P<0.001, respectively). Of interest, there were significant correlation between pretreatment or percent changes in MMP-9 levels and pretreatment or percent changes in PAI-1 antigen (r=0.293, P=0.019 and r=0.375, P=0.034, respectively). However, no significant correlations between lipoprotein levels and levels of plaque stability or thrombogenicity markers were determined. Reduction of plaque stability and thrombogenicity markers with statin may contribute to the cardiovascular event reduction and explain the early clinical benefit in clinical trials, independent of lipoprotein changes.",2003.0,0,0 2017,12659994,C-reactive protein and oxidative stress in atrial fibrillation.,Panagiotis Korantzopoulos; Dimitrios Galaris; Dimitrios Papaioannides; Stelianos Kokkoris,,2003.0,0,0 2018,12660532,Statins and fibrates for the treatment of hyperlipidaemia in HIV-infected patients receiving HAART.,Leonardo Calza; Roberto Manfredi; Francesco Chiodo,"The aim of our work is to evaluate the role of statins and fibrates in the management of hyperlipidaemia in HIV-infected patients receiving highly active antiretroviral therapy. Open-label, randomized, prospective study of the efficacy and safety of bezafibrate, gemfibrozil, fenofibrate, pravastatin and fluvastatin as pharmacologic treatment for protease inhibitor-related dyslipidaemia. Plasma lipid levels of 656 HIV-infected patients who referred to our tertiary care centre and were on protease inhibitor-based antiretroviral therapy for at least 12 months have been evaluated. All patients had HIV viral load < 50 copies/ml and presented with hypertriglyceridaemia of at least 6 months duration that was unresponsive to a hypolipidaemic diet; all have been treated with bezafibrate, gemfibrozil, fenofibrate, pravastatin, or fluvastatin for 12 months. Of the 656 patients observed 113 (17.2%) received pharmacological therapy, while seven patients were excluded from evaluation due to early drop-out. Of the 106 evaluable subjects, bezafibrate was used in 25 cases, gemfibrozil in 22, fenofibrate in 22, pravastatin in 19, and fluvastatin in 18. At the close of 1-year follow-up, fibrates led to a reduction of 40.7% and 21.9% versus baseline triglyceridaemia and cholesterolaemia, respectively (P < 0.001), and statins led to a reduction of 34.8% and 25.2% versus baseline triglyceride and total cholesterol levels, respectively (P < 0.001), without significant differences according to each different administered hypolipidaemic drug. All administered statins and fibrates revealed a similar, significant efficacy in the treatment of diet-resistant hyperlipidaemia, and showed a favourable tolerability profile.",2003.0,0,0 2019,12660659,Treating dyslipidemia with statins: the risk-benefit profile.,Luther T Clark,"Coronary heart disease (CHD), the result of coronary atherosclerosis, is the largest single killer of Americans. Central to the pathogenesis of atherosclerosis are the deposition and retention of cholesterol in the arterial walls. Lipid modification, therefore, is key to CHD prevention. Data from trials evaluating the safety and efficacy of several pharmacologic agents for dyslipidemia were thoroughly reviewed. Agents such as bile acid sequestrants, fibric acids, and nicotinic acid have a role in treating dyslipidemia. However, statins are the safest and most effective of the lipid-modifying drugs, reducing the incidence of CHD by as much as 21% to 43%. Despite the overall safety and efficacy of these agents, many patients undergoing statin therapy fail to achieve the treatment goals specified in the National Cholesterol Education Program Adult Treatment Panel III guidelines, often because of suboptimal use, tolerability problems, or lack of compliance. Although adverse effects of statins are generally mild and transient, more serious adverse effects, including myotoxicity, liver toxicity, and rhabdomyolysis, are still possible with statin monotherapy and are more common in patients receiving concomitant therapy with other drugs metabolized by the cytochrome P-450 enzyme system. Because of the overall safety and efficacy of the statins, more patients with or at risk for CHD should be receiving aggressive therapy to lower low-density lipoprotein cholesterol levels and reduce CHD risk.",2003.0,0,0 2020,12661042,"Inflammatory myopathies: clinical, diagnostic and therapeutic aspects.",Frank L Mastaglia; Michael J Garlepp; Beverley A Phillips; Paul J Zilko,"The three major forms of immune-mediated inflammatory myopathy are dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). They each have distinctive clinical and histopathologic features that allow the clinician to reach a specific diagnosis in most cases. Magnetic resonance imaging is sometimes helpful, particularly if the diagnosis of IBM is suspected but has not been formally evaluated. Myositis-specific antibodies are not helpful diagnostically but may be of prognostic value; most antibodies have low sensitivity. Muscle biopsy is mandatory to confirm the diagnosis of an inflammatory myopathy and to allow unusual varieties such as eosinophilic, granulomatous, and parasitic myositis, and macrophagic myofasciitis, to be recognized. The treatment of the inflammatory myopathies remains largely empirical and relies upon the use of corticosteroids, immunosuppressive agents, and intravenous immunoglobulin, all of which have nonselective effects on the immune system. Further controlled clinical trials are required to evaluate the relative efficacy of the available therapeutic modalities particularly in combinations, and of newer immunosuppressive agents (mycophenolate mofetil and tacrolimus) and cytokine-based therapies for the treatment of resistant cases of DM, PM, and IBM. Improved understanding of the molecular mechanisms of muscle injury in the inflammatory myopathies should lead to the development of more specific forms of immunotherapy for these conditions.",2003.0,0,0 2021,12662125,Lopinavir/ritonavir: a review of its use in the management of HIV infection.,Risto S Cvetkovic; Karen L Goa,"Lopinavir is a novel protease inhibitor (PI) developed from ritonavir. Coadministration with low-dose ritonavir significantly improves the pharmacokinetic properties and hence the activity of lopinavir against HIV-1 protease. Coformulated lopinavir/ritonavir was developed for ease of administration and to ensure both drugs are taken together, as part of combination therapy with other antiretroviral agents. Coformulated lopinavir/ritonavir-based regimens provide adequate and durable suppression of viral load and sustained improvements in CD4+ cell counts, as demonstrated in randomised trials in antiretroviral therapy-naive and -experienced adults and children. To date, development of primary resistance to lopinavir/ritonavir has not been observed in 470 antiretroviral therapy-naive patients treated for >48 weeks. The lopinavir/ritonavir-based regimen was more effective than nelfinavir in antiretroviral therapy-naive HIV-1-infected patients in a phase III trial. The coformulation is also effective as 'salvage' therapy, as shown by low cross-resistance rates in patients who failed to respond to treatment with other PIs in phase II trials. Coformulated lopinavir/ritonavir was well tolerated in both antiretroviral therapy-naive and -experienced HIV-1-infected adults and children with low rates of study drug-related treatment discontinuations. The most common adverse event in adults associated with lopinavir/ritonavir was diarrhoea, followed by other gastrointestinal disturbances, asthenia, headache and skin rash. The incidence of moderate-to-severe adverse events in children was low, skin rash being the most common. Changes in body fat composition occurred with equal frequency in lopinavir/ritonavir- and nelfinavir-treated naive patients, through week 60 in a phase III study. Although laboratory abnormalities occurred with similar frequency in both treatment groups, triglycerides grade 3/4 elevations were significantly more frequent with lopinavir/ritonavir. Total cholesterol and triglycerides grade 3/4 elevations appear to occur more frequently in PI-experienced than in PI-naive lopinavir/ritonavir-treated patients. A number of clinically important drug interactions have been reported with lopinavir/ritonavir necessitating dosage adjustments of lopinavir/ritonavir and/or the interacting drugs, and several other drugs are contraindicated in patients receiving the coformulation. Coformulated lopinavir/ritonavir is a novel PI that, in combination with other antiretroviral agents, suppresses plasma viral load and enhances immunological status in therapy-naive and -experienced patients with HIV-1 infection. Lopinavir/ritonavir appears more effective than nelfinavir in 'naive' patients and is also suitable for 'salvage' therapy, because of its high barrier to development of resistance. Given its clinical efficacy, a tolerability profile in keeping with this class of drugs, favourable resistance profile and easy-to-adhere-to administration regimen, coformulated lopinavir/ritonavir should be regarded as a first-line option when including a PI in the management of HIV-1 infection. Lopinavir/ritonavir is a coformulation of two structurally related protease inhibitor (PI) antiretroviral agents. Lopinavir is a highly potent and selective inhibitor of the HIV type 1 (HIV-1) protease, an essential enzyme for production of mature, infective virus. It acts by arresting maturation of HIV-1 thereby blocking its infectivity. Thus, the main antiviral action of lopinavir is to prevent subsequent infections of susceptible cells; it has no effect on cells with already integrated viral DNA. Lopinavir has an approximate, equals 10-fold higher in vitro activity against both wild-type and mutant HIV-1 proteases than ritonavir; however, its in vivo activity is greatly attenuated by a high first-pass hepatic metabolism. The low-dose ritonavir coadministered with lopinavir inhibits metabolic inactivation of lopinavir and acts only as its pharmacokinetic enhancer. Therefore, the antiretroviral activity of roviral activity of coformulated lopinavir/ritonavir 400/100mg twice daily is derived solely from lopinavir plasma concentrations. Combining lopinavir with low-dose ritonavir produces lopinavir concentrations far exceeding those needed to suppress 50% of in vitro and in vivo viral replication in CD4+ cells and monocyte/macrophages (main human reservoirs of HIV-1 infection). Thus far, no resistance to lopinavir has been detected in clinical trials in antiretroviral therapy-naive patients treated for up to 204 weeks and only 12% of HIV-1 strains from patients in whom prior treatment with multiple PIs have failed, have been observed to develop resistance to coformulated lopinavir/ritonavir. A strong negative correlation was found between the number of PI mutations at baseline and the viral response rates achieved with lopinavir/ritonavir-based regimens in PI-experienced patients, indicating that resistance to lopinavir increases with increasing number of PI mutations and that five PI mutations represent the clinically relevant genotypic breakpoint for lopinavir. The absolute bioavailability of lopinavir coformulated with ritonavir in humans has not yet been established. Multiple-dosage absorption pharmacokinetics of lopinavir/ritonavir 400/100mg twice daily (the mean peak [C(max)] and trough [C(trough)] plasma concentrations at steady-state and the 12-hour area under the plasma concentration-time curve [AUC(12)] of either drug) were stable in antiretroviral therapy-naive and single PI-experienced adult patients receiving therapy over a 24-week evaluation period. The C(trough) values of lopinavir, achieved with lopinavir/ritonavir 400/100mg twice daily, were median 84-fold higher than the protein binding-adjusted 50% effective concentration (EC(50)) of lopinavir against wild-type HIV-1 in antiretroviral therapy-naive HIV-1-infected patients in a phase II study. Bioavailability of lopinavir administered in either the capsule or the liquid lopinavir/ritonavir formulation can be increased substantially with concurrent ingestion of food with moderate-to-high fat content. At steady state, lopinavir is approximately 98-99% plasma protein bound and the percentage of its unbound (i.e. pharmacologically active) fraction is dependent on total drug plasma concentration. Both lopinavir and ritonavir penetrate poorly into the human genital tracts and the cerebrospinal fluid. Both agents undergo extensive and rapid first-pass metabolism by hepatic cytochrome P450 (CYP) 3A4 isoenzyme. However, ritonavir also potently inhibits this enzyme and acts as a pharmacokinetic enhancer of lopinavir. The elimination half-life and apparent oral clearance of lopinavir average approximately 4-6 hours and approximately 6-7 L/h, respectively, with lopinavir/ritonavir 400/100mg twice daily administration. Less than 3% and 20% of the lopinavir dose is excreted unchanged in the urine and faeces, respectively. Limited data show similar pharmacokinetics of lopinavir in children as in adults. Coformulated lopinavir/ritonavir has the potential to interact with wide variety of drugs via several mechanisms, mostly involving the CYP enzymes. Coadministration of lopinavir/ritonavir is contraindicated with certain drugs (i.e. flecainide, propafenone, astemizole, terfenadine, ergot derivatives, cisapride, pimozide, midazolam and triazolam) that are highly dependent on CYP3A or CYP2D6 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Coadministration with lopinavir/ritonavir is also not recommended for drugs or herbal products (i.e. rifampicin [rifampin] and St. John's wort [Hypericum perforatum]) that may substantially reduce lopinavir plasma concentrations, or drugs whose plasma concentrations elevated by the coformulation may lead to serious adverse reactions (i.e. simvastatin and lovastatin). However, a recent study in healthy volunteers suggests that adequate lopinavir concentrations may be achieved during rifampicin coadministration by increasing the twice-daily dosage of lopinavir/ritonavir in conjunction with therapeutic drug monitoring. The liquid (but not the capsule) formulation of lopinavir/ritonavir contains 42.4% ethanol (v/v) and should not be coadministered with drugs capable of producing disulfiram-like reactions (e.g. disulfiram, metronidazole). Coadministration with saquinavir or indinavir requires no dosage adjustment, whereas coadministration with amprenavir, nevirapine or efavirenz requires a dosage increase of the coformulation typically by 33%. As the oral bioavailability of both didanosine and lopinavir/ritonavir is significantly affected by concurrent food ingestion, didanosine should be administered 1 hour before or 2 hours after lopinavir/ritonavir has been taken with food. Interactions between lopinavir/ritonavir and other nucleoside reverse transcriptase inhibitors (NRTIs) are not expected. The coformulation is also likely to increase plasma concentrations of non-antiretroviral drugs metabolised through the CYP3A pathway. To reduce the risk of their toxicity when coadministered with lopinavir/ritonavir, the recommended actions include: (i) monitoring of the drug plasma concentration (antiarrhythmics and immunosuppressants) or the international normalised ratio (warfarin); (ii) the use of alternative treatment (atorvastatin) or birth control methods (ethinylestradiol); and (iii) dosage adjustment (clarithromycin [only in patients with renal failure], rifabutin, dihydropyridine calcium-channel blockers, atorvastatin, ketoconazole and itraconazole). (ABSTRACT TRUNCATED)",2003.0,0,0 2022,12663406,Cross sectional survey of effectiveness of lipid lowering drugs in reducing serum cholesterol concentration in patients in 17 general practices.,Julia Hippisley-Cox; Ruth Cater; Mike Pringle; Carol Coupland,"To compare the effectiveness of lipid lowering drugs in lowering serum cholesterol concentrations. Cross sectional study. 17 practices within 17 primary care groups in Trent region, United Kingdom. Patients aged 35 years or over taking lipid lowering drugs and with at least two serum cholesterol concentrations recorded on computer. Proportion of patients achieving serum cholesterol concentration of < or =5 mmol/l and mean percentage reduction in serum cholesterol concentration. 1353 of 2469 (54.8%) patients receiving lipid lowering treatment had a last recorded serum cholesterol concentration of < or =5 mmol/l. Significantly more patients taking statins achieved the target value for serum cholesterol (5 mmol/l) than those taking fibrates (1307 (57%) v 46 (26%); P<0.0001). Atorvastatin and simvastatin were the most effective drugs in achieving the target. Significant differences were found between lipid lowering drugs for the pretreatment serum cholesterol concentration, the most recent cholesterol concentration, and the associated percentage reduction. Atorvastatin and simvastatin achieved the greatest percentage reduction in serum cholesterol concentrations (30.1%, 95% confidence interval 28.8% to 31.4%, and 28.0%, 26.7% to 29.3%, respectively). Although the mean serum cholesterol concentrations in this unselected population tended to be higher than those in clinical trials, the percentage reduction was consistent with the trials. The ability of individual statins to lower serum cholesterol concentration varied, with atorvastatin and simvastatin being the most effective. The percentage reductions agreed with those of randomised controlled trials indicating likely benefits in unselected patients in primary care. As the initial serum cholesterol concentrations were higher than those in randomised controlled trials, target serum cholesterol values of < or =5 mmol/l may be unrealistic even for patients taking the most efficacious drugs. Also, the higher initial levels could mean that the absolute reduction in cardiovascular risk in primary care patients is greater than thought.",2003.0,0,0 2023,12663600,Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes.,Francine V van Venrooij; Ronald P Stolk; Jan-Dirk Banga; Tjeerd P Sijmonsma; Arie van Tol; D Willem Erkelens; Geesje M Dallinga-Thie; DALI Study Group,"The cholesteryl ester transfer protein (CETP) plays a key role in the remodeling of triglyceride (TG)-rich and HDL particles. Sequence variations in the CETP gene may interfere with the effect of lipid-lowering treatment in type 2 diabetes. We performed a 30-week randomized double-blind placebo-controlled trial with atorvastatin 10 mg (A10) and 80 mg (A80) in 217 unrelated patients with diabetes. CETP TaqIB and A-629C polymorphisms were tightly concordant (P < 0.001). At baseline, B1B1 carriers had lower plasma HDL cholesterol (0.99 +/- 0.2 vs. 1.11 +/- 0.2 mmol/l, P < 0.05), higher CETP mass (2.62 +/- 0.8 vs. 2.05 +/- 0.4 mg/l, P < 0.001), and slightly increased, though not significant, plasma TGs (2.7 +/- 1.05 vs. 2.47 +/- 0.86, P = 0.34) compared with B2B2 carriers. Atorvastatin treatment significantly reduced CETP mass dose-dependently by 18% (A10) and 29% (A80; both vs. placebo P < 0.001, A10-A80 P < 0.001). CETP mass and activity were strongly correlated (r = 0.854, P < 0.0001). CETP TaqIB polymorphism appeared to modify the effect of atorvastatin on HDL cholesterol elevation (B1B1 7.2%, B1B2 6.1%, B2B2 0.5%; P < 0.05), TG reduction (B1B1 39.7%, B1B2 38.4%, B2B2 18.4%; P = 0.08), and CETP mass reduction (B1B1 32.1%, B1B2 29.6%, B2B2 21.9%; P = 0.27, NS). Similar results were obtained for the A-629C polymorphism. In conclusion, the B1B1/CC carriers of the CETP polymorphisms have a more atherogenic lipid profile, including low HDL, and they respond better to statin therapy. These results favor the hypothesis that CETP polymorphisms modify the effect of statin treatment and may help to identify patients who will benefit most from statin therapy.",2003.0,0,0 2024,12665389,Transient ischaemic attacks : new approaches to management.,Ramesh Madhavan; Seemant Chaturvedi,"The fact that transient ischaemic attacks are a harbinger for the possible development of ischaemic stroke has been recognised for several decades. However, within the past decade, our concepts regarding transient ischaemic attacks as a distinct entity from stroke and the prognosis for transient ischaemic attack patients have been challenged. In addition, clinical trials have clarified that modern transient ischaemic attack management is more complex than in the past, with the addition of newer pharmacological options to the stroke prevention armamentarium. Recent information regarding newer antiplatelet agents is reviewed in this article, along with results of clinical trials pertaining to warfarin in stroke prevention. The evolving role of statins, ACE inhibitors and estrogen replacement is reviewed. Finally, the appropriate use of surgery following transient ischaemic attacks is outlined. Recent studies have shown that many patients will benefit from a multimodal pharmacological approach following transient cerebral ischaemia, and the potential for combination therapy is highlighted.",2003.0,0,0 2025,12665416,Novel therapies for osteoporosis.,Diane M Biskobing,"Osteoporosis remains a significant clinical problem despite effective therapies. Many patients cannot or will not take currently available therapies. For this reason research continues in search of more effective and more tolerable agents. Anabolic agents offer a unique mechanism of action. The anabolic agents parathyroid hormone and strontium will be discussed. The investigational bisphosphonates ibandronate, minodronate and zoledronic acid may offer the advantage of less frequent dosing. Arzoxifene, bazedoxifene, lasofoxifene, MDL-103,323 and ospemifene are investigational selective oestrogen receptor modulators shown to be effective in animal studies and are now in clinical studies. Tibolone is a tissue-specific steroid that is currently used in Europe for prevention and treatment of osteoporosis. Multiple studies have shown efficacy in improving bone mineral density, but no fracture studies have been conducted to date. While studies of the effect of isoflavones on bone mineral density have been encouraging, a large, multi-centre study in Europe showed no effect of isoflavones on fractures. The newly described agent osteoprotegerin has been shown in early studies to inhibit bone turnover. Other agents with unique mechanisms of action in early development include cathepsin K inhibitors, integrin receptor inhibitors, nitrosylated non-steroidal anti-inflammatory agents and Src inhibitors. The efficacy of statins in bone continues to be debated with no prospective, randomised studies yet to confirm the suggestion of benefit seen in epidemiological studies.",2003.0,0,0 2026,12665424,Disease-modifying therapies in multiple sclerosis: an update on recent and ongoing trials and future strategies.,Heinz Wiendl; Bernd C Kieseier,"Multiple sclerosis (MS) is the prototype inflammatory autoimmune disorder of the central nervous system and the most common cause of neurological disability in young adults exhibiting considerable clinical, radiological and pathological heterogeneity. Novel insights in the immunopathological processes, advances in biotechnology, development of powerful magnetic resonance imaging technologies together with improvements in clinical trial design led to a variety of evaluable therapeutic approaches. Therapy has changed dramatically over the past decade, yielding significant progress for the treatment of relapsing-remitting and secondary progressive MS. A substantial number of pivotal and preliminary reports continue to demonstrate encouraging new evidence that advances are being made in the care of MS patients. This review summarises recent progress with currently available disease-modifying therapies and - on the basis of present immunopathogenetic concepts - outlines ongoing studies as well as future treatment strategies.",2003.0,0,0 2027,12667121,Warfarin and aspirin give more benefit than aspirin alone but also more bleeding after myocardial infarction.,Sheila A Doggrell,"The anticoagulant, warfarin, and the antiplatelet agent, aspirin, have been shown to have similar benefits after myocardial infarction. As these agents have different mechanisms of action, the beneficial effects of warfarin and aspirin may be additive after myocardial infarction. In the Warfarin, Aspirin, Reinfarction Study (WARIS II), the main outcome was a composite of death, non-fatal reinfarction or thromboembolic stroke, whichever came first over 4 years. Compared to aspirin alone (160 mg/day), the risk reduction was 19% (p = 0.03) with warfarin alone (INR of 2.8 IU) and 29% (p = 0.001) with the combination of aspirin and warfarin (aspirin, 75 mg/day; warfarin, INR of 2.2 IU). This difference in the first event with warfarin alone or the combination, represented a reduction in reinfarction and thromboembolic stroke rather than death. For reinfarction, compared to aspirin alone (117 of 1206), there was a reduction with warfarin alone (90 of 1216) and a further reduction with the combination (69 of 1208). For thromboembolic stroke, compared to aspirin (32 of 1206), there were similar reductions with warfarin and the combination. There were more major and minor bleeding in the warfarin groups than the aspirin group, with major bleeding occurring in 8, 33 and 28 patients taking aspirin, warfarin and aspirin and warfarin, respectively. In conclusion, as compared with aspirin alone, therapy with moderate-intensity warfarin combined with aspirin and high-intensity warfarin alone, resulted in a reduced risk of reinfarction and ischemic stroke but a higher risk of bleeding.",2003.0,0,0 2028,12667571,Effect of atorvastatin on endothelium-dependent vasodilation in patients with coronary artery disease.,Joseph A Vita; Noyan Gokce; Stephen J Duffy; David Kahn; Douglas Tomasian; Joseph Palmisano; Shane Thomas; Monika Holbrook; John F Keaney,,2003.0,0,0 2029,12667578,Results of two clinical trials on the safety and efficacy of pravastatin 80 and 160 mg per day.,Robert S Rosenson; Harold E Bays,,2003.0,0,0 2030,12668486,Are antiplatelet effects of clopidogrel inhibited by atorvastatin? A research question formulated but not yet adequately tested.,Victor L Serebruany; Steven R Steinhubl; Charles H Hennekens,,2003.0,0,0 2031,12669727,Imatinib: new preparation. For Chronic myeloid leukaemia: further assessment required.,,"(1) Chronic myeloid leukaemia goes through three clinical phases: a chronic phase, an acceleration phase, and a terminal blast crisis. In the chronic phase, interferon alfa-2 is more effective than cytotoxic chemotherapies but it also has more adverse effects. (2) Imatinib inhibits tyrosine kinase, an enzyme encoded by the pathological gene BCR-ABL, which is created during a reverse translocation between chromosomes 9 and 22 (characteristic of chronic myeloid leukaemia). This translocation almost always creates the pathological chromosome Philadelphia in blood cell lines. (3) 1 027 patients were recruited to three non comparative trials of imatinib, each focusing on a different phase of chronic myeloid leukaemia. Efficacy was evaluated largely on the basis of blood cell count and clearance of cells harbouring the Philadelphia chromosome. (4) During the chronic phase, in patients in whom interferon alfa-2 had failed or been poorly tolerated, a major cytogenetic response, lasting at least one month, occurred in 35% of patients on imatinib, compared to 20% of patients on interferon alfa-2 + cytarabine (historical comparison). It is not known whether this translated into longer survival. (5) Preliminary results from a randomised but unblinded trial comparing imatinib with interferon + cytarabine seem to favour imatinib. Some patients developed relapses resistant to imatinib, owing to mutations in the BCR-ABL gene. (6) In patients going through the acceleration phase or blast crisis, imatinib did not improve survival compared with standard treatments. (7) The main adverse effects so far described with imatinib are gastrointestinal problems, oedema and fluid retention, and muscle and joint pain, which prompted patients to stop treatment in no more than 5% of cases. (8) Imatinib has a strong potential to interact with other drugs, including paracetamol, but few specific studies have been done. (9) In practice imatinib may be a useful option during the chronic phase, after interferon alfa-2 has failed or been stopped because of adverse effects, provided that its benefits, so far shown only in surrogate endpoints, translate into longer survival. During the acceleration phase and blast crisis imatinib may cause fewer side effects than existing treatments.",2003.0,0,0 2032,12672343,Statins and coenzyme Q10.,C J Ellis; R Scott,,2003.0,0,0 2033,12672737,,,,,0,0 2034,12675696,Arterial hypertension and ischaemic stroke.,D W Droste; M A Ritter; R Dittrich; S Heidenreich; T Wichter; M Freund; E B Ringelstein,"Arterial hypertension is, besides age, the number one risk factor for ischaemic stroke. Patients with arterial hypertension frequently present with additional coexisting vascular risk factors interacting in a complex way. This paper reviews the benefit of antihypertensive treatment, as well as different treatment options of arterial hypertension and their side-effects. Patients with definite arterial hypertension, but also patients with so-called normal or high-normal blood pressure are at increased risk to develop stroke and other cardiovascular complications. Vascular remodelling of small and large vessels provoked by arterial hypertension is the initial step in the development of atherosclerosis and lipohyalinosis. Vascular remodelling can be improved or even normalized by antihypertensive treatment with angiotensin-converting-enzyme inhibitors and angiotensin-I-receptor antagonists showing the most convincing effects. Angiotensin-converting-enzyme inhibitors and angiotensin-I-receptor antagonists have the lowest rate of side-effects, however, economic restraints hinder their general application. Statins are needed to treat dyslipidaemia. They also lower blood pressure and have a synergistic effect with the above two antihypertensive components in lowering blood pressure. In hypertensive patients, risk of stroke and other cardiovascular complications is determined by the blood pressure level and the presence or absence of target organ damage and the interaction with other risk factors, such as cigarette smoking, dyslipidaemia, and diabetes. These high-risk patients should be treated even more aggressively than usual. In the vast majority of patients and healthy individuals, target blood pressure should be as high as or below 120/80 mmHg to minimize the occurrence of stroke and other cardiovascular complications.",2003.0,0,0 2035,12676174,Inflammation and angiotensin II.,Yusuke Suzuki; Marta Ruiz-Ortega; Oscar Lorenzo; Monica Ruperez; Vanesa Esteban; Jesus Egido,"Angiotensin II (AngII), the major effector peptide of renin-angiotensin system (RAS), is now recognized as a growth factor that regulates cell growth and fibrosis, besides being a physiological mediator restoring circulatory integrity. In the last few years, a large number of experimental studies has further demonstrated that AngII is involved in key events of the inflammatory process. Here, we summarize the wide variety of AngII functions and discuss them in relation with the inflammatory cascade. AngII increases vascular permeability (via the release of prostaglandins and vascular endothelial cell growth factor or rearrangement of cytoskeletal proteins) that initiates the inflammatory process. AngII could contribute to the recruitment of inflammatory cells into the tissue through the regulation of adhesion molecules and chemokines by resident cells. Moreover, AngII could directly activate infiltrating immunocompetent cells, including chemotaxis, differentiation and proliferation. Recent data also suggest that RAS activation could play a certain role even in immunologically-induced inflammation. Transcriptional regulation, predominantly via nuclear factor-kappaB (NF-kappaB) and AP-1 activation, and second mediator systems, such as endothelin-1, the small G protein (Rho) and redox-pathways are shown to be involved in the molecular mechanism by which AngII exerts those functions. Finally, AngII participates in tissue repair and remodeling, through the regulation of cell growth and matrix synthesis. In summary, recent data support the hypothesis that RAS is key mediator of inflammation. Further understanding of the role of the RAS in this process may provide important opportunities for clinical research and treatment of inflammatory diseases.",2003.0,0,0 2036,12678210,Isoflavones and the prevention and treatment of prostate disease: is there a role?,Mitchell Lee Gaynor,"Epidemiologic and experimental data suggest that isoflavones have benefits for preventing and treating some prostate disease. Isoflavone supplements may therefore be an important tool for men concerned about prostate disease, such as those with benign prostatic hypertrophy undergoing watchful waiting or those concerned about the potential for prostate cancer. Conclusive proof of a relationship between isoflavones and the prevention and treatment of prostate disease can only come from prospective, randomized, controlled clinical trials.",2003.0,0,0 2037,12678218,The ALLHAT Trial. Diuretics are still the preferred initial drugs for high blood pressure.,Donald G Vidt,"The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) compared four antihypertensive agents in patients 55 years and older: chlorthalidone, doxazosin, amlodipine, and lisinopril. The doxazosin arm was terminated early because of an excess of congestive heart failure. Chlorthalidone was at least equivalent to amlodipine and lisinopril in all of the outcomes measured, and was better in some, notably heart failure.",2003.0,0,0 2038,12678574,Statin treatment and progression of atherosclerotic plaque burden.,Diederick E Grobbee; Michiel L Bots,"Atherosclerosis is a progressive systemic disorder that, in the initial stages, is often asymptomatic. The measurement of atherosclerotic burden using imaging techniques enables the clinical benefits of lipid-modifying therapies to be assessed in early atherosclerosis and facilitates more rapid evaluation of interventions in clinical trials compared with the measurement of clinical outcome. The effect of HMG-CoA reductase inhibitors, commonly referred to as 'statins', on disease progression has been assessed in a number of imaging studies both in patients with established coronary heart disease (CHD) and in those with subclinical atherosclerosis. Statins slow plaque progression and, in early atherosclerosis, they have been demonstrated to promote regression of atherosclerotic lesions. The benefits of statin therapy on soft atherosclerotic plaques that are still developing support the use of vascular measures to detect subclinical atherosclerosis, and the subsequent early intervention with statin therapy. Moreover, given that the effects of statins on atherosclerosis progression are evident even in normocholesterolaemic patients at increased risk of developing CHD, early intervention with statin therapy may be effective in preventing CHD, irrespective of lipid level.",2003.0,0,0 2039,12678682,A helping hand for the good guy; novel pharmacological approaches for augmenting the cardiovascular benefits of high density lipoproteins.,Richard W James,"Pharmacological modulation of serum lipid levels is a powerful means of favourably modifying the risk and incidence of coronary disease. High density lipoproteins (HDL) exert a beneficial influence on atherosclerotic disease, in part by modulating blood lipid metabolism. Three factors have contributed to the growing interest in HDL as a therapeutic target. Firstly, recent, if limited, clinical trials have demonstrated the cardiovascular benefits of modulating HDL. Secondly, on-going studies have clarified several aspects of HDL metabolism and opened new avenues for pharmacological intervention. Thirdly, the WHO foresees an enormous global increase in the incidence of type 2 diabetes, as well as a related disorder, the metabolic syndrome. Both have, as their primary complication, cardiovascular disease whilst one of the principal lipid disorders is a reduction in HDL. Thus for several cogent reasons, HDL has become a primary target for drug development. The review covers our understanding of HDL metabolism, and notably the contribution of recent studies, in the context of potential sites for intervention. The rationale for targeting such sites, and available human and animal data on the cardiovascular consequences of modulating their activities, is discussed. Finally, the current status of drugs developed with a view to influencing HDL metabolism is presented.",2003.0,0,0 2040,12678859,Sirolimus eluting stent: a new era in interventional cardiology?,Stephan Windecker; Marco Roffi; Bernhard Meier,"Coronary artery stents have emerged as the preferred tool for percutaneous coronary interventions during the past decade by eliminating abrupt vessel closure and reducing restenosis compared with balloon angioplasty. While coronary artery stents prevent constrictive arterial remodeling and elastic recoil, the implantation is associated with more severe arterial vascular injury than balloon angioplasty alone. The arterial injury initiates a vasculoproliferative response with smooth muscle cell proliferation and migration as well as extracellular matrix formation, which may lead to severe neointimal hyperplasia with in-stent restenosis in 10-30% of cases. Sirolimus, a naturally occurring macrocyclic lactone, has been identified as a pharmacological cell cycle inhibitor with potent antiproliferative and antimigratory effects on vascular smooth muscle cells in vitro. The systemic administration of sirolimus has been shown to effectively reduce neointimal hyperplasia in experimental restenosis models. Subsequently, sirolimus has been incorporated at therapeutically important doses into biocompatible polymers, which made it suitable for stent-based drug elution. Investigation of sirolimus eluting stents in both experimental and clinical restenosis studies have demonstrated dramatic reductions in neointimal hyperplasia. Accordingly, sirolimus eluting stents offer an attractive mode of local drug delivery by minimizing systemic toxicity and maximizing local dose requirements. In addition, sirolimus eluting stents hold great promise to effectively prevent restenosis.",2003.0,0,0 2041,12679222,Improved endothelial function by the thromboxane A2 receptor antagonist S 18886 in patients with coronary artery disease treated with aspirin.,Laurent Belhassen; Gabriel Pelle; Jean-Luc Dubois-Rande; Serge Adnot,"In this study, we evaluated the effect of S 18886, a specific thromboxane A(2) receptor antagonist, on endothelial function in patients with coronary artery disease (CAD). Impaired release of endothelial vasodilator substances and increased release of vasoconstrictor prostanoids both contribute to endothelial dysfunction in atherosclerosis. One unresolved question is whether vasoconstrictor prostanoids are still produced and affect vascular tone or alter endothelium-dependent vasodilation in patients treated with aspirin. Twenty patients with stable CAD treated with 100 mg/day aspirin were evaluated in a randomized, double-blinded, placebo-controlled study. Twelve patients received a single oral dose of 10 mg S 18886, and eight patients received placebo. Before and 60 min after a single oral dose of S 18886 or placebo, flow-mediated vasodilation (FMD) was evaluated using an echo-tracking device. Venous occlusion plethysmography was used to evaluate the effects on forearm blood flow (FBF) of a brachial artery infusion of acetylcholine (ACh), sodium nitroprusside (SNP), or norepinephrine before and after treatment. Baseline FBF was not affected by S 18886 or placebo. The vasodilator response to ACh was significantly potentiated by S 18886 as compared with placebo (p = 0.03 by analysis of co-variance), whereas the effects of norepinephrine and SNP were unchanged. Flow-mediated dilation increased from 2.50 +/- 1.14% to 3.84 +/- 1.80% (p < 0.01) after S 18886, but was unchanged after placebo. Single administration of S 18886 improved FMD and ACh-induced vasodilation in aspirin-treated patients with CAD. These results suggest that release of endogenous agonists of TP receptors may contribute to endothelial dysfunction, despite aspirin treatment, in patients with atherosclerosis.",2003.0,0,0 2042,12679223,"Antioxidants, statins, and atherosclerosis.",Antonio M Gotto,"Research into the oxidation of lipoproteins has yielded many new insights into the pathogenesis of atherosclerosis. However, despite lipoprotein oxidation's biologically plausible role in atherogenesis, several studies have reported inconsistent effects of antioxidants on clinical coronary end points, in sharp contrast with the studies of lipid modification with the 3-hydroxy-3-methylglutaryl coenzyme A inhibitors, or statins. There appears to be little support for the use of antioxidants in coronary prevention. However, the picture remains incomplete. What are the limitations of available antioxidant studies and the agents used? Until the picture can be clarified, lipid modification with strategies proved to reduce the risk for coronary events, such as statins or dietary changes in the style of the Mediterranean diet, should be better implemented in clinical practice.",2003.0,0,0 2043,12679230,Statistical versus clinical significance of the CURE study in acute coronary syndromes.,Campbell D Joyner; Marcus Flather,,2003.0,0,0 2044,12679753,,,,,0,0 2045,12679760,Effect of pravastatin on cardiovascular events and mortality in 1516 women with coronary heart disease: results from the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study.,Wendy Hague; Peta Forder; John Simes; David Hunt; Andrew Tonkin; LIPID Investigators,"The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study showed that cholesterol-lowering therapy prevented further events in patients with coronary heart disease and average cholesterol levels. The aim of this subgroup analysis was to assess the effects of pravastatin in women. A total of 1516 women (756 assigned to take pravastatin) in a cohort of 9014 patients with previous myocardial infarction or unstable angina and a baseline plasma cholesterol level of 4.0 to 7.0 mmol/L (155-271 mg/dL) were assigned to receive pravastatin (40 mg/d) or placebo. Major cardiovascular disease events in 6 years were measured. Women were at a lesser risk than men for death from any cause (10.3% vs 14.8%, P <.01), death from coronary heart disease (6.6% vs 8.6%, P =.04), and coronary revascularization (13.6% vs 16.2%, P =.05) and at a similar risk of myocardial infarction (9.2% vs 10.5%, P =.26), stroke (3.6% vs 4.7%, P =.11), and hospitalization for unstable angina (25.1% vs 24.5%, P = 0.90). Pravastatin significantly reduced the risk of all prespecified cardiovascular events in all LIPID patients. Relative treatment effects in women did not differ significantly from those in men (P >.05) for any events except hospitalization for unstable angina. There were too few events to demonstrate separately significant effects in women; the estimated relative risk reduction with pravastatin was 11% (95% CI -18%-33%) for coronary heart disease death or nonfatal myocardial infarction, 18% (95% CI -25%-46%) for coronary heart disease death, 16% (95% CI -19%-41%) for myocardial infarction, and 17% (95% CI -2%-33%) for coronary heart disease death, myocardial infarction, or coronary revascularization. The study had the largest secondary-prevention female cohort studied thus far, but was not adequately powered to show separate effects in women. Nevertheless, the results were consistent with the main results of this and other trials in showing reduced risks with cholesterol-lowering treatment.",2003.0,0,0 2046,12680480,The importance of in-hospital statin therapy for patients with acute coronary syndromes.,Fran L Paradiso-Hardy; Wendy L Gordon; Cynthia A Jackevicius; Heather R Kertland; Glen J Pearson; Jennifer L Pickering; Luc Poirier; Bill M Semchuk; Lucie Verret,"Starting lipid-lowering therapy in the hospital, especially with statins, has become an important component in the management of patients with acute coronary syndromes (ACS). It improves outcomes and increases patient motivation and long-term adherence. In addition, discontinuation of statin therapy in patients with ACS after hospital admission is associated with an increased risk of adverse outcomes. Recent non-ST elevation ACS guidelines recommend beginning statin therapy, along with dietary intervention, in patients whose low-density lipoprotein cholesterol levels exceed 130 mg/dl within 24-96 hours after hospital admission. Various strategies have been developed to aid in the implementation of in-hospital lipid-lowering therapy. Pharmacists can play a valuable role in optimizing drug therapy for dyslipidemia and ensuring long-term adherence.",2003.0,0,0 2047,12680984,Stroke prevention: what's new?,R P Gerraty,"Abstract Antithrombotic treatment has now been joined by other evidence-based drug interventions for prevention of stroke, including angiotensin-converting enzyme inhibitors and hydroxymethylglutaryl-CoA reductase inhibitors. The efficacy of oral anticoagulation in atrial fibrillation has not been seen in other stroke-prone groups, although trials are continuing. Diffusion-weighted magnetic resonance imaging improves diagnostic accuracy in acute stroke, which is important in arriving at the right secondary prevention strategy. Carotid endarterectomy has been shown to be beneficial for 50-69% symptomatic -stenosis but with a much narrower therapeutic index than for 70-99% stenosis. A comparison of endarterectomy with angioplasty and/or stent placement has been the subject of one small trial suggesting similar procedural stroke and mortality risks. Device closure of cardiac abnormalities increases in the absence of any trial data, and in spite of a low subsequent stroke risk for young patients with isolated patent foramen ovale treated with aspirin.",2003.0,0,0 2048,12682802,The effect of erythromycin on the pharmacokinetics of rosuvastatin.,K J Cooper; P D Martin; A L Dane; M J Warwick; A Raza; D W Schneck,"To examine in vivo the effect of erythromycin on the pharmacokinetics of rosuvastatin [an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase]. Erythromycin is a potent inhibitor of CYP3A4 that markedly increases circulating levels of some other HMG-CoA reductase inhibitors. In this randomised, double-blind, two-way cross-over, placebo-controlled trial 14 healthy volunteers were given 500 mg erythromycin or placebo four times daily for 7 days. A single dose of 80 mg rosuvastatin was co-administered on day 4 of dosing. Plasma concentrations of rosuvastatin and active and total HMG-CoA reductase inhibitors were measured up to 96 h after dosing. Eleven volunteers had data available from both dosing periods. There was no increase in rosuvastatin plasma exposure following co-administration with erythromycin compared to placebo. In fact, following co-administration with erythromycin, rosuvastatin geometric least square mean AUC((0-t)) and C(max) were 20% and 31%, respectively, lower than with placebo. Individual treatment ratios for AUC((0-t)) ranged from 0.48 to 1.17, and for C(max) ranged from 0.33 to 2.19. Essentially all of the circulating active HMG-CoA reductase inhibitors and most (>94%) of the total inhibitors were accounted for by rosuvastatin. Erythromycin did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. Erythromycin did not produce any increase in rosuvastatin plasma exposure. This indicates that CYP3A4 metabolism is not an important clearance mechanism for rosuvastatin, a result consistent with previous findings. The small decreases in rosuvastatin AUC((0-t)) and C(max) that occurred as a consequence of short-term treatment with erythromycin are unlikely to have relevance to long-term treatment with rosuvastatin.",2003.0,0,0 2049,12683265,Understanding the new and evolving profile of adverse drug effects in schizophrenia.,Donna A Wirshing; Joseph M Pierre; Stephen M Erhart; Jennifer A Boyd,"This article has reviewed the emerging side-effect profiles of second-generation antipsychotic medications. Although these medications have favorable extrapyramidal side-effect profiles, clinicians must be aware of their propensity to cause weight gain, glucose and lipid abnormalities, and cardiac and sexual side effects. If clinicians are proactive about warning patients about these side effects and appropriately monitoring them, further morbidity and mortality may be prevented in this patient population. Initial choices of medication should be made based on the relative side-effect profiles in light of a particular patient's medical status. In the future, new treatments may be developed, with even fewer side effects.",2003.0,0,0 2050,12685616,"A dose-ranging study of a new, once-daily, dual-component drug product containing niacin extended-release and lovastatin.",Donald B Hunninghake; Mark E McGovern; Michael Koren; Ronald Brazg; David Murdock; Stuart Weiss; Thomas Pearson,"Combination therapy for dyslipidemia holds promise as effective treatment for patients with multiple lipid disorders, especially those at high risk. This study evaluated dose-response relationships and safety of a new dual-component drug product containing niacin extended-release (niacin ER) and lovastatin. The 28-week double-blind multicenter trial randomized 237 patients with type IIA or IIB hyperlipidemia to one of four escalating-dose treatment groups: niacin ER/lovastatin 1,000/20 mg, niacin ER/lovastatin 2,000/40 mg, niacin ER 2,000 mg, or lovastatin 40 mg. Niacin ER/lovastatin was more effective than each of its components for improving levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), and exhibited a clear dose-response effect and additivity across the dosage range. The 2,000/40 dose achieved greater mean reductions in LDL-C (-42%) than 1,000/20 (-28%, p < 0.001), lovastatin 40 mg (-32%, p < 0.05), or niacin ER 2,000 mg (-14%, p < 0.05). The 2,000/40 dose was significantly more effective in increasing HDL-C levels (+30%) than the 1,000/20 dose (+21%, p = 0.016). The decrease in TG was greater with 2,000/40 (-43%) than with 1,000/20 (-26%, p = 0.009). All three niacin-containing treatments were more effective than lovastatin monotherapy in reducing lipoprotein (a) [Lp(a)] levels. Flushing caused 12 (11%) patients receiving niacin ER/lovastatin and I patient receiving lovastatin alone to withdraw. No drug-related myopathy was noted. One patient each in the 2,000/40 group and the lovastatin 40-mg group had reversible elevations in liver transaminases. Niacin ER/lovastatin is well tolerated and effective for patients with multiple lipid disorders.",2003.0,0,0 2051,12686031,What are the odds at ASCOT today?,Lars H Lindholm; Ola Samuelsson; ASCOT,,2003.0,0,0 2052,12686036,"Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.",Peter S Sever; Björn Dahlöf; Neil R Poulter; Hans Wedel; Gareth Beevers; Mark Caulfield; Rory Collins; Sverre E Kjeldsen; Arni Kristinsson; Gordon T McInnes; Jesper Mehlsen; Markku Nieminen; Eoin O'Brien; Jan Ostergren; ASCOT investigators,"The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome. No study, however, has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease (CHD) in hypertensive patients who are not conventionally deemed dyslipidaemic. Of 19342 hypertensive patients (aged 40-79 years with at least three other cardiovascular risk factors) randomised to one of two antihypertensive regimens in the Anglo-Scandinavian Cardiac Outcomes Trial, 10305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were randomly assigned additional atorvastatin 10 mg or placebo. These patients formed the lipid-lowering arm of the study. We planned follow-up for an average of 5 years, the primary endpoint being non-fatal myocardial infarction and fatal CHD. Data were analysed by intention to treat. Treatment was stopped after a median follow-up of 3.3 years. By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50-0.83], p=0.0005). This benefit emerged in the first year of follow-up. There was no significant heterogeneity among prespecified subgroups. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56-0.96], p=0.024), total cardiovascular events (389 vs 486, 0.79 [0.69-0.90], p=0.0005), and total coronary events (178 vs 247, 0.71 [0.59-0.86], p=0.0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71-1.06], p=0.16). Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months, and by 1.1 mmol/L after 3 years of follow-up. The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time. These findings may have implications for future lipid-lowering guidelines.",2003.0,1,1 2053,12686335,Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome.,Gloria Lena Vega; Patrick T S Ma; Nilo B Cater; Neil Filipchuk; Shinichi Meguro; Ana Barbara Garcia-Garcia; Scott M Grundy,"Combined hyperlipidemia predisposes subjects to coronary heart disease. Two lipid abnormalities--increased cholesterol and atherogenic dyslipidemia--are potential targets of lipid-lowering therapy. Successful management of both may require combined drug therapy. Statins are effective low-density lipoprotein (LDL) cholesterol-lowering drugs. For atherogenic dyslipidemia (high triglycerides, small LDL, and low high-density lipoprotein [HDL]), fibrates are potentially beneficial. The present study was designed to examine the safety and efficacy of a combination of low-dose simvastatin and fenofibrate in the treatment of combined hyperlipidemia. It was a randomized, placebo-controlled trial with a crossover design. Three randomized phases were employed (double placebo, simvastatin 10 mg/day and placebo, and simvastatin 10 mg/day plus fenofibrate 200 mg/day). Each phase lasted 3 months, and in the last week of each phase, measurements were made of plasma lipids, lipoprotein cholesterol, plasma apolipoproteins B, C-II, and C-III and LDL speciation on 3 consecutive days. Simvastatin therapy decreased total cholesterol by 27%, non-HDL cholesterol by 30%, total apolipoprotein B by 31%, very low-density lipoprotein (VLDL) + intermediate-density lipoprotein (IDL) cholesterol by 37%, VLDL + IDL apolipoprotein B by 14%, LDL cholesterol by 28%, and LDL apolipoprotein B by 21%. The addition of fenofibrate caused an additional decrease in VLDL + IDL cholesterol and VLDL + IDL apolipoprotein B by 36% and 32%, respectively. Simvastatin alone caused a small increase in the ratio of large-to-small LDL, whereas the addition of fenofibrate to simvastatin therapy caused a marked increase in the ratio of large-to-small LDL species. Simvastatin alone produced a small (6%) and insignificant increase in HDL cholesterol concentrations. When fenofibrate was added to simvastatin therapy, HDL cholesterol increased significantly by 23%. No significant side effects were observed with either simvastatin alone or with combined drug therapy. Therefore, a combination of simvastatin 10 mg/day and fenofibrate 200 mg/day appears to be effective and safe for the treatment of atherogenic dyslipidemia in combined hyperlipidemia.",2003.0,0,0 2054,12686348,Comparison of the frequency of adverse events in patients treated with atorvastatin or simvastatin.,Heather M Abourjaily; Alawi A Alsheikh-Ali; Richard H Karas,,2003.0,1,1 2055,12689687,Effect of simvastatin treatment on bone mineral density and bone turnover in hypercholesterolemic postmenopausal women: a 1-year longitudinal study.,A Montagnani; S Gonnelli; C Cepollaro; S Pacini; M S Campagna; M B Franci; B Lucani; C Gennari,"Although several studies have reported a lower risk of osteoporotic fracture in hypercholesterolemic patients treated with statins, so far longitudinal studies on the effects of statins on bone are lacking. The aim of the present study was to evaluate bone mineral density (BMD) and bone turnover changes induced by 1-year simvastatin treatment on postmenopausal women. Thirty consecutive postmenopausal hypercholesterolemic women (61.2 +/- 4.9 years) were treated for 12 months with 40 mg/day simvastatin and 30 normocholesterolemic age-matched postmenopausal women provided control data. In all subjects, at baseline and at 3-month intervals, serum lipids, calcium, phosphate, total and bone alkaline phosphatase (Bone-ALP), and carboxy-terminal fragment of type I collagen (CTx) were measured in a fasting blood sample. At baseline and after 6 and 12 months BMD was measured at lumbar spine (BMD-LS) and at femur (BMD-Ftot) and at femoral neck (BMD-Fn) by DXA. In the simvastatin-treated group Bone-ALP showed a significant increase (P < 0.05) with respect to baseline from the sixth month, whereas serum CTx showed a weak and nonsignificant increase over the study period. In treated women BMD-LS, BMD-Fn, and BMD-Ftot increased respectively by 1.1, 0.9, and 0.4% at Month 6; and by 2.8, 1.0, and 0.8% at Month 12. In controls BMD-LS, BMD-Fn, and BMD-Ftot at the end of the study period decreased by 1.6, 1.4, and 1.2%, respectively. The difference between controls and simvastatin-treated patients was significant (P < 0.05) for both BMD-LS and BMD-Fn only at Month 12. In conclusion our results, although obtained from a small sample of postmenopausal hypercholesterolemic women, suggest a probable positive effect of simvastatin on bone formation and BMD.",2003.0,0,0 2056,12690915,Current perspectives. Heart failure woman: does she make any difference?,Cristina Opasich; Federica De Giuli; Giuseppina Majani; Antonia Pierobon; Stefania De Feo,"Significant differences between sexes may influence the prevalence, incidence and severity of the heart failure syndrome. These differences may also interfere with treatment and management. In this review sex differences and similarities have been analyzed focusing on epidemiology, drug therapy and psychological implications. Pathophysiological differences but also a selection bias are evident; such differences bear an influence on clinical management. Gender differences exist even in the health-related quality of life, depression and coping ability. No studies have been specifically designed to investigate gender differences and the exclusion of elderly persons (mainly women) from large trials may compromise the quality of their care.",2003.0,0,0 2057,12690917,"Effects of carbon-coated coronary stents on the markers of inflammation, thrombin generation and platelet and endothelial activation.",Fabrizio Tomai; Anna S Ghini; Claudio Ferri; Giovambattista Desideri; Francesco Versaci; Achille Gaspardone; Luca Altamura; Giulia Magliano; Filippo Crea; Luigi Chiariello,"The effects of stent carbon coating on the activation of inflammatory and endothelial cells and of coagulation were assessed in patients undergoing coronary artery stent implantation. Forty-four consecutive patients with stable angina and an isolated significant stenosis in a native coronary vessel undergoing stent implantation were randomized to a carbon-coated stent (Carbostent, n = 23) or an uncoated stent with a similar design (Multilink, n = 21). The markers of inflammation, of hemostasis and of platelet and endothelial activation were determined before and 6, 24, 48 and 72 hours after the procedure. Procedural success was achieved in all cases and no patient presented with major in-hospital adverse events. In both the Carbostent and Multilink groups, the median (interquartile range) plasma levels of C-reactive protein significantly increased after the procedure (p < 0.001 and p = 0.002 vs baseline levels, respectively), reaching a peak at 48 hours, without any difference between groups (p = 0.76). Similarly, in both groups the plasma levels of fibrinogen, thrombin-antithrombin III complexes, prothrombin fragments F1 + 2, plasminogen activator inhibitor-1, soluble E-selectin, soluble P-selectin and von Willebrand factor significantly increased after the procedure (all p < 0.05 vs baseline values), without any difference between groups (all p = NS). This study confirms that the markers of inflammation, of endothelial and platelet activation and of thrombin generation significantly increase after successful coronary artery stent implantation. More importantly, it demonstrates that carbon coating does not modify the biologic response of the vessel wall to stent implantation.",2003.0,0,0 2058,12692746,ALLHAT: definitive answers or continuing uncertainty?,Peter Sever; ALLHAT,,2003.0,0,0 2059,12693729,"Beta-blockers for heart failure: why, which, when, and where.",John G F Cleland,"Beta-blockers are a highly effective treatment for patients with all grades of heart failure secondary to LV systolic dysfunction. Beta-blockers are best deployed as a form of tertiary prevention in heart failure but have a very limited role for the treatment of a heart failure crisis. Physicians and patients need to understand the time course of the effects of beta-blocker therapy. The initial effects are often neutral or adverse, though the benefits, at least of carvedilol, may be apparent within days in patients with severe heart failure. Benefits accumulate gradually over a period of weeks to months. Some patience, perseverance, and education are required in order to allow patients to reap the full benefits of beta-blocker therapy for this malignant disease. Initiation of treatment early in the course of the disease maximizes the effectiveness and acceptance of therapy. Trials are under way to determine whether the benefits of beta-blockers extend to patients over 80 years of age and to those with preserved LV systolic function. It is likely that important differences exist between beta-blockers in terms of their clinical benefit, though whether differences exist between the agents that have been reported to be effective so far awaits the outcome of a large clinical trial. It is unclear whether the target doses of beta-blockers currently recommended are optimal.",2003.0,0,0 2060,12693732,The role of anticytokine therapy in heart failure: recent lessons from preclinical and clinical trials?,Arthur M Feldman; Toshiaki Kadokami; Yoshiro Higuichi; Ravi Ramani; Charles F McTiernan,"In summary, over a decade of investigation has demonstrated the pathophysiologic importance of TNF in the development and progression of cardiac dilatation and heart failure. Although the signaling pathways that regulate the cardiac production of TNF have not yet been identified and the potential benefits of TNF expression to the heart are not understood, the benefits of anticytokine therapy in animal models is marked. Unfortunately, these salutary effects in the laboratory have not transitioned to the bedside. To accomplish the translational portion of the cytokine story, we must identify the point in time during the transition from compensated to decompensated heart failure in which TNF is expressed. In addition, we must better understand the role that other down-stream and non-TNF-dependent cytokines play in the development of heart failure. Not all patients are the same; therefore, we must pursue clinical trials that will allow us to elucidate the optimal degree of TNF inhibition, identify the patients who are most likely to respond to TNF inhibition, and determine what the true, long-term effects of TNF inhibition may be. Finally, we must recognize that inflammatory activities can exist in tissues and organs in the absence of TNF. Thus, anticytokine strategies alone might not be effective in ameliorating the signs and symptoms of heart failure. It is hoped that the failure of recent studies to demonstrate salutary benefits in patients with class II to IV heart failure will not diminish enthusiasm for the long-term potential of anticytokine therapy.",2003.0,0,0 2061,12695460,Simvastatin attenuates leucocyte-endothelial interactions after coronary revascularisation with cardiopulmonary bypass.,M Chello; P Mastroroberto; G Patti; A D'Ambrosio; M Cortez Morichetti; G Di Sciascio; E Covino,"To investigate the effects of preoperative simvastatin treatment on leucocyte-endothelial interactions following coronary artery bypass surgery with cardiopulmonary bypass. Double blind crossover study. Experiments on polymorphonuclear cells (neutrophils) were done at the end of cardiopulmonary bypass and one hour postoperatively. Endothelial P-selectin expression and neutrophil/endothelial adhesion were evaluated under either normoxic or hypoxic conditions. University hospital (tertiary referral centre). Three groups of patients undergoing coronary bypass surgery: 20 patients taking simvastatin for cholesterol control, 16 patients not responsive to simvastatin, and 20 controls. Expression of neutrophil CD11b and endothelial P-selectin; adhesion of neutrophils to endothelium. Cardiopulmonary bypass resulted in a significant increase in neutrophil CD11b expression in all groups. Similarly, the exposure of saphenous vein to hypoxia/reoxygenation induced an augmentation of endothelial P-selectin. However, both neutrophil CD11b expression and endothelial P-selectin exocytosis were less in the simvastatin groups than in the controls. Cardiopulmonary bypass and controlled hypoxia/reoxygenation stimulated neutrophil/endothelial adhesion, but the number of adhering cells was less in the simvastatin groups than in the controls, irrespective of the cholesterol concentration. Treatment of endothelial cells with L-NAME completely reversed the effects of simvastatin. Pretreatment with simvastatin reduces neutrophil adhesion to the venous endothelium in patients undergoing coronary surgery, irrespective of its efficacy at lowering cholesterol concentration.",2003.0,0,0 2062,12695469,DD ACE gene polymorphism is associated with increased coronary artery endothelial dysfunction: the PREFACE trial.,H J G H Mulder; P P van Geel; M J Schalij; W H van Gilst; A H Zwinderman; A V G Bruschke; PREFACE trial,,2003.0,0,0 2063,12695723,Congestive heart failure in patients with chronic kidney disease and on dialysis.,Brian D Schreiber,"CHF is highly prevalent in ESRD and is a leading cause of death in such patients. Hypertension, renal anemia, and comorbid conditions such as coronary artery disease are particularly important risk factors for CHF in ESRD. Dialysis hypotension may be a marker of poor prognosis in such persons. Recent studies suggest that lipid peroxidation and L-carnitine deficiency may contribute to CHF in some patients with ESRD. All forms of renal replacement therapy are capable of ameliorating symptoms of CHF, but their effect on cardiovascular mortality has not been firmly established. Drug therapy, particularly angiotensin-converting enzyme inhibitors and beta-adrenergic receptor blockers, is under-used in patients with ESRD and CHF. Heart/kidney transplantation may be a viable option for some patients with advanced CHF and ESRD.",2003.0,0,0 2064,12695727,"Diagnosis and therapy of coronary artery disease in renal failure, end-stage renal disease, and renal transplant populations.",Christine M Logar; Charles A Herzog; Srinivasan Beddhu,"Even though cardiovascular disease is the leading cause of death in patients with CRF and end-stage renal disease (ESRD), ill-conceived notions have led to therapeutic nihilism as the predominant strategy in the management of cardiovascular disease in these populations. The recent data clearly support the application of proven interventions in the general population, such as angiotensin-converting enzyme inhibitors and statins to patients with CRF and ESRD. The advances in coronary stents and intracoronary irradiation have decreased the restenosis rates in renal failure patients. Coronary artery bypass with internal mammary graft might be the procedure of choice for coronary revascularization in these patients. The role of screening for asymptomatic coronary disease is established as a pretransplant procedure, but it is unclear whether this will be applicable to all patients with ESRD. Future studies need to focus on unraveling the mechanisms by which uremia leads to increased cardiovascular events to design optimal therapies targeted toward these mechanisms and improve cardiovascular outcomes.",2003.0,0,0 2065,12698208,Modulation of the inflammatory process by statins.,Milita Crisby,"Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes.",2003.0,0,0 2066,12698311,Under-prescribing of cardiovascular therapies for diabetes in primary care.,K E Bennett; D Williams; J Feely,"To determine the extent to which cardiovascular therapies are prescribed in primary care for those with diabetes, compared with those without diabetes. Population study of patients with and without diabetes identified using a national primary care prescribing database. All patients receiving a prescription for any diabetes therapy, including insulin and oral hypoglycaemic drugs, or diagnostic test kit for glucose ( n=8523) and those receiving no such therapies ( n=145,756) during a 1-year period (September 1999-August 2000) in the Eastern Regional Health Authority of Ireland were identified. In addition, a sub-set of patients receiving a nitrate prescription, a marker for ischaemic heart disease (IHD), were also identified ( n=14,826). Odds ratios and 95% confidence intervals for prescribing of cardiovascular therapies between those with diabetes and those without, adjusted for age and gender, were calculated using logistic regression. The proportion of those (and 95% CES) with diabetes and IHD prescribed secondary preventative therapies was 37.3% (35.0, 39.6) for statins, 55.3% (53.0, 57.6) for angiotension converting enzyme inhibitors, 34.7% (32.5, 36.9) for beta blockers, 73.3% (71.2, 75.4) for aspirin, 4.4% (3.4, 5.4) for angiotensin-II antagonists and 2.5% (1.8, 3.2) for fibrates. The adjusted odds ratios for prescribing in those with diabetes compared with those without are 1.44 (1.30, 1.61) for statins, 3.09 (2.79, 3.42) for angiotension converting enzyme inhibitors, 0.82 (0.74, 0.91) for beta blockers, 1.23 (1.09, 1.38) for aspirin, 1.47 (1.13, 1.87) for angiotensin-II receptor blockers and 4.23 (2.88, 6.14) for lipid-lowering fibrates. The greater rate of prescribing of cardiovascular therapies in those with diabetes relative to those without is not unexpected given the higher risk of coronary heart disease in those with diabetes. However, the proportion of patients with diabetes, particularly those with established IHD, prescribed cardiovascular therapies is considerably below that recommended in local and international guidelines.",2003.0,0,0 2067,12699071,Pleiotropic effects of statins: how important are they in the prevention of vascular disease?,J L Mehta,,2003.0,0,0 2068,12699073,3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect against oxidized low-density lipoprotein-induced endothelial dysfunction.,Dayuan Li; Jawahar L Mehta,"Endothelial dysfunction is recognized as an early event in the pathogenesis of atherosclerosis. Many risk factors cause endothelial dysfunction, such as hypercholesterolemia, hypertension, cigarette smoking, and diabetes mellitus. The precise steps leading to endothelial dysfunction are still being elucidated. Increasing evidence indicates that oxidized low-density lipoprotein (LDL) cholesterol (ox-LDL) plays an important role in endothelial dysfunction. Ox-LDL induces endothelial injury; inhibits apoptosis, monocyte adhesion, and platelet aggregation; and inhibits endothelial nitric oxide synthase (eNOS) expression/activity, all of which contribute to atherosclerotic process. Several pharmacologic agents, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), have been shown to provide endothelial stabilization through mechanisms that go beyond their primary therapeutic effect. Alteration in the endothelial function might result from increase in eNOS activity, reduction in the production of free radicals, inhibition of ox-LDL action, or other undefined mechanisms. This review will focus on the protective role and some of the mechanisms of statins in ox-LDL-induced endothelial dysfunction.",2003.0,0,0 2069,12699074,Interrelationship of free oxygen radicals and endothelial dysfunction--modulation by statins.,Sven Wassmann; Georg Nickenig,"3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are successfully used for the treatment of hypercholesterolemia and profoundly reduce cardiovascular morbidity and mortality in hypercholesterolemic patients. Endothelial dysfunction is the early state of atherosclerosis and predicts adverse cardiac events and mortality. Reduced nitric oxide (NO) bioactivity in the vascular wall, caused by increased free oxygen-radical generation and decreased NO production, seems to be an important underlying mechanism. It is well established that statins improve endothelial dysfunction in hypercholesterolemic patients. However, results from in vitro studies, animal experiments, and small clinical trials suggest that statins may improve vascular function after short-term treatment in hyper- and normocholesterolemic individuals. The underlying mechanisms may at least in part be related to the cholesterol-independent effects of statins on vascular cells. Cellular antioxidative properties of statins, leading to decreased oxidative stress and restoration of NO bioactivity, may be of special relevance for the improvement of vascular function. However, further studies and clinical intervention trials are required to clarify the clinical importance of the pleiotropic effects in humans and their contribution to the well-established clinical benefits of statins and to confirm a beneficial effect of statin therapy on endothelial dysfunction and cardiovascular events in normocholesterolemic patients.",2003.0,0,0 2070,12699076,Lymphocyte function-associated antigen-1 blockade by statins: molecular basis and biological relevance.,Gabriele Weitz-Schmidt,Lymphocyte function-associated antigen-1 (LFA-1) belongs to the integrin family and plays an important role in leukocyte trafficking and in T-cell activation. Random screening of chemical libraries identified the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin as an inhibitor of the LFA-1/intercellular adhesion molecule (ICAM)-1 interaction. The effect of lovastatin on LFA-1 was found to be unrelated to the inhibition of HMG-CoA reductase and to be mediated by lovastatin binding to a novel allosteric site within LFA-1. The biological relevance of LFA-1 inhibition by statins with respect to the overall benefit of this drug class is reviewed. The implications of the statin effect on LFA-1 for future drug design and therapy are discussed.,2003.0,0,0 2071,12699077,Potential anticancer effects of statins: fact or fiction?,Varsha Kaushal; Manish Kohli; Paulette Mehta; Jawahar L Mehta,"Deregulation of any of the steps in cell growth, proliferation and apoptosis may result in its malignant transformation. Statins, along with their lipid-lowering potential, modify several processes in the cell cycle. These agents inhibit cell proliferation and arrest cell cycle progression by interrupting growth-promoting signals. Statins selectively induce proapoptotic protential in tumor cells and synergistically enhance proapoptotic potential of several cytotoxic agents. Statins alter angiogenic potential of cells by modulating apoptosis inhibitory effects of VEGF and decrease secretion of metalloproteases. Statins also alter adhesion and migration of tumor cells, thereby inhibiting tumor invasion and metastasis. Statins suppress rate of activation of multiple coagulation factors and thus prevent coagulation-mediated angiogenesis. Statins have been shown to have anti-tumor activity in experimental models. Various anti-neoplastic properties of statins are probably a result of inhibition of posttranslational modifications of growth regulatory proteins. Molecular mechanisms of antiproliferative, proapoptotic and antiangiogenic effects of statins are reviewed in this chapter.",2003.0,0,0 2072,12700376,Adverse drug events in ambulatory care.,Tejal K Gandhi; Saul N Weingart; Joshua Borus; Andrew C Seger; Josh Peterson; Elisabeth Burdick; Diane L Seger; Kirstin Shu; Frank Federico; Lucian L Leape; David W Bates,"Adverse events related to drugs occur frequently among inpatients, and many of these events are preventable. However, few data are available on adverse drug events among outpatients. We conducted a study to determine the rates, types, severity, and preventability of such events among outpatients and to identify preventive strategies. We performed a prospective cohort study, including a survey of patients and a chart review, at four adult primary care practices in Boston (two hospital-based and two community-based), involving a total of 1202 outpatients who received at least one prescription during a four-week period. Prescriptions were computerized at two of the practices and handwritten at the other two. Of the 661 patients who responded to the survey (response rate, 55 percent), 162 had adverse drug events (25 percent; 95 percent confidence interval, 20 to 29 percent), with a total of 181 events (27 per 100 patients). Twenty-four of the events (13 percent) were serious, 51 (28 percent) were ameliorable, and 20 (11 percent) were preventable. Of the 51 ameliorable events, 32 (63 percent) were attributed to the physician's failure to respond to medication-related symptoms and 19 (37 percent) to the patient's failure to inform the physician of the symptoms. The medication classes most frequently involved in adverse drug events were selective serotonin-reuptake inhibitors (10 percent), beta-blockers (9 percent), angiotensin-converting-enzyme inhibitors (8 percent), and nonsteroidal antiinflammatory agents (8 percent). On multivariate analysis, only the number of medications taken was significantly associated with adverse events. Adverse events related to drugs are common in primary care, and many are preventable or ameliorable. Monitoring for and acting on symptoms are important. Improving communication between outpatients and providers may help prevent adverse events related to drugs.",2003.0,0,0 2073,12701338,"Gender, hyperlipidemia, and coronary artery disease.",Dale R Shepard; Hani Jneid; Holly L Thacker,"The importance of statins for the prevention and treatment of coronary artery disease (CAD), the recent paradoxical effects of hormone replacement therapy on prevention of CAD, and the role of nontraditional risk factors in CAD in women are examined.",2003.0,0,0 2074,12701787,Quality of life after mitral valve surgery: differences between reconstruction and replacement.,Franz E Immer; Olivio Donati; Thomas Wyss; Alexsandra S Immer-Bansi; Jürg Schmidli; Pascal A Berdat; Thierry P Carrel,"Quality of life (QoL) is of increasing interest in major surgical procedures. Mitral valve reconstruction (MRr) is assumed to be better tolerated than mitral valve replacement (MVR). The study aim was to assess mid-term QoL in patients undergoing isolated mitral valve surgery. QoL was monitored in 115 consecutive patients who had isolated mitral valve surgery (62 with MVR, 53 with MRr). Mid-term survival was assessed after a mean of 37 +/- 18 months using the SF-36 health survey questionnaire. Patients undergoing MVR were younger (61.9 +/- 12.7 versus 64.9 +/- 12.5 years; p <0.01) and had significantly more frequently a history of left heart failure (43.5% versus 13.2%; p <0.01) than patients with MRr. No significant difference was found between the two groups when considering preoperative NYHA functional class and left ventricular function. In-hospital mortality was significant higher in MVR than in MRr patients (6.4% versus 0%; p <0.01). QoL was significantly impaired in patients with MVR in physical function (PF), role function (RF) and general health (GH) compared with patients undergoing MRr. Nevertheless, only slight impairments in two of eight aspects in MVR, and in one of eight aspects in MRr, were found compared with an age- and sex-matched standard population. Mid-term survival was similar in both groups. Outcome after MVR was excellent, though these patients had a more advanced stage of the disease preoperatively than MRr patients. Mid-term outcome and QoL was, however, similar in the two groups.",2003.0,0,0 2075,12701992,Practical tips for warfarin dosing and monitoring.,Amir Jaffer; Lee Bragg,"Patients on warfarin and their physicians must constantly balance the risks of bleeding and clotting. We offer practical tips for safe and effective warfarin therapy, based on the practices of the Anticoagulation Clinic of The Cleveland Clinic.",2003.0,0,0 2076,12704478,The 2002/3 Canadian Cardiovascular Society consensus guideline update for the diagnosis and management of heart failure.,P Liu; J M Arnold; I Belenkie; C Demers; P Dorian; N Gianetti; H Haddad; J Howlett; A Ignazewski; P Jong; R McKelvie; G Moe; J D Parker; V Rao; J L Rouleau; K Teo; R Tsuyuki; M White; V Huckel; D Issac; D Johnstone; M-H LeBlanc; H Lee; G Newton; J Niznick; H Ross; S Roth; D Roy; S Smith; B Sussex; S Yusuf; Canadian Cardiovascular Society,,2003.0,0,0 2077,12704978,Statins and stroke prevention.,P Laloux,,2003.0,0,0 2078,12707064,Reduction in levels of 24S-hydroxycholesterol by statin treatment in patients with Alzheimer disease.,Gloria Lena Vega; Myron F Weiner; Anne M Lipton; Klaus Von Bergmann; Dieter Lutjohann; Carol Moore; Doris Svetlik,"The statin treatment of dyslipidemia is associated with a reduced risk of development of Alzheimer disease (AD). The effect may be mediated by a reduction in cholesterol biosynthesis in the brain, by lowering levels of apolipoprotein E (apo E)-containing lipoproteins, or by pleitropic effects such as reduction in beta-amyloid production. In the brain, cholesterol from damaged or dying neurons is converted to 24S-hydroxycholesterol by cholesterol 24-hydroxylase (CYP46). The oxysterol is subsequently transferred across the blood-brain barrier, transported to the liver by low-density lipoproteins (LDLs), and excreted as bile acids. Most of plasma 24S-hydroxycholesterol is derived from brain cholesterol; consequently, plasma levels of the oxysterol reflect brain cholesterol catabolism. To examine the effect of 3 statins and a nonstatin hypolipidemic agent on plasma levels of 24S-hydroxycholesterol and apo E in patients with AD. The study had a sequential parallel design. It was open-labeled and involved lipoprotein and 24S-hydroxycholesterol evaluations at baseline and at 6 weeks of treatment with 40 mg of lovastatin, simvastatin, or pravastatin sodium per day, or 1 g of extended-release niacin per day. Blood samples were drawn after a 12-hour fast for measurement of plasma sterols, oxysterols, lipoprotein cholesterol, and levels of apo E, plasma transaminases, and glucose. Measurements were made at baseline and during treatment. Statin treatment reduced levels of plasma lathosterol by 49.5%, 24S-hydroxycholesterol by 21.4%, LDL cholesterol by 34.9%, and total cholesterol by 25%. The ratios of lathosterol-campesterol and 24S-hydroxycholesterol-LDL cholesterol were reduced significantly, but the ratio of 24S-hydroxycholesterol-total cholesterol was unchanged. Extended-release niacin also significantly reduced levels of 24S-hydroxycholesterol by 10% and LDL cholesterol by 18.1%. None of the agents lowered plasma concentration of apo E. Statins lowered levels of plasma 24S-hydroxycholesterol without affecting levels of apo E. The LDL lowering was more pronounced than 24S-hydroxycholesterol reductions. The effect of statins on LDL partially explains the reduction of plasma oxysterol level.",2003.0,0,0 2079,12707251,Prevention of cardiovascular ischemic events: high-risk and secondary prevention.,Jacques Genest; Terje R Pedersen,,2003.0,0,0 2080,12710288,"[Trends in discharge prescriptions for patients hospitalized for acute coronary syndromes in France from 1995 to 2000. Data from the Usik 1995, Prevenir 1, Prevenir 2 and Usic 2000 surveys].",N Danchin; G Hanania; O Grenier; L Vaur; E Amelineau; P Guéret; D Blanchard; J Ferrières; N Genès; J M Lablanche; C Cantet; J P Cambou,"The use of cardiovascular secondary prevention medications in patients with acute coronary syndromes was compared in 4 sequential observational surveys carried out in France from 1995 to 2000. The Usik 1995 and Usic 2000 surveys included patients admitted for acute myocardial infarction, while the 2 Prevenir surveys (1998 and 1999) assessed the medications prescribed in patients with acute coronary syndromes. Antiplatelet agents were prescribed in 91% of the patients in 1995, 93% in 1998 and 1999 and 96% in 2000; for beta-blockers, the respective figures were: 64%, 68%, 75% and 76%. For ACE-Inhibitors, the figures were: 46%, 41%, 41% and 50%. For statins, the prescription increased from 10% to 36%, 59% and 64%. In 1995, 8% of the patients received both antiplatelet agents, beta-blockers and statins (4% of them also had an ACE-Inhibitor); in 2000, the respective figures were 53% and 27%. The results of the recent trials of secondary prevention medications have had a considerable impact on real-life practice in France during the late 1990s.",2003.0,0,0 2081,12710848,Undertreatment of dyslipidemia in peripheral arterial disease and other high-risk populations: an opportunity for cardiovascular disease reduction.,Alan T Hirsch; Antonio M Gotto,"Atherosclerosis is a form of arterial disease that manifests in the coronary circulation as coronary artery disease (CAD), in the carotid arteries as cerebrovascular disease, and in the aorta and lower extremity arteries as peripheral arterial disease (PAD). The systemic nature of the disease is reflected in the fact that individuals with PAD or carotid artery disease are more likely to have CAD than those without. Since individuals with PAD are at markedly increased risk of cardiovascular ischemic events, early identification of this population and more aggressive medical interventions could substantially improve both morbidity and survival. The incidence of PAD in the general population is high, and currently affects 8-10 million Americans. The risk of developing PAD is predicted by both age and common atherosclerosis risk factors (e.g., smoking and diabetes). Efficient office-based PAD detection depends on the application of objective techniques to establish this diagnosis. Objective noninvasive tests, such as measurement of the ankle-brachial index (ABI), are known to be more sensitive than traditional clinical assessments. Since the major threat to patients with PAD is from secondary cardiovascular ischemic events, a primary therapeutic goal is to modify atherosclerotic risk factors. While national recommendations mandate aggressive lowering of serum low-density lipoprotein cholesterol (LDL-C) levels as a primary treatment goal in all patients with overt atherosclerosis, as 'coronary heart disease risk equivalent' syndromes, individuals with PAD are less intensively treated than those with CAD. Statins are the most effective of current treatments in lowering LDL-C, and have proven efficacy in secondary prevention among patients with established CAD. The use of statin medications in high-risk groups such as PAD patients could prove particularly beneficial in reducing cardiovascular morbidity and mortality and therefore merits prospective clinical investigation.",2003.0,0,0 2082,12711884,Long-term prognosis of patients with acute coronary syndrome and moderate coronary artery stenosis.,Thierry Maurin; Marianne Zeller; Yves Cottin; Claude Touzery; Jean Claude Beer; Isabelle L'Huillier; Michel Fraison; Philippe Buffet; Pierre Louis; Jean Eric Wolf,"We evaluated the clinical outcome and the prognostic factors at 6-year follow-up of patients with acute coronary syndrome without critical coronary arterial narrowing. The mean follow-up was 73 +/- 19 months. Mortality rate was 13%, and 20 patients (12%) had major cardiac event, 8 patients (5%) had stroke and 10 patients (6%) underwent revascularization. Multivariate analysis matched for age and ejection factor showed that moderate disease (stenosis 40-59%) (OR = 2.713, p < 0.024) was an independent predictive factor of major cardiac event.",2003.0,0,0 2083,12713683,Bosentan.,Judy W M Cheng,"Bosentan is the first endothelin (ET) receptor antagonist approved by the Food and Drug Administration for the management of pulmonary arterial hypertension (PAH). In patients with World Health Organization Class III and IV PAH, bosentan has demonstrated improvement in dyspnea and exercise tolerance. ET also plays an important role in the pathophysiology of different vascular diseases. Therefore, bosentan also may have the potential to alter the outcome of many other diseases, such as heart failure, hypertension, ischemic heart disease, and renal disease, as well as cerebrovascular disorders. Because of the rarity and the poor prognosis of patients with PAH, as well as the requirement of close monitoring of bosentan (due to its potential of causing liver dysfunction and its teratogenic effects), bosentan is currently available only through a special access program and is distributed by certain selected pharmacies. Patients who are receiving bosentan should be taught to recognize early signs and symptoms of liver dysfunction and possible pregnancy. In addition, bosentan is not only a substrate but also an inducer of CYP3A4 and CYP2C9. Therefore, it is anticipated that numerous drug interactions may occur. Patients should be advised to consult their physicians or pharmacists should they need to consume other prescription or nonprescription medications.",2003.0,0,0 2084,12713763,Combined lipid lowering drug therapy for the effective treatment of hypercholesterolaemia.,James Shepherd,,2003.0,0,0 2085,12713766,"Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.",Lorenzo Melani; Richard Mills; David Hassman; Robert Lipetz; Leslie Lipka; Alexandre LeBeaut; Ramachandran Suresh; Pabak Mukhopadhyay; Enrico Veltri; Ezetimibe Study Group,"To evaluate the efficacy and safety of ezetimibe 10 mg administered with pravastatin in patients with primary hypercholesterolemia. After dietary stabilization, 2-12 week screening/washout period, and 4-week, single-blind, placebo lead-in period, 538 patients with baseline LDL-C > or =3.8 to < or =6.5 mmol/l and TG < or =4.0 mmol/l were randomized to one of eight possible treatments administered daily for 12 weeks: ezetimibe 10mg; pravastatin 10, 20, or 40 mg; ezetimibe 10 mg plus pravastatin 10, 20, or 40 mg; or placebo. The primary efficacy endpoint was percent reduction in LDL-C from baseline to study endpoint for ezetimibe 10 mg plus pravastatin (pooled doses) compared to pravastatin alone (pooled doses) and ezetimibe alone. The combined use of ezetimibe and pravastatin resulted in significant incremental reductions in LDL-C and TG compared to pooled pravastatin alone (p<0.01). Coadministration therapy reduced LDL-C by 34-41%, TG by 21-23%, and increased HDL-C by 7.8-8.4%, depending on the dose of pravastatin. The combined regimen was well tolerated, with a safety profile similar to pravastatin alone and placebo. When coadministered with pravastatin, ezetimibe provided significant incremental reductions in LDL-C and TG and was well tolerated with a safety profile similar to pravastatin alone.",2003.0,0,0 2086,12714109,Biological markers for therapeutic trials in Alzheimer's disease. Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer's disease.,Richard A Frank; Douglas Galasko; Harald Hampel; John Hardy; Mony J de Leon; Pankaj D Mehta; Joseph Rogers; Eric Siemers; John Q Trojanowski; National Institute on Aging Biological Markers Working Group,,2003.0,0,0 2087,12714124,Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease.,Sergio Mondillo; Piercarlo Ballo; Riccardo Barbati; Francesco Guerrini; Tiziana Ammaturo; Eustachio Agricola; Monica Pastore; Francesco Borrello; Mirko Belcastro; Andrea Picchi; Renato Nami,"To analyze the effects of short-term therapy with simvastatin on walking performance in hypercholesterolemic patients with peripheral vascular disease. Eighty-six patients with peripheral arterial disease (Fontaine stage II), intermittent claudication, and total cholesterol levels >220 mg/dL were enrolled in a randomized, placebo-controlled, double-blind study. Forty-three patients were assigned to simvastatin (40 mg/d); the remaining 43 patients were assigned to placebo treatment. All patients underwent an exercise test and clinical examination, and completed a self-assessment questionnaire at 0, 3, and 6 months. Pain-free and total walking distance, resting and postexercise ankle-brachial indexes, and questionnaire scores were determined at each follow-up. At 6 months, the mean pain-free walking distance had increased 90 meters (95% confidence interval [CI]: 64 to 116 meters; P <0.005) more in the simvastatin group than in the placebo group. Similar results were seen for the total walking distance (mean between-group difference in the change, 126 meters; 95% CI: 101 to 151 meters; P <0.001), and for the ankle-brachial index at rest (mean, 0.09; 95% CI: 0.06 to 0.12; P <0.01) and after exercise (mean, 0.19; 95% CI: 0.14 to 0.24; P <0.005). There was also a greater improvement in claudication symptoms among patients treated with simvastatin. The effects on walking performance, ankle-brachial indexes, and questionnaire scores had also been significant at 3 months. High-dose short-term therapy with simvastatin may improve walking performance, ankle-brachial pressure indexes, and symptoms of claudication in hypercholesterolemic patients with peripheral vascular disease.",2003.0,0,0 2088,12714133,Treating dyslipidemia to slow the progression of chronic renal failure.,Biff F Palmer; Robert J Alpern,,2003.0,0,0 2089,12714156,Association between short-term simvastatin therapy before coronary artery bypass grafting and postoperative myocardial blood flow as assessed by positron emission tomography.,M Imran Dotani; Anthony P Morise; Reyaz Haque; Abnash C Jain; Naresh Gupta; C Michael Gibson,,2003.0,0,0 2090,12714159,Usefulness of quinapril and irbesartan to improve the anti-inflammatory response of atorvastatin and aspirin in patients with coronary heart disease.,Wright B Lauten; Qamar A Khan; Sanjay Rajagopalan; Stamatios Lerakis; Syed T Rahman; Sampath Parthasarathy; Bobby V Khan,,2003.0,0,0 2091,12714164,Evaluation by electron beam tomography of changes in calcified coronary plaque in treated and untreated asymptomatic patients and relation to serum lipid levels.,Harvey S Hecht; S Mitchell Harman,,2003.0,0,0 2092,12715145,[From risk factors to symptomatic coronary artery disease. Update cardiology 2001/2002--part I].,Roland Fries; Michael Böhm,"The cardiovascular continuum describes the way from risk factors to atherosclerosis, acute cardiovascular events (unstable angina and myocardial infarction), and development of terminal heart failure and its complications. Following this way, advances are reported in the prevention of cardiovascular disease, in noninvasive diagnostics and revascularization of coronary artery disease, and in new therapeutic options of acute myocardial infarction. The following issues are reported in detail: (1) significance of statins, inhibition of platelet aggregation and vitamins in primary and secondary prevention of cardiovascular disease, (2) comparison of the angiotensin receptor blocker losartan and the beta-blocker atenolol in hypertension (LIFE study), (3) magnetic resonance angiography for the detection of coronary stenoses, (4) advantages and disadvantages of operative and interventional coronary revascularization considering elderly patients and sirolimus-eluting stents, and (5) efficacy of glycoprotein IIb/IIIa inhibition and low molecular weight heparin in acute myocardial infarction.",2003.0,0,0 2093,12716220,The management of idiopathic nephrotic syndrome in children.,Elisabeth Hodson,"Childhood nephrotic syndrome is a rare condition with an incidence of 1-2 per 100000 children aged below 16 years. Untreated idiopathic nephrotic syndrome (INS) is associated with increased risks of life-threatening infection, thromboembolism, lipid abnormalities, and malnutrition. The aim of the management of INS in children is to induce and maintain complete remission with resolution of proteinuria and edema without serious adverse effects of therapy. The majority of children have corticosteroid sensitive idiopathic nephrotic syndrome (CSINS), and in these children, corticosteroid therapy is the mainstay of therapy to induce remission. Data from a meta-analysis of randomized controlled trials (RCTs) indicate that prolonged courses of corticosteroids (up to 7 months) given in the first episode of CSINS reduce the risk of relapse. Nevertheless, many children relapse, and are at risk of corticosteroid toxicity if frequent courses of corticosteroids are required. Data from RCTs supports the use of alkylating agents (cyclophosphamide, chlorambucil), cyclosporine, and levamisole in these children to achieve prolonged periods of remission. The specific management of corticosteroid-resistant idiopathic nephrotic syndrome (CRINS) is more difficult since few therapies are consistently effective, and data from RCTs are limited. In such children, cyclosporine, alkylating agents, and high dose intravenous methylprednisone may be used. In addition to specific therapies for INS, supportive therapies are commonly used to control edema (loop diuretics, aldosterone antagonists, albumin infusions, angiotensin-converting enzyme inhibitors), reduce the risk of infection (antibacterials, pneumococcal vaccination) and thromboembolism (aspirin [acetylsalicylic acid]), and to control hyperlipidemia (HMG-CoA reductase inhibitors), especially in children with CRINS.",2003.0,0,0 2094,12717402,Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference.,Brent A Neuschwander-Tetri; Stephen H Caldwell,"Fatty liver disease that develops in the absence of alcohol abuse is recognized increasingly as a major health burden. This report summarizes the presentations and discussions at a Single Topic Conference held September 20-22, 2002, and sponsored by the American Association for the Study of Liver Diseases. The conference focused on fatty liver disorders. Estimates based on imaging and autopsy studies suggest that about 20% to 30% of adults in the United States and other Western countries have excess fat accumulation in the liver. About 10% of these individuals, or fully 2% to 3% of adults, are estimated to meet current diagnostic criteria for nonalcoholic steatohepatitis (NASH). Sustained liver injury leads to progressive fibrosis and cirrhosis in a fraction, possibly up to one third, of those with NASH, and NASH may be a cause of cryptogenic cirrhosis. NASH is now a significant health issue for obese children as well, leading to cirrhosis in some. The diagnostic criteria for NASH continue to evolve and rely on the histologic findings of steatosis, hepatocellular injury (ballooning, Mallory bodies), and the pattern of fibrosis. Generally recognized indications for biopsy include establishing the diagnosis and staging of the injury, but strict guidelines do not exist. Liver enzymes are insensitive and cannot be used reliably to confirm the diagnosis or stage the extent of fibrosis. Older age, obesity, and diabetes are predictive of fibrosis. The pathogenesis of NASH is multifactorial. Insulin resistance may be an important factor in the accumulation of hepatocellular fat, whereas excess intracellular fatty acids, oxidant stress, adenosine triphosphate (ATP) depletion, and mitochondrial dysfunction may be important causes of hepatocellular injury in the steatotic liver. Efforts are underway to refine the role of insulin resistance in NASH and determine whether improving insulin sensitivity pharmacologically is an effective treatment. An altered lifestyle may be a more effective means of improving insulin sensitivity. The research agenda for the future includes establishing the role of insulin resistance and abnormal lipoprotein metabolism in NASH, determining the pathogenesis of cellular injury, defining predisposing genetic abnormalities, identifying better noninvasive predictors of disease, and defining effective therapy.",2003.0,0,0 2095,12717482,Effects of long term cholesterol lowering on coronary atherosclerosis in patient risk factor subgroups: the Simvastatin/enalapril Coronary Atherosclerosis Trial (SCAT).,Jeffrey R Burton; Koon K Teo; Christopher E Buller; Sylvain Plante; Diane Catellier; Wayne Tymchak; Dylan Taylor; Vladimir Dzavik; Terrence J Montague; SCAT investigators,"This study examined the effects of long term cholesterol lowering therapy with simvastatin on progression and regression of coronary atherosclerosis, as determined by quantitative angiographic end points, in subgroups of patients with known coronary risk factors. In this randomized, placebo controlled clinical trial, the effect of simvastatin on coronary atherosclerosis was compared with that of placebo in 394 patients who had paired coronary angiograms taken an average of four years apart. The effects of treatment on the following prespecified subgroups were examined: sex, age (less than 65 years versus at least 65 years), smoking status (current or previous/never), history of diabetes mellitus or hypertension, and severity of coronary artery lesions (diameter at least 50% versus less than 50%). There were significantly smaller decreases in the average minimum diameters, between closeout and baseline angiograms, in all simvastatin-treated subgroups, compared with placebo. Trends toward or significantly smaller decreases in the average of the mean diameters, and similar smaller increases in percentage diameter stenosis were also seen in all subgroups. The slowing of angiographically demonstrable coronary atherosclerotic narrowing supports the contention that this treatment effect is causally related to the reduction of coronary events repeatedly seen in large outcome clinical trials of lipid lowering therapy. Also, this treatment effect occurs in the presence or absence of the traditional coronary risk factors.",2003.0,0,1 2096,12719279,"Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.",Christie M Ballantyne; John Houri; Alberto Notarbartolo; Lorenzo Melani; Leslie J Lipka; Ramachandran Suresh; Steven Sun; Alexandre P LeBeaut; Philip T Sager; Enrico P Veltri; Ezetimibe Study Group,"Despite the established efficacy of statins, many patients do not achieve recommended LDL cholesterol (LDL-C) goals. Contributing factors may be inadequate dosing, increased risk for adverse effects with high-dose monotherapy, and increased potential for intolerance and adverse effects with combinations of available agents. In a double-blind study, 628 patients with baseline LDL-C 145 to 250 mg/dL and triglycerides < or =350 mg/dL were randomly assigned to receive 1 of the following for 12 weeks: ezetimibe (10 mg/d); atorvastatin (10, 20, 40, or 80 mg/d); ezetimibe (10 mg) plus atorvastatin (10, 20, 40, or 80 mg/d); or placebo. The primary efficacy end point was percentage reduction in LDL-C for pooled ezetimibe plus atorvastatin versus pooled atorvastatin treatment groups. Ezetimibe plus atorvastatin significantly improved LDL-C, HDL cholesterol (HDL-C), triglycerides, total cholesterol:HDL-C, and high-sensitivity C-reactive protein (hs-CRP) compared with atorvastatin alone (P<0.01). Coadministration of ezetimibe provided a significant additional 12% LDL-C reduction, 3% HDL-C increase, 8% triglyceride reduction, and 10% hs-CRP reduction versus atorvastatin alone. Ezetimibe plus atorvastatin provided LDL-C reductions of 50% to 60%, triglyceride reductions of 30% to 40%, and HDL-C increases of 5% to 9%, depending on atorvastatin dose. LDL-C reductions with ezetimibe plus 10 mg atorvastatin (50%) and 80 mg atorvastatin alone (51%) were similar. Ezetimibe plus atorvastatin was well tolerated, with a safety profile similar to atorvastatin alone and to placebo. When coadministered with atorvastatin, ezetimibe provided significant incremental reductions in LDL-C and triglycerides and increases in HDL-C. Coadministration of ezetimibe and atorvastatin offers a well-tolerated and highly efficacious new treatment option for patients with hypercholesterolemia.",2003.0,0,0 2097,12720487,New developments in the pharmacological treatment of chronic heart failure.,Henry Krum; Danny Liew,"In recent years, rapid growth in the understanding of the pathophysiology of chronic heart failure has allowed for insights into many potential new therapeutic strategies. Yet until now, despite sound biological basis for efficacy and success in early-Phase studies, novel agents have not stood up to the scrutiny of late-Phase clinical trials. Indeed, remarkably negative results have been observed for vasopeptidase inhibitors, endothelin receptor antagonists and agents which block immune activation. However, efficacy data from other novel agents are still awaited, including the selective aldosterone receptor antagonist eplerenone, arginine vasopressin inhibitors, erythropoietin and hydroxy-methyl-glutaryl coenzyme A reductase inhibitors. Other classes of drugs which may enter clinical development include cardiac metabolic agents, matrix metalloproteinase inhibitors and advanced glycation end product antagonists. That the mortality and morbidity of patients with chronic heart failure remain unacceptably high makes the ongoing commitment to exploration of new drug therapies for the condition critical.",2003.0,0,0 2098,12720497,Implications of the LIFE trial.,Sunil Nadar; Hoong Sern Lim; Gregory Y H Lip,"The recent Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study was conducted in patients with essential hypertension with electrocardiogram evidence of left ventricular hypertrophy. This showed that losartan compared to atenolol resulted in a significant reduction in the primary endpoint of cardiovascular morbidity and mortality, as well as a greater reduction in electrocardiographically-defined left ventricular hypertrophy. Importantly, this was despite a mean blood pressure reduction which was similar in both groups. Furthermore, the atenolol arm was associated with higher incidence of newly diagnosed diabetics. The LIFE study has firmly confirmed a place for losartan (and other angiotensin receptor blockers) in the management of hypertension. Losartan has also been shown to be effective in diabetics and in patients with atrial fibrillation, as well as in left ventricular hypertrophy regression. This trial also raises the possibility that beta-blockers should perhaps not be used as first-line monotherapy.",2003.0,0,0 2099,12722551,Statins: maid-of-all-work in cardiovascular diseases!,G Nalbone; D Bernot; F Peiretti; M C Alessi,"Inhibitors of HMG-CoA reductase (statins) lower the level of circulating LDL-C by blocking the activity of HMG-CoA reductase. Their efficiency to prevent cardiovascular events was demonstrated in several clinical trials for primary and secondary prevention. However, subgroups analysis of trials together with experimental studies have increasingly documented that the beneficial effects of statins extend beyond the sole reduction in LDL-C. These effects include improvements of vasoreactivity, haemostasis and plaque stability, reduction of pro-inflammatory events such as a decrease in monocyte adhesion and infiltration, oxidation level and pericellular proteolysis. Possible repair of ischemic tissues through enhancement of mobilization of endothelial progenitor cells are also described, although more investigation are needed to clearly identify the role and safety of statins in angiogenesis. These pleiotropic effects are generally explained by the fact that statins inhibit the intracellular production of metabolites located downstream of mevalonate in the cholesterol pathway, such as isoprenoids (farnesyl pyrophosphate and geranylgeranylpyrophosphate). These hydrophobic metabolites allow the membrane anchorage of small G proteins (Ras and Rho) as well as the Gy subunit of heterotrimeric G proteins, a post-translational step that is critical in the regulation of G protein signaling activity. These drugs are therefore a valuable tool not only for the clinician but also for the biologist, allowing to investigate the regulation of gene expression that is controlled by the intracellular activity of membrane-anchored prenylated signaling proteins.",2003.0,0,0 2100,12723464,"Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthy volunteers.",Jianguo Zhi; Rema Moore; Linda Kanitra; Thomas E Mulligan,"To investigate the effect of orlistat on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin), the authors performed double-blind, placebo-controlled, randomized two-period crossover (for fluoxetine and simvastatin) or parallel (for amiodarone) studies in healthy volunteers ages 18 to 65 years of a body mass index between 18 and 30 kg/m2. During treatment with orlistat or matching placebo for 5 to 13 1/3 days, a single oral dose of highly lipophilic drug was administered, followed by obtaining serial blood samples for measuring plasma (for fluoxetine and simvastatin) or serum (for amiodarone) concentrations of the lipophilic drug and its active metabolite. Treatments were compared for the pharmacokinetic parameters AUC0-infinity, Cmax, tmax, and t 1/2 of highly lipophilic drugs and active metabolites. Analysis of variance was performed to assess the significance of the sequence effect and provide the variance estimate for the 90% confidence intervals. Subjects were also evaluated for adverse events, vital signs, and clinical and laboratory safety. The absorption of amiodarone (and active metabolite) was significantly reduced by approximately one-quarter using parameters of Cmax and AUC, while no inhibition of absorption was observed for fluoxetine and simvastatin as well as their active metabolites. There were no clinically significant differences in t 1/2 and tmax for all three drugs tested. Due to expected gastrointestinal adverse events known to occur with orlistat, there was a higher incidence of adverse events under regimen B (highly lipophilic drugs and orlistat) than under regimen A (highly lipophilic drugs and placebo). Other adverse events were sporadic and unremarkable. There were no clinically relevant changes in vital signs or laboratory values. In conclusion, except for amiodarone, there was no effect of orlistat on the pharmacokinetics of highly lipophilic drugs when these drugs were taken concomitantly with orlistat.",2003.0,0,0 2101,12725884,Statin use and the risk of breast cancer.,Patricia Beck; Diane K Wysowski; Winanne Downey; David Butler-Jones,"The study objective was to investigate a possible association between statin use and breast cancer (BRCA). An historical cohort design based on Saskatchewan's population health services databases was used. All eligible women with > or = 1 statin prescription from 1989 to mid-1997 and an age-sex-matched nonexposed group were followed up to 8.5 years (mean 4.2 years). Relative rates (RR) of BRCA were estimated and stratified by age, statin exposure time, and prior hormone use. Thirteen thousand five hundred ninety-two statin users and 53,880 nonexposed subjects were identified. Eight hundred seventy-nine incident BRCA cases were identified. Statins were not associated with BRCA risk in women < or = 55 years. Among subjects >55 years, the RR for BRCA was 1.15 (0.97, 1.37). Stratified analyses revealed increases in risk in short-term statin users and statin users with long-term hormone replacement therapy (HRT) exposure. More studies are needed to determine if short-term statin use and statin use with long-term HRT exposure increases postmenopausal BRCA risk. Published by Elsevier Science Inc.",2003.0,0,1 2102,12727001,Familial hypercholesterolemia--improving treatment and meeting guidelines.,Paul N Hopkins,"Familial hypercholesterolemia (FH) is a common, inherited disorder that affects around one in 500 individuals in the heterozygous form. By the year 2001, more people in the US had FH than were infected by the human immunodeficiency virus. The disease is caused by mutations within the low-density lipoprotein (LDL) receptor gene. FH is associated with elevated plasma LDL-cholesterol (LDL-C) levels, xanthomatosis, early onset of atherosclerosis and premature cardiac death. Patients with heterozygous FH commonly have plasma LDL-C levels that are two-fold higher than normal, while homozygotes have four- to five-fold elevations in plasma LDL-C. Although FH patients have a high risk of developing premature coronary heart disease (CHD), they remain underdiagnosed and undertreated. Early detection of FH is critical to prolonging the life of these patients. Once identified, patients with heterozygous FH can be placed on a diet and drug management program. As the most efficacious and well-tolerated agents, hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are usually the drugs of first choice; bile acid sequestrants, niacin, and occasionally fibrates may be used as supplemental agents. Statins may also provide a realistic option for the treatment of some FH homozygotes with genes that produce partially functional LDL receptors. However, a number of patients are still failing to reach treatment guidelines even with the most effective of the currently available statins. The development of new more efficacious statins or the use of new combination therapies such as statins with the cholesterol absorption inhibitor, ezetimibe may help to reduce the current problem of undertreatment in FH patients.",2003.0,0,0 2103,12727151,Under utilisation of evidence-based treatment partially explains for the unfavourable prognosis in diabetic patients with acute myocardial infarction.,Anna Norhammar; Klas Malmberg; Lars Rydén; Per Tornvall; Ulf Stenestrand; Lars Wallentin; Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA),"The prognosis after an acute myocardial infarction is worse for patients with diabetes mellitus than for those without. We investigated whether differences in the use of evidence-based treatment may contribute to the differences in 1-year survival in a large cohort of consecutive acute myocardial infarction patients with and without diabetes mellitus. We included patients below the age of 80 years from the Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA), which included all patients admitted to coronary care units at 58 hospitals during 1995-1998. In all 5193 patients had the combination of acute myocardial infarction and diabetes mellitus while 20440 had myocardial infarction but no diabetes diagnosed. Multivariate logistical regression analyses were performed to evaluate the influence of diabetes mellitus on the use of evidence-based treatment and its association with survival during the first year after the index hospitalisation. The prevalence of diabetes mellitus was 20.3% (males 18.5%; females 24.4%). The 1-year mortality was substantially higher among diabetic patients compared with those without diabetes mellitus (13.0 vs. 22.3% for males and 14.4 vs. 26.1% for female patients, respectively) with an odds ratio (OR) (95% confidence interval (CI)) in three different age groups: <65 years 2.65 (2.23-3.16); 65-74 years 1.81 (1.61-2.04) and >75 years 1.71 (1.50-1.93). During hospital stay patients with diabetes mellitus received significantly less treatment with heparins (37 vs. 43%; p<0.001), intravenous beta blockade (29 vs. 33%; p<0.001), thrombolysis (31 vs. 41%; p<0.001) and acute revascularisation (4 vs. 5%; p<0.003). A similar pattern was apparent at hospital discharge. After multiple adjustments for dissimilarities in baseline characteristics between the two groups, patients with diabetes were significantly less likely to be treated with reperfusion therapy (OR 0.83), heparins (OR 0.88), statins (OR 0.88) or to be revascularised within 14 days from hospital discharge procedures (OR 0.86) while the use of ACE-inhibitors was more prevalent among diabetic patients compared to non-diabetic patients (OR 1.45). The mortality reducing effects of evidence-based treatment like reperfusion, heparins, aspirin, beta-blockers, lipid-lowering treatment and revascularisation were, in multivariate analyses, of equal benefit in diabetic and non-diabetic patients. Diabetes mellitus continues to be a major independent predictor of 1-year mortality following an acute myocardial infarction, especially in younger age groups. This may partly be explained by less use of evidence-based treatment although treatment benefits are similar in both patients with and without diabetes mellitus. Thus a more extensive use of established treatment has a potential to improve the poor prognosis among patients with acute myocardial infarction and diabetes mellitus.",2003.0,0,0 2104,12727577,"A randomized trial of aggressive lipid reduction for improvement of myocardial ischemia, symptom status, and vascular function in patients with coronary artery disease not amenable to intervention.",Robert Fathi; Brian Haluska; Leanne Short; Thomas H Marwick,"To determine the effects of aggressive lipid lowering on markers of ischemia, resistance vessel function, atherosclerotic burden, and symptom status in patients with symptomatic coronary artery disease. Sixty consecutive patients with coronary artery disease that was unsuitable for revascularization were assigned randomly to either usual therapy of lipids for patients with a low-density lipoprotein (LDL) cholesterol target level <116 mg/dL, or to a more aggressive lipid-lowering strategy involving up to 80 mg/d of atorvastatin, with a target LDL cholesterol level <77 mg/dL. The extent and severity of inducible ischemia (by dobutamine echocardiography), vascular function (brachial artery reactivity), atheroma burden (carotid intima-media thickness), and symptom status were evaluated blindly at baseline and after 12 weeks of treatment. After 12 weeks of treatment, patients in the aggressive therapy group had a significantly greater decrease in mean (+/- SD) LDL cholesterol level than those in the usual care group (29 +/- 38 mg/dL vs. 7 +/- 24 mg/dL, P = 0.03). Patients in the aggressive therapy group had a reduction in the number of ischemic wall segments (mean between-group difference of 1.3; 95% confidence interval: 0.1 to 2.0; P = 0.04), flow-mediated dilatation (mean between-group difference of 5.9%; 95% confidence interval: 2.5% to 9.4%; P = 0.001), and angina score after 12 weeks. There were no significant changes in atherosclerotic burden in either group. Patients with symptomatic coronary artery disease who are treated with aggressive lipid lowering have improvement of symptom status and ischemia that appears to reflect improved vascular function but not atheroma burden.",2003.0,0,0 2105,12727581,Potential cost-effectiveness of C-reactive protein screening followed by targeted statin therapy for the primary prevention of cardiovascular disease among patients without overt hyperlipidemia.,Gavin J Blake; Paul M Ridker; Karen M Kuntz,"Evidence suggests that statin therapy reduces the rate of cardiovascular events among patients with low lipid levels but elevated C-reactive protein levels. However, no cost-effectiveness analyses have been performed to assist in determining whether large-scale randomized trials are merited to test this hypothesis. We used a Markov model to estimate the benefits, costs, and incremental cost-effectiveness of C-reactive protein screening followed by targeted statin therapy for elevated C-reactive protein levels, compared with dietary counseling alone, for the primary prevention of cardiovascular events among patients with low-density lipoprotein cholesterol levels <149 mg/dL. All costs were in 2000 U.S. dollars. The potential incremental cost-effectiveness ratio for screening followed by statin therapy compared with no screening and no statin therapy was $48,100 per quality-adjusted life-year (QALY) for 58-year-old men and $94,400 per QALY for 58-year-old women. Screening was most cost-effective for 65-year-old men ($42,600 per QALY) and least cost-effective for 35-year-old women ($207,300 per QALY). Our results were most sensitive to the baseline risk of coronary heart disease, the cost of statin therapy, and the efficacy of statin therapy for preventing myocardial infarction in patients with high C-reactive protein levels. If a 58-year-old man who smokes and is hypertensive was considered, screening for C-reactive protein followed by statin therapy would be cost saving if the cost of statin therapy was reduced to $500 per year. If the cost of statin therapy was reduced to $1 per day, the cost-effectiveness of screening would be $4900 per QALY for 58-year-old men and $19,600 per QALY for women of the same age. If the costs associated with elective revascularization (percutaneous coronary intervention or coronary artery bypass surgery) were included in the base case analyses, the incremental cost-effectiveness ratios for screening would be $40,100 per QALY for 58-year-old men and $87,300 per QALY for women. A strategy involving C-reactive protein screening to target statin therapy for the primary prevention of cardiovascular disease among middle-aged patients without overt hyperlipidemia could be relatively cost-effective and, in some cases, cost saving.",2003.0,0,0 2106,12728973,Prevalence of antilipemic drug use in Taiwan: analysis of a sampling cohort within the national health insurance.,Tzeng-Ji Chen; Shing-Jong Lin; Liang-Kung Chen; Shinn-Jang Hwang; Li-Fang Chou,"Hyperlipidemia is a major risk factor of cardiovascular diseases. We investigated the utilization ofantilipemic drugs at the outpatient sector within the National Health Insurance in Taiwan. We obtained the first cohort (n = 50,000) dataset from the National Health Insurance Research Database and analyzed the outpatient claim files of the cohort in 2000. The antilipemic drugs were defined as the drug items belonging to the group C10 (serum lipid reducing agents) of the Anatomical Therapeutic Chemical classification system. Among the cohort with 46,614 eligible people, 760 patients had ever received antilipemic drugs (prevalence: 1.6%). The group 60-69 years of age had the greatest age-specific prevalence (7.2%), followed by the group over 70 years of age (6.0%). There were more male than female patients, but female patients outnumbered male patients before the age of 49 years. The antilipemic drugs had been prescribed 3,850 times totally with 70,272 defined daily doses (DDDs). On an average, a patient with antilipemic therapy received 5.1 (+/- 4.5) prescriptions of antilipemic drugs in one year and a prescription contained 18.3 (+/- 11.5) DDDs. We measured 4.1 DDDs per 1,000 inhabitants per day for all antilipemic drug use in 2000. The statins and fibrates predominated the antilipemic drug use. While gemfibrozil was most popular in respect of recipients and prescription items, simvastatin had the largest amount of use in unit of DDDs. Diabetes mellitus co-existed in 37.8% of the patients with antilipemic therapy and the standardized morbidity ratio (SMR) was 3.34. The other concomitant diseases included essential hypertension (rate: 48.8%, SMR: 2.40) and other heart disease (rate: 30.7%, SMR: 2.36). Statins were the leading antilipemic drugs in Taiwan. The users of antilipemic drugs were more likely to have concomitant diabetes mellitus, hypertension and heart disease.",2003.0,0,0 2107,12729396,Analyzing randomized dose finding studies with a primary and a secondary endpoint.,Ludwig A Hothorn; Gernot Wassmer,"The identification of the minimum effective dose for both the primary and secondary endpoint under a priori importance ordering assumption is described. Stepwise testing procedures, which conditionally test each elementary hypotheses at level alpha, but control the experimentwise Type I error rate, can be used.",2003.0,0,0 2108,12732381,"A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.",Dalya Marks; Margaret Thorogood; H Andrew W Neil; Steve E Humphries,"Familial hypercholesterolaemia (FH) affects approximately 1 in 500 people (10 million world-wide) and the elevated serum cholesterol concentrations lead to a more than 50% risk of fatal or non-fatal coronary heart disease by age 50 years in men and at least 30% in women aged 60 years. Based on a systematic literature search, we review the natural history of FH, describe the diagnostic criteria, and consider the effectiveness of treatment. A comprehensive review was conducted of the literature on the diagnosis of FH, the morbidity and mortality related to treated and untreated FH, and the evidence on the effectiveness of treatment of FH in adults and children. Treatment options have changed since statin treatment became available, and we have not considered pre-statin therapy studies of treatment effectiveness. A clinical diagnosis of FH is widely used, but a definitive diagnosis can be made by genetic screening, although mutations are currently only detected in 30-50% of patients with a clinical diagnosis. Under-diagnosis of FH has been reported world-wide ranging from less than 1% to 44%. The relative risk of death of FH patients not treated with statins is between three and fourfold but treatment is effective, and delays or prevents the onset of coronary heart disease. Early detection and treatment is important. Aggressive LDL therapy is more effective in the regression of the carotid intima media thickness than conventional LDL therapy. Diagnosis at birth is problematic, and should be delayed until at least 2 years of age. Statins are not generally recommended for the treatment of children up to adolescence. Resins may be used but poor adherence is a problem. Technical advances in mutation detection, and the identification of other genes that cause FH, are likely to have important implications for the cost effectiveness of genetic diagnosis of FH.",2003.0,0,0 2109,12732396,A novel functional polymorphism in the PECAM-1 gene (53G>A) is associated with progression of atherosclerosis in the LOCAT and REGRESS studies.,Mohamed A Elrayess; Karen E Webb; David M Flavell; Mikko Syvänne; Marja-Riitta Taskinen; M Heikki Frick; Markku S Nieminen; Y Antero Kesäniemi; Amos Pasternack; J Wouter Jukema; John J P Kastelein; Aeilko H Zwinderman; Steve E Humphries,"A 53G>A polymorphism identified in the 5' untranslated region (5'UTR) of the platelet endothelial cell adhesion molecule-1 (PECAM-1) gene alters a putative shear stress responsive element (SSRE). PECAM-1 was shown to be responsive to shear stress and transient transfection of human umbilical vein endothelial cell (HUVECs) with two luciferase reporter constructs driven by the PECAM-1 promoter and 5'UTR showed a response of the 53G allele, not the 53A allele, to shear stress. Association between the 53G>A, and the previously published L125V polymorphism, and coronary atherosclerosis was examined in two angiographic studies. The frequencies of the rare alleles of the 53G>A and L125V polymorphisms were 0.01 and 0.49, respectively, in the Lopid Coronary Angiography Trial (LOCAT) study and 0.02 and 0.49, respectively, in the Regression Growth Evaluation Statin Study (REGRESS) study. Compared with 53G homozygotes, carriers of the 53A allele showed less focal progression of disease in the LOCAT study and a similar trend in the diffuse progression of disease in the REGRESS study, whereas no association between L125V and coronary atherosclerosis was observed in either study. These data demonstrate that the PECAM-1 gene is responsive to shear stress in vitro and that decreased PECAM-1 gene expression in 53A carriers may influence reduced progression of vessel stenosis in patients with coronary artery disease.",2003.0,0,0 2110,12732798,LIFE and ARBITER.,Philip R Liebson,,2003.0,0,0 2111,12735230,Therapeutic implications of cholesteryl ester transfer protein inhibitors in hyperlipidemia and low high-density lipoprotein-cholesterolemia.,Akihiro Inazu; Hiroshi Mabuchi,"Low levels of high-density lipoprotein cholesterol (HDL-C) in plasma are an independent coronary risk factor. Therapies that lower cholesteryl ester transfer protein (CETP) have preventative effects on aortic atherosclerosis in cholesterol-fed rabbits. CETP inhibitors are a new class of compounds that can increase HDL-C levels by up to 70%, according to data from phase I and II clinical trials. CETP inhibitors are therefore likely to be beneficial in patients with moderate hypercholesterolemia and HDL-C levels lower than 40 mg/dl. CETP inhibitors should, however, be viewed with caution as their effects on triglyceride metabolism are currently unknown.",2003.0,0,0 2112,12735237,Eflucimibe. Pierre Fabre/Eli Lilly.,John R Burnett,Eflucimibe is an acyl coenzyme A:cholesterol acyltransferase inhibitor under development by Pierre Fabre SA and Eli Lilly & Co for the potential treatment of hypercholesterolemia and atherosclerosis. Phase II clinical trials commenced during 2002.,2003.0,0,0 2113,12739307,Pathogenesis of COPD.,Stephen I Rennard,"Chronic obstructive pulmonary disease (COPD) is not a single disorder. Rather, it is a collection of disorders characterized by the progressive development of airflow limitation. Patients afflicted with COPD experience systemic effects that are often responsible for major clinical problems. Lesions with differing pathogenetic bases can contribute to airflow limitation, and these differing and overlapping pathogenetic mechanisms account for the heterogeneous clinical features of COPD.",2003.0,0,0 2114,12740000,Colesevelam HCl: a non-systemic lipid-altering drug.,Harold Bays; Carlos Dujovne,"Colesevelam HCl (WelChol, Sankyo Pharmaceuticals Inc.) is a bile acid sequestrant polymer, which has been shown to significantly lower low density lipoprotein cholesterol and favourably affect high-density lipoprotein cholesterol blood levels in monotherapy and in combination with statins (HMG-CoA reductase inhibitors). Although it is similar to other bile acid sequestrants in that it binds bile acids and is non-systemic, colesevelam HCl differs in that it has a unique polymer structure that allows for greater tolerability with less potential drug interactions than with resins. Currently, statins are the most commonly prescribed lipid-altering drugs. However, it is not uncommon that patients demonstrate true or perceived intolerances to statin therapy, that are often dose-related and may include elevations in liver or muscle enzyme blood levels, or myalgias or muscle weakness without muscle enzyme elevation. In rare circumstances, myopathy and even rhabdomyolysis can occur with statins. In addition, many statins also have important potential drug interactions. Finally, statin monotherapy is often not sufficient in achieving lipid treatment goals in many severely dyslipidaemic patients and the availability of colesevelam HCl provides a lipid-altering treatment addition to other lipid-altering drugs. From a clinical perspective, such combination therapy is often required to achieve treatment goals [1] in patients with more complicated or severe dyslipidaemia. Colesevelam HCl may also be an alternative in monotherapy for many patients with mild-to-moderate hypercholesterolaemia, as well as in some patients at potential risk from systemic exposure to alternative lipid-altering drugs (such as young children and fertile women).",2003.0,0,0 2115,12740551,Atheroprotective effects of long-acting dihydropyridine-type calcium channel blockers: evidence from clinical trials and basic scientific research.,R Preston Mason,"Atherosclerosis is a systemic disease that can ultimately lead to ischaemia and infarction in the heart, brain and peripheral vasculature. According to the ""response to injury"" hypothesis, endothelial dysfunction is the early event that allows penetration of lipids and inflammatory cells into the arterial wall, contributing to the development of the atherosclerotic lesion. Endothelial dysfunction is causally related to a variety of risk factors for atherosclerosis, including hyperlipidaemia and hypertension. Agents that restore endothelial function and NO bioavailability have beneficial anti-atherogenic activities and can improve cardiovascular outcomes; this has been observed with angiotensin-converting enzyme (ACE) inhibitors, statins and certain dihydropyridine-type calcium channel blockers (CCBs). In the Prospective Randomised Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), the CCB amlodipine provided significant clinical benefits compared with placebo, including a marked reduction in cardiovascular morbidity and a reduction in the progression of carotid atherosclerosis. As these beneficial effects of amlodipine have not been observed with other dihydropyridine-type CCBs, it has been proposed that this agent has distinct anti-atherosclerotic properties related to its strong lipophilicity and membrane location. Experimental support for this hypothesis has been obtained from various in vitro and in vivo models of atherosclerosis. These findings support a broader therapeutic role for third-generation dihydropyridine-type CCBs in the treatment of atherosclerosis.",2003.0,0,0 2116,12740553,Clinical trials: Evidence and unanswered questions--hyperlipidaemia.,John E Deanfield,"It is now clear that the management of hypercholesterolaemia is important for the reduction of morbidity and mortality caused by cerebrovascular and coronary events. The landmark Scandinavian Simvastatin Survival Study was the first to show conclusively that lipid-lowering therapy with statins reduces the incidence of stroke. Subsequent trials, undertaken in a variety of different patient populations, have confirmed that statin therapy reduces the incidence of stroke by approximately one-third. This important benefit has been observed in men and women, the young and the elderly, and also in subjects with diabetes mellitus. In the recent Heart Protection Study, which recruited ""high-risk"" vascular subjects, stroke risk reduction was demonstrated even among those subjects considered to have ""low"" low-density lipoprotein (LDL) cholesterol levels. The benefits of statin therapy in stroke have been attributed to reductions in cholesterol and to other non-lipid-lowering effects of statins. Ongoing clinical trials such as TNT (Treating to New Targets) and IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid lowering) will test the ""lower is better"" hypothesis. Using statins to lower LDL cholesterol to levels that are below current guidelines will provide additional benefits in stroke risk reduction. Most of the data on cholesterol reduction and cerebrovascular events have been derived from studies of patients with documented coronary heart disease (CHD). The ongoing SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial will examine the benefits of LDL cholesterol lowering in patients with previous stroke or transient ischaemic attack (TIA), but no history of coronary problems.",2003.0,0,0 2117,12740554,Blood pressure and lipid lowering in the prevention of stroke: a note to neurologists.,Pierre Amarenco,"Stroke is the leading cause of adult disability and dependency in western society. Despite the determined efforts of basic science and clinical investigators, neuroprotective therapies for acute stroke have yet to be realised. Stroke prevention, therefore, remains the key route for reducing morbidity and mortality. Hypertension and hypercholesterolaemia are the most important modifiable risk factors for stroke. Several recent landmark studies have shown that lipid lowering with statins can reduce the risk of ischaemic stroke, as well as coronary heart disease. In addition, clinical trials evaluating the effects of blood pressure lowering have shown that antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs) and angiotensin II receptor antagonists can reduce stroke risk. Accumulating evidence suggests certain antihypertensive agents such as CCBs might also prevent the formation and progression of carotid atheroma, independently of their blood-pressure-lowering effects. It follows that rigorous identification and targeting of high- risk or stroke-prone individuals for blood pressure and lipid-lowering interventions should be of practical importance to all physicians involved in the management of stroke.",2003.0,0,0 2118,12741415,Does vitamin E supplementation prevent cardiovascular events?,JoAnn E Manson; Shari S Bassuk; Meir J Stampfer,"In recent years, vitamin E has been investigated as a cardioprotective agent. Experimental studies have identified potential mechanisms by which vitamin E may inhibit the development of atherosclerosis, and observational studies of individuals without coronary disease suggest that vitamin E intake may prevent future cardiovascular events. Secondary prevention trials to date have demonstrated little benefit from vitamin E supplementation. It remains possible, however, that supplementation may be useful among certain high-risk groups, including those with nutritional deficiencies. Limited data from completed primary prevention trials also indicate minimal cardioprotection from vitamin E, but large-scale trials now in progress may yet show benefit. Results from ongoing trials will contribute powerfully to the totality of evidence on which to formulate both appropriate clinical recommendations for individual patients and a rational public health policy for the population as a whole. At this time, there is insufficient evidence for issuing a public health recommendation to use vitamin E supplements to prevent cardiovascular disease (CVD). Rather, increased intake of fruits, vegetables, and other antioxidant-rich foods should be promoted as part of a healthy diet because they provide nutritional benefits beyond any potential antioxidant effect. Moreover, even if found to reduce CVD risk, vitamin supplement use should be considered an adjunct, not an alternative, to established cardioprotective measures, such as smoking abstention, avoidance of obesity, adequate physical activity, and control of high blood pressure and hyperlipidemia.",2003.0,0,0 2119,12741437,Treating dyslipidemic patients with lipid-modifying and combination therapies.,Chad R Worz; Michael Bottorff,"Updated guidelines from the National Cholesterol Education Program give greater emphasis to lipoproteins other than low-density lipoprotein cholesterol (LDL) than previous guidelines. Although statins remain first-line therapy for most patients to lower LDL, combination therapy is the next logical step in achieving goals in patients with mixed dyslipidemia or elevated LDL despite statin therapy. As the prevalence of diabetes, metabolic syndrome, and atherogenic dyslipidemia rises, the importance of treating the total lipid profile becomes even more crucial. Niacin, fibrates, and bile acid sequestrants are effective in combination with statins in lowering LDL, triglycerides, and total cholesterol levels and increasing high-density lipoprotein cholesterol (HDL). Although combination therapies may increase the risk of myopathy, both fibrate-statin and niacin-statin combinations are considered safe. In addition, niacin-statin therapy reduces atherosclerotic progression and coronary events. New pharmacologic formulations exist that will further affect treatment: a single-tablet combination of lovastatin and extended-release niacin is available, as is ezetimibe, a cholesterol-absorption inhibitor. In all, both HDL and triglyceride levels correlate with cardiovascular risk and should be considered secondary targets of therapy. Combination therapy can be safe and effective and can be constructed to affect all lipoprotein parameters.",2003.0,0,0 2120,12742282,Hydroxymethylglutaryl coenzyme a reductase inhibitors down-regulate chemokines and chemokine receptors in patients with coronary artery disease.,Torgun Waehre; Jan K Damås; Lars Gullestad; Are M Holm; Terje R Pedersen; Kjell E Arnesen; Harald Torsvik; Stig S Frøland; Anne G Semb; Pål Aukrust,"We sought to investigate whether the activation of the chemokine network observed in patients with coronary artery disease (CAD) could be modified by treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Chemokines and chemokine receptors are important mediators in atherogenesis, and we hypothesized that the statins could affect the chemokine network in CAD. Thirty CAD patients without previous statin therapy were randomized to receive atorvastatin (80 mg/day, n = 15) or simvastatin (20 mg/day, n = 15). Peripheral blood mononuclear cells (PBMCs) and plasma were obtained at baseline and after six months of statin therapy. Messenger ribonucleic acid (mRNA) expression of chemokines and chemokine receptors in PBMCs was analyzed by ribonuclease protection assay and real-time reverse-transcription polymerase chain reaction. Chemokines were also examined in the supernatants from unstimulated and lipopolysaccharide-stimulated PBMCs (and in plasma). Our main findings were: 1) gene expression of several chemokines (i.e., macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, and interleukin [IL]-8) and chemokine receptors (i.e., CC chemokine receptor [CCR]1, CCR2, CCR4, and CCR5) was markedly increased among CAD patients compared with healthy control subjects; 2) treatment with atorvastatin and simvastatin markedly reduced the mRNA levels of some of these chemokines (i.e., MIP-1alpha, MIP-1beta, IL-8) and receptors (i.e., CCR1 and CCR2), with the most pronounced effect in the atorvastatin group; and 3) statin therapy reduced the spontaneous release of IL-8 and MIP-1alpha from PBMCs in CAD patients. This study demonstrates a down-regulatory effect of statins on the chemokine network in CAD patients, possibly contributing to the beneficial effects of statins in this disorder.",2003.0,0,0 2121,12742802,Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study.,Zaldy Sy Tan; Sudha Seshadri; Alexa Beiser; Peter W F Wilson; Douglas P Kiel; Michael Tocco; Ralph B D'Agostino; Philip A Wolf,"Previous studies examining the association of plasma cholesterol levels with the risk for development of Alzheimer disease (AD) have been inconclusive. We examined the impact of baseline and lifetime plasma total cholesterol levels averaged across many years on the risk for AD in a large, population-based cohort. Five thousand two hundred nine subjects from the Framingham Study original cohort underwent biennial evaluation for cardiovascular risk factors since 1950, with estimations of serum total cholesterol levels at 19 of these 25 biennial examinations. The study sample consisted of 1026 subjects from this cohort who were alive and free of stroke and dementia at examination cycle 20 (1988-1989) and had undergone apolipoprotein E (APOE) genotyping. The main outcome measure was incident AD diagnosed using standard criteria, according to average total cholesterol levels across biennial examination cycles 1 to 15 and baseline total cholesterol level measured at the 20th biennial examination cycle. Alzheimer disease developed in 77 subjects from 1992 to 2000. After adjustment for age, sex, APOE genotype, smoking, body mass index (calculated as weight in kilograms divided by the square of height in meters), coronary heart disease, and diabetes, we found no significant association between the risk for incident AD and average cholesterol level at biennial examination cycles 1 to 15 (hazard ratio per 10-mg/dL [0.3-mmol/L] rise, 0.95; 95% confidence interval, 0.87-1.04) or baseline total cholesterol level at examination 20 (hazard ratio, 0.97; 95% confidence interval, 0.90-1.05). In this large, population-based cohort, baseline and long-term average serum total cholesterol levels were not associated with the risk for incident AD.",2003.0,0,0 2122,12742999,Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events.,S Matthijs Boekholdt; Willem R P Agema; Ron J G Peters; Aeilko H Zwinderman; Ernst E van der Wall; Pieter H Reitsma; John J P Kastelein; J Wouter Jukema; REgression GRowth Evaluation Statin Study Group,"Atherosclerosis is increasingly considered to be a chronic inflammatory process. We examined whether genetic variants of the toll-like receptor 4 (TLR4), which are correlated with impaired innate immunity and with progression of carotid atherosclerosis, are also associated with coronary atherosclerosis and predict the risk of cardiovascular events. Two polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) were determined in 655 men with angiographically documented coronary atherosclerosis. All patients participated in a prospective cholesterol-lowering trial evaluating the effect on coronary artery disease and were randomly assigned to either pravastatin or placebo for 2 years. There were no significant differences between genetically defined subgroups with respect to baseline risk factors, treatment, or in-trial changes of lipid, lipoprotein, or angiographic measurements. Genotype was not associated with progression of atherosclerosis. In the pravastatin group, 299Gly carriers had a lower risk of cardiovascular events during follow-up than noncarriers (2.0% versus 11.5%, P=0.045). Among noncarriers, pravastatin reduced the risk of cardiovascular events from 18.1% to 11.5% (P=0.03), whereas among 299Gly carriers this risk was strikingly reduced from 29.6% to 2.0% (P=0.0002, P=0.025 for interaction). Among symptomatic men with documented coronary artery disease, the TLR4 Asp299Gly polymorphism was associated with the risk of cardiovascular events. This variant also modified the efficacy of pravastatin in preventing cardiovascular events, such that carriers of the variant allele had significantly more benefit from pravastatin treatment.",2003.0,0,0 2123,12743334,Mechanisms of oxidative stress and vascular dysfunction.,Z S Nedeljkovic; N Gokce; J Loscalzo,"The endothelium regulates vascular homoeostasis through local elaboration of mediators that modulate vascular tone, platelet adhesion, inflammation, fibrinolysis, and vascular growth. Impaired vascular function contributes to the pathogenesis of atherosclerosis and acute coronary syndromes. There is growing pathophysiological evidence that increased generation of reactive oxygen species and oxidative stress participates in proatherogenic mechanisms of vascular dysfunction and atherothrombosis. In this review, the role of oxidative stress in mechanisms of vascular dysfunction is discussed, and potential antioxidant strategies are reviewed.",2003.0,0,0 2124,12743640,Ezetimibe.,Matthey Harris; Warren Davis; W Virgil Brown,"Ezetimibe is the first of a new class of drugs that specifically reduces the intestinal absorption of cholesterol. The drug is absorbed into the intestinal epithelial cell and remains associated in great part with the apical cell membrane where it is believed to interfere with the putative sterol transporter system. This apparently prevents both free cholesterol and plant sterols (phytosterols) from being transported into the cell from the intestinal lumen. The mechanism is very different from the reduction produced by phytosterol esters and phytostanol esters that have been documented previously as interfering with the micellar presentation of sterols to the cell surface. The drug is rapidly absorbed and glucuronidated in the intestinal cell before secretion into the blood. Ezetimibe is avidly taken up by the liver from the portal blood and excreted into the bile, resulting in low peripheral blood concentrations. The glucuronide conjugate is hydrolyzed and absorbed and is equally effective in inhibiting sterol absorption. This enterohepatic recycling is responsible for a half-life in the body of more than 20 h. The principle medical benefit appears to be a reduction in low-density lipoprotein cholesterol (LDLc). There is also a reduction in the cholesterol content of chylomicrons, which may provide some reduction in the atherogenic potential of the plasma lipoprotein pool. Triglycerides fall moderately and a modest rise in high-density lipoprotein cholesterol (HDLc) has been consistently observed in groups of treated patients. The maximum mean reduction of LDL cholesterol is approximately 20-25% in small studies at the maximal dose tested of 40 mg/day and the reduction is usually in the 16-20% range at the dosage of 10 mg/day. Most subsequent studies have been completed with the 10 mg/day dose. The medication is effective as a single daily dose due to its long residence time in the body. Combinations of ezetimibe with all available statins have been completed and demonstrate LDLc reductions of approximately 25% as additive effects to any statin dose alone. There are also small additional increases in HDL (2-3%) and reductions in triglycerides (10-15%). Additive effects to statin therapy have also been documented in patients with homozygous familial hypercholesterolemia. Reduction of plant sterols has been demonstrated in phytosterolemia, offering the first drug treatment for this rare inherited disease.",2003.0,0,0 2125,12745107,Comparative effects of diet and simvastatin on markers of thrombogenicity in patients with coronary artery disease.,Kwang Kon Koh; Ji Won Son; Jeong Yeal Ahn; Dae Sung Kim; Seung Hwan Han; Tae Hoon Ahn; In Suck Choi; Gi Soo Park; Eak Kyun Shin,,2003.0,0,0 2126,12745113,Usefulness of an acute coronary syndrome pathway to improve adherence to secondary prevention guidelines.,Angelo B Biviano; LeRoy E Rabbani; Furcy Paultre; Eileen Hurley; Jennifer Sullivan; James Giglio; Lori Mosca,,2003.0,0,0 2127,12745796,Women--a neglected risk group for atherosclerosis and vascular disease.,Leif R Erhardt,"Women are a neglected group for cardiovascular disease. Whereas young women tend to have lower incidences of coronary artery disease, stroke and myocardial infarctions than men, the situation changes drastically at menopause, after which women are at greater risk than men. Despite this, women at all ages receive less treatment, less attention and not enough information about health risks. Most risk factors, e.g. hypertension, elevated blood lipid levels, diabetes and changes in oestrogen levels, differ between women and men. As a consequence of this, secondary prevention from coronary artery disease is likely to have different effects in women to those in men. Different kinds of antihypertensive therapy, hormone-replacement therapy and lipid-lowering treatment may be more or less suitable in women than in men. The recent development of angiotensin-receptor blockers may have beneficial effects which make them particularly effective in women.",2003.0,0,0 2128,12746442,Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase.,Núria Casals; Paulino Gómez-Puertas; Juan Pié; Cecilia Mir; Ramón Roca; Beatriz Puisac; Rosa Aledo; Josep Clotet; Sebastián Menao; Dolors Serra; Guillermina Asins; Jacqueline Till; Alun C Elias-Jones; Juan C Cresto; Nestor A Chamoles; Jose E Abdenur; Ertan Mayatepek; Guy Besley; Alfonso Valencia; Fausto G Hegardt,"This study describes three novel homozygous missense mutations (S75R, S201Y, and D204N) in the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase gene, which caused 3-hydroxy-3-methylglutaric aciduria in patients from Germany, England, and Argentina. Expression studies in Escherichia coli show that S75R and S201Y substitutions completely abolished the HMG-CoA lyase activity, whereas D204N reduced catalytic efficiency to 6.6% of the wild type. We also propose a three-dimensional model for human HMG-CoA lyase containing a (betaalpha)8 (TIM) barrel structure. The model is supported by the similarity with analogous TIM barrel structures of functionally related proteins, by the localization of catalytic amino acids at the active site, and by the coincidence between the shape of the substrate (HMG-CoA) and the predicted inner cavity. The three novel mutations explain the lack of HMG-CoA lyase activity on the basis of the proposed structure: in S75R and S201Y because the new amino acid residues occlude the substrate cavity, and in D204N because the mutation alters the electrochemical environment of the active site. We also report the localization of all missense mutations reported to date and show that these mutations are located in the beta-sheets around the substrate cavity.",2003.0,0,0 2129,12746636,Control of diabetes and cardiovascular risk factors in patients with type 2 diabetes: a nationwide French survey.,G Charpentier; N Genès; L Vaur; J Amar; P Clerson; J P Cambou; P Guéret; ESPOIR Diabetes Study Investigators,"To evaluate in France in 2001 the therapeutic management and control of diabetes and of modifiable cardiovascular risk factors in patients with type 2 diabetes receiving specialist care. The study was proposed to 575 diabetologists across France. The first 8 consecutive ambulatory patients with type 2 diabetes treated by oral antidiabetic drugs (OADs) and/or insulin attending for consultation with a diabetologist were eligible for inclusion in the survey. The following data were collected: demographics, diabetic and cardiovascular history, cardiovascular risk factors, blood pressure, last recorded measurements of HbA(1c) and LDL cholesterol, and details of diabetes medication and cardiovascular medication. 4, 930 patients (53% men) aged 62 +/- 11 years were recruited by 410 specialists in diabetes care. The mean duration of diabetes was 12 +/- 9 years. 71% of patients were treated with OADs, 18% with an OAD + insulin and 9% with insulin alone. Mean HbA(1c) was 7.6 +/- 1.6%; HbA(1c) was<=6.5% in 27% of patients, between 6.6% and 8% in 39% of patients, and > 8% in 34% of patients. Mean blood pressure was 140 +/- 16/80 +/- 9 mmHg. In the study population as a whole the target blood pressure (systolic BP<140 mmHg and diastolic BP<80 mmHg) was attained by 29% of patients. Among the 3, 085 patients (63%) treated for hypertension, this target was attained in only 23% of patients; 40% of patients treated for hypertension received one single antihypertensive treatment, 36% received 2 treatments and 24% received 3 treatments or more. Among the 1, 845 patients considered by the investigators as not having hypertension, the target blood pressure was attained by 39%. A measurement for LDL cholesterol was available in 4, 036 patients (82%). 58% of these patients had LDL cholesterol<1.3 g/l, 29% had values between 1.3 and 1.6 g/l, and 13% had values > 1.6 g/l. 52% of patients were not receiving any lipid-lowering agents, 28% were treated with statins, 19% with fibrates, and 1% with statins + fibrates. LDL cholesterol was<1.3 g/l in only 66% of the 646 patients with associated coronary heart disease. According to this large nationwide survey, the prevalence of cardiovascular risk factors remains high. Control of glycaemia, blood pressure and LDL cholesterol does not appear to be optimal. This is due in part to the severity of diabetes in these patients seen by specialists in diabetes care; however, both awareness and application of published recommendations need to be reinforced.",2003.0,0,0 2130,12748238,A rational basis for selection among drugs of the same class.,Morris J Brown,,2003.0,0,0 2131,12749507,"An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers.",Paul D Martin; Aaron L Dane; Dennis W Schneck; Michael J Warwick,"Rosuvastatin and fenofibrate are lipid-regulating agents with different modes of action. Patients with dyslipidemia who have not achieved treatment targets with monotherapy may benefit from the combination of these agents. The effect of coadministration of rosuvastatin and fenofibrate on the steady-state pharmacokinetics of rosuvastatin and fenofibric acid (the active metabolite of fenofibrate) was assessed in healthy volunteers. This was an open-label, randomized, 3-way crossover trial consisting of three 7-day treatment periods. Healthy male volunteers received one of the following treatment regimens in each period: rosuvastatin 10 mg orally once daily; fenofibrate 67 mg orally TID; and rosuvastatin + fenofibrate dosed as above. The steady-state pharmacokinetics of rosuvastatin and fenofibric acid, both as substrate and as interacting drug, were investigated on day 7 of dosing. Treatment effects were assessed by construction of 90% CIs around the ratios of the geometric least-square means for rosuvastatin + fenofibrate/rosuvastatin and rosuvastatin + fenofibrate/fenofibrate for the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (derived from analysis of variance of log-transformed parameters). Fourteen healthy male volunteers participated in the study. When rosuvastatin was coadministered with fenofibrate, there were minor increases in the AUC from 0 to 24 hours and maximum concentration (Cmax) of rosuvastatin: the respective geometric least-square means increased by 7% (90% CI, 1.00-1.15) and 21% (90% CI, 1.14-1.28). The pharmacokinetic parameters of fenofibric acid were similar when fenofibrate was dosed alone and with rosuvastatin: the geometric least-square means for fenofibric acid AUC from 0 to 8 hours and Cmax decreased by 4% (90% CI, 0.90-1.02) and 9% (90% CI, 0.84-1.00), respectively. The treatments were well tolerated alone and in combination. Coadministration of rosuvastatin and fenofibrate produced minimal changes in rosuvastatin and fenofibric acid exposure.",2003.0,0,0 2132,12752842,Income-related differences in the use of evidence-based therapies in older persons with diabetes mellitus in for-profit managed care.,Arleen F Brown; Amy G Gross; Peter R Gutierrez; Luohua Jiang; Martin F Shapiro; Carol M Mangione,"To determine whether income influences evidence-based medication use by older persons with diabetes mellitus in managed care who have the same prescription drug benefit. Observational cohort design with telephone interviews and clinical examinations. Managed care provider groups that contract with one large network-model health plan in Los Angeles County. A random sample of community-dwelling Medicare beneficiaries with diabetes mellitus aged 65 and older covered by the same pharmacy benefit. Patients reported their sociodemographic and clinical characteristics. Annual household income (> or =$20,000 or <$20,000) was the primary predictor. The outcome variable was use of evidence-based therapies determined by a review of all current medications brought to the clinical examination. The medications studied included use of any cholesterol-lowering medications, use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) for cholesterol lowering, aspirin for primary and secondary prevention of cardiovascular disease, and angiotensin-converting enzyme (ACE) inhibitors in those with diabetic nephropathy. The influence of income on evidence-based medication use was adjusted for other patient characteristics. The cohort consisted of 301 persons with diabetes mellitus, of whom 53% had annual household income under $20,000. In unadjusted analyses, there were lower rates of use of all evidence-based therapies and lower rates of statin use for persons with annual income under $20,000 than for higher-income persons. In multivariate models, statin use was observed in 57% of higher-income versus 30% of lower-income respondents with a history of hyperlipidemia (P =.01) and 66% of higher-income versus 29% of lower-income respondents with a history of myocardial infarction (P =.03). There were no differences by income in the rates of aspirin or ACE inhibitor use. Among these Medicare managed care beneficiaries with diabetes mellitus, all of whom had the same pharmacy benefit, there were low rates of use of evidence-based therapies overall and substantially lower use of statins by poorer persons.",2003.0,0,0 2133,12753880,Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure.,Richard D Swartz; Leslie J Crofford; Sem H Phan; Robert W Ike; Lyndon D Su,"Nephrogenic fibrosing dermopathy is a newly recognized cutaneous fibrosing disorder marked by the acute onset of induration involving the upper and lower limbs in patients with acute or chronic renal failure. The etiology, pathogenesis, associated clinical conditions (other than renal failure), and ultimate course have not been defined in the few cases studied. Presently, there is no effective treatment, and the condition persists in most patients. Clinical and histopathologic data on 13 patients from our institution with the diagnosis of nephrogenic fibrosing dermopathy were reviewed. Several clinical and laboratory parameters were examined to see if any were consistently associated with the disease. Biopsy specimens were analyzed to determine if there was a pattern to the evolution of fibrosis in these patients. All 13 patients had renal failure before disease onset: 8 were undergoing chronic hemodialysis, 2 were undergoing chronic peritoneal dialysis, and 3 with acute renal failure had never undergone dialysis before the development of dermopathy. Most patients had other serious underlying medical conditions. Many patients were taking erythropoietin, cyclosporine, or both before the onset of disease. In transplant patients, no histocompatibility antigens were found to be associated with the disease. There were various laboratory abnormalities, but none were consistently associated with the condition. In skin biopsy specimens taken 7 to 180 days after disease onset, there were histopathologic changes suggestive of a tissue reaction to injury, as well as the development of smooth muscle actin-positive myofibroblasts. Nephrogenic fibrosing dermopathy is a novel cutaneous fibrosing disorder that is distinguished from other sclerosing or fibrosing skin disorders by distinctive clinical and histopathologic findings occurring in the setting of renal failure. There were no additional clinical risk factors or laboratory findings common to the 13 patients studied, other than renal failure. The resemblance to a tissue injury reaction and the presence of myofibroblasts in the tissue specimens suggest that fibrogenic cytokines may be involved in the evolution of the disease.",2003.0,0,0 2134,12754715,Interim analysis of continuous long-term endpoints in clinical trials with longitudinal outcomes.,Sally Galbraith; Ian C Marschner,"This paper discusses interim analysis for clinical trials where the primary endpoint is observed at a specific long-term follow-up time, but where repeated measures of the same outcome are also taken at earlier times. Methods are considered for improving the efficiency with which the long-term treatment difference is estimated, making use of information from shorter-term follow-up times. This approach to interim analysis has previously been studied for binary endpoints assessed at two time points during follow-up. Here we adapt and extend this methodology to include continuous endpoints assessed at an arbitrary number of follow-up times, making use of methods for analysing multivariate normal data subject to monotone missingness and unstructured mean and covariance relationships. The magnitude of efficiency gains obtained by using short-term measurements is considered, as well as how these gains depend on the number and timing of the short-term measurements. Sequential analysis of treatment differences is discussed, including the extent to which efficiency gains translate into reductions in the expected duration of a sequentially monitored trial. The methods are illustrated on a data set involving a placebo-controlled comparison of longitudinal cholesterol measurements.",2003.0,0,0 2135,12755126,Statins--the heart of the matter.,Christian Downton; Iain Clark,,2003.0,0,0 2136,12756041,Pilot study describing the use of pravastatin in pediatric renal transplant recipients.,Lavjay Butani; Monica V Pai; Sudesh P Makker,"Renal transplant (Tx) recipients frequently develop hypercholesterolemia. Pravastatin (P) has been shown to be effective in adult renal Tx recipients, not only in reducing serum cholesterol, but possibly also in decreasing graft rejection. However, there are no data on the use of P in children following renal transplantation. We conducted a retrospective case-control study evaluating the safety and efficacy of P (10-20 mg/day) in reducing hypercholesterolemia, when used pre-emptively in the post-Tx period in seven children, compared with an historical control (C) group of nine children who had not received P. The two groups were comparable with respect to their demographics and in their pretransplant serum cholesterol. Compared with the C group, the mean serum cholesterol in the P group was lower at 3 months (159 mg/dL vs. 225 mg/dL), 6 months (134 mg/dL vs. 200 mg/dL), 9 months (134 mg/dL vs. 209 mg/dL), and 12 months (125 mg/dL vs. 195 mg/dL) (p < 0.005 for all, Student's two-tailed t-test). At 1 month only 43% of the P group had hypercholesterolemia compared with 67% of the controls; by 12 months this difference was even more significant (0% in the P group vs. 45% in the C group). None of the treated patients developed any adverse reactions. This study demonstrates that the pre-emptive use of P in pediatric renal Tx recipients appears to be effective in significantly reducing serum cholesterol. Whether this effect will translate into improved allograft and patient survival in the long term cannot be predicted at present and will require additional studies to evaluate.",2003.0,0,0 2137,12756145,Should the multicenter carotid endarterectomy trials be repeated?,Seemant Chaturvedi,,2003.0,0,0 2138,12756147,How should we design studies for stroke prevention?,Steven T DeKosky,,2003.0,0,0 2139,12756427,Melanoma chemoprevention: a role for statins or fibrates?,Robert P Dellavalle; M Kelly Nicholas; Lisa M Schilling,"Although numerous second-generation isoprenylation inhibitors are proposed or under investigation for the treatment and/or prevention of cancer (eg, R115777, SCH 66336, L-778,123, BMS-214662), the chemotherapeutic and chemopreventive potential of commonly prescribed first-generation isoprenylation inhibitors, the statins, and other classes of lipid-lowering medications, the fibrates, has yet to be seriously explored. Two lipid-lowering medications, lovastatin and gemfibrozil, have been associated with a decreased incidence of melanoma in large, prospective, randomized, double-blind, placebo-controlled clinical cardiology trials. This article reviews melanoma biology and the clinical evidence for the use of lipid-lowering medications for melanoma chemoprevention and/or adjuvant chemotherapy.",2003.0,0,0 2140,12756561,,,,,0,0 2141,12756679,Statins. Evidence of effectiveness in older patients.,David T Nash,"As the population ages, increasing numbers of older adults are becoming candidates for lipid-lowering therapy with HMG CoA reductase inhibitors (statins) and lifestyle modification. Available evidence shows that statins reduce cardiovascular events and invasive revascularization in older adults. Statins have not only been shown to be safe and effective for lowering LDL cholesterol, but appear to have ancillary pleiotropic effects that are beneficial in other conditions to which older adults are prone. Despite these benefits, older adults are currently undertreated for this highly treatable cardiovascular risk factor.",2003.0,0,0 2142,12761259,Predictors of renal and patient outcomes in atheroembolic renal disease: a prospective study.,Francesco Scolari; Pietro Ravani; Alessandra Pola; Simona Guerini; Roberto Zubani; Ezio Movilli; Silvana Savoldi; Fabio Malberti; Rosario Maiorca,"Atheroembolic renal disease (AERD) is part of a multisystemic disease accompanied by high cardiovascular comorbidity and mortality. Interrelationships between traditional risk factors for atherosclerosis, vascular comorbidities, precipitating factors, and markers of clinical severity of the disease in determining outcome remain poorly understood. Patients with AERD presenting to a single center between 1996 and 2002 were followed-up with prospective collection of clinical and biochemical data. The major outcomes included end-stage renal disease (ESRD) and death. Ninety-five patients were identified (81 male). AERD was iatrogenic in 87%. Mean age was 71.4 yr. Twenty-three patients (24%) developed ESRD; 36 patients (37.9%) died. Cox regression analysis showed that significant independent predictors of ESRD were long-standing hypertension (hazard ratio [HR] = 1.1; P < 0.001) and preexisting chronic renal impairment (HR = 2.12; P = 0.02); use of statins was independently associated with decreased risk of ESRD (HR = 0.02; P = 0.003). Age (HR = 1.09; P = 0.009), diabetes (HR = 2.55; P = 0.034), and ESRD (HR = 2.21; P = 0.029) were independent risk factors for patient mortality; male gender was independently associated with decreased risk of death (HR = 0.27; P = 0.007). Cardiovascular comorbidities, precipitating factors, and clinical severity of AERD had no prognostic impact on renal and patient survival. It is concluded that AERD has a strong clinical impact on patient and renal survival. The study clearly shows the importance of preexisting chronic renal impairment in determining both renal and patient outcome, this latter being mediated by the development of ESRD. The protective effect of statins on the development of ESRD should be evaluated in a prospective study.",2003.0,0,0 2143,12761262,Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease.,Marcello Tonelli; Lemuel Moyé; Frank M Sacks; Thom Cole; Gary C Curhan; Cholesterol and Recurrent Events Trial Investigators,"Limited data suggest that HMG-CoA reductase inhibitors (statins) may slow loss of renal function in individuals with chronic renal insufficiency. This study was conducted to determine whether pravastatin reduced rates of loss of renal function in people with moderate chronic renal insufficiency. This was a post hoc subgroup analysis of a randomized double-blind placebo controlled trial. Data were analyzed from the CARE study (a randomized trial of pravastatin versus placebo in 4159 participants with previous myocardial infarction and total plasma cholesterol < 240 mg/dl). Participants with estimated GFR (MDRD-GFR) < 60 ml/min per 1.73 m(2) body surface area at baseline were considered to have moderate chronic renal insufficiency. Multivariate regression was used to calculate rates of decline in MDRD-GFR for individuals receiving pravastatin and placebo, controlling for prospectively determined covariates that might influence rates of renal function loss. Change in renal function could be calculated in 3384 individuals, of whom 690 (20.4%) had MDRD-GFR < 60 ml/min per 1.73 m(2) and were eligible for inclusion. Among all individuals with MDRD-GFR < 60 ml/min per 1.73 m(2)), the MDRD-GFR decline in the pravastatin group was not significantly different from that in the placebo group (0.1 ml/min per 1.73 m(2)/yr slower; 95% CI, -0.2 to 0.4; P = 0.49). However, there was a significant stepwise inverse relation between MDRD-GFR before treatment and slowing of renal function loss with pravastatin use, with more benefit in those with lower MDRD-GFR at baseline (P = 0.04). Rate of change in MDRD-GFR in the pravastatin group was 0.6 ml/min per 1.73 m(2)/yr slower than placebo (95% CI, -0.1 to 1.2; P = 0.07) in those with MDRD-GFR < 50 ml/min, and 2.5 ml/min per 1.73 m(2)/yr slower (95% CI, 1.4 to 3.6 slower; P = 0.0001) in those with MDRD-GFR < 40 ml/min per 1.73 m(2)/yr. Pravastatin also reduced rates of renal loss to a greater extent in participants with than without proteinuria at baseline (P = 0.006). It is concluded that pravastatin may slow renal function loss in individuals with moderate to severe kidney disease, especially those with proteinuria. These findings require confirmation by a large randomized trial conducted specifically in people with chronic renal insufficiency.",2003.0,0,0 2144,12763512,The menopause and HRT. Prevention and management of osteoporosis.,Michael R McClung,"Post-menopausal osteoporosis is characterized by increased fracture risk due to deficiencies in both the quantity and quality of bone. Assessing fracture risk involves combining clinical risk factors, including fall risks, with bone density testing. Treatment strategies are aimed at reducing fracture risk. General nutritional and lifestyle measures are appropriate for all women. Drug treatment is most clearly indicated in post-menopausal women at high current fracture risk. Treatment should also be considered for women at intermediate fracture risk, including those who have both low bone density and other risk factors for fracture. Whether there is practical clinical value in treating low-risk patients is much less clear. Non-pharmacological approaches addressing the consequences of fractures are integral parts of a comprehensive treatment programme. Reducing both the frequency and the effects of falls complements the efforts of treating osteoporosis to reduce the incidence of fractures and their important clinical consequences.",2003.0,0,0 2145,12763513,"The menopause and HRT. Hormone replacement therapy, cardiovascular and cerebrovascular disease.",Helena J Teede,"Historically, research into vascular effects of hormone replacement therapy (HRT) poignantly highlights the difficulties in extrapolating from medical research into clinical practice. Original observational trials encouraged great enthusiasm that HRT was protective against coronary heart disease (CHD) in post-menopausal women. This was supported by a plethora of beneficial mechanistic effects of HRT on the vascular system. In contrast, recent controlled trials have shown that a specific combined oral HRT actually causes a small increased risk of cardiovascular and cerebrovascular events, compared to placebo. The absolute risks were small, yet were accompanied by increased venous thrombosis and breast cancer. Although many controversies still remain regarding the vascular effects of specific types of HRT, currently, in my opinion, all HRT should be considered as causing a small increased risk of vascular events, until proven otherwise. However, the apparent lack of HRT effectiveness in the prevention of vascular disease should not deter enthusiasm for the use of established preventive therapies, especially lifestyle measures.",2003.0,0,0 2146,12763516,Breast cancer and post-menopausal hormone therapy.,P Kenemans; A Bosman,"From the introduction of post-menopausal hormone replacement therapy (HRT) there has been great concern that HRT could possibly increase the risk of breast cancer. Prolonged exposure to endogenous oestrogens undeniably increases the risk of breast cancer. Questions that are important and until now only partly answered, are the following. Are oestrogens tumour promoters, as they induce mitosis, lead to proliferation and, therefore, accelerated growth of clinically occult pre-existing tumours? In addition to this, are they genotoxic mutagenic carcinogens, or could they initiate tumours by way of accumulation of incessant DNA-replication damage mechanism? Opinions vary as to the effect of the addition of a progestogen. There is a multitude of different progestogens which could bind with differing affinity to progesterone receptor PR-A or PR-B, and which have different physiological functions via differential gene regulation. The action of a progestogen on the oestrogen-induced cellular mitotic activity could be synergistic or antagonistic (by different pathways: oestrogen receptor downregulation, activating of metabolic pathways within the breast or stimulation of apoptosis)? Over 60 observational studies and two randomized trials provide evidence that the small but significant increase in risk appears with long-term current post-menopausal hormone use. The addition of a progestogen does not decrease the risk as seen with oestrogens alone and might increase the risk further. It is not clear whether there is a difference in risk with sequentially combined versus continuously combined HRT. Many questions nevertheless still remain. Is the risk increase limited to lean women only? What about risk-modifying factors such as alcohol use and a positive family history for breast cancer? Are tumours detected under HRT less aggressive, is there a better prognosis and is the mortality not increased while morbidity is? And is HRT contraindicated for women with a positive family history for breast cancer or in those women who have been treated for breast cancer? And finally, are there alternative options for these women?",2003.0,0,0 2147,12763518,Hormone therapy and venous thromboembolism.,Roger E Peverill,"Convincing data from randomized trials and observational studies have demonstrated a two- to threefold increased risk of venous thromboembolism (VTE) with the use of hormone replacement therapy (HRT) in post-menopausal women. This risk is highest in the first year of use, but an increased risk persists after the first year if HRT use is ongoing. The risk of VTE is increased for oral oestrogen alone, oral oestrogen combined with progestin and probably for transdermal HRT. There is an increase in both idiopathic and non-idiopathic VTE with HRT. Early evidence suggests an interaction of HRT with thrombophilic states such as the factor V Leiden mutation, resulting in a synergistic increase in the risk of VTE. There is also an increased risk of VTE with raloxifene and tamoxifen, but the effects of low-dose HRT and tibolone on VTE risk are less clear.",2003.0,0,0 2148,12765509,Recruitment to randomised studies.,Wendy E Hague; Val J Gebski; Anthony C Keech,,2003.0,0,0 2149,12767421,Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with a combined hyperlipidemia and low high-density lipoprotein cholesterol levels.,David M Capuzzi; John M Morgan; Robert J Weiss; Rohini R Chitra; Howard G Hutchinson; Michael D Cressman,"Patients with combined hyperlipidemia and low high-density lipoprotein (HDL) cholesterol levels may benefit from combination therapy with a statin and niacin; therefore, we assessed the efficacy and safety of rosuvastatin and extended-release (ER) niacin alone and in combination in 270 patients with this atherogenic dyslipidemia. Men and women > or =18 years with fasting total cholesterol levels > or =200 mg/dl, triglycerides 200 to 800 mg/dl, apolipoprotein B > or cf=110 mg/dl, and HDL cholesterol <45 mg/dl were randomized to 1 of 4 treatments in this 24-week, open-label, multicenter trial: rosuvastatin 10 to 40 mg; ER niacin 0.5 to 2 g; rosuvastatin 40 mg/ER niacin 0.5 to 1 g; or rosuvastatin 10 mg/ER niacin 0.5 to 2 g. Percent changes from baseline in low-density lipoprotein (LDL) cholesterol, non-HDL cholesterol, and other lipid measurements at week 24 were determined by analysis of variance, with statistical testing performed separately between the rosuvastatin monotherapy group and each remaining treatment group. Daily doses of rosuvastatin 40 mg reduced LDL and non-HDL cholesterol significantly more than either ER niacin 2 g or rosuvastatin 10 mg/ER niacin 2 g (-48% vs -0.1% and -36% for LDL cholesterol and -49% vs -11% and -38% for non-HDL cholesterol, respectively; p <0.01 for all comparisons); no additional reduction in LDL or non-HDL cholesterol was observed with the combination of rosuvastatin 40 mg/ER niacin 1.0 g (-42% and -47%; p = NS). Triglyceride reductions ranged from -21% (ER niacin monotherapy) to -39% (rosuvastatin 40 mg/ER niacin 1 g), but no observed differences were statistically significant. Compared with rosuvastatin alone, rosuvastatin 10 mg/ER niacin 2 g produced significantly greater increases in HDL cholesterol (11% vs 24%, p <0.001) and apolipoprotein A-I (5% vs 11%, p <0.017). Similar increases in HDL cholesterol and apolipoprotein A-I were noted between the monotherapy groups. Over 24 weeks, rosuvastatin alone was better tolerated than either ER niacin alone or the combinations of rosuvastatin and ER niacin.",2003.0,0,0 2150,12767434,Effect of atorvastatin (80 mg) on recurrent ischemia in unstable angina pectoris or non-ST-elevation acute myocardial infarction.,Luis C L Correia; Luiz P Magalhães; Oto Santana; Mário S Rocha; Luiz C S Passos; Argemiro D'Oliveira; J Péricles Esteves; Andrei C Spósito,,2003.0,0,0 2151,12767534,Current concepts of cardiovascular diseases in diabetes mellitus.,Jaffar Ali Raza; Assad Movahed,"The incidence of diabetes has reached epidemic proportions across the world. In patients with diabetes, there is a two to four times increased risk of developing coronary artery disease (CAD). Diabetes seems to eliminate the protective benefits of hormones in women against CAD. Patients with type II diabetes also have hypertension, dyslipidemia, obesity, endothelial dysfunction and prothrombotic factors, called 'the metabolic syndrome'. Not only the incidence of CAD is higher in diabetes, the mortality of the diabetic patients after a cardiac event is significantly increased as compared to non-diabetics, including sudden death. Although in the past 35 years there has been a decline in the rate of death due to CAD in the general population, this has not been seen among patients with diabetes. Primary prevention can play an important role in decreasing the incidence of CAD in diabetic patients. Aggressive treatment of hyperlipidemia and hypertension is essential. Recent knowledge about the protective effects of aspirin, statins, angiotension converting enzyme inhibitors, and glitazones in the diabetic patients, if used appropriately will go a long way in primary and secondary prevention of CAD in patients with diabetes.",2003.0,0,0 2152,12767951,Renin-angiotensin system and atherothrombotic disease: from genes to treatment.,Douglas S Jacoby; Daniel J Rader,"The renin-angiotensin system plays a central role in the pathogenesis of cardiovascular disease. At the molecular and cellular levels, angiotensin II, the main effector peptide of the system, stimulates key components of atherosclerosis. Trials in animals and humans indicate that blocking renin-angiotensin system pathways decreases atherosclerotic plaque progression and ischemic events. This review provides a broad overview of the entire role of the renin-angiotensin system in atherothrombotic disease, ranging from molecular pathways to human genetics to the latest clinical trials.",2003.0,0,0 2153,12768071,"Atorvastatin and simvastatin in patients on hemodialysis: effects on lipoproteins, C-reactive protein and in vivo oxidized LDL.",Judith M van den Akker; Sebastian J H Bredie; Sabine H A Diepenveen; Lambertus J H van Tits; Anton F H Stalenhoef; Rob van Leusen,"Cardiovascular disease as a result of accelerated atherogenesis is common in patients with end-stage renal disease (ESRD). Dyslipidemia may be a major contributor in this process and can be influenced by lipid-lowering drugs (statins). Moreover, statins may exhibit additional inhibitory effects on the atherogenesis, such as a modulation of the immune system as triggered by oxidatively modified LDL and a reduction of the inflammatory marker C-reactive protein (CRP). We evaluated in a single-blind randomized trial of 28 ESRD patients on hemodialysis, the dose-depending effects of both atorvastatin and simvastatin on lipids, lipoproteins, LDL particle heterogeneity, high sensitive-CRP, and markers of in vivo LDL oxidation. Both statin therapies significantly lowered total plasma cholesterol and LDL-cholesterol concentrations to the same extent, whereas reduction in the concentrations of triglyceride-rich particles was less pronounced. Furthermore, statin therapy reduced LDL cholesterol in all LDL subfractions, without altering the overall LDL particle density. After both statins plasma hs-CRP concentrations were not significantly reduced; parameters of in vivo LDL oxidation (plasma ox-LDL concentration and the oxidation level of isolated LDL), were significantly decreased. Autoantibodies against ox-LDL, however, did not change during this trial period. These results show that atorvastatin and simvastatin exhibit comparable favourable effects on lipid profiles in ESRD. Moreover, the reduction of in vivo oxidatively modified LDL as shown in this ESRD population, may indicate that these statins exhibit favourable effects on oxidative stress in vivo.",2003.0,0,0 2154,12771114,Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial.,Sylvia Wassertheil-Smoller; Susan L Hendrix; Marian Limacher; Gerardo Heiss; Charles Kooperberg; Alison Baird; Theodore Kotchen; J David Curb; Henry Black; Jacques E Rossouw; Aaron Aragaki; Monika Safford; Evan Stein; Somchai Laowattana; W Jerry Mysiw; WHI Investigators,"The Women's Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group. To assess the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups, and to determine whether the effect of estrogen plus progestin was modified by baseline levels of blood biomarkers. Multicenter double-blind, placebo-controlled, randomized clinical trial involving 16 608 women aged 50 through 79 years with an average follow-up of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and 513 controls. Participants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102). Overall strokes and stroke subtype and severity were centrally adjudicated by stroke neurologists. One hundred fifty-one patients (1.8%) in the estrogen plus progestin and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen plus progestin on stroke risk. Estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined.",2003.0,0,0 2155,12773075,Ezetimibe for management of hypercholesterolemia.,Vincent F Mauro; Chad E Tuckerman,"To review the primary literature describing the pharmacology of ezetimibe and clinical trials investigating its use in the management of hypercholesterolemia. A MEDLINE search (1966-December 2002) was performed using SCH 48461, SCH 58235, ezetimibe, and 2-azetidinone as key words. English-language articles were identified and the references of these articles were used to further identify pertinent articles and abstracts. Given the paucity of published articles available on ezetimibe, many of the references cited are abstracts. All acquired articles that discussed the pharmacology, pharmacokinetics, chemistry, and clinical efficacy of ezetimibe were reviewed. Articles were selected based on content regarding the medicinal chemistry, pharmacology, and clinical use of ezetimibe. Ezetimibe, approved for use in October 2002, belongs to a new class of antihyperlipidemic agents that uniquely inhibit the absorption of cholesterol by inhibiting the cholesterol transport system located within intestinal cell walls. In humans, ezetimibe reduced cholesterol absorption by >50%. In clinical trials, ezetimibe 10 mg/d reduced low-density lipoprotein cholesterol (LDL-C) by approximately 18% and further enhanced the LDL-C-lowering effect of statin medications by an additional 15-20%. In addition, ezetimibe lowered triglycerides about 5% and increased high-density lipoprotein cholesterol (HDL-C) approximately 3%. Ezetimibe is well tolerated. At present, no serious adverse effects have been directly attributable to ezetimibe. Based on the data currently available, it appears that ezetimibe has a potential role in the treatment of primary hypercholesterolemia; however further data are needed to determine its long-term tolerability and efficacy. The potential roles for ezetimibe include its concurrent use with a statin to further enhance the lowering of LDL-C. Other possible roles for ezetimibe include its concurrent use with a statin to permit a lowering of statin dosage to avoid statin-related complications or its use as monotherapy to treat hypercholesterolemia when statin use cannot be tolerated or is contraindicated. Outcome data demonstrating that cardiovascular morbidity and/or mortality are reduced by ezetimibe therapy have yet to be generated.",2003.0,0,0 2156,12773078,Chromium as adjunctive treatment for type 2 diabetes.,Gina J Ryan; Nancy S Wanko; Andrea R Redman; Curtiss B Cook,"To review the chemistry, pharmacology, efficacy, and safety of trivalent chromium in the treatment of type 2 diabetes and hyperlipidemia. The English literature was searched from 1966 through May 2002 using MEDLINE, International Pharmaceutical Abstracts, and EMBASE. The key words included chromium, glucose, lipids, and diabetes. Pertinent references from review articles and studies were used as additional sources. Trivalent chromium is an essential nutrient and has a key role in lipid and glucose metabolism. Supplementation with chromium does not appear to reduce glucose levels in euglycemia. It may, however, have some efficacy in reducing glucose levels in hyperglycemia. The effects of chromium on lipid levels are variable. Chromium in doses <1000 microg/d appears to be safe for short-term administration. Kidney function and dermatologic changes need to be monitored. Chromium appears to be a safe supplement and may have a role as adjunctive therapy for treatment of type 2 diabetes. Additional large-scale, long-term, randomized, double-blind studies examining the effect of various doses and forms of chromium are needed.",2003.0,0,0 2157,12775947,Anti-atherosclerotic effects of statins: lessons from prevention trials.,Santhi K Ganesh; Caitlin M Nass; Roger S Blumenthal,"Statins are best-known for their lipid-lowering effects and have been shown to significantly impact the natural progression of coronary atherosclerosis. The mechanism through which they exert this effect is thought to be primarily due to their ability to reduce low-density lipoprotein cholesterol levels. However, there is increasing evidence that statins exert a myriad of other beneficial effects on the vascular wall, thus altering the course of atherosclerotic disease. This article will review the prevention trial literature as it pertains to the effects of statin therapy on atherosclerosis.",2003.0,0,0 2158,12775948,Statins and plaque stability.,Mardi Gomberg-Maitland; Valentin Fuster; Zahi Adel Fayad; Juan Jose Badimon; Roberto Corti,"3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are now the standard of care for patients with hypercholesterolaemia. This class of inhibitors, known as 'statins', has been shown to reduce cardiovascular morbidity and mortality. Accumulating data demonstrates a variety of mechanisms in which HMG-CoA reductase inhibition benefits the cardiovascular system. This review will discuss the pharmacology, clinical trials, and mechanisms, besides lipid lowering, of statin therapy.",2003.0,0,0 2159,12775949,HMG-CoA reductase inhibition: anti-inflammatory effects beyond lipid lowering?,Winfried März; Wolfgang Köenig,"Atherosclerosis has many features of a chronic inflammatory disease. Atherosclerotic lesions contain inflammatory cells. Systemic markers of inflammation, such as white blood cells, C-reactive protein, serum amyloid A, interleukin-6, and soluble adhesion molecules are predictive of future cardiovascular events. Atherogenic lipoprotein particles, in particular modified low-density lipoproteins (LDL), elicit pro-inflammatory responses of cellular elements of the vessel wall, including endothelial dysfunction and activation of monocyte-derived macrophages. High-density lipoproteins (HDL) oppose these effects by inhibiting the oxidation of LDL, and by down-regulating the expression of adhesion molecules and selectins. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) has proven the most successful strategy to reduce the concentration of LDL in the circulation. These compounds lower LDL cholesterol by inhibiting the mevalonate pathway in the liver. Prospective clinical trials have convincingly demonstrated that HMG-CoA reductase inhibitors can effectively lower the incidence of cardiovascular events in primary and secondary prevention. Post hoc analyses of these trials suggest that the clinical benefit brought about by statins may not entirely be due to their effect on the levels of circulating lipoproteins. In vitro observations of anti-inflammatory actions of statins on vascular cells may contribute to explain effects beyond lipid lowering. It is, however, not clear whether these findings are relevant to the in vivo situation. Further investigation is now necessary in order to determine the relative significance of cholesterol lowering and of ancillary effects on the net clinical benefit of statin treatment.",2003.0,0,0 2160,12777316,Less heart is more.,Douglas P Zipes,,2003.0,0,0 2161,12783420,"Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke.",Jieli Chen; Zheng Gang Zhang; Yi Li; Ying Wang; Lei Wang; Hao Jiang; Chenling Zhang; Mei Lu; Mark Katakowski; Carolyn S Feldkamp; Michael Chopp,"We demonstrate that the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors atorvastatin and simvastatin enhance functional outcome and induce brain plasticity when administered after stroke to rats. With atorvastatin treatment initiated 1 day after stroke, animals exhibited significant increases in vascular endothelial growth factor, cyclic guanosine monophosphate, angiogenesis, endogenous cell proliferation and neurogenesis, and an increase in the synaptic protein, synaptophysin. Atorvastatin-induced angiogenesis in a tube formation assay was reduced by an antibody against the vascular endothelial growth factor receptor 2 (FIK-1) and by the nitric oxide synthase inhibitor, N-mono-methyl-L-arginine (L-NAME). Atorvastatin also induced phosphorylation of Akt and Erk in cultured primary cortical neurons. These data indicate that atorvastatin induced brain plasticity and has neurorestorative activity after experimental stroke.",2003.0,0,0 2162,12783592,Imatinib mesylate in the treatment of chronic myeloid leukaemia.,Brian J Druker,"Imatinib mesylate (Gleevec, Glivec), formerly STI571; Novartis Pharmaceuticals) is an inhibitor of the Bcr-abl tyrosine kinase that is central to the pathogenesis of chronic myeloid leukaemia (CML). The remarkable results of imatinib mesylate in clinical trials have rapidly and profoundly changed the management of patients with CML. This article will review the development of this molecularly targeted agent. The clinical trials with imatinib mesylate will be summarised along with the pharmacology of this agent. Despite the impressive responses seen in chronic-phase patients, numerous questions remain. For example, how durable will responses to imatinib mesylate be and is it necessary or possible to improve upon these results? Ongoing efforts to address these issues will be discussed.",2003.0,0,0 2163,12783629,ALLHAT: is the final answer in?,Domenic A Sica,,2003.0,0,0 2164,12783634,"Gender, ethnicity, and genes in cardiovascular disease. Part 2: implications for pharmacotherapy.",Benjamin M Schaefer; Vincent Caracciolo; William H Frishman; Pamela Charney,"Women are underrepresented in clinical trials. Lower doses of beta-blockers are required for Southeast Asians. ACE and ARB's are teratogenic in the second trimester. Torsades de Pointes is more common in women related to a longer QT-interval. Lower dose OCPs decrease the risk of MI, stroke and thrombosis. HRTs are not effective for CAD prevention.",2003.0,0,0 2165,12789600,"Statins, super-statins and cholesterol absorption inhibitors.",Margaret E Brousseau,"An elevated level of low-density lipoprotein cholesterol (LDL-C) is an independent risk factor for premature coronary heart disease (CHD), with a value of > or = 160 mg/dl designated as high-risk by the National Cholesterol Education Program Adult Treatment Panels I, II and III. Current goals of therapy for all patients with elevated LDL-C include reducing levels to: (i) < 160 mg/dl in those with < or = 1 CHD risk factor; (ii) < 130 mg/dl in those with more than or equal to 2 CHD risk factors; and (iii) < 100 mg/dl in patients with established CHD or CHD risk equivalents, one of which is diabetes. The discovery of drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis, constituted a major advance in the treatment of patients with elevated plasma concentrations of LDL-C. The efficacy of statins in LDL-lowering and CHD risk reduction has clearly been demonstrated in a number of primary and secondary intervention trials. Emerging options for the treatment of patients with elevated LDL-C include the super-statins rosuvastatin and pitavastatin, as well as the cholesterol absorption inhibitor ezetimibe. This article reviews large-scale clinical trials in which statins have been used to reduce LDL-C concentrations. Studies that have examined the efficacy and safety of rosuvastatin, pitavastatin and ezetimibe will also be discussed.",2003.0,0,0 2166,12789870,Niacin for dyslipidemia: considerations in product selection.,James McKenney,"The efficacy and safety profiles of various forms of niacin for treating dyslipidemia are described. Niacin is well recognized for treating dyslipidemia in adults and has been shown to be effective in reducing coronary events. It has a broad range of effects on serum lipids and lipoproteins, including lowering total cholesterol, low-density-lipoprotein (LDL) cholesterol, and triglycerides. Niacin is the most effective lipid-modifying drug for raising high-density-lipoprotein (HDL) cholesterol levels and has been shown to lower Lp(a) lipoprotein. Niacin reduces triglycerides and very-low-density-lipoprotein and LDL cholesterol synthesis, primarily by decreasing fatty acid mobilization from adipose tissue. Niacin appears to raise HDL cholesterol by reducing hepatic apolipoprotein A-l clearance and enhancing reverse cholesterol transport. Niacin is metabolized through a conjugation or nicotinamide pathway. Standard immediate-release niacin is metabolized primarily through the conjugation pathway, which results in a high frequency of flushing. Long-acting niacin is metabolized through the nicotinamide pathway, which results in less flushing but increases the risk of hepatotoxicity. Extended-release niacin has a more balanced metabolism and causes fewer of both types of adverse effects. Improved serum lipid levels during niacin therapy have been associated with clinical and angiographic evidence of reduced coronary artery disease, especially when combined with statins. Niacin is particularly useful for managing high triglyceride and low HDL cholesterol levels as well as the lipid abnormalities associated with metabolic syndrome, including those commonly encountered in patients with diabetes. Several niacin products are available with significant differences in their safety and efficacy profiles. Health care providers must consider the differences between agents when recommending niacin for dyslipidemia treatment.",2003.0,0,0 2167,12791748,Acute coronary syndrome: unstable angina and non-ST segment elevation myocardial infarction.,Ever D Grech; David R Ramsdale,,2003.0,0,0 2168,12792664,Increased lipid peroxidation during long-term intervention with high doses of n-3 fatty acids (PUFAs) following an acute myocardial infarction.,H Grundt; D W T Nilsen; M A Mansoor; A Nordøy,"To assess the oxidative burden of a highly concentrated compound of n-3 PUFAs as compared to corn oil by measuring thiobarbituric acid-malondialdehyde complex (TBA-MDA) by HPLC. We also studied the influence on TBA-MDA of statins combined with n-3 PUFAs or corn oil. A prospective, randomised, double-blind, controlled study. One hospital centre in Stavanger, Norway. A total of 300 subjects with an acute myocardial infarction (MI). Gelatine capsules, containing 850-882 mg EPA and DHA as concentrated ethylesters, or 1 g of corn oil, were ingested in a dose of two capsules twice a day for at least 1 y. Alpha-tocopherol (4 mg) was added to all capsules to protect the PUFAs against oxidation. After 1 y TBA-MDA increased modestly in the n-3 PUFA group (n=125), as compared to the corn oil group (n=130), P=0.027. Multiple linear regression analyses of fatty acids in serum total phospholipids (n=56) on TBA-MDA measured after 12 months intervention, showed no dependency. Performing best subsets regression, serum phospholipid concentration of arachidonic acid (20:4 n-6 PUFA) was identified as a predictor of TBA-MDA at 12 months follow-up, P=0.004. We found no impact of statins on TBA-MDA. TBA-MDA increased modestly after long-term intervention with n-3 PUFAs compared to corn oil post-MI, suggesting biological changes induced by n-3 PUFAs, rather than simply reflecting their concentration differences. The peroxidative potential of n-3 PUFAs was not modified by statin treatment. : Pharmacia A/S and Pronova A/S, Norway.",2003.0,0,0 2169,12793598,Role of statin pleiotropism in acute coronary syndromes and stroke.,James K Liao,"Several landmark clinical trials have demonstrated the benefit of lipid-lowering with statins for the primary and secondary prevention of coronary heart disease. The clinical data in support of lowering cholesterol by statins are unequivocal. The established mechanism of action is via sterol regulatory element binding protein (SREBP) activation due to reduced hepatic cholesterol synthesis and secondary upregulation of the low-density lipoprotein (LDL)-receptor, leading to enhanced clearance of circulating cholesterol and lipids. Although it is widely accepted that most clinical benefit obtained with statins is a direct result of their lipid-lowering properties, there is still some debate as to whether the so-called 'pleiotropic effects' of statins contribute to the clinical outcome in vascular disease, or whether all the beneficial effects of statins are simply due to lipid-lowering. For example, these agents appear to display additional cholesterol-independent effects on various aspects of cardiovascular disease, including improving endothelial function, decreasing vascular inflammation and enhancing plaque stability. Thus, further studies are needed to understand the full impact of statin therapy on each of these processes and whether these effects contribute to the clinical benefits of statins in acute coronary syndromes and stroke.",2003.0,0,0 2170,12793855,Statins and their role in vascular protection.,Justin C Mason,"The statins reduce cholesterol synthesis through inhibition of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase and are widely prescribed for hyperlipidaemia to reduce the risk of atherosclerotic complications. The beneficial effect of lipid lowering by statins in the treatment of coronary heart disease has been demonstrated in large clinical trials. However, statins appear to have additional benefits on vascular function above and beyond their lipid lowering effects. Through inhibition of L-mevalonate synthesis, statins also prevent the synthesis of isoprenoid intermediates, including farnesylpyrophosphate and geranylgeranylpyrophosphate. Isoprenylation is important in the post-translational modification of a variety of proteins, including the small GTPases Rho, Rac and Ras, and hence plays an integral role in cellular signalling. Moreover, interference with isoprenylation underlies many of the beneficial actions of the statins on vascular endothelium, which include increased endothelial nitric oxide synthase expression, pro-angiogenic effects, increased fibrinolytic activity, immunomodulatory and anti-inflammatory actions, including increased resistance to complement. This has led to interest in the use of this class of drugs outside the realm of cardiovascular disease.",2003.0,0,0 2171,12796749,Role of single photon emission computed tomography imaging in the evaluation of therapy for angina pectoris.,Amar D Patel; Ami E Iskandrian,,2003.0,0,0 2172,12796760,Comparison of the dose-response relationships of 2 lipid-lowering agents: a Bayesian meta-analysis.,Donald A Berry; Scott M Berry; John McKellar; Thomas A Pearson,"Comparing the dose-response of a new drug to that of a previously studied drug can aid in understanding their relative potencies. Two dose-finding studies addressed the effect of a new drug, rosuvastatin, on its ability to decrease low-density lipoprotein cholesterol (LDL-C) levels. One of these studies included 2 doses of atorvastatin, and substantial additional information is available in the literature about the effect of atorvastatin on LDL-C level lowering. The 2 dose-finding studies of rosuvastatin considered otherwise healthy patients who had hypercholesterolemia. Comparable studies of atorvastatin were identified via a MEDLINE search in December 1999. Multiple reviewer consensus identified 15 of 41 studies on atorvastatin published since 1996 that met these selection criteria: reporting of LDL-C level change from baseline at least 6 weeks after treatment initiation, doses administered, and treatment group sizes. Eligible populations had clinical evidence of hypercholesterolemia. We excluded studies with patients who had severe illness or a previous history of transplantation. Data extraction of the mean, sample sizes, and SDs (or CIs) by dose was carried out independently by multiple reviewers. We combined the results from the various studies with Bayesian hierarchical modeling and analyzed them with Markov chain Monte Carlo techniques. Combining this study and literature results substantially increased the power to compare the dose-response relationships of rosuvastatin and atorvastatin. Rosuvastatin reduced LDL-C level by an estimated 10 to 17 percentage points more than atorvastatin when both were given at the same dose. Approximately one quarter of the dose of rosuvastatin achieved about the same magnitude of LDL-C level reduction as atorvastatin at dosages as high as 80 mg. This finding does not imply a 4-fold difference in efficacy overall and specifically does not describe the results at higher dosage levels. Bayesian meta-analysis of results from related studies allows the comparison of the dose-response relationships of 2 drugs, better estimates of a particular dose-response relationship within an individual study, and the expression of relative benefits (of dose and drug) in terms of probabilities. Explicitly comparing a study's results with historical data using Bayesian meta-analysis allows clinicians to view the study in the larger context of medical research.",2003.0,0,0 2173,12797474,"Effects of simvastatin and L-arginine on vasodilation, nitric oxide metabolites and endogenous NOS inhibitors in hypercholesterolemic subjects.",Edimar C Pereira; Marcelo C Bertolami; André A Faludi; Mohamed Salem; Daniela Bersch; Dulcineia S P Abdalla,"Hypercholesterolemia is linked to endothelial dysfunction and enhancement of the endogenous inhibitor of NO synthase. The statins have lipid-lowering and pleiotropic properties, which could exert protective effects on the endothelium in hypercholesterolemia. The association of L-arginine with simvastatin could promote a further improvement on endothelial function in this condition. Thus, we investigated whether simvastatin, with or without supplementation with L-arginine, could improve endothelium-dependent vasodilation. In this study, 25 hypercholesterolemic subjects were treated according to the following protocol: washout period of 1 month; simvastatin (20 mg/day) for 2 months; simvastatin (20 mg/day) + L-arginine (7 g/day) for 2 months. From these patients, 10 were chosen at random for evaluation of vascular function by high resolution ultrasonography of the brachial artery. In subjects treated with simvastatin plus L-arginine, an increase of L-arginine levels (68%) and L-arginine/asymmetric dimethylarginine (ADMA) ratio (67%) were observed. Simvastatin reduced the plasma concentrations of NO metabolites nitrite + nitrate (NOx: 34%), S-nitrosothiols (RSNO: 42%), total cholesterol (25%), low density lipoprotein (LDL)-cholesterol (36%) and the LDL-cholesterol/high density lipoprotein (HDL-cholesterol ratio (34%). Simvastatin, associated or not to L-arginine, did not affect ADMA levels and endothelium-dependent vasodilation. Our data showed that simvastatin reduced the plasma concentrations of NOx and RSNO without affecting either the levels of ADMA or endothelium-dependent vasodilation in hypercholesterolemia.",2003.0,0,0 2174,12798444,Reduction of arteriosclerotic nanoplaque formation and size by fluvastatin in a receptor-based biosensor model.,G Siegel; C Abletshauser; M Malmsten; A Schmidt; K Winkler,"Proteoheparan sulfate can be adsorbed onto a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. Due to electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution, thereby representing a receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. The binding process was studied by ellipsometric techniques suggesting that HDL has a high binding affinity and a protective effect on interfacial heparan sulfate proteoglycan layers with respect to LDL and Ca(2+) complexation. LDL was found to be deposited strongly at the proteoheparan sulfate-coated surface, particularly in the presence of Ca(2+), apparently through complex formation 'proteoglycan-low density lipoprotein-calcium'. This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. In a receptor-based biosensor application, this system was tested on its reliability to unveil possible acute pleiotropic effects of the lipid lowering drug fluvastatin. The VLDL/IDL/LDL and VLDL/IDL/LDL/HDL plasma fractions from a high risk patient with dyslipoproteinaemia and type 2 diabetes mellitus showed the start of arteriosclerotic nanoplaque formation at a normal blood Ca(2+) concentration, with a strong increase at higher Ca(2+) concentrations. Nanoplaque formation and size of the HDL-containing lipid fraction remained well below that of the LDL-containing lipid fraction. Fluvastatin, whether applied acutely to the patient (one single 80 mg slow release matrix tablet) or in a 2-month medication regimen, markedly slowed down this process of ternary aggregational nanoplaque build-up and substantially inhibited nanoplaque size development at all Ca(2+) concentrations used. The acute action gave no significant change in lipid concentrations of the patient. Furthermore, after nanoplaque generation, fluvastatin, similar to HDL, was able to reduce nanoplaque formation and size. These immediate effects of fluvastatin have to be taken into consideration when interpreting the clinical outcome of long-term studies.",2003.0,0,0 2175,12798569,Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease.,Stefan Blankenberg; Hans J Rupprecht; Christoph Bickel; Xian-Cheng Jiang; Odette Poirier; Karl J Lackner; Jürgen Meyer; François Cambien; Laurence Tiret; AtheroGene Investigators,"We sought to evaluate the association between cholesteryl ester transfer protein (CETP) genotypes and the risk of future cardiovascular mortality in patients with coronary artery disease (CAD). Polymorphisms of the CETP gene influence CETP activity and high-density lipoprotein (HDL) cholesterol concentration and might affect the long-term prognosis and response to statin therapy in patients with CAD. We used serum samples and deoxyribonucleic acid collected at baseline from a prospective cohort of 1,211 patients with CAD prospectively followed up (median follow-up of 4.1 years), 82 of whom experienced a fatal cardiovascular event. The CETP/C-629A and I405V polymorphisms, CETP activity, and HDL cholesterol were determined. Patients carrying the -629A allele had significantly lower CETP activity and higher HDL cholesterol levels. There was a significant association between this polymorphism and the risk of future cardiovascular death. Mortality decreased from 10.8% in CC homozygotes to 4.6% in CA heterozygotes and 4.0% in AA homozygotes (p < 0.0001). This association was independent of potential confounders, particularly HDL cholesterol and CETP activity levels. The clinical benefit of statin therapy was restricted to CC homozygotes, in whom cardiovascular mortality was divided by half (p = 0.01 for treatment x genotype interaction). Similar trends were observed with the CETP/I405V polymorphism, but these effects seemed to be mainly the consequence of linkage disequilibrium with the CETP/C-629A polymorphism. In patients with CAD, the CETP/-629A allele had a strong protective effect on future mortality from cardiovascular causes, independent of its role on HDL cholesterol and CETP activity levels. Additionally, this common polymorphism appeared to predict which patients with CAD will experience a survival benefit from statin therapy.",2003.0,0,0 2176,12798570,"Genetic polymorphisms of hepatic lipase and cholesteryl ester transfer protein, intermediate phenotypes, and coronary risk: do they add up yet?",Jeffrey L Anderson; John F Carlquist,,2003.0,0,0 2177,12798839,"Update of clinical trials from the American College of Cardiology 2003. EPHESUS, SPORTIF-III, ASCOT, COMPANION, UK-PACE and T-wave alternans.",John G F Cleland; Alison P Coletta; Nikolay Nikitin; Amala Louis; Andrew Clark,"The American College of Cardiology provided much useful new information to inform those who care for patients with heart failure about what they should and should not adopt into current clinical practice. The EPHESUS trial suggests a much wider role for aldosterone antagonists for the management of heart failure and left ventricular systolic dysfunction. SPORTIF-III indicates we may have a safer, simpler warfarin substitute soon. ASCOT reinforces the potential futility of statin therapy unless it is well targeted. The results of the COMPANION study investigating cardiac resynchronisation devices and implantable defibrillators were encouraging but inconclusive and/or hard to interpret. UK-PACE again questions the use of dual chamber pacing. T-wave alternans is an interesting experimental technique that may be useful in selecting which patients need an implantable defibrillator, although the technology needs testing in an appropriate patient population.",2003.0,0,0 2178,12800452,Aggressive lipid-lowering therapy in high-risk groups: warranted or excessive?,Anthony S Wierzbicki,,2003.0,0,0 2179,12800463,Omega-3 fatty acids: their role in the prevention and treatment of atherosclerosis related risk factors and complications.,D Bhatnagar; P N Durrington,"Fatty acids are an important source of energy which can have an influence on serum lipids. Omega-3 and omega-6 fatty acids, both polyunsaturated fatty acids, have been advocated as replacement for saturated fat. Omega-3 fatty acids, derived from fish and certain green plants, lower serum triglycerides, but they have also been shown to have a direct effect on myocardial contractility, blood pressure, platelet function, coagulation factors, cell-mediated immunity and markers of inflammation. Recently available clinical trial data, including those using the concentrated omega-3 fatty acid preparation Omacor, indicate that omega-3 fatty acids are valuable in preventing sudden death following myocardial infarction. Studies indicate that omega-3 fatty acids are just as effective as, or have a benefit superior to, statins in secondary prevention. Omacor is also useful in the treatment of hypertriglyceridaemia, both as monotherapy and in combination with statins.",2003.0,0,0 2180,12800468,"52nd Annual Scientific Session of the American College of Cardiology, Chicago, March 30-April 2, 2003.",Olwen Glynn Owen,,2003.0,0,0 2181,12800478,Cardiovascular complications of diabetes: prevention and management.,Alan J Garber,"Cardiovascular (CV) complications are by far the most prevalent in patients with type 2 diabetes and the principal cause of mortality. Renal complications of type 1 diabetes were the principal cause of death. However, with the advent of dialysis and renal transplantation and because of further increases caused by such management techniques on the already accelerated atherosclerosis of type 1 diabetes patients, CV complications have now become the principal cause of morbidity and mortality. For successful prevention of CV complications in diabetes, clinicians should therefore pay particular attention to the means of attaining goals for the management of established traditional as well as nontraditional CV risk factors. For the most part, such management has been proven to reduce CV events in patients with diabetes, particularly type 2 diabetes.",2003.0,0,0 2182,12801602,High density lipoproteins (HDLs) and atherosclerosis; the unanswered questions.,Philip Barter; John Kastelein; Alistair Nunn; Richard Hobbs; Future Forum Editorial Board,"The concentration of high density lipoprotein-cholesterol (HDL-C) has been found consistently to be a powerful negative predictor of premature coronary heart disease (CHD) in human prospective population studies. There is also circumstantial evidence from human intervention studies and direct evidence from animal intervention studies that HDLs protect against the development of atherosclerosis. HDLs have several documented functions, although the precise mechanism by which they prevent atherosclerosis remains uncertain. Nor is it known whether the cardioprotective properties of HDL are specific to one or more of the many HDL subpopulations that comprise the HDL fraction in human plasma. Several lifestyle and pharmacological interventions have the capacity to raise the level of HDL-C, although it is not known whether all are equally protective. Indeed, despite the large body of information identifying HDLs as potential therapeutic targets for the prevention of atherosclerosis, there remain many unanswered questions that must be addressed as a matter of urgency before embarking wholesale on HDL-C-raising therapies as strategies to prevent CHD. This review summarises what is known and highlights what we still need to know.",2003.0,0,0 2183,12801612,Apo A-I promoter polymorphism influences basal HDL-cholesterol and its response to pravastatin therapy.,Carlos Lahoz; Rocío Peña; Jose M Mostaza; Javier Jiménez; Enric Subirats; Xavier Pintó; Manuel Taboada; Angela López-Pastor; RAP Study Group,"Statins decrease cardiovascular morbidity and mortality, essentially, by reducing LDL-cholesterol levels and, additionally, by increasing HDL-cholesterol concentrations. Environmental and genetic factors are known to affect LDL-C response to statins but less is known regarding HDL-C. We have evaluated the lipid and lipoprotein response to 20 mg/day of pravastatin for 16 weeks in relation to the G/A polymorphism in the promoter region of the apo A-I gene in 397 hypercholesterolaemic subjects followed-up on an out-patient basis. In the study population, 61.7% were homozygous for the G allele and 36% were heterozygous. The A allele carriers had an HDL-C 6.5% higher than the G allele homozygotes (P=0.021 in univariate analysis; P=0.009 in multivariate analysis). However, on segregation by gender and smoking status the effect was significant only in non-smoking males. The A allele carriers did not increase their HDL-C concentrations after treatment (-0.3, 95%CI -3.3 to 2.7%) while G allele homozygotes had a 4.9% increase (95%CI 2.5-7.3%). Differences in the response between both groups were significant before (P=0.008) and after adjustment for confounding variables such as age and baseline HDL-C concentration (P=0.046). We conclude that the G/A polymorphism of the apo A-I promoter region affects not only baseline HDL-C concentrations but also its response to pravastatin treatment.",2003.0,0,0 2184,12801618,Cholesterol synthesis and absorption in coronary patients with lipid triad and isolated high LDL cholesterol in a 4S subgroup.,Tatu A Miettinen; Helena Gylling,"We assumed that assaying serum cholesterol precursors (synthesis markers) and plant sterols and cholestanol (absorption markers of cholesterol) reveals differences in cholesterol synthesis and absorption in the Finnish 4S subgroup divided in high triglyceride-low HDL cholesterol (lipid triad=HTG) and isolated high LDL cholesterol (ILDL) groups. Serum squalene and non-cholesterol sterol ratios to cholesterol were measured with gas-liquid chromatography at baseline, 6 weeks, 1 year, and 5 years on simvastatin. Patients with HTG (n=135) exhibited features of metabolic syndrome and, in spite of similar serum total and LDL cholesterol levels, ratios of synthesis markers were higher and those of absorption markers lower than in ILDL (n=133). The latter patients accumulated to a subgroup shown earlier to be clinical non-responders to simvastatin in 4S. Serum cholesterol reduction by simvastatin only tended to be higher in HTG than ILDL. The synthesis marker ratios were markedly reduced, and more effectively in HTG than ILDL, while the absorption marker ratios were increased, and for plant sterols more in ILDL than HTG. In conclusion, HTG is associated with high synthesis and low absorption of cholesterol, these events being opposite in ILDL. Synthesis is more effectively reduced by simvastatin in HTG than ILDL in spite of similar reduction in serum cholesterol. Patients defined by highest baseline absorption marker ratios in ILDL group are poor coronary event-reducers on regular simvastatin treatment.",2003.0,0,0 2185,12801620,Atorvastatin markedly improves type III hyperlipoproteinemia in association with reduction of both exogenous and endogenous apolipoprotein B-containing lipoproteins.,Masato Ishigami; Shizuya Yamashita; Naohiko Sakai; Ken-ichi Hirano; Hisatoyo Hiraoka; Tadashi Nakamura; Yuji Matsuzawa,"Remnant lipoproteins are known to promote atherosclerosis especially in patients with type III hyperlipoproteinemia (HLP). In the current study, the effects of atorvastatin were investigated with special reference to the exogenous and endogenous apolipoprotein (apo) B-containing lipoprotein metabolism in type III HLP. Four Japanese male patients with type III HLP associated with homozygous apoE2 were studied. One-month administration of atorvastatin (20 mg once daily), after a 4-week dietary run-in, strikingly reduced serum total cholesterol and triglyceride (TG) levels by 52 (P<0.01) and 56% (P<0.05), respectively. Atorvastatin further decreased remnant-like particle (RLP)-cholesterol by 73% and RLP-TG by 65% (P<0.05), respectively. Distribution analysis by polyacrylamide gel disc electrophoresis clearly showed that atorvastatin diminished very low-, intermediate- and low-density lipoprotein particles. The relative particle diameter of intermediate-density lipoprotein became smaller after atorvastatin treatment (P<0.01). Furthermore, ultracentrifugal analysis demonstrated that atorvastatin significantly decreased cholesterol, TG and phospholipid concentrations in all apoB-containing lipoprotein fractions and very low-density lipoprotein (VLDL)-cholesterol/serum TG ratio (P<0.05), implying atorvastatin-induced reduction of beta-VLDL. Finally, newly developed assays of apoB-48 and apoB-100 revealed that atorvastatin markedly reduced these apolipoproteins by 43 and 52%, respectively (P<0.01), suggesting that atorvastatin decreased the number of both exogenous and endogenous apoB-containing lipoproteins. Taken together, atorvastatin improves remnant lipoprotein metabolism in type III HLP both in quality and in quantity. Atorvastatin can be one of the optimal options for the treatment of patients with type III HLP.",2003.0,0,0 2186,12801625,Non-high density lipoprotein cholesterol and coronary events during long-term statin treatment.,Vasilios G Athyros; Athanasios A Papageorgiou; Athanasios N Symeonidis; Moses Elisaf,,2003.0,0,0 2187,12802815,Assessing the appropriateness of combining economic data from multinational clinical trials.,John R Cook; Michael Drummond; Henry Glick; Joseph F Heyse,"Because of the potential for large variability among countries in the utilization and cost of health care resources, it is important to assess the appropriateness of combining economic data across the countries in a multinational clinical economic trial. We show how available tests for interaction can be applied to economic endpoints, including cost-effectiveness ratios and net health benefits. This analysis includes a characterization of possible interactions being quantitative or qualitative in nature. In the absence of interaction, a pooled estimate of the economic endpoint should be representative of the participating countries. We explore the analytic issues by further analysing data from the Scandinavian Simvastatin Survival Study (4S).",2003.0,0,0 2188,12802842,Three new drugs for hyperlipidemia.,,,2003.0,0,0 2189,12804701,The lipid and non-lipid effects of statins.,Anthony S Wierzbicki; Robin Poston; Albert Ferro,"The 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, more commonly known as statins, are a class of drug widely used for the treatment of hypercholesterolaemia in patients with established cardiovascular disease as well as those at high risk of developing atherosclerosis. Their predominant action is to reduce circulating levels of low-density lipoprotein (LDL) cholesterol; to a smaller degree, they also increase high-density lipoprotein (HDL) cholesterol and reduce triglyceride concentrations. In recent years, however, there has been an increasing body of evidence that their effects on lipid profile cannot fully account for their cardiovascular protective actions: their beneficial effects are too rapid to be easily explained by their relatively slow effects on atherogenesis and too large to be accounted for by their relatively small effects on plaque regression. Experimental models have revealed that statins exert a variety of other cardiovascular effects, which would be predicted to be of clinical benefit: they possess anti-inflammatory properties, as evidenced by their ability to reduce the accumulation of inflammatory cells in atherosclerotic plaques; they inhibit vascular smooth muscle cell proliferation, a key event in atherogenesis; they inhibit platelet function, thereby limiting both atherosclerosis and superadded thrombosis; and they improve vascular endothelial function, largely through augmentation of nitric oxide (NO) generation. The relative importance of the lipid- and non-lipid-related effects of the statins in the clinical situation remains the subject of much continuing research.",2003.0,0,0 2190,12804728,Effectiveness of aggressive management of dyslipidemia in a collaborative-care practice model.,Michael J Ryan; Joan Gibson; Phillip Simmons; Eric Stanek,"The Cardiovascular Risk Identification and Treatment Center was established in 1997, adopting a collaborative-care clinic model for the purpose of improving the management of high-risk patients with dyslipidemia. This was a retrospective analysis of 417 high-risk patients with > or =1 year of follow-up laboratory data. Analysis included changes in total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), non-HDL, triglycerides, and total cholesterol to HDL ratio; lipoprotein goal achievement; Framingham risk score; liver function; and cardiovascular events. At baseline, 66% of patients had coronary heart disease (CHD) or equivalent risk, 45% were not receiving dyslipidemia therapy, and 29% were on statin monotherapy. After 3 years in the program, 56% were receiving combination therapy, 41% were on monotherapy, and 2% were not on therapy. The 3 most common treatment regimens were statin plus niacin (36%), statin alone (22%), and niacin alone (14%). All lipoproteins improved from baseline (p <0.001). Overall, 62% to 74% of patients reached singular lipid goals and 35% achieved combined lipid goals. Patients with Framingham 10-year CHD risk of >20% were reduced from 6% to <1%. Only 29 patients (7.0%) had a cardiovascular event, including 5 (1.0%) who experienced a myocardial infarction. Aspartate aminotransferase/alanine transferase elevation >3 times normal occurred in 1% of patients. In conclusion, a collaborative-care practice model adopting individualized, aggressive pharmacologic and nonpharmacologic treatment strategies is highly effective in achieving lipid goals, is sustainable, and is safe. Furthermore, this approach yields reduced projected 10-year CHD risk. A low rate of cardiovascular events was observed.",2003.0,0,0 2191,12806569,The lateral spread of epileptiform discharges in rat neocortical slices: effect of focal phencyclidine application.,A Gorji; D Scheller; E-J Speckmann,"In vitro and in vivo brain slice techniques were used to examine phencyclidine (PCP) effects on the lateral propagation of epileptiform field potentials (EFP) across adjacent areas of rat frontal neocortex. Epileptiform activity was induced by perfusing slices with Mg 2+-free artificial cerebrospinal fluid. Simultaneous field potential recordings of EFP were obtained from four microelectrodes placed 2-3 mm apart across coronal slices in the third layer. PCP, applied focally between recording sites, blocked rapid propagation across treated areas and resulted in the emergence of spatially separate, independent pacemakers. The characteristics of paroxysmal depolarization shifts did not change significantly by the blockade of lateral propagation of EFP. The same asynchronized pattern of EFP conduction was observed after local application of the N-methyl-D-aspartate (NMDA)-receptor antagonist DL-2-amino-5-phosphono-valeric acid. Local administration of haloperidol as well as NMDA before PCP application reversibly prevented appearance of multiple pacemakers. Focal application of dopamine produced an abnormal pattern of lateral conduction of EFP in 50 % of tested slices. Pacemaker failure as an indicator of functional impairment of cortical integration is the proposed mechanism for developing of schizophrenia-like psychosis associated with epilepsy. Abbreviations. APV: DL-2-amino-5-phosphono-valeric acid EEG:electroencephalogram EFP:epileptiform field potentials NMDA:N-methyl-D-aspartate PCP:phencyclidine SLPE:Schizophrenialike psychosis associated with epilepsy",2003.0,0,0 2192,12808877,The impact of statin treatment on diabetic patients.,Hiroyuki Koshiyama,"Retrospective analysis of secondary prevention trials indicates that 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors (statins) reduce the risk of recurrent coronary heart disease events in individuals with diabetes. Diabetic individuals may receive greater benefit from statin treatment than non-diabetic individuals, because of a higher absolute risk. Available data are limited, although several randomized trials of primary prevention with diabetic patients are ongoing. The low-density lipoprotein cholesterol goal is now considered to be < 100 mg/dl for individuals with diabetes. Pleiotropic effects of statins may be involved in anti-atherogenic or other actions of statin.",2003.0,0,0 2193,12808879,Thiazolidinediones in diabetes: current status and future outlook.,Heidi S Camp,"Thiazolidinediones have recently emerged as promising antidiabetic drugs. Unlike other oral antidiabetic drugs, thiazolidinediones function to ameliorate insulin resistance, a primary factor for the development of type 2 diabetes. Thiazolidinediones are ligands of the nuclear receptor, peroxisome proliferator-activated receptor-gamma, and their antidiabetic effects appear to be mediated by activation of this receptor. The two currently marketed thiazolidinediones, rosiglitazone and pioglitazone, display similar efficacies in their glucose lowering activities, but interestingly display slightly different clinical and side effect profiles. Understanding the molecular basis for these differences will help in the development of next generation thiazolidinediones that are more efficacious and safer for the treatment of type 2 diabetes.",2003.0,0,0 2194,12809960,"Randomized, double-blind, placebo-controlled comparison of the action of orlistat, fluvastatin, or both an anthropometric measurements, blood pressure, and lipid profile in obese patients with hypercholesterolemia prescribed a standardized diet.",Giuseppe Derosa; Amedeo Mugellini; Leonardina Ciccarelli; Roberto Fogari,"The aim of this study was to assess obese patients with hypercholesterolemia whom were prescribed a standardized diet, comparing the action of orlistat, fluvastatin, orlistat with fluvastatin, and placebo on anthropometric measurements, blood pressure (BP), and lipid profile. This was a 1-year, randomized, double-blind, placebo-controlled trial. The patients were prescribed a controlled-energy diet and were randomly allocated to receive placebo, orlistat 120 mg TID (O group), fluvastatin 80 mg/d (F group), or olistat 120 mg TID with fluvastatin 80 mg/d (OF group). Clinical measurements (body weight, body mass index [BMI], waist circumference, and BP) and lipid profile assessment (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides [TGs]) were performed at baseline and after 6 months and 1 year of treatment. The study included 99 obese patients with hypercholesterolemia (48 men and 51 women; mean [SD] age, 51 [9] years). There were no significant differences between groups in baseline demographic, BP, or plasma lipid values. Three patients dropped out (2 women in the O group and 1 man in the OF group) due to adverse events related to orlistat treatment, including gastrointestinal events (oily spotting and fecal urgency). Ninety-six patients completed the study. There were significant differences from baseline (mean [SD]) in BMI, waist circumference reduction (WCR), and body weight loss (BWL) at 6 months in the OF group (29.9 [1.1] kg/m(2), 2.7 [0.8] cm, and 7.4 [0.9] kg, respectively; all P < 0.05), and BMI, WCR, and BWL at 1 year in the O group (29.0 [1.0] kg/m(2), 3.0 [1.0] cm, and 8.6 [1.0] kg, respectively; all P < 0.02), the F group (29.3 [1.6] kg/m(2), 2.4 [1.0] cm, and 8/0 [1.0] kg, respectively; all P < 0.05), and the OF group (28.4 [0.6] kg/m(2), 4.0 [0.6] cm, and 11.4 [1.0] kg, respectively; all P < 0.01). Significant reductions from baseline in systolic and diastolic BP were observed at 1 year in the O and F groups (all P < 0.05) and the OF group (both P < 0.01). At 6 months, there were significant reductions from baseline in TC and LDL-C in the F group (both P < 0.05) and in TC, LDL-C, and TGs in the OF group (P < 0.02, P < 0.02, and P < 0.05, respectively), as well as a significant increase in HDL-C in the OF group (P < 0.02). At 1 year, there were significant reduction from baseline in TC in the O, F, and OF groups (P < 0.05 and P < 0.01, respectively), LDL-C (P < 0.05, P < 0.02, and P < 0.01, respectively), and TGs (P < 0.02, P < 0.05, and P < 0.02, respectively). Also at 1 year, HDL-C was significantly higher than baseline in the F and OF groups (P < 0.02 and P < 0.01, respectively). Improvements in clinical and lipid-profile parameters were found at 1 year with all 3 treatments.",2003.0,0,0 2195,12809965,An analysis of cholesterol control and statin use in the Losartan Intervention for Endpoint Reduction in Hypertension Study.,Krister Kristianson; Frej Fyhrquist; Richard B Devereux; Sverre E Kjeldsen; Lars H Lindholm; Paulette A Lyle; Markku S Nieminen; Steven M Snapinn,"There is general agreement that patients who have elevated lipid levels and/or risk factors for or existing cardiovascular disease should receive aggressive cholesterol-lowering therapy. However, it is not clear whether patients are receiving the recommended treatment. This study evaluated cholesterol control and statin use in the setting of a large, long-term cardiovascular end point trial. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was conducted between 1995 and 2001 to compare the incidence of cardiovascular morbidity and mortality with losartan- or atenolol-based treatment in 9193 patients aged 55 to 80 years with hypertension and left ventricular hypertrophy. The mean (SD) duration of follow-up was 4.8 (0.9) years. Use of lipid-lowering therapy was at the discretion of the investigator. In the present study, analyses of baseline and end-of-study mean total cholesterol (TC) and high-density lipoprotein cholesterol levels and statin use were performed for the combined treatment groups. Based on generally accepted guidelines, achievement of a TC level <5.0 mmol/L (193.5 mg/dL) was used as the treatment target for the purpose of these analyses. The proportions of patients with TC levels above this cutoff were calculated at baseline and at the final visit. A total of 8653 patients had baseline and end-of-study cholesterol measurements and were included in this analysis. At baseline, 528 (6.1%) patients were receiving statins; TC levels were above the cutoff in 381 (72.2%) of these patients, who had a mean TC level of 6.07 mmol/L (234.7 mg/dL). Of 8125 (93.9%) patients who were not receiving statins at baseline, TC levels were above the cutoff in 6859 (84.4%), with a mean TC level of 6.37 mmol/L (246.4 mg/dL). At the end of the study, 1892 (21.9%) patients were receiving a statin; TC levels were above the cutoff in 1096 (57.9%) of these patients, who had a mean TC level of 5.99 mmol/: (231.6 mg/dL). Of 6761 (78.1%) patients who were not receiving statins at the end of the study, TC levels were above the cutoff in 5316 (78.6%), with a mean TC level of 6.24 mmol/L (241.4 mg/dL). In this long-term cardiovascular end point study in patients with moderate to severe hypertension and left ventricular hypertrophy, statins were not optimally administered and cholesterol levels were poorly controlled.",2003.0,0,0 2196,12811417,[Update cardiology 2001/2002-part II. From unstable coronary syndrome to terminal heart failure].,Roland Fries; Michael Böhm,"The cardiovascular continuum describes the way from risk factors to atherosclerosis, acute cardiovascular events (unstable angina and myocardial infarction), and development of terminal heart failure and its complications. Following this way, advances are reported in the therapy of acute coronary syndrome, heart failure, ventricular and supraventricular tachyarrhythmias, and stroke in patients with patent foramen ovale. The following issues are reported in detail: (1) significance of statins and statin withdrawal, glycoprotein IIb/IIIa receptor blocker, acute coronary interventions, aspirin and clopidogrel in unstable coronary syndromes, (2) pathogenesis of acute pulmonary edema associated with hypertension, (3) cardiac regeneration capability after transplantation and myocardial infarction, (4) beta-blocker therapy, efficacy of additional angiotensin receptor blocker therapy and multisite biventricular pacing in symptomatic (advanced) heart failure, (5) prognosis after ablation of the atrioventricular node in patients with atrial fibrillation, (6) primary prevention with an implantable defibrillator and resumption of driving after implantation, and (7) therapeutic options after cryptogenic stroke and patent foramen ovale.",2003.0,0,0 2197,12814710,MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.,Rory Collins; Jane Armitage; Sarah Parish; Peter Sleigh; Richard Peto; Heart Protection Study Collaborative Group,"Individuals with diabetes are at increased risk of cardiovascular morbidity and mortality, although typically their plasma concentrations of LDL cholesterol are similar to those in the general population. Previous evidence about the effects of lowering cholesterol in people with diabetes has been limited, and most diabetic patients do not currently receive cholesterol-lowering therapy despite their increased risk. 5963 UK adults (aged 40-80 years) known to have diabetes, and an additional 14573 with occlusive arterial disease (but no diagnosed diabetes), were randomly allocated to receive 40 mg simvastatin daily or matching placebo. Prespecified analyses in these prior disease subcategories, and other relevant subcategories, were of first major coronary event (ie, non-fatal myocardial infarction or coronary death) and of first major vascular event (ie, major coronary event, stroke or revascularisation). Analyses were also conducted of subsequent vascular events during the scheduled treatment period. Comparisons are of all simvastatin-allocated versus all placebo-allocated participants (ie, intention to treat), which yielded an average difference in LDL cholesterol of 1.0 mmol/L (39 mg/dL) during the 5-year treatment period. Both among the participants who presented with diabetes and among those who did not, there were highly significant reductions of about a quarter in the first event rate for major coronary events, for strokes, and for revascularisations. For the first occurrence of any of these major vascular events among participants with diabetes, there was a definite 22% (95% CI 13-30) reduction in the event rate (601 [20.2%] simvastatin-allocated vs 748 [25.1%] placebo-allocated, p<0.0001), which was similar to that among the other high-risk individuals studied. There were also highly significant reductions of 33% (95% CI 17-46, p=0.0003) among the 2912 diabetic participants who did not have any diagnosed occlusive arterial disease at entry, and of 27% (95% CI 13-40, p=0.0007) among the 2426 diabetic participants whose pretreatment LDL cholesterol concentration was below 3.0 mmol/L (116 mg/dL). The proportional reduction in risk was also about a quarter among various other subcategories of diabetic patient studied, including: those with different duration, type, or control of diabetes; those aged over 65 years at entry or with hypertension; and those with total cholesterol below 5.0 mmol/L (193 mg/dL). In addition, among participants who had a first major vascular event following randomisation, allocation to simvastatin reduced the rate of subsequent events during the scheduled treatment period. The present study provides direct evidence that cholesterol-lowering therapy is beneficial for people with diabetes even if they do not already have manifest coronary disease or high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of first major vascular events by about a quarter in a wide range of diabetic patients studied. After making allowance for non-compliance, actual use of this statin regimen would probably reduce these rates by about a third. For example, among the type of diabetic patient studied without occlusive arterial disease, 5 years of treatment would be expected to prevent about 45 people per 1000 from having at least one major vascular event (and, among these 45 people, to prevent about 70 first or subsequent events during this treatment period). Statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations.",2003.0,1,1 2198,12814712,"Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.",Hallvard Holdaas; Bengt Fellström; Alan G Jardine; Ingar Holme; Gudrun Nyberg; Per Fauchald; Carola Grönhagen-Riska; Søren Madsen; Hans-Hellmut Neumayer; Edward Cole; Bart Maes; Patrice Ambühl; Anders G Olsson; Anders Hartmann; Dag O Solbu; Terje R Pedersen; Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators,"Renal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population. We did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4.0-9.0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5-6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, non-fatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat. After a mean follow-up of 5.1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0.83 [95% CI 0.64-1.06], p=0.139) was not significant, although there were fewer cardiac deaths or non-fatal MI (70 vs 104, 0.65 [0.48-0.88] p=0.005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups. Although cardiac deaths and non-fatal MI seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations.",2003.0,1,1 2199,12815379,Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors.,Jonathan A Tobert,"In the 1950s and 1960s, it became apparent that elevated concentrations of plasma cholesterol were a major risk factor for the development of coronary heart disease, which led to the search for drugs that could reduce plasma cholesterol. One possibility was to reduce cholesterol biosynthesis, and the rate-limiting enzyme in the cholesterol biosynthetic pathway, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, was a natural target. Here, I describe the discovery and development of lovastatin--the first approved inhibitor of HMG-CoA reductase--and the clinical trials that have provided the evidence for the ability of drugs in this class to reduce the morbidity and mortality associated with cardiovascular disease.",2003.0,0,0 2200,12815556,Attenuated T-lymphocyte response to HIV therapy in individuals receiving HMG-CoA reductase inhibitors.,Shanil Narayan; Nanci Hawley; Pierre Giguère; Andrew D Badley,"The protease inhibitor class of antiretroviral agents is associated with the unwanted side effect of hypertriglyceridemia, which is usually treated with either HMG-CoA reductase inhibitors (statins) or fibrates. However, since statin therapy is intrinsically immunomodulatory, we questioned whether the T-cell response of patients who received PI-based therapy plus statin differed from the response of patients on PI therapy alone or on PI therapy with a fibrate. Retrospective cohort study. Thirty-five patients who had received ritonavir/saquinavir (R/S)-based antiretroviral therapy for 5 or more years were evaluated and stratified into four treatment groups: patients on R/S alone (n = 9), patients on R/S and stavudine/lamivudine (d4T/3TC) (n = 10), patients on R/S with or without d4T/3TC and statin (n = 11), or patients on R/S with or without d4T/3TC and fibrate (n = 5). All patients had suppressed levels of viral replication at all time points. T-cell responses were similar in all four groups before they were exposed to lipid-lowering agents. After the addition of lipid-lowering agents, absolute CD4 T-cell responses were lower in the statin group than in all other groups (p <.05), when measured after 6, 12, and 18 months of treatment. These data suggest that T-cell responses are influenced by the choice of anti-lipid agent and suggest that a prospective comparison is needed to determine the clinical relevance of these findings.",2003.0,0,0 2201,12816020,Policosanol.,Joseph Pepping,,2003.0,0,0 2202,12817528,"Influence of drugs interacting with CYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of the prandial glucose regulator repaglinide.",Vibeke Hatorp; Kristian T Hansen; Mikael S Thomsen,"The object of this study was to analyze drug interactions between repaglinide, a short-acting insulin secretagogue, and five other drugs interacting with CYP3A4: ketoconazole, rifampicin, ethinyloestradiol/levonorgestrel (in an oral contraceptive), simvastatin, and nifedipine. In two open-label, two-period, randomized crossover studies, healthy subjects received repaglinide alone, repaglinide on day 5 of ketoconazole treatment, or repaglinide on day 7 of rifampicin treatment. In three open-label, three-period, randomized crossover studies, healthy subjects received 5 days of repaglinide alone; 5 days of ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine alone; or 5 days of repaglinide concomitant with ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. Compared to administration of repaglinide alone, concomitant ketoconazole increased mean AUC0-infinity for repaglinide by 15% and mean Cmax by 7%. Concomitant rifampicin decreased mean AUC0-infinity for repaglinide by 31% and mean Cmax by 26%. Concomitant treatment with CYP3A4 substrates altered mean AUC0-5 h and mean Cmax for repaglinide by 1% and 17% (ethinyloestradiol/levonorgestrel), 2% and 27% (simvastatin), or 11% and 3% (nifedipine). Profiles of blood glucose concentration following repaglinide dosing were altered by less than 8% by both ketoconazole and rifampicin. In all five studies, most adverse events were related to hypoglycemia, as expected in a normal population given a blood glucose regulator. The safety profile of repaglinide was not altered by pretreatment with ketoconazole or rifampicin or by coadministration with ethinyloestradiol/levonorgestrel. The incidence of adverse events increased with coadministration of simvastatin or nifedipine compared to either repaglinide or simvastatin/nifedipine treatment alone. No clinically relevant pharmacokinetic interactions occurred between repaglinide and the CYP3A4 substrates ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. The pharmacokinetic profile of repaglinide was altered by administration of potent inhibitors or inducers, such as ketoconazole or rifampicin, but to a lesser degree than expected. These results are probably explained by the metabolic pathway of repaglinide that involves other enzymes than CYP3A4, reflected to some extent by a small change in repaglinide pharmacodynamics. Thus, careful monitoring of blood glucose in repaglinide-treated patients receiving strong inhibitors or inducers of CYP3A4 is recommended, and an increase in repaglinide dose may be necessary. No safety concerns were observed, except a higher incidence in adverse events in patients receiving repaglinide and simvastatin or nifedipine.",2003.0,0,0 2203,12818407,"The effect of atorvastatin on serum lipids, lipoproteins and NMR spectroscopy defined lipoprotein subclasses in type 2 diabetic patients with ischaemic heart disease.",S S Soedamah-Muthu; H M Colhoun; M J Thomason; D J Betteridge; P N Durrington; G A Hitman; J H Fuller; K Julier; M I Mackness; H A W Neil; CARDS Investigators,"The effect of statin therapy on subclasses of LDL, VLDL and HDL lipoproteins is unclear. We compared changes in serum lipids, apolipoproteins and nuclear magnetic resonance (NMR) spectroscopy measured lipoprotein subclass concentration and average particle size over a minimum 6 months treatment period of atorvastatin 10 mg vs. placebo in 122 men and women. All subjects had type 2 diabetes and a modest dyslipidaemia (mean LDL-cholesterol 3.2 mmol/l and median triglycerides 1.8 mmol/l) and had a previous myocardial infarction. Compared with placebo, atorvastatin therapy was associated with a greater decrease in medium VLDL (median within person change -13.4 vs. -5.9 nmol/l, P<0.001 adjusted for baseline level), small VLDL (median change -17.8 vs. -8.1 nmol/l, P=0.002), large LDL (mean within person change -167.9 vs. -48.6 nmol/l, P<0.001) and medium LDL (median within person change -101.8 vs. -22.3 nmol/l, P=0.017). Atorvastatin therapy was also associated with a greater increase in large HDL than placebo (median change 1.40 vs. 0.80 micromol/l, P=0.02) and there was little change in small HDL so that average HDL particle size increased significantly with atorvastatin (P=0.04). In addition to reducing levels of (enzymatically measured) triglyceride, LDL-cholesterol and apolipoprotein B in diabetic patients, atorvastatin significantly reduces NMR measured medium and small VLDL and large and medium LDL, and increases large HDL.",2003.0,0,0 2204,12819995,[Drug therapy of coronary heart disease--are therapeutic guidelines being paid attention to?].,G I Böger; M Hoopmann; R Busse; M Budinger; T Welte; R H Böger,"Drug therapy of coronary heart disease (CHD) is a life-long treatment. With every change from in-patient to out-patient care and back, changes in medication may occur. If a drug is chosen which provides no proven long-term benefit in terms of reduced morbidity and mortality, the expected therapeutic benefit may be missed. We investigated in 224 patients admitted to the medical departments of two hospitals (one with a specialized Cardiology Unit, one with a General Internal Medicine Unit) the prescriptions for CHD by the general practitioner before admittance into the hospital, the prescriptions recommended at the time of discharge, and the prescriptions made by the general practitioner three months after discharge. Of the drug classes with proven effects on morbidity and mortality (acetylsalicylic acid, beta-blockers, statins, ACE inhibitors), none had sufficiently high prescription rates. Prescription rates at discharge were 30% for beta-blockers and statins, 70% for acetylsalicylic acid, and 60% for ACE inhibitors. Only in patients with acute myocardial infarction were the prescription rates for these drug classes higher at this time point. The presence of contraindications was not of prime importance for the low prescription rates, as even in patients without contraindications prescription rates were not significantly higher than in the total patient cohort. Out of the patients with hypercholesterolemia, one third of those treated in the Cardiology Department and two thirds of those treated in the General Internal Medicine Department were not given any lipid-lowering medication. Prescription rates for those drug classes that provide symptomatic relief but have little impact on mortality rates (calcium channel blockers, nitrates) were high in both hospitals. The present study shows that evidence-based guidelines for the drug treatment of coronary heart disease are not adequately put into practice.",2003.0,0,0 2205,12820814,The role of lipid-lowering drugs in cognitive function: a meta-analysis of observational studies.,Mahyar Etminan; Sudeep Gill; Ali Samii,"To quantify the risk of cognitive impairment with use of lipid-lowering drugs. Literature search through MEDLINE and EMBASE databases; data from seven observational studies were analyzed. We quantified the risk of cognitive impairment first with the use of any lipid-lowering drug, and then specifically with the statins, using the random effects model. We tested for heterogeneity using the Q statistic as well as quantitatively using the Ri statistic. All seven studies provided data for statin users, and five provided data only on use of lipid-lowering drugs. Compared with patients not receiving lipid-lowering drugs, the relative risk of cognitive impairment with any lipid-lowering drug was 0.62 but was not statistically significant (95% confidence interval [CI] 0.28-1.38), and the relative risk with statins was 0.43 and was statistically significant (95% CI 0.31-0.62). Lipid-lowering drugs--in particular, the statins--seem to lower the odds of developing cognitive impairment. Randomized, controlled trials are needed to address the efficacy of these agents specifically in different types of dementia.",2003.0,0,0 2206,12821213,Secondary prevention in coronary heart disease patients with low HDL: which options do we have?,A H Liem; J W Jukema; D J van Veldhuisen,"Low levels of high-density lipoprotein cholesterol (HDL-C) are frequently encountered in patients with coronary artery disease (CAD), most often in combination with elevated triglycerides as part of a dysmetabolic syndrome. Although no large secondary prevention trials with statin therapy with special emphasis on low HDL-C have been performed, some guidance can be extracted from a number of post-hoc analyses on how to treat patients with low levels of HDL-C. In terms of risk reduction, statin therapy appears to be at least as effective in patients with low compared to normal HDL-C levels. Fibrate therapy seems only effective when low HDL-C coincides with a level of low-density lipoprotein cholesterol (LDL-C) in the low-normal range. Before considering combination therapy of statins with fibrates, much emphasis should be put on dietary changes, weight reduction, smoking cessation and regular exercise, since these measures are effective tools to raise HDL-C levels. Moreover, one should be aware of the fact that combination therapy of statins and fibrates is not evidence-based and confers some potential risk of myopathy. Future therapy options may include CETP (cholesterol ester transfer protein) inhibitors, but these agents are still in an experimental phase. As most patients with low HDL-C levels share features of the dysmetabolic syndrome, one could also consider a combination therapy of statins and ACE-inhibitors, since this combination is not only safe, but the individual preventive effects of these compounds appear to be cumulative.",2003.0,0,0 2207,12821221,The effect of statin therapy on ventricular late potentials in acute myocardial infarction.,Meral Kayikcioglu; Levent Can; Harun Evrengul; Serdar Payzin; Hakan Kultursay,"To determine whether early statin therapy in acute myocardial infarction has any effect on ventricular late potentials which are considered as a noninvasive tool for evaluation of arrhythmogenic substrate. Study population consisted of prospectively enrolled 72 patients presenting with acute myocardial infarction (<6 h). Thirty-four of the patients were randomized to pravastatin (40 mg/day) on admission irrespective of lipid levels. All patients received thrombolytic therapy. Signal-averaged ECG recordings were obtained serially prior to thrombolytic therapy, 48 h after and 10 days later. Late potentials were defined as positive if signal-averaged ECG met at least two of Gomes criteria: filtered total QRS duration >114 ms, root mean square voltage of the last 40 ms of the QRS <20 mV, or the duration of the terminal low (<40 mV) amplitude signals >38 ms. Changes observed in signal-averaged ECG recordings after thrombolysis were evaluated statistically with regard to statin usage. There were no significant differences between the clinical characteristics of the two randomized groups. There was a significant decrease in the rates of late potentials between the first and third signal-averaged ECG recordings after thrombolytic therapy in pravastatin group. Pravastatin group also had lower incidence of ventricular arrhythmias compared with control group (26 vs. 63%, P=0.021). The in-hospital cardiovascular event rates were also lower in statin group. Early use of pravastatin reduces the incidence of late potentials following thrombolytic therapy in acute myocardial infarction. Statin therapy also seems to be reducing the incidence of in-hospital ventricular arrhythmias. These beneficial effects of statins might be explained through prevention of new myocardial ischemic episodes due to early plaque stabilization or regulation of endothelial and platelet functions.",2003.0,0,0 2208,12822200,Statins and stroke.,Didier Leys; Dominique Deplanque,"An important issue for stroke prevention is the identification and treatment of risk factors such as hypercholesterolaemia. The 4 reasons to test if the statins have a role in stroke prevention are: (i) a statistical link between elevated low density lipoprotein-cholesterol or decreased high density lipoprotein-cholesterol and ischaemic stroke; (ii) a reduction in vascular risk with statins in randomised trials in patients with coronary heart disease; (iii) evidence of a decreased plaque progression under statins; and (iv) pooled analyses of primary and secondary prevention trials showing that reduction of total serum cholesterol reduces the incidence of stroke, especially with the highest rate of cholesterol reduction, and in patients with the highest risk of stroke (i.e. with statins in secondary prevention trials). The question of whether statins also have a neuroprotective effect in humans and reduce the risk of post-stroke dementia remains unsettled.",2003.0,0,0 2209,12822202,[Anticholesteremic agents in children].,Jean-Philippe Girardet,"The treatment of hypercholesterolaemia in children is often discussed as part of the primary prevention strategy for premature coronary disease in adults. Cholesterol-lowering drugs are appropriate in children with hereditary autosomal dominant diseases such as familial hypercholesterolaemia, familial Apo B100 deficiency, or combined familial dyslipidaemia. Indeed, these diseases are associated with a high risk of cardiovascular attacks in young adults. In children suffering from these diseases, cholesterol-lowering drugs are considered when the plasma low density-lipoprotein (LDL)-cholesterol concentration remains above 190 mg/dL after a 6-month dietary treatment. The drug of first choice remains bile acid-binding resines (colestyramine) because their efficacy and safety are well documented in children. HMG-CoA reductase inhibitors can be used in children older than 8 or 9 years of age in cases of an altered observance of colestyramine treatment, but their long-term tolerance is unknown. Fibrates are also efficient, however, their safety has not been evaluated in controlled studies through in children.",2003.0,0,0 2210,12824720,Rosuvastatin--a highly effective new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor: review of clinical trial data at 10-40 mg doses in dyslipidemic patients.,Herbert Schuster,"Rosuvastatin (Crestor; licensed to AstraZeneca, Macclesfield, UK from Shionogi, Osaka, Japan) is a new statin with pharmacologic characteristics that translate into selectivity of effect in hepatic cells and enhanced potency in 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition. It is approved for use at doses of 10-40 mg once daily to reduce low-density lipoprotein (LDL) cholesterol, increase high-density lipoprotein (HDL) cholesterol and improve other lipid measures in dyslipidemic patients. In a dose-ranging study in mild/moderate hypercholesterolemia, rosuvastatin reduced LDL cholesterol by 52-63% at 10-40 mg. Rosuvastatin 10 mg reduces LDL cholesterol significantly more than atorvastatin 10 mg, simvastatin 10-40 mg and pravastatin 10-40 mg, and enables significantly more patients to achieve National Cholesterol Education Program and Joint European Societies LDL cholesterol goals compared with each of these statins. Rosuvastatin also produces marked elevations in HDL cholesterol and maintains this effect across the dose range. Rosuvastatin favorably modifies triglycerides, LDL cholesterol and other lipid measures in patients with hypertriglyceridemia or mixed dyslipidemia, including diabetic patients, and may constitute a monotherapy option for many such patients. Rosuvastatin is well tolerated when used alone or in combination, exhibiting a safety profile similar to that of other available statins. Rosuvastatin offers considerable advantages for use in routine clinical practice.",2003.0,0,0 2211,12826791,What should we advise our patients about taking antioxidants?,Thomas G Pickering,,2003.0,0,0 2212,12826933,Simvastatin inhibits interleukin-6 release in human monocytes stimulated by C-reactive protein and lipopolysaccharide.,Jian-Jun Li; Xue-Jun Chen,"The accumulating evidence suggests that C-reactive protein (CRP) may have direct inflammatory effects on the vascular wall and that statin therapy may have important non-lipid anti-inflammatory effects confirmed by decreasing serum inflammatory markers, such as CRP. However, the effect of simvastatin on interleukin-6 (IL-6) release in cultured human monocytes was not investigated. DESIGN A prospective, human monocyte culture, simvastatin intervention study. Monocytes were isolated from blood of healthy volunteers by the Ficoll density gradient and stimulated by broad concentrations of CRP (1-20 microg/ml) and lipopolysaccharide (LPS, 1-10 ng/ml) at indicated time points (0, 2, 4, 8, 16 and 24 h). Also 10-8-10-6 mol/l simvastatin was coincubated with cells in the presence of CRP and LPS. Measurements of IL-6 were performed from supernatants of cultured medium in duplicate, using a commercial assay kit. CRP and LPS induced the rapid release of IL-6, with significantly elevated levels in cultured supernatants at 4 h in the CRP group and at 2 h in the LPS group. The effects of CRP and LPS on IL-6 release of monocytes were dose and time dependent. A greater than 11-fold increase of IL-6 in the CRP group (20 microg/ml) and a greater than 26-fold increase in the LPS group (10 ng/ml) were observed at 24 h compared with the control group (945.7+/-98.3 pg/ml compared with 94.3+/-12.4 pg/ml and 1720.4+/-690.1 pg/ml compared with 70.1+/-16.7 pg/ml, P<0.001, respectively). However, 10-8-10-6 mol/l simvastatin inhibited significantly the production of IL-6 in monocytes stimulated by CRP and LPS in a dose-dependent manner, with the maximal inhibiting effect at a concentration of 10-6 mol/l (945.7+/-98.3 pg/ml compared with 180.9+/-31.2 pg/ml and 1720.4+/-690.1 pg/ml compared with 824.0+/-206.2 pg/ml, P<0.001 respectively). CRP and LPS could induce IL-6 release in human monocytes and simvastatin could inhibit this response in a dose-dependent manner, which may provide an insight into the mechanisms of anti-inflammatory or anti-atherosclerotic actions of simvastatin.",2003.0,0,0 2213,12828227,The Lescol Intervention Prevention Study (LIPS): start all patients on statins early after PCI.,Adrian W Messerli; Herbert D Aronow; Dennis L Sprecher,"The Lescol Intervention Prevention Study (LIPS) was the first randomized trial to show a significant reduction in the risk of cardiac events in patients started on fluvastatin immediately after a successful percutaneous coronary intervention. The benefit was independent of baseline cholesterol levels. The results suggest that all patients should be discharged on lipid-lowering therapy after a percutaneous coronary intervention. Currently, this is seldom done.",2003.0,0,0 2214,12829553,A strategy to reduce cardiovascular disease by more than 80%.,N J Wald; M R Law,"To determine the combination of drugs and vitamins, and their doses, for use in a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. The strategy was to simultaneously reduce four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels. We quantified the efficacy and adverse effects of the proposed formulation from published meta-analyses of randomised trials and cohort studies and a meta-analysis of 15 trials of low dose (50-125 mg/day) aspirin. Proportional reduction in ischaemic heart disease (IHD) events and strokes; life years gained; and prevalence of adverse effects. The formulation which met our objectives was: a statin (for example, atorvastatin (daily dose 10 mg) or simvastatin (40 mg)); three blood pressure lowering drugs (for example, a thiazide, a beta blocker, and an angiotensin converting enzyme inhibitor), each at half standard dose; folic acid (0.8 mg); and aspirin (75 mg). We estimate that the combination (which we call the Polypill) reduces IHD events by 88% (95% confidence interval 84% to 91%) and stroke by 80% (71% to 87%). One third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke. Summing the adverse effects of the components observed in randomised trials shows that the Polypill would cause symptoms in 8-15% of people (depending on the precise formulation). The Polypill strategy could largely prevent heart attacks and stroke if taken by everyone aged 55 and older and everyone with existing cardiovascular disease. It would be acceptably safe and with widespread use would have a greater impact on the prevention of disease in the Western world than any other single intervention.",2003.0,0,0 2215,12829554,"Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.",M R Law; N J Wald; A R Rudnicka,"To determine by how much statins reduce serum concentrations of low density lipoprotein (LDL) cholesterol and incidence of ischaemic heart disease (IHD) events and stroke, according to drug, dose, and duration of treatment. Three meta-analyses: 164 short term randomised placebo controlled trials of six statins and LDL cholesterol reduction; 58 randomised trials of cholesterol lowering by any means and IHD events; and nine cohort studies and the same 58 trials on stoke. Reductions in LDL cholesterol according to statin and dose; reduction in IHD events and stroke for a specified reduction in LDL cholesterol. Reductions in LDL cholesterol (in the 164 trials) were 2.8 mmol/l (60%) with rosuvastatin 80 mg/day, 2.6 mmol/l (55%) with atorvastatin 80 mg/day, 1.8 mmol/l (40%) with atorvastatin 10 mg/day, lovastatin 40 mg/day, simvastatin 40 mg/day, or rosuvastatin 5 mg/day, all from pretreatment concentrations of 4.8 mmol/l. Pravastatin and fluvastatin achieved smaller reductions. In the 58 trials, for an LDL cholesterol reduction of 1.0 mmol/l the risk of IHD events was reduced by 11% in the first year of treatment, 24% in the second year, 33% in years three to five, and by 36% thereafter (P < 0.001 for trend). IHD events were reduced by 20%, 31%, and 51% in trials grouped by LDL cholesterol reduction (means 0.5 mmol/l, 1.0 mmol/l, and 1.6 mmol/l) after results from first two years of treatment were excluded (P < 0.001 for trend). After several years a reduction of 1.8 mmol/l would reduce IHD events by an estimated 61%. Results from the same 58 trials, corroborated by results from the nine cohort studies, show that lowering LDL cholesterol decreases all stroke by 10% for a 1 mmol/l reduction and 17% for a 1.8 mmol/l reduction. Estimates allow for the fact that trials tended to recruit people with vascular disease, among whom the effect of LDL cholesterol reduction on stroke is greater because of their higher risk of thromboembolic stroke (rather than haemorrhagic stroke) compared with people in the general population. Statins can lower LDL cholesterol concentration by an average of 1.8 mmol/l which reduces the risk of IHD events by about 60% and stroke by 17%.",2003.0,0,0 2216,12831816,Possibilities of multifactorial cardiovascular disease prevention in patients aged 75 and older: a randomized controlled trial: Drugs and Evidence Based Medicine in the Elderly (DEBATE) Study.,Timo E Strandberg; Kaisu Pitkala; Saila Berglind; Markku S Nieminen; Reijo S Tilvis,"The effectiveness of multifactorial cardiovascular disease prevention in patients aged 75 years or older is uncertain, because these patients have often been excluded from trials. The aim of this pre-planned, first-year analysis of the Drugs and Evidence-Based Medicine in the Elderly (DEBATE) Study was to determine the feasibility of prevention efforts in elderly cardiovascular patients. For DEBATE, home-dwelling individuals aged 75 years and over with cardiovascular diseases (n=400, mean age 80 years, 65% women) were recruited from the community. These high-risk participants were randomly assigned to the intervention group (n=199) where both lifestyle modification and pharmacological cardiovascular treatments are individualized by a geriatrician according to current European guidelines. The control group (n=201) receives the usual care. Interim analysis of the study groups at one year shows that intervention has succeeded in increasing the use of statins, aspirin, beta-blockers, and ACE inhibitors, and decreasing serum cholesterol (p<0.0001), LDL-cholesterol (p<0.0001), and hsCRP (p=0.04). Body mass index, blood pressure, and blood glucose were similar at one year in both groups. No safety problems or adverse effects on health-related quality of life were observed and compliance was good. It is possible and safe to institute evidence-based cardiovascular treatments in the 75+ cardiovascular patients in a real life setting, but only serum cholesterol and hsCRP are significantly decreased.",2003.0,0,0 2217,12835406,"Perspectives in cholesterol-lowering therapy: the role of ezetimibe, a new selective inhibitor of intestinal cholesterol absorption.",Eric Bruckert; Philippe Giral; Philippe Tellier,,2003.0,0,0 2218,12836860,Use of lipid-lowering agents (statins) during pregnancy.,Akiko Hosokawa; Benjamin Bar-Oz; Shinya Ito,"A 34-year-old patient of mine is taking a 'statin' for hyperlipidemia. She is planning pregnancy and is worried about the safety of the drug. How should I advise her? Limited evidence from animal and human studies indicates that statins should not be taken during pregnancy. If a patient is inadvertently exposed during pregnancy, however, termination does not appear to be medically indicated.",2003.0,0,0 2219,12836863,Effect of statin therapy on total mortality. Trial in a more varied population.,Abdullah Alkhenizan,,2003.0,0,0 2220,12837046,Effects of policosanol and lovastatin on lipid profile and lipid peroxidation in patients with dyslipidemia associated with type 2 diabetes mellitus.,G Castaño; R Menéndez; R Más; A Amor; J L Fernández; R L González; M Lezcay; E Alvarez,"In this pilot, randomized, double-blind study, we compared the effects of policosanol and lovastatin on lipid profile and lipid peroxidation in patients with dyslipidemia and type 2 diabetes mellitus. After 4 weeks on a cholesterol-lowering diet, 36 patients were randomized to policosanol (10 mg/day) or lovastatin (20 mg/day) tablets o.i.d. for 8 weeks. Policosanol significantly (p < 0.001) lowered serum low-density lipoprotein-cholesterol (LDL-C) (29.9%), total cholesterol (21.1%), triglycerides (13.6%) and the LDL-C/high-density lipoprotein-cholesterol (HDL-C) (36.7%) and total cholesterol/HDL-C (28.9%) ratios and significantly (p < 0.01) increased HDL-C (12.5%). Lovastatin significantly (p < 0.001) lowered LDL-C (25%), total cholesterol (18%), triglycerides (10.9%) and the LDL-C/HDL-C (30.4%) and total cholesterol/HDL-C ratios (23.9%) and significantly (p < 0.01) raised HDL-C (8.3%). Policosanol was more effective (p < 0.05) than lovastatin in reducing both ratios and in increasing (p < 0.05) HDL-C. Policosanol, but not lovastatin, significantly raised the lag time (20.9%) of Cu+2-induced LDL peroxidation and total plasma antioxidant activity (24.2%) (p < 0.05). Both policosanol and lovastatin significantly decreased the propagation rate (41.9% and 41.6% respectively, p < 0.001), maximal diene production (8.3% and 5.7%) and plasma levels of thiobarbituric acid reactive substances (9.7% and 11.5%, p < 0.001). Both treatments were well tolerated. Only one patient in the lovastatin group withdrew from the trial due to adverse events. In conclusion, policosanol and lovastatin administered short term to patients with dyslipidemia secondary to type 2 diabetes were effective in lowering cholesterol and in inhibiting the extent of lipid peroxidation. Policosanol (10 mg/day) was slightly more effective than lovastatin (20 mg/day) in reducing the LDL-C/HDL-C and total cholesterol/HDL-C ratios, in increasing HDL-C levels and in preventing LDL oxidation. Nevertheless, since this was a pilot study, further clinical studies performed in larger sample sizes of diabetic patients are needed for definitive conclusions.",2003.0,0,0 2221,12838521,Early ischemic lesion recurrence within a week after acute ischemic stroke.,Dong-Wha Kang; Lawrence L Latour; Julio A Chalela; James Dambrosia; Steven Warach,"Previous observations suggested that multiple ischemic lesions on diffusion-weighted imaging (DWI) are common in acute stroke patients. We hypothesized that a source of these multiple lesions was the recurrence of ischemic lesions within a week after a clinically symptomatic stroke. We analyzed 99 acute ischemic stroke patients scanned within 6 hours of onset and at subsequent times within the first week. Ischemic lesion recurrence was defined as any new lesion separate from the index lesion. Recurrent lesions occurring outside initial perfusion deficit were termed 'distant lesion recurrence'. We estimated the hazard ratio (HR) of recurrence associated with clinical and imaging characteristics using log-rank test. Any lesion recurrence was found in 34%, with distant lesion recurrence in 15%, while clinical recurrence was evident in 2%. Initial multiple DWI lesions were associated with any lesion recurrence (HR, 2.83; 95% confidence interval [CI], 1.65-10.29; p = 0.002) and with distant lesion recurrence (HR, 5.99; 95% CI, 4.05-64.07; p < 0.0001). Large-artery atherosclerosis was the most frequent stroke subtype associated with any lesion recurrence (p = 0.026). These results may indicate a prolonged state of increased ischemic risk over the first week and suggest DWI as a possible surrogate measure for recurrent stroke.",2003.0,0,0 2222,12838983,"Clinical trials in neuroprotection. 23-25 January 2003, Key Biscayne, FL, USA.",Asla Pitkänen,"The basis for this meeting ras the fact that many neurological and psychiatric disorders are accompanied by neuronal loss, either acutely or chronically. Furthermore, many of the underlying mechanisms of neural tissue damage are similar across a wide variety of neurodegenerative conditions, including stroke, central nervous system damage secondary to cardiac surgery,epilepsy, traumatic brain and spinal cord injury, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and even some psychiatric diseases. Despite a large number of animal studies with promising neuroprotective agents, no successful strategy for neuroprotection from any of these conditions has been successfully demonstrated. The aim of the meeting was to review the current status of neuroprotection and provide new ideas on how to get further in research, preclinical and clinical study designs, and perhaps to generate 'out of the box' ideas for future progress by bringing together experts from different fields of neuroprotection.",2003.0,0,0 2223,12838988,"American Stroke Association--28th International Conference. 13-15 February 2003, Phoenix, AZ, USA.",David S Liebeskind,,2003.0,0,0 2224,12838990,"HDL Cholesterol 2003--Fourth Annual International Conference. Metabolic pathways and drug targets. 2-4 March 2003, Cambridge, MA, USA.",Charles Q Meng,,2003.0,0,0 2225,12839042,Cholesterol absorption inhibitors: defining new options in lipid management.,W Virgil Brown,"Although many studies have documented that reduction of plasma cholesterol levels decreases the risk of coronary artery disease, it remains the most common cause of death in the Western world. Current therapeutic options are effective in lowering cholesterol, especially in clinical trials, but clinical application is not optimized for many reasons. Dietary restriction for long-term management of hypercholesterolemia is helpful but usually insufficient to reduce low-density lipoprotein cholesterol (LDL-C) to goal levels. Powerful drugs are available, but these are often insufficient to meet the clinical demands for cholesterol-lowering therapy. Phytosterols and phytostanols have been partially effective by providing some inhibition of absorption of cholesterol. Compounds that specifically and more effectively block intestinal absorption of dietary and biliary cholesterol should provide a significant new agent for altering lipoprotein concentrations favorably. Ezetimibe is the first of this class of compounds that act at the gut epithelium to reduce cholesterol absorption in the milligram dose range markedly. Clinical studies indicate that ezetimibe effectively decreases LDL-C by 15 to 20% as monotherapy, with a favorable safety profile. Moreover, results from preliminary clinical trials indicate that ezetimibe given concomitantly with a statin provides additive efficacy. The combination represents a new approach to lipid management, achieving greater LDL-C and triglyceride reductions and greater improvements in HDL-C than statin monotherapy. This could offer another important option in clinical practice for management of hypercholesterolemic patients.",2003.0,0,0 2226,12841204,"PPARs--second international symposium. From basic science to clinical applications. 19-22 March 2003, Florence, Italy.",Monica Gomaraschi,,2003.0,0,0 2227,12841820,Potential nontraditional applications of statins.,James M McKenney,"To review the current evidence for use of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) in nontraditional lipid-related applications, including acute coronary syndromes, peripheral arterial disease, stroke, and renal disease, and to describe ongoing trials evaluating the role of statins in these conditions. Clinical literature was identified by a MEDLINE search (1990-November 2002) using >/=1 of the following search terms: acute coronary syndrome(s), angina pectoris, atherosclerosis, atorvastatin, clinical trials, diabetes mellitus, end-stage renal disease, fluvastatin, lovastatin, myocardial infarction, peripheral arterial disease, pravastatin, simvastatin, statins, and stroke. Treatment guidelines issued by professional and governmental organizations, such as the American Diabetes Association, American Heart Association, National Cholesterol Education Program, National Kidney Foundation, and National Stroke Foundation, were reviewed. Articles identified from the data sources were included if they pertained to the conditions described in the objectives and provided unique information concerning use of statins. Substantial evidence exists for the use of statins in acute coronary syndromes. Meta-analyses of data from major clinical trials indicate that statins prevent first and recurrent stroke, and large-scale trials are underway to evaluate the efficacy of statins in this setting. Accumulating evidence suggests that statins may be beneficial in reducing the morbidity and mortality associated with peripheral arterial disease and end-stage renal disease, and results from ongoing trials may confirm these benefits. Statins may also have a future role in amelioration of other conditions associated with atherosclerosis, such as diabetes mellitus. A large body of evidence supports the evaluation of statins in clinical settings beyond primary and secondary prevention of morbidity and mortality associated with coronary atherosclerosis.",2003.0,0,0 2228,12842237,Effect of atorvastatin on postcardiac transplant increase in low-density lipoprotein cholesterol reduces development of intimal hyperplasia and progression of endothelial dysfunction.,Vincent Y See; David DeNofrio; Lee Goldberg; Gene Chang; Brett Sasseen; Daniel M Kolansky; Faith Pickering; Andrew Kao; Evan Loh; Robert L Wilensky,"Following cardiac transplantation, accelerated coronary disease limits long-term survival. Because statins may reduce the progression of the disease in part by their anti-inflammatory effects, this study was designed to assess if atorvastatin prevented neointimal hyperplasia and endothelial dysfunction independently of baseline cholesterol levels. Patients were randomized to usual therapy (n = 13) or to 10 to 20 mg of atorvastatin (n = 12). Control subjects received niacin when their low-density lipoprotein (LDL) cholesterol levels were >130 mg/dl (n = 4). Neointimal hyperplasia by intracoronary ultrasonography, endothelial dependent vascular reactivity, and coronary flow reserve were measured at baseline and 1 year. Control group total cholesterol (203 +/- 11 to 200 +/- 13 mg/dl) and LDL (116 +/- 10 to 119 +/- 11 mg/dl) remained stable, whereas there was a nonsignificant reduction at 12 months in the atorvastatin group (total cholesterol 216 +/- 28 to 178 +/- 21 mg/dl; LDL 126 +/- 17 to 100 +/- 18 mg/dl). At 2 to 3 months there was a significant increase in total cholesterol and LDL cholesterol that was reduced with atorvastatin. At 1 year, patients taking atorvastatin showed a decrease in new or progressing lesions (2.5 +/- 1.7 vs 4.2 +/- 1.8 lesions/patient, p = 0.02), progression of maximal intimal thickness (0.12 +/- 0.07 vs 0.52 +/- 0.17 mm, p = 0.04), and percent area stenosis (5.9 +/- 2.2% vs 19.0 +/- 5.5%, p = 0.04). Atorvastatin ameliorated progressive endothelial dysfunction, whereas coronary flow reserve was unchanged in both groups. Atorvastatin administered to patients with normal or mild hypercholesterolemia in the initial year after transplant reduced the initial increase in LDL cholesterol, and, by doing so, prevented the development and progression of coronary artery lesions and endothelial dysfunction with only mild long-term decreases in cholesterol levels.",2003.0,0,0 2229,12842255,Effectiveness of statin titration on low-density lipoprotein cholesterol goal attainment in patients at high risk of atherogenic events.,Kathleen A Foley; Ross J Simpson; John R Crouse; Thomas W Weiss; Leona E Markson; Charles M Alexander,,2003.0,0,0 2230,12843167,"Efficacy of atorvastatin and gemfibrozil, alone and in low dose combination, in the treatment of diabetic dyslipidemia.",Ana M Wägner; Oscar Jorba; Rosa Bonet; Jordi Ordóñez-Llanos; Antonio Pérez,"To compare the effects of atorvastatin, gemfibrozil, and their combination on the components of diabetic dyslipidemia, 44 type 2 diabetic patients with low density lipoprotein cholesterol (LDLc) levels greater than 100 mg/dl and triglyceride levels less than 400 mg/dl were included. Twelve-week treatments with atorvastatin (10-20 mg/d) and gemfibrozil (900-1200 mg/d) were given in random order in an open, cross-over study and then combined (10 mg atorvastatin and 900 mg gemfibrozil) for 12 additional wk. Triglyceride, LDLc, high density lipoprotein cholesterol (HDLc), non-HDLc, apolipoprotein B (apoB), and LDL size were measured at baseline and after each treatment. Atorvastatin was more effective (P < 0.001) in lowering LDLc, non-HDLc, and apoB and in achieving treatment goals, whereas gemfibrozil lowered triglyceride levels more effectively (P < 0.001) and increased LDL size (from 25.59 +/- 0.06 to 25.69 +/- 0.06 nm; P < 0.05). Combined treatment with both drugs reduced LDLc, triglyceride, non-HDLc, and apoB by 26.5%, 24.1%, 30.4%, and 21.8%, respectively; increased HDLc by 4.8% and LDL size by 0.1 nm; and was the most effective treatment in reaching the therapeutic targets, especially in patients with triglyceride levels higher than 150 mg/dl. In conclusion, statins are first choice drugs in diabetic patients with low to moderate risk LDLc, although their combination with fibrates might be the most appropriate treatment, especially when triglyceride levels are above the therapeutic goal.",2003.0,0,0 2231,12844470,Ongoing trials: what should we expect after ALLHAT?,Ji-Guang Wang; Jan A Staessen; Anthony M Heagerty,"The publication of the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, when used in conjunction with a new meta-analysis, provides hypertension research with a watershed. Data demonstrate clearly that lowering blood pressure is the most important aspect of hypertension management, and that all agents are similarly effective. There is little sustainable evidence for pressure-independent advantages for any class of drug at this time. Therefore, by combining these findings with additional information on target levels of blood pressure and safety, plus the use of aspirin and statins, we can formulate health care policies that attack hypertension in a holistic risk-based way. The future will focus on gaining extra benefit for patients by testing the efficacy and superiority of drug combinations using novel agents that favorably influence intermediate markers such as arterial stiffness, and arresting the ever-increasing burden of cognitive impairment and dementia.",2003.0,0,0 2232,12845248,Effect of atorvastatin on total lipid profiles assessed by analytical capillary isotachophoresis.,Bo Zhang; Keita Noda; Keijiro Saku,,2003.0,0,0 2233,12845391,Evolution of cholesterol management therapies: exploiting potential for further improvement.,Michael Clearfield,"The development of therapies for the control of atherosclerosis is an important example of the drug discovery process. Findings from population studies initiated 4 decades ago have been gradually translated to today's therapies, the most effective of which are the statins. Driven by an increased understanding of the atherosclerotic process and shortfalls of current treatments, the development of therapies for cholesterol control continues, with new agents in the pipeline promising therapeutic benefits over existing treatments. The advent of new statins such as rosuvastatin and pitavastatin, with improved efficacy for reducing cholesterol and the ability to positively affect other disease risk factors, may exploit the potential for improvement of current treatments.",2003.0,0,0 2234,12846506,Serum lipid comparison in patients treated by statins or fibrates: existence of bad HDL-C responders to statins.,Dirk Devroey; Brigitte Velkeniers; William Duquet; Willem Betz,"Major cardiac events are strongly associated with high levels of low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C). The HDL-C target level (40 mg/dl) is often not achieved with statins. The aim of this study was to compare the proportions of patients achieving the HDL-C target levels after one year of treatment with statins or fibrates. Furthermore, a subgroup with low HDL-C levels during statin treatment was investigated and suggestions are made for a better management of these patients. A survey of lipid levels, cardiovascular disease and risk factors in 120 outpatients treated with a statin or a fibrate for hyperlipidaemia (total cholesterol (TC) > 250 mg/dl or triglycerides (TG) > 200 mg/dl after diet). After one year of treatment the proportions of patients achieving the target levels for TC, LDL-C, HDL-C,TG,TC/HDL-C and LDL-C/HDL-C are compared for statins and fibrates. The proportions of patients achieving the target lipid levels with statins or fibrates are comparable except for HDL-C. Compared to the baseline, the proportion of patients achieving the HDL-C target level of 40 mg/dl increases only by 8.3% for statins and by 42.9% for fibrates. In total, 38.5% of the statin group had low HDL-C-levels after one year of treatment. Among these patients, eight were treated with a fibrate before the statin and six were treated with a fibrate afterwards. In those 14 patients, mean HDL-C increased during fibrate treatment by 48.5% and TC/HDL-C and LDL-C/HDL-C decreased by 25.7 and 26.5%, respectively as compared with statins. Patients with low levels of HDL-C during statin treatment had far better levels of HDL-C, TC/HDL-C and LDL-C/HDL-C with fibrates. A randomised double-blind crossover trial with simvastatin and fenofibrate has been initiated to corroborate these findings.",2003.0,0,0 2235,12847415,"Acute renal allograft rejections, a role for statins?",H Holdaas; A Jardine,"Acute rejection of kidney allografts during the first months following transplantation is one of the most important risk factor for long-term graft failure. Some small open studies have indicated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co-A), statins, might act as immunosuppressive agents, and reduce acute rejection rates. Moreover, the use of statin in transplant recipients is quite common, despite no data from prospective large multi-centre studies are available to demonstrate any beneficial effect for acute rejections or long-term cardiovascular protection in this population. In this overview, recent clinical and experimental data will be provided for assessing statins as immunosuppressive agents. Although in vitro studies have provided a theoretical basis for the use of statins as immunosuppressive agents, more recent clinical placebo controlled studies have failed to confirm the initial optimism of this effect of statins.",2003.0,0,0 2236,12848779,Discontinuation and switching of therapy after initiation of lipid-lowering drugs: the effects of comorbidities and patient characteristics.,Chen-Chang Yang; Susan S Jick; Marcia A Testa,"To evaluate the effects of comorbidities and patient characteristics on treatment continuation among patients starting their first course of lipid-lowering drug (LLD) therapy. Within the UK General Practice Research Database (GPRD), we identified 22 408 patients who started LLD therapy due to coronary heart disease, hyperlipidaemia, or other atherosclerotic diseases, and who received > or = two prescriptions for LLD between January 1 1990 and December 31 1997. Differences in potential predictors of treatment continuation between patients who continued, and patients who discontinued/switched lipid-lowering therapy within 1 year after treatment initiation were compared by fitting multivariate logistic regression models. The effects of baseline characteristics on treatment continuation after switching of LLDs were also analysed. Discontinuation/switching of lipid-lowering therapy was common during the study period, especially among patients who received nonstatin, nonfibrate LLDs (log-rank test P = 0.0001). Statin use, more frequent physician visits, more concurrent cardiovascular medications, diabetes, and fewer noncardiovascular medications were associated with treatment continuation of LLDs. Among patients who switched therapy, prescribing of a statin as the substituted LLD, more concurrent cardiovascular medications, and later treatment switching were related to a higher probability of treatment continuation after switching LLDs. Treatment continuation after initiation or switching of lipid-lowering therapy largely increased with concomitant cardiovascular comorbidities, and more health care utilization, and is more common for statins than for other LLDs. Practice guidelines, patient education, and quality of care assessment for lipid-lowering therapy should emphasize factors that predispose patients to discontinuation/switching, in an effort to optimize the choice of therapeutic regimens and to improve patient adherence.",2003.0,0,0 2237,12849290,Potential of statins for the treatment of multiple sclerosis.,David Baker; Peter Adamson; John Greenwood,,2003.0,0,0 2238,12851516,Effect of statins combined with estradiol on the proliferation of human receptor-positive and receptor-negative breast cancer cells.,Alfred O Mueck; Harald Seeger; Diethelm Wallwiener,"Combination of a statin plus estrogen may reveal benefits on the cardiovascular system in postmenopausal women by additively ameliorating both the lipid profile and vascular function. Long-term therapy with estrogens, however, is associated with an increase of breast cancer risk. In contrast, evidence is accumulating that statins may inhibit carcinogenesis because of their central action on important cellular functions. It is of special clinical interest whether a statin/estrogen combination may reduce the most undesired side effect of estrogen therapy, that is, an increase in breast cancer risk. Therefore, in the present in vitro study, for the first time we have compared the effect of five statins on the proliferation of human breast cancer cells alone and in the presence of stimulatory estradiol (E(2)). As cell models, the receptor-positive cell line MCF-7 and the receptor-negative cell line MDA-MB 231 were used. The statins atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin were tested in the concentration range of 1.6 microm to 50 microm alone and in the range of 0.01 nm to 10 microm in combination with E(2). Cell proliferation was measured after 4 days by the adenosinetriphosphate-chemosensitivity test. All statins except pravastatin were able to significantly inhibit dose dependently the cell proliferation of both cell lines. The inhibitory values were between 10% and 90%, whereby the potency was greater in the case of receptor-negative cancer cells. A significant difference in the efficacy of the statins was observed for MCF-7 cells, in which atorvastatin was less effective than the other statins. In contrast, in the presence of E(2), the statins showed similar antiproliferative actions in MCF-7 cells when tested in the concentration range of 0.01 nm to 10 microm. A reduction of cell proliferation of less than 10% was observed at the lower concentrations and between 15% and 25% at the highest concentration of 10 microm. The present data indicate that statins can inhibit the proliferation of receptor-positive and -negative human breast cancer cells but failed to completely abrogate the E(2)-induced proliferation of receptor-positive breast cancer cells. Clinical trials, however, are necessary to prove this anticarcinogenic action of statins.",2003.0,0,0 2239,12852707,Comparison of treatment with fluvastatin extended-release 80-mg tablets and immediate-release 40-mg capsules in patients with primary hypercholesterolemia.,Jonathan L Isaacsohn; James LaSalle; George Chao; Leonard Gonasun,"According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines, hypercholesterolemic patients with greater risk for cardiovascular heart disease require more aggressive lowering of low-density lipoprotein cholesterol (LDL-C) levels. Numerous studies have demonstrated that despite these guidelines, patients often do not reach their target levels, and that physicians frequently do not titrate the drug beyond the starting dose. For these patients, it may be more suitable to initiate treatment with a higher starting dose of statin. With the immediate-release (IR) formulation of fluvastatin, the maximal dose of 80 mg is recommended to be administered in divided doses (40 mg BID). An extended-release (ER) formulation of fluvastatin at a higher dose (fluvastatin ER 80 mg) was designed to provide greater LDL-C lowering with QD dosing. Use of this formulation should bring more patients into compliance with target LDL-C levels. This analysis compared the efficacy and tolerability of fluvastatin ER 80 mg QD and fluvastatin IR 40 mg QD in lowering total cholesterol, LDL-C, triglyceride, and apolipoprotein (apo) B levels and raising high-density lipoprotein cholesterol (HDL-C) and apo A-I levels in patients with hypercholesterolemia over a 12-week treatment period. This was a prospective, multicenter, double-blind, double-dummy, randomized, parallel-group, active-controlled study Patients with primary hypercholesterolemia who qualified for lipid-lowering drug therapy based on NCEP ATP II guidelines were randomized to fluvastatin ER 80 mg QD or fluvastatin IR 40 mg QD, and treated for 12 weeks. A total of 173 patients were randomized to treatment: 86 to the fluvastatin ER 80-mg group and 87 to the fluvastatin IR 40-mg group. Compared with fluvastatin IR 40 mg, fluvastatin ER 80 mg produced greater mean reductions in LDL-C (32% vs 22%, respectively; P < 0.001). For each of the 3 coronary heart disease (CHD) risk groups (defined by the NCEP), as well as for the total population studied, more patients from the fluvastatin ER 80-mg group than the IR 40 group achieved NCEP ATP II target LDL-C levels (79% vs 47%, respectively [P = NS], for patients with < 2 risk factors; 58% vs 15%, respectively [P < 0.001], for patients with > or = 2 risk factors; and 40% vs 14%, respectively [P = 0.012], for patients with CHD). The 80-mg ER dose of fluvastatin provided 9.1% greater LDL-C lowering than the 40-mg IR dose. The incidence of elevations in transaminase levels was low and similar for both doses, with 1 patient in each of the treatment groups being discontinued due to repeated elevation of transaminases > 3 x the upper limit of normal (ULN). Clinically relevant elevations in creatine kinase (ie, > or = 10x ULN) were not observed with either dose. Nine patients (5 in the fluvastatin ER group and 4 in the fluvastatin IR group) discontinued because of adverse events. Treatment with fluvastatin ER 80 mg resulted in greater reductions in LDL-C, total cholesterol, and apo B levels compared with fluvastatin IR 40 mg, with clinically equivalent reduction in triglyceride levels and elevation of HDL-C levels. Furthermore, there were few tolerability concerns of clinical relevance with either formulation and no clinically meaningful difference in the tolerability parameters between the 2 formulations. For patients with higher baseline LDL-C levels, and for patients who require greater LDL-C lowering, it may be appropriate to initiate therapy with fluvastatin ER 80 mg. Use of the higher starting dose likely would bring a greater proportion of high-risk patients into compliance with NCEP ATP II target LDL-C levels and would provide LDL-C lowering that is in the same range that has been proved in clinical trials to be associated with reductions in CHD event rates.",2003.0,0,0 2240,12858078,Statins as potential therapeutic agents in neuroinflammatory disorders.,Olaf Stüve; Sawsan Youssef; Lawrence Steinman; Scott S Zamvil,"Multiple sclerosis is a central nervous system inflammatory demyelinating disease that is thought to have an autoimmune pathogenesis. Recent results indicate that 'statins', 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are the most commonly used oral cholesterol-lowering drugs, have immunomodulatory properties. In this article we will review those findings that indicate that statins may be beneficial in the treatment of multiple sclerosis, neurodegenerative disease, and ischemic stroke. It was reported that statin treatment could either inhibit or reverse chronic and relapsing experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Several immunomodulatory properties of statins may account for their beneficial clinical effect: Statins decreased the migration of leukocytes into the central nervous system, inhibited MHC class II and costimulatory signals required for activation of proinflammatory T cells, induced a T(H)2 phenotype in T cells, and decreased the expression of inflammatory mediators in the central nervous system, including nitric oxide and tumor necrosis factor alpha. It was also demonstrated that statin use significantly reduced beta-amyloid secretion in the cerebrospinal fluid of experimental animals. Clinically, there is emerging evidence that statins have beneficial effects in patients with multiple sclerosis, Alzheimer's disease, and ischemic stroke. In-vitro studies have indicated that statins may have anti-inflammatory properties. Results from in-vivo animal models suggest that statins may be beneficial in treatment of different central nervous system conditions. Larger scale, randomized, double-blind trials are needed to validate the role of statins as a treatment of inflammatory central nervous system diseases.",2003.0,0,0 2241,12858127,Emerging importance of HDL cholesterol in developing high-risk coronary plaques in acute coronary syndromes.,Juan F Viles-Gonzalez; Valentin Fuster; Roberto Corti; Juan J Badimon,"Cardiovascular disease is the principal cause of death in industrialized countries. Hyperlipidemia, with high low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol levels (<40 mg/dL in men and <45 mg/dL in women), is a known major cardiovascular risk factor. Statins are considered the most potent and effective agents to reduce low-density lipoprotein cholesterol, but they have a variable effect on high-density lipoprotein cholesterol and triglycerides. Different clinical trials with statins have shown a decrease in low-density lipoprotein cholesterol by 35% and a reduction of the incidence of coronary events by as much as 30%. However, 60 to 70% of events still occur, despite remarkable reduction of low-density lipoprotein cholesterol concentration. Recent National Cholesterol Education Program guidelines highlighted the importance of high-density lipoprotein cholesterol concentration in the prevention and treatment of cardiovascular disease. High-density lipoprotein cholesterol is considered an independent risk factor and has an inverse relation with coronary events. The association of low levels of high-density lipoprotein cholesterol with an increased incidence of cardiovascular events implies a critical role of high-density lipoprotein in the protection against atherosclerotic disease and in the progression of coronary atherosclerotic disease. High-density lipoprotein cholesterol appears to exert this protective effect through multiple mechanisms. High-density lipoprotein is not only involved in reverse cholesterol transport, but also prevents endothelial dysfunction; inhibits the homing of monocytes, apoptosis, platelet activation, and factor X activation; and has antioxidant properties. In this article the authors review the available experimental and clinical evidence supporting the importance of high-density lipoprotein cholesterol as a protective factor in coronary artery disease, and the strategies developed to increase high-density lipoprotein cholesterol.",2003.0,0,0 2242,12859032,Improving the prediction of cardiovascular risk: interaction between LDL and HDL cholesterol.,Steven A Grover; Marc Dorais; Louis Coupal,"The ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol (or the ratio of low-density lipoprotein [LDL] to HDL) is currently advocated to estimate the coronary risk associated with LDL and HDL cholesterol levels. We analyzed the relation between LDL and HDL cholesterol levels to predict the risk of future coronary events. Using data from the Lipid Research Clinics Follow-up Cohort, we developed multivariate equations to predict coronary deaths among 4684 men and women followed for approximately 12 years. We used these equations to compare the predictive power of the LDL/HDL ratio with the independent effects of LDL and HDL and an LDL-HDL interaction term. We then used each model to forecast the 10-year risk of coronary death based on various lipid levels after adjustment for conventional risk factors (eg, blood pressure, gender, cigarette smoking). Levels of LDL and HDL and the interaction between them are all independent risk factors for coronary death. The benefits of increasing HDL are strongest among persons with high LDL. Conversely, the benefits of decreasing LDL are greatest among those with low HDL. We confirmed these observations in a published dataset showing the effects of treatment of hyperlipidemia. Predictions of benefits of treatment that were based on interaction of LDL and HDL were more accurate than predictions without interaction. The LDL/HDL ratio alone may not fully capture the complex interaction between LDL and HDL and the relation of each to coronary risk.",2003.0,0,0 2243,12859159,"Statin use, clinical fracture, and bone density in postmenopausal women: results from the Women's Health Initiative Observational Study.",Andrea Z LaCroix; Jane A Cauley; Mary Pettinger; Judith Hsia; Douglas C Bauer; Joan McGowan; Zhao Chen; Cora E Lewis; S Gene McNeeley; Maureen D Passaro; Rebecca D Jackson,"3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to stimulate bone formation in laboratory studies, both in vitro and in vivo. While early epidemiologic studies showed lower risk for hip fracture among statin users than nonusers, subsequent studies have produced mixed results. To examine the association of statin use with incidence of hip, lower arm or wrist, and other clinical fractures and with baseline levels of bone density. Prospective study. Women's Health Initiative Observational Study conducted in 40 clinical centers in the United States. 93 716 postmenopausal women ages 50 to 79 years. Rates of hip, lower arm or wrist, and other clinical fractures were compared among 7846 statin users and 85 870 nonusers over a median follow-up of 3.9 years. In 6442 women enrolled at three clinical centers, baseline levels of total hip, posterior-anterior spine, and total-body bone density measured by using dual-energy x-ray absorptiometry were compared according to statin use. Age-adjusted rates of hip, lower arm or wrist, and other clinical fractures were similar between statin users and nonusers regardless of duration of statin use. The multivariate-adjusted hazard ratios for current statin use were 1.22 (95% CI, 0.83 to 1.81) for hip fracture, 1.04 (CI, 0.85 to 1.27) for lower arm or wrist fracture, and 1.11 (CI, 1.00 to 1.22) for other clinical fracture. Bone density levels did not statistically differ between statin users and nonusers at any skeletal site after adjustment for age, ethnicity, body mass index, and other factors. Statin use did not improve fracture risk or bone density in the Women's Health Initiative Observational Study. The cumulative evidence does not warrant use of statins to prevent or treat osteoporosis.",2003.0,0,0 2244,12860210,Effect of pravastatin on intermediate-density and low-density lipoproteins containing apolipoprotein CIII in patients with diabetes mellitus.,Sung-Joon Lee; Frank M Sacks,"The apolipoprotein (apo) B lipoproteins, intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL) that contain apo-CIII are associated with coronary heart disease in patients with diabetes mellitus. Apo-CIII is prominent in diabetic dyslipidemia. We studied whether these apo-B lipoprotein types containing apo-CIII in diabetics are reduced by 1 year of pravastatin treatment. We randomly selected 45 age- and gender-matched placebo/pravastatin pairs from diabetic patients in the Cholesterol and Recurrent Events trial, a randomized, double-blinded trial of pravastatin 40 mg monotherapy. Very-low-density lipoproteins (VLDL) and IDL + LDL particles were subdivided based on the presence of apo-E and apo-CIII to yield 3 particle types: E+CIII+, E-CIII+, and E-CIII-. Compared with placebo, pravastatin reduced IDL + LDL apo-B concentrations for E+CIII+, E-CIII+, and E-CIII- by 42% (p = 0.02), 17% (p = 0.7), and 29% (p = 0.002), respectively, commensurate with IDL + LDL cholesterol concentration reductions in the particle types of 29% (p = 0.002), 25% (p = 0.2), and 36% (p <0.0001), respectively. These IDL + LDL CIII+ particles are rich in triglycerides and cholesterol and are likely to be remnant particles of VLDL. Thus, pravastatin reduced potentially atherogenic remnant particles, a prominent component of diabetic dyslipidemia associated with coronary events; these results may contribute to its demonstrated effectiveness in reducing coronary heart disease in diabetics.",2003.0,0,0 2245,12860216,"Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial).",Peter H Jones; Michael H Davidson; Evan A Stein; Harold E Bays; James M McKenney; Elinor Miller; Valerie A Cain; James W Blasetto; STELLAR Study Group,"The primary objective of this 6-week, parallel-group, open-label, randomized, multicenter trial was to compare rosuvastatin with atorvastatin, pravastatin, and simvastatin across dose ranges for reduction of low-density lipoprotein (LDL) cholesterol. Secondary objectives included comparing rosuvastatin with comparators for other lipid modifications and achievement of National Cholesterol Education Program Adult Treatment Panel III and Joint European Task Force LDL cholesterol goals. After a dietary lead-in period, 2,431 adults with hypercholesterolemia (LDL cholesterol > or =160 and <250 mg/dl; triglycerides <400 mg/dl) were randomized to treatment with rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg. At 6 weeks, across-dose analyses showed that rosuvastatin 10 to 80 mg reduced LDL cholesterol by a mean of 8.2% more than atorvastatin 10 to 80 mg, 26% more than pravastatin 10 to 40 mg, and 12% to 18% more than simvastatin 10 to 80 mg (all p <0.001). Mean percent changes in high-density lipoprotein cholesterol in the rosuvastatin groups were +7.7% to +9.6% compared with +2.1% to +6.8% in all other groups. Across dose ranges, rosuvastatin reduced total cholesterol significantly more (p <0.001) than all comparators and triglycerides significantly more (p <0.001) than simvastatin and pravastatin. Adult Treatment Panel III LDL cholesterol goals were achieved by 82% to 89% of patients treated with rosuvastatin 10 to 40 mg compared with 69% to 85% of patients treated with atorvastatin 10 to 80 mg; the European LDL cholesterol goal of <3.0 mmol/L was achieved by 79% to 92% in rosuvastatin groups compared with 52% to 81% in atorvastatin groups. Drug tolerability was similar across treatments.",2003.0,1,1 2246,12860491,Comparative effects of simvastatin and atorvastatin in hypercholesterolemic patients with characteristics of metabolic syndrome.,Donald B Hunninghake; Christie M Ballantyne; Darbie L Maccubbin; Arvind K Shah; Barry Gumbiner; Yale B Mitchel,"Hypercholesterolemic patients with metabolic syndrome (MS) are at high risk for coronary heart disease. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines provide the option of aggressively lowering low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients with MS. The lipid-modifying efficacy of simvastatin and atorvastatin in hypercholesterolemic patients with MS as defined by NCEP ATP III was assessed. A post hoc subgroup analysis was performed on data from a 36-week, multicenter (54 sites worldwide), randomized, double-blind, parallel-group, dose-escalation (forced-titration) study designed to assess the effects of simvastatin (40-80 mg) and atorvastatin (20-80 mg) on high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (apo) A-I levels in patients with LDL-C > or = 160 mg/dL. Patients were classified as having MS if they met >/=3 of the following criteria: (1) triglyceride (TG) level > or =150 mg/dL; (2) HDL-C <40 mg/dL (men) or <50 mg/dL (women); (3) secondary diagnosis of type 2 diabetes mellitus and/or taking antidiabetic medication and/or fasting serum glucose (FSG) level > or =110 mg/dL; (4) secondary diagnosis of hypertension and/or taking antihypertensive medication and/or systolic blood pressure (SBP)/diastolic blood pressure (DBP) > or =130/ > or =85 mm Hg; and (5) body mass index (BMI) > or =30 kg/m(2) (surrogate for waist circumference). Of 808 evaluable patients, 212 (26.2%) were classified as having MS at baseline. Compared with the non-MS subgroup, MS patients were slightly older and more likely to be female. They also had higher BMI, SBP/DBP, FSG, and TG levels, and lower HDL-C and apo A-I levels than non-MS patients. The simvastatin group contained 99 patients; the atorvastatin group, 113 patients. Both drugs produced large reductions in total cholesterol, LDL-C, non-HDL-C, TG, and apo B, with atorvastatin producing slightly greater reductions in TG. However, simvastatin consistently produced larger increases in HDL-C and apo A-I than atorvastatin, especially at higher doses. After 36 weeks of treatment, 47.7% and 48.5% in the simvastatin and atorvastatin groups, respectively, no longer met > or =3 of the MS criteria. In hypercholesterolemic patients with characteristics of MS, simvastatin and atorvastatin had comparable beneficial effects on apo B-containing atherogenic lipids and lipoproteins, and MS status was effectively modified by both drugs. However, although atorvastatin produced slightly larger decreases in TG, simvastatin produced larger increases in HDL-C.",2003.0,0,0 2247,12860867,Long term statin treatment reduces lipoprotein(a) concentrations in heterozygous familial hypercholesterolaemia.,S van Wissen; T J Smilde; M D Trip; Th de Boo; J J P Kastelein; A F H Stalenhoef,"Raised plasma lipoprotein(a) (Lp(a)) is associated with increased risk of cardiovascular disease. It is unknown whether increased Lp(a) is an additional risk factor for coronary artery disease in familial hypercholesterolaemia (FH) or whether statin treatment can reduce Lp(a) concentrations in the long term. To investigate Lp(a) concentrations in relation to statin treatment and the progression of atherosclerosis in a large cohort of FH patients. A two year, randomised, double blind trial (the ASAP trial). 325 heterozygous FH patients. Treatment with 80 mg atorvastatin or 40 mg simvastatin. Change in Lp(a) concentrations and intima-media thickness of carotid artery segments at one year and two years. At baseline, median Lp(a) concentrations were 327 mg/l and 531 mg/l in the atorvastatin and simvastatin arms, respectively (p = 0.03). In the atorvastatin arm, Lp(a) concentrations decreased to 243 mg/l after one year (p < 0.001) and to 263 mg/l after two years (p < 0.001). In the simvastatin arm, Lp(a) concentrations decreased to 437 mg/l after one year (p < 0.001) and to 417 mg/l after two years (p < 0.001). The difference in Lp(a) reduction between the two treatment arms was significant after one year (p = 0.004), but not after two years (p = 0.086). Lp(a) concentrations at baseline were not related to cardiovascular events at baseline. There was no correlation between baseline Lp(a) concentrations and low density lipoprotein cholesterol concentrations or intima-media thickness at baseline. Change in Lp(a) concentrations was not correlated with change in intima-media thickness after one or two years. Long term statin treatment significantly lowers Lp(a) in FH patients. However, this reduction was unrelated to changes in intima-media thickness and casts doubt on the importance of Lp(a) in the progression of atherosclerotic disease in these patients.",2003.0,0,0 2248,12860911,Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study.,Naveed Sattar; Allan Gaw; Olga Scherbakova; Ian Ford; Denis St J O'Reilly; Steven M Haffner; Chris Isles; Peter W Macfarlane; Chris J Packard; Stuart M Cobbe; James Shepherd,"The National Cholesterol Education Program (NCEP) recently proposed a simple definition for metabolic syndrome. Information on the prospective association of this definition for coronary heart disease (CHD) and type 2 diabetes is currently limited. We used a modified NCEP definition with body mass index in place of waist circumference. Baseline assessments in the West of Scotland Coronary Prevention Study were available for 6447 men to predict CHD risk and for 5974 men to predict incident diabetes over 4.9 years of follow-up. Mean LDL cholesterol was similar but C-reactive protein was higher (P<0.0001) in the 26% of men with the syndrome compared with those without. Metabolic syndrome increased the risk for a CHD event [univariate hazard ratio (HR)=1.76 (95% CI, 1.44 to 2.15)] and for diabetes [univariate HR=3.50 (95% CI 2.51 to 4.90)]. Metabolic syndrome continued to predict CHD events (HR=1.30, 95% CI, 1.00 to 1.67, P=0.045) in a multivariate model incorporating conventional risk factors. Men with 4 or 5 features of the syndrome had a 3.7-fold increase in risk for CHD and a 24.5-fold increase for diabetes compared with men with none (both P<0.0001). C-reactive protein enhanced prognostic information for both outcomes. With pravastatin, men with the syndrome had similar risk reduction for CHD as compared with those without (HR, 0.73 and 0.69; pravastatin versus placebo). A modified NCEP metabolic syndrome definition predicts CHD events, and, more strikingly, new-onset diabetes, and thus helps identify individuals who may receive particular benefit from lifestyle measures to prevent these diseases.",2003.0,0,0 2249,12860913,Statins promote potent systemic antioxidant effects through specific inflammatory pathways.,Mehdi H Shishehbor; Marie-Luise Brennan; Ronnier J Aviles; Xiaoming Fu; Marc S Penn; Dennis L Sprecher; Stanley L Hazen,"The pleiotropic actions of hydroxymethylglutaryl CoA reductase inhibitors (statins) include antiinflammatory and antioxidant actions. We recently reported that statins induce reductions in plasma protein levels of nitrotyrosine (NO2Tyr), a modification generated by nitric oxide-derived oxidants. Whether alternative oxidative pathways are suppressed in vivo after statin administration has not yet been reported. As an extension of our prior study, hypercholesterolemic subjects with no known coronary artery disease were evaluated at baseline and after 12 weeks of atorvastatin therapy (10 mg/d). Plasma levels of protein-bound chlorotyrosine, NO2Tyr, dityrosine, and orthotyrosine, specific molecular fingerprints for distinct oxidative pathways upregulated in atheroma, were determined by mass spectrometry. In parallel, alterations in lipoproteins and C-reactive protein were determined. Statin therapy caused significant reductions in chlorotyrosine, NO2Tyr, and dityrosine (30%, 25%, and 32%, respectively; P<0.02 each) that were similar in magnitude to reductions in total cholesterol and apolipoprotein B-100 (25% and 29%, P<0.001 each). Nonsignificant decreases in orthotyrosine and C-reactive protein levels were observed (9% and 11%, respectively; P>0.10 each). Statin-induced reductions in oxidation markers were independent of decreases in lipids and lipoproteins. Statins promote potent systemic antioxidant effects through suppression of distinct oxidation pathways. The major pathways inhibited include formation of myeloperoxidase-derived and nitric oxide-derived oxidants, species implicated in atherogenesis. The present results suggest potential mechanisms that may contribute to the beneficial actions of statins. They also have important implications for monitoring the antiinflammatory and antioxidant actions of these agents.",2003.0,0,0 2250,12862032,Therapeutic potential of lovastatin in multiple sclerosis.,Armando Sena; Rui Pedrosa; M Graça Morais,,2003.0,0,0 2251,12868997,Fluvastatin reduces atherogenic lipids without any effect on native endothelial function early after kidney transplantation.,Anders Asberg; Hallvard Holdaas; Alan G Jardine; Cecilie Edvardsen; Anders Hartmann,"Cardiovascular risk is greatly increased in renal transplant recipients. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy may reduce cardiovascular risk by improving both dyslipidemia and endothelial function. We therefore performed this study to assess the effect of fluvastatin on endothelial function in renal transplant recipients. This randomized, placebo-controlled, double-blind designed study investigated the effect of fluvastatin on endothelial function. Thirty-seven recipients received fluvastatin 40 mg/d and 35 received placebo during the first 12 wk following transplantation. All patients initially received cyclosporin A, prednisolone and azathioprine. At the end of treatment, endothelial function was assessed in the forearm skin microvasculature by laser Doppler flowmetry following acetylcholine stimulation. Samples were taken for measurements of serum lipids and vasoactive markers. There were no differences in endothelial function between fluvastatin recipients and controls, AUCACh was 656 +/- 479 and 627 +/- 518 AU min, respectively (fluv vs. control, p > 0.65). In the placebo limb, total cholesterol and LDL cholesterol increased 22 +/- 12% and 22 +/- 18%, respectively in the first 12 wk following transplantation. The respective values were 18 +/- 13% (p = 0.010) and 34 +/- 19% (p = 0.0013) lower at 12 wk in the fluvastatin treated patients. Plasma ET-1, BigET-1 and urinary excretion of cGMP were not significantly different between treatment groups (p > 0.55). Although fluvastatin 40 mg/d significantly lowers cholesterol it does not affect endothelial function the first 3 months after renal transplantation. The lack of effect on endothelial function is consistent with a lack of effect on vasoactive substances.",2003.0,0,0 2252,12871130,Perspectives on the cardioprotective effects of statins.,Jian-Dong Luo; Alex F Chen,"Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme of cholesterol synthesis. In recent years, statins have become the major choice of treatment for hypercholesterolemia. Emerging evidence from both animal and human studies indicates that mechanisms independent of cholesterol lowering effects contribute to the observed clinical benefits of statins. The anti-hypertrophy effect of statins on the cardiac tissue represents one of such mechanisms. The beneficial effects of statins on cardiac hypertrophy and cardioprotection may be attributed to their functional influences on small G proteins such as Ras and Rho, resulting in an increase of endogenous nitric oxide (NO), reduction of oxidative stress, inhibition of inflammatory reaction, and decrease of the renin-angiotensin system activity as well as C-reactive protein (CRP) levels in cardiac tissues. Recent findings from in vitro and in vivo studies of statins on cardioprotective effects are summarized in this review. The unveiled novel mechanisms support the use of statins as the new mainstay therapeutic agents for various cardiovascular diseases and complications.",2003.0,0,0 2253,12873852,Age but not diagnosis is the main predictor of plasma amyloid beta-protein levels.,Hiroaki Fukumoto; Marsha Tennis; Joseph J Locascio; Bradley T Hyman; John H Growdon; Michael C Irizarry,"Plasma amyloid beta-protein Abeta42 levels are increased in patients with familial Alzheimer disease (AD) mutations, and high levels reportedly identify individuals at risk to develop AD. To determine whether there are characteristic changes in plasma Abeta40 and Abeta42 levels in sporadic AD, and to examine the relationship of plasma Abeta measures with clinical, demographic, and genetic variables in a prospectively characterized outpatient clinic population. A total of 371 outpatients with sporadic AD (n = 146), mild cognitive impairment (n = 37), or Parkinson disease (n = 96) and nondemented control cases (n = 92). We collected plasma samples and determined Abeta40 and Abeta42 levels by sandwich enzyme-linked immunosorbent assay with the use of the capture antibody BNT77 (anti-Abeta11-28) and the detector antibodies horseradish peroxidase-linked BA27 (anti-Abeta40) and BC05 (anti-Abeta42). Mean Abeta40 and Abeta42 levels increased significantly with age in each diagnostic group. When covaried for age, mean plasma levels of Abeta40 and Abeta42 did not differ significantly among the 4 diagnostic groups. Within the mild cognitive impairment and AD groups, Abeta40 and Abeta42 levels did not correlate with duration of memory impairment or with cognitive test scores. The Abeta measures were not influenced by family history of AD, apolipoprotein E genotype, or current medication use of cholinesterase inhibitors, vitamin E, statins, nonsteroidal anti-inflammatory drugs, or estrogen. Plasma Abeta measures increase with age, but, in contrast to reports on familial AD, plasma Abeta measures were neither sensitive nor specific for the clinical diagnosis of mild cognitive impairment or sporadic AD.",2003.0,0,0 2254,12876093,Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein.,David J A Jenkins; Cyril W C Kendall; Augustine Marchie; Dorothea A Faulkner; Julia M W Wong; Russell de Souza; Azadeh Emam; Tina L Parker; Edward Vidgen; Karen G Lapsley; Elke A Trautwein; Robert G Josse; Lawrence A Leiter; Philip W Connelly,"To enhance the effectiveness of diet in lowering cholesterol, recommendations of the Adult Treatment Panel III of the National Cholesterol Education Program emphasize diets low in saturated fat together with plant sterols and viscous fibers, and the American Heart Association supports the use of soy protein and nuts. To determine whether a diet containing all of these recommended food components leads to cholesterol reduction comparable with that of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Randomized controlled trial conducted between October and December 2002. Forty-six healthy, hyperlipidemic adults (25 men and 21 postmenopausal women) with a mean (SE) age of 59 (1) years and body mass index of 27.6 (0.5), recruited from a Canadian hospital-affiliated nutrition research center and the community. Participants were randomly assigned to undergo 1 of 3 interventions on an outpatient basis for 1 month: a diet very low in saturated fat, based on milled whole-wheat cereals and low-fat dairy foods (n = 16; control); the same diet plus lovastatin, 20 mg/d (n = 14); or a diet high in plant sterols (1.0 g/1000 kcal), soy protein (21.4 g/1000 kcal), viscous fibers (9.8 g/1000 kcal), and almonds (14 g/1000 kcal) (n = 16; dietary portfolio). Lipid and C-reactive protein levels, obtained from fasting blood samples; blood pressure; and body weight; measured at weeks 0, 2, and 4 and compared among the 3 treatment groups. The control, statin, and dietary portfolio groups had mean (SE) decreases in low-density lipoprotein cholesterol of 8.0% (2.1%) (P =.002), 30.9% (3.6%) (P<.001), and 28.6% (3.2%) (P<.001), respectively. Respective reductions in C-reactive protein were 10.0% (8.6%) (P =.27), 33.3% (8.3%) (P =.002), and 28.2% (10.8%) (P =.02). The significant reductions in the statin and dietary portfolio groups were all significantly different from changes in the control group. There were no significant differences in efficacy between the statin and dietary portfolio treatments. In this study, diversifying cholesterol-lowering components in the same dietary portfolio increased the effectiveness of diet as a treatment of hypercholesterolemia.",2003.0,0,0 2255,12876098,"Diet first, then medication for hypercholesterolemia.",James W Anderson,,2003.0,0,0 2256,12877794,Lipid-lowering efficacy and safety of varying doses of Simvastatin in patients with early stage acute coronary syndromes: one-year follow-up study.,Yangchun Zou; Dayi Hu; Xianchun Yang; Zhimin Xu; Liang Cui; Xiaohui Liu; Yu Wei; Mingming Gao,"To investigate whether patients, who are at risk of major acute coronary events, are safe to undergo and benefit from early intervention after using simvastatin. The study was a randomized, open, two-dosage-controlled trial to evaluate the safety and benefits of simvastatin administered to 197 patients (10 mg group, n = 98 and 20 mg group, n = 99), within 48 hours of hospitalization for a diagnosis of unstable angina or acute myocardial infarction (MI), with total cholesterol (TC) >/= 180 mg/dL or low-density lipoprotein cholesterol (LDL-C) >/= 100 mg/dL. Lipid levels were measured immediately, followed by the 3rd, 6th and 12th month after admission and all adverse events were recorded during follow-up. TC levels fell by 10.15% and 14.52% in the 10 mg and 20 mg groups (P < 0.05), and LDL-C levels fell 13.87% and 19.38% in the 10 mg and 20 mg groups, respectively (P < 0.01), 12 months after using simvastatin. The rates of achieving target TC reached 26.3% and 36.5% in the 10 mg and 20 mg groups (P < 0.01), and that of LDL-C reached 28.2% and 40.3% in the 10 mg and 20 mg groups, respectively (P < 0.01). There were higher rates of MI and re-hospitalization resulting from angina pectoris and revascularization in the 10 mg group compared with the 20 mg group. The results suggest that early intervention with the HMG-CoA reductase inhibitor, simvastatin, in acute coronary syndromes is possible and safe. It also indicates that the clinical dosage of simvastatin are relatively smaller than that for satisfactory lipid control in patients with acute coronary syndromes.",2003.0,0,0 2257,12879992,Hepatotoxicity of hypolipidemic drugs.,Javier L Parra; K Rajender Reddy,"Dyslipidemic conditions and their cardiovascular related complications are common. Effective primary and secondary prevention strategies include therapies to lower LDL and total cholesterol and to increase HDL. Further, it seems that there is a need for therapeutic reduction in triglycerides as it emerges as an independent risk factor for CVD. Many clinical trials have been designed to evaluate pharmacologic compounds in the treatment of the dyslipidemias and they seem to have shown a safe profile, both in the experiment phases and in post-marketing observation studies. Nevertheless, sporadic reports of hepatotoxicity with statins and niacin still arise (Table 2). Although routine hepatic biochemical test monitoring is recommended, the cost-effectiveness is questionable because often these reactions are idiosyncratic and may not be identified by this routine screening. The risk/benefit ratio is in favor of using these medications in individuals at risk. There is no evidence to suggest intrinsic hepatotoxic activity as such. Drugs that lower triglycerides such as fibrates, have been observed to improve hepatic biochemical tests, although in small series. This leads to speculation whether treatment with fibrates would be beneficial for non-alcoholic fatty liver disease (NAFLD), a condition that is emerging as one of enormous magnitude.",2003.0,0,0 2258,12885101,Statin-associated memory loss: analysis of 60 case reports and review of the literature.,Leslie R Wagstaff; Melinda W Mitton; Beth McLendon Arvik; P Murali Doraiswamy,"To review case reports of statin-associated memory loss as well as the available published evidence for and against such a link. We searched the MedWatch drug surveillance system of the Food and Drug Administration (FDA) from November 1997-February 2002 for reports of statin-associated memory loss. We also reviewed the published literature (using MEDLINE) and prescribing information for these drugs. Of the 60 patients identified who had memory loss associated with statins, 36 received simvastatin, 23 atorvastatin, and 1 pravastatin. About 50% of the patients noted cognitive adverse effects within 2 months of therapy. Fourteen (56%) of 25 patients noted improvement when the statin was discontinued. Memory loss recurred in four patients who were rechallenged with the drug. None of the 60 reported cognitive test results. Two placebo-controlled trials found no benefits for statins on cognition or disability. One randomized controlled trial of simvastatin found no effects on cerebrospinal amyloid levels. In one small, randomized study, patients receiving statins showed a trend toward lower cognitive performance than those receiving placebo. Five observational studies found a lower risk of dementia among patients receiving statins. Current literature is conflicting with regard to the effects of statins on memory loss. Experimental studies support links between cholesterol intake and amyloid synthesis; observational studies indicate that patients receiving statins have a reduced risk of dementia. However, available prospective studies show no cognitive or antiamyloid benefits for any statin. In addition, case reports raise the possibility that statins, in rare cases, may be associated with cognitive impairment, though causality is not certain.",2003.0,0,0 2259,12885571,Lovastatin enhances Abeta production and senile plaque deposition in female Tg2576 mice.,In-Ho Park; Eun Mi Hwang; Hyun Seok Hong; Jung Hyun Boo; Sang Soo Oh; Jeewoo Lee; Min Whan Jung; Oh Young Bang; Seung U Kim; Inhee Mook-Jung,"A recent clinical study showed that statins, which are inhibitors of cholesterol biosynthesis pathway, reduced the prevalence of Alzheimer's disease (AD). Animal studies that have employed high cholesterol diet indicate significant relationship between cholesterol level and senile plaque deposition. Here, we investigated the effects of lovastatin on beta-amyloid production and senile plaque deposition in an animal model of AD (Tg2576 mice). As expected, lovastatin treatment reduced plasma cholesterol level in both male and female mice. However, lovastatin enhanced the amounts of beta-amyloid and other beta-secretase derived peptides in females, but not in males. Likewise, lovastatin increased the number of plaques in the hippocampus and cortex of females, but not in males. Lovastatin did not change the amounts of full-length or alpha-secretase processed amyloid precursor protein (APP), or presenilin 1 (PS1) in either sex. Thus, lovastatin lowers cholesterol level in both genders, but enhances beta-amyloid production and senile plaque deposition only in brains of female Tg2576 mice. Our results suggest that low plasma cholesterol levels might be a risk factor for AD in females.",2003.0,0,0 2260,12885745,Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy.,Koichi Node; Masashi Fujita; Masafumi Kitakaze; Masatsugu Hori; James K Liao,"Chronic heart failure is associated with inflammation and neurohormonal imbalance. The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, exert anti-inflammatory and vascular protective effects. We hypothesized that short-term statin therapy may have beneficial effects in patients with nonischemic heart failure. Sixty-three patients with symptomatic, nonischemic, dilated cardiomyopathy were randomly divided into 2 groups. One group received simvastatin (n=24), and the other group received placebo (n=27). The initial dose of simvastatin was 5 mg/d, which was increased to 10 mg/d after 4 weeks. After 14 weeks, patients receiving simvastatin exhibited a modest reduction in serum cholesterol level compared with patients receiving placebo (130+/-13 versus 148+/-18, P<0.05). Patients treated with simvastatin had a lower New York Heart Association functional class compared with patients receiving placebo (2.04+/-0.06 versus 2.32+/-0.05, P<0.01). This corresponded to improved left ventricular ejection fraction in the simvastatin group (34+/-3 to 41+/-4%, P<0.05) but not in the placebo group. Furthermore, plasma concentrations of tumor necrosis factor-alpha, interleukin-6, and brain natriuretic peptide were significantly lower in the simvastatin group compared with the placebo group. Short-term statin therapy improves cardiac function, neurohormonal imbalance, and symptoms associated with idiopathic dilated cardiomyopathy. These findings suggest that statins may have therapeutic benefits in patients with heart failure irrespective of serum cholesterol levels or atherosclerotic heart disease.",2003.0,0,0 2261,12888133,Comparison of clinical benefits of clopidogrel therapy in patients with acute coronary syndromes taking atorvastatin versus other statin therapies.,Harm Wienbergen; Anselm Kai Gitt; Rudolf Schiele; Claus Juenger; Tobias Heer; Christina Meisenzahl; Peter Limbourg; Claus Bossaller; Jochen Senges; MITRA PLUS Study Group,"In clinical practice, we found no significant difference between atorvastatin therapy or other statin therapies in the clinical outcomes of patients with acute coronary syndromes receiving clopidogrel therapy. In patients receiving atorvastatin therapy, clopidogrel therapy was associated with a significant decrease in mortality and stroke during univariate analysis and a moderate trend of reduced mortality and stroke without statistical significance in the multivariate analysis.",2003.0,0,0 2262,12888137,Anti-inflammatory effect of atorvastatin (80 mg) in unstable angina pectoris and non-Q-wave acute myocardial infarction.,Luis C L Correia; Andrei C Spósito; José C Lima; Luiz P Magalhães; Luiz C S Passos; Mário S Rocha; Argemiro D'Oliveira; J Péricles Esteves,"In this randomized trial, C-reactive protein increased during the first 5 days of an acute coronary syndrome in patients treated with placebo, but this phenomenon was not observed in those randomized to atorvastatin 80 mg/day. This suggests that short-term statin therapy inhibits inflammation in patients with non-ST-elevation acute coronary syndromes.",2003.0,0,0 2263,12888140,Effects of statins on C-reactive protein and interleukin-6 (the Ludwigshafen Risk and Cardiovascular Health study).,Winfried März; Karl Winkler; Markus Nauck; Bernhard O Böhm; Bernhard R Winkelmann,This report provides preliminary evidence that statins may lower C-reactive protein levels by interfering with the generation and/or release of C-reactive protein in the liver rather than by modulating inflammatory processes in the vessel wall.,2003.0,0,0 2264,12888149,Relation of aggressiveness of lipid-lowering treatment to changes in calcified plaque burden by electron beam tomography.,Harvey S Hecht; S Mitchell Harman,"The comparative effects of more versus less aggressive low-density lipoprotein (LDL) cholesterol lowering (to 80 mg/dl) on calcified coronary plaque progression by electron beam tomography were evaluated in 182 consecutive asymptomatic patients after 1.2 years of treatment with statins alone or in combination with niacin. Despite the greater improvement in lipids in the 80 mg/dl groups, there were no differences in calcified plaque progression (9.3%/year vs 9.1%/year). We conclude that, with respect to LDL cholesterol lowering, ""lower is better"" is not supported by changes in calcified plaque progression.",2003.0,0,0 2265,12888150,Effect of atorvastatin and fenofibrate on autonomic tone in subjects with combined hyperlipidemia.,Vojtech Melenovsky; Dan Wichterle; Jan Simek; Jan Malik; Tomas Haas; Richard Ceska; Marek Malik,"This randomized open-label trial investigated whether autonomic cardiovascular control is altered in middle-aged men with combined hyperlipidemia and whether such alterations are affected by short-term, lipid-lowering therapy with atorvastatin and/or fenofibrate. Compared with normolipidemic subjects, untreated subjects with combined hyperlipidemia had several abnormalities of autonomic tone, indicating increased sympathetic tone and decreased baroreflex sensitivity. The alterations in autonomic cardiovascular control were partially reversible by each of the lipid-lowering drugs.",2003.0,0,0 2266,12888702,Short-term efficacy and safety of extended-release fluvastatin in a large cohort of elderly patients.,Eric Bruckert; Michel Lièvre; Philippe Giral; Gaetano Crepaldi; Luis Masana; Matthias Vrolix; Eran Leitersdorf; Sylvie Dejager,"The efficacy and safety of lipid-lowering agents in elderly individuals have not been extensively assessed. This population generally takes more drugs concurrently than middle-aged patients, and are therefore at higher risk of drug-drug interactions. This large-scale, randomized, double-blind, placebo-controlled study investigated the efficacy and safety of extended-release (XL) fluvastatin 80 mg once daily for up to 1 year in elderly patients with primary hypercholesterolemia. A total of 1229 patients (mean age, 75.5 years) were randomized. After 2 months of treatment, fluvastatin XL 80 mg significantly decreased plasma lipid levels from baseline compared with placebo; fluvastatin reduced total cholesterol by 25% compared with a decrease of 2.5% in the placebo group, low-density lipoprotein cholesterol was -33% vs. -2.5%, respectively, and triglycerides were -13.3% vs. 2.9%, respectively (p<0.00001). The safety profile of fluvastatin XL was similar to that of placebo. Fluvastatin XL 80 mg once daily was well tolerated and effectively managed plasma lipid profiles in a large cohort of elderly patients. These findings are consistent with data obtained previously in younger recipients of fluvastatin XL 80 mg, and reinforce the safety of fluvastatin in a population at high risk of drug-drug interactions.",2003.0,0,1 2267,12892391,Cardiac disease in the antiphospholipid syndrome: recommendations for treatment. Committee consensus report.,M Lockshin; F Tenedios; M Petri; G McCarty; R Forastiero; S Krilis; A Tincani; D Erkan; M A Khamashta; Y Shoenfeld,"The Committee reviewed cardiac involvement in the antiphospholipid antibody syndrome. The Committee's recommendations are: Valve abnormalities: anticoagulation is recommended for symptomatic patients with valvulopathy. Prophylactic antiplatelet therapy may be appropriate for asymptomatic patients (recommended by 13/17 experts in an independent review). Committee members disagreed whether corticosteroid therapy is helpful, but agree that distinguishing among presumptive valvulitis (valve thickening on echocardiogram), valve deformity and vegetations is important, as treatment implications may differ. Occlusive arterial disease (angina, myocardial infarction): the Committee recommends aggressive treatment of all risk factors for atherosclerosis (hypertension, hypercholesterolaemia, smoking) and liberal use of folic acid, B vitamins and cholesterol-lowering drugs (preferably statins). Hydroxychloroquine for cardiac protection in APS patients may be considered. The Committee also recommends warfarin anticoagulation for those who have suffered thrombosis in the absence of atherosclerosis, but recognizes that developing data may support the use of antiplatelet agents instead. Intracardiac thrombi: the Committee recommends intensive warfarin anticoagulation, and consultation with cardiac surgeons when appropriate. Ventricular dysfunction: the Committee has no recommendations on this aspect of cardiac disease. Pulmonary hypertension: the Committee recommends intensive anticoagulation with warfarin and clinical trials of bosentan, epoprostenol and other new agents.",2003.0,0,0 2268,12893392,C-reactive protein and coronary events following percutaneous coronary angioplasty.,Robbert J de Winter; Karel T Koch; Jan P van Straalen; Gerlind Heyde; Matthijs Bax; Carl E Schotborgh; Karla J Mulder; Gerard T Sanders; Johan Fischer; Jan G P Tijssen; Jan J Piek,"We investigated the associations between baseline C-reactive protein levels in patients undergoing percutaneous coronary angioplasty and death, nonfatal myocardial infarction, and repeat revascularization during 14 months of follow-up. In a single-center, prospective, cohort study, plasma levels of C-reactive protein were measured in 1458 consecutive patients undergoing elective or urgent coronary angioplasty. Patients were followed at 12 to 14 months for the occurrence of death, nonfatal myocardial infarction, and repeat revascularization. The incidence of death or myocardial infarction was 6.1% (44/716) in patients with an increased C-reactive protein level (>3 mg/L) and 1.5% (11/742) in patients with a normal level (relative risk [RR] = 4.4; 95% confidence interval [CI]: 2.2 to 8.5; P <0.0001). In a multivariate logistic regression model, an increased C-reactive protein level was an independent predictor of death or nonfatal myocardial infarction (RR = 3.6; 95% CI: 1.8 to 7.2; P =0.0001). The incidence of repeat revascularization was similar in patients with or without an increased C-reactive protein level (23% [168/716] vs. 22% [163/742], P = 0.54). Statin therapy at the time of the procedure was associated with a lower mean (+/- SD) C-reactive protein level (5.8 +/- 9.7 mg/L vs. 7.2 +/- 12.1 mg/L, P =0.02), but was not associated with the risk of death, nonfatal myocardial infarction, and repeat revascularization during follow-up. An increased C-reactive protein level is an independent prognostic indicator for the occurrence of death or nonfatal myocardial infarction following coronary angioplasty, but is not associated with the need for repeat revascularization.",2003.0,0,0 2269,12893398,Evaluating the benefits of treating dyslipidemia: the importance of diabetes as a risk factor.,Steven A Grover; Louis Coupal; Hanna Zowall; Thomas W Weiss; Charles M Alexander,"Diabetes mellitus is associated with an increased risk of cardiovascular disease. We compared the clinical effects of treating dyslipidemia in patients who had diabetes mellitus but no diagnosed cardiovascular disease with the effects of similar treatment in patients who had cardiovascular disease but no diabetes mellitus. We estimated the number of adults (ages 30 to 74 years) requiring lipid therapy using data from the third National Health and Nutrition Examination Survey and current lipid treatment guidelines. Using the Cardiovascular Life Expectancy Model, we estimated the mean increase in life expectancy that would result from lowering low-density lipoprotein cholesterol levels by 35% and increasing high-density lipoprotein cholesterol levels by 8% based on results from the Scandinavian Simvastatin Survival Study. The mean number of years of life saved ranged from 3 to 3.4 years for men with diabetes versus 2.4 to 2.7 years for men with cardiovascular disease. In women, the estimated benefits were 1.6 to 2.4 years for those with diabetes versus 1.6 to 2.1 years for those with cardiovascular disease. Total population benefits were also substantial for patients with diabetes (25.4 million person-years of life saved) and those with cardiovascular disease (16.0 million person-years of life saved). The clinical benefits of treating dyslipidemia in patients with diabetes should be at least equivalent to, if not more substantial than, the benefits observed among those with cardiovascular disease.",2003.0,0,0 2270,12893402,Restenosis after coronary intervention: narrowing C-reactive protein's prognostic potential?,Jeffrey L Anderson; Joseph B Muhlestein,,2003.0,0,0 2271,12895195,Tacrolimus and cerivastatin pharmacokinetics and adverse effects after single and multiple dosing with cerivastatin in renal transplant recipients.,Lutz Renders; Christian S Haas; Jan Liebelt; Martin Oberbarnscheidt; Harald O Schöcklmann; Ulrich Kunzendorf,"In contrast to cyclosporin, only limited information exists on the interaction potential between the immunosuppressive agent tacrolimus and HMG-CoA reductase inhibitors, which are metabolized via the cytochrome P450 system. The aim of this study was to investigate the pharmacokinetics, and adverse effects of cerivastatin combined with tacrolimus in renal transplant patients. Ten patients with stable kidney graft functions and LDL-cholesterol serum concentrations > 110 mg dl-1 were included in the study. After an observation period of 3 months, cerivastatin (0.2 mg daily) was administered for an additional 3 months. Tacrolimus steady-state pharmacokinetics and cerivastatin single- and multiple-dose pharmacokinetics were determined. Lipid concentrations, routine laboratory parameters and adverse events were obtained and analysed throughout the study period of 6 months. Blood tacrolimus trough concentrations were not affected by cerivastatin (mean +/- SD 8.6 +/- 2.1 ng ml(-1) before, and 8.7 +/- 2.4 ng ml(-1) at day 90 of cerivastatin dosing, with a 95% confidence interval on the difference = 0.97, 1.08). The mean area under the blood concentration-time curve to 24 h (AUC(0,24 h)) for cerivastatin was 14.5 +/- 2.53 micro g l(-1) h(-1) at day 1 after starting treatment and 19.02 +/- 3.55 micro g l(-1) h(-1) (3 months later), resulting in a 35% higher (AUC(0,24 h)) compared with the first dose. Total cholesterol, LDL-cholesterol and triglyceride concentrations were significantly lowered by cerivastatin whereas no significant effect of cerivastatin on serum creatininkinase concentrations was observed and no adverse effects were documented. Tacrolimus increased the AUC(0, 24 h) of cerivastatin by a mean of 35% in renal transplant patients. Cerivastatin had no detectable effect on the pharmacokinetics of tacrolimus.",2003.0,0,0 2272,12899509,Gastrointestinal cancer and the long-term use of pravastatin in the elderly.,Dirk Devroey; Frank Buntinx; Willem Betz; Jan Vandevoorde; Jan Kartounian,,2003.0,0,0 2273,12904106,Combination lipid-lowering therapy with statins: safety issues in the postcerivastatin era.,Terry A Jacobson,"Combination lipid-altering regimens represent an emerging clinical paradigm to meet increasingly stringent consensus lipoprotein targets for coronary prevention. This practice, together with escalating prevalences of coronary artery disease in certain ageing (western industrial) populations, polypharmacy in the elderly and the recent voluntary market withdrawal of cerivastatin, warrants a re-examination of the safety profiles of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (i.e., statins). These agents are exceedingly well-tolerated in the vast majority of patients, very infrequently precipitating musculoskeletal symptoms and/or signs. Statins vary in their pharmacological profiles, leading to distinct levels of systemic exposure and capacities to penetrate skeletal myocytes. Pharmacokinetic interactions with certain agents increase the likelihood of statin-induced myopathy and, in exceedingly rare instances, potentially fatal rhabdomyolysis with myoglobinuria and renal failure. As with other medical decisions, the anticipated benefits of long-term statin therapy, with or without other lipid-altering agents, need to be weighed against the prospects of clinically significant drug interactions. In clinical trials and postmarketing surveillance, the two statins that are not metabolised by the cytochrome P450 3A4 system (fluvastatin and pravastatin) have exhibited very low propensities to elicit myopathy when combined with other agents. These agents should be considered initially when contemplating combination lipid-lowering regimens for coronary prevention.",2003.0,0,0 2274,12904142,A safety look at currently available statins.,Mohammed H Moghadasian,"In this mini-review, the evidence for safety and efficacy of currently available statins is discussed. Large-scale, long-term clinical studies have documented an outstanding efficacy and safety profile for statin monotherapy when used at pharmacological doses. Non-life-threatening side effects may occur in up to 15% of patients receiving one statin. Sporadic reports show possible adverse effects of statins on nervous system function including mood alterations. More serious side effects may also occur but at much lower rates. Significant elevations in the activity of serum aminotransferase and creatine kinase alone or in combination with muscle pain in statin-treated patients should be taken seriously; under these conditions, monitoring the statin dose or its discontinuation must be considered. Unlike monotherapy, combination therapy is more problematic. Particularly, combination of the statins with gemfibrozil results in higher rates of drug toxicity. Co-administration of statins with other drugs, especially those which may interfere with the cytochrome P450 system, should be considered carefully. Special attention must be paid to the tolerability of the statins in elderly and transplant patients. The safety of statins in children and adolescents has not yet been well-documented, thus, statin therapy is not routinely recommended in this group of hyperlipidaemic subjects. Future clinical studies and surveillance information will warrant long-term safety of each member of this class of lipid-lowering agents.",2003.0,0,0 2275,12904155,,,,,0,0 2276,12904707,"Dyslipidemia, statins, and venous thromboembolism: a potential risk factor and a potential treatment.",Joel G Ray,"The optimal drug for the prevention of venous thromboembolism is one that is efficacious, associated with minimal bleeding risk, and easy to administer. Statins fulfill the latter two criteria, but their efficacy remains unproved. By examining the association between dyslipidemia and venous thromboembolism, as well as the evidence that statins might prevent venous thromboembolism, there may be a new rationale for the use of this class of drugs. There may be a common link between arterial and venous thrombosis. Dyslipidemia may be one of the many systemic factors associated not only with arterial thrombosis, but with venous thromboembolism as well. This may occur through the effects of circulating lipid molecules on the vascular endothelium, platelet function, and coagulation factors. By impeding these mechanisms, statins may be protective against venous thrombosis, but epidemiologic studies are few in number, and no randomized clinical trials have been conducted. Better epidemiologic evidence is required to establish whether dyslipidemia is a risk factor for venous thromboembolism. If future observational studies can demonstrate that statins are associated with a lower risk of venous thromboembolism, then consideration should be given to conducting a randomized clinical trial comparing statins with placebo for the prevention of venous thromboembolism. Until then, the efficacy of statins for the prevention or treatment of venous thromboembolism remains uncertain.",2003.0,0,0 2277,12904816,"Drug research: myths, hype and reality.",Hugo Kubinyi,,2003.0,0,0 2278,12906976,Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients.,Aina Hognestad; Knut Endresen; Ragnhild Wergeland; Oddvar Stokke; Odd Geiran; Torbjorn Holm; Svein Simonsen; John K Kjekshus; Arne K Andreassen,"This study was initiated to determine whether heart transplant recipients (HTRs) with cardiac allograft vasculopathy (CAV) have increased levels of high-sensitivity C-reactive protein (hsCRP) and to examine whether an increase in hsCRP after heart transplantation predicts the development of CAV. Furthermore, the effect of pravastatin on plasma levels of hsCRP in HTRs was investigated. The relationship between CAV and hsCRP, as well as the effect of statins on hsCRP in HTRs, has not been well established. On referral for their annual angiographic control study, 150 consecutive HTRs (mean 6.5 years since transplantation) were included. Plasma levels of hsCRP were measured before angiography and compared with patients with (n = 52) and without (n = 98) CAV. In 49 of these patients, we additionally analyzed hsCRP in blood samples stored from their six-month visit after the transplantation procedure. Furthermore, in a randomized, crossover study, hsCRP was analyzed in 17 male HTRs before and after six weeks of treatment with 20 mg pravastatin. Median levels of CRP were elevated among patients with CAV compared with those with normal angiograms [3.86 (1.78 to 7.00) vs. 1.08 (0.72 to 2.13) mg/l, p < 0.001]. Prospectively evaluated hsCRP levels from six months to follow-up were significantly higher among those who developed CAV compared with those with normal angiograms [+2.76 (1.56 to 5.00) vs. +0.07 (-0.57 to 0.41) mg/l, p < 0.001]. On multivariate analysis, the increase in hsCRP was the only significant predictor of CAV. Six weeks of treatment with pravastatin significantly reduced hsCRP levels by 25%, without any relation to changes in lipid values. Elevated plasma levels of CRP are associated with angiographic evidence of CAV, and the increase in hsCRP is a strong predictor of development of CAV. Statin treatment reduces levels of hsCRP and should be used in HTRs, regardless of their lipid levels.",2003.0,0,0 2279,12908497,Statins: new data in secondary prevention and diabetes. Pravastatin and simvastatin are the best-assessed statins.,,"The efficacy of pravastatin and simvastatin was first shown several years ago in patients with coronary heart disease. Other trials have since been published. In the HPS trial, which studied patients with coronary heart disease, other cardiovascular conditions, or diabetes, simvastatin significantly reduced the risk of death, coronary events and stroke when compared with placebo. In the ALLHAT-LLT trial, in patients with treated hypertension, pravastatin did not reduce overall mortality. In the PROSPER trial, in patients aged over 70 with cardiovascular disease or cardiovascular risk factors, pravastatin reduced the incidence of coronary events relative to placebo, but did not reduce overall mortality. Pharmacovigilance studies suggest there is no difference between these four statins in terms of their potential to cause rhabdomyolysis. Taken together, these trials show that statin use can be extended to patients with levels of LDL-cholesterol over 2.4 mmol/l (0.9 g/l) if they have coronary heart disease (and no hypercholesterolaemia), a history of ischaemic stroke, or lower-limb arterial disease. Statins can also be prescribed for diabetic patients with no signs of cardiovascular disease but whose LDL-cholesterol exceeds 3.4 mmol/l (1.3 g/l). Clinical trial data support the use of pravastatin or simvastatin in these situations, at a dose of 20 or 40 mg daily. Plasma creatine phosphokinase assay should be done if muscle symptoms occur or if the patient has a particular risk of rhabdomyolysis.",2003.0,0,0 2280,12911845,Implications of the heart protection study for reducing coronary events in high-risk patients.,William Virgil Brown; Warren Davis; Matthey Harris,,2003.0,0,0 2281,12911850,In-hospital initiation of statin therapy in patients with acute coronary events.,Gregg C Fonarow,,2003.0,0,0 2282,12912693,Relation of statin use to the 5-year incidence and progression of age-related maculopathy.,Ronald Klein; Barbara E K Klein; Sandra C Tomany; Lorraine G Danforth; Karen J Cruickshanks,"To examine the association of hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) with the 5-year incidence of age-related maculopathy (ARM). Population-based cohort study. Participants included persons 48 to 91 years old examined March 1, 1993, through June 14, 1995, living in Beaver Dam, Wis (N = 3684), of whom 2780 participated in a follow-up 5 years later. Standardized procedures were used for physical examinations, blood sample collection, and questionnaire administration. Age-related maculopathy was determined by grading images of the posterior pole using a standard protocol. Standard univariate and multivariate analyses were performed. Incidence and progression of ARM was measured over the 5-year interval. While controlling for age and sex, statin use was not found to be associated with the 5-year incidence of early ARM (odds ratio [OR], 1.12; 95% confidence interval [CI], 0.47-2.67), progression of ARM (OR, 1.22; 95% CI, 0.54-2.76), or incidence of late ARM (OR, 0.41; 95% CI, 0.12-1.45). These findings do not suggest an association between statin use and incident ARM over a 5-year period. Further investigation of these relationships in larger studies over a longer period is needed.",2003.0,0,0 2283,12914359,Asymptomatic carotid lesion as a marker of future cerebrovascular and cardiovascular events.,S Novo; E Corrado,,2003.0,0,0 2284,12915827,"Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial.",Brian W McCrindle; Leiv Ose; A David Marais,"To determine the safety and efficacy of atorvastatin (10 to 20 mg) in children and adolescents with familial hypercholesterolemia or severe hypercholesterolemia. Subjects (n=187) were randomly assigned to 26 weeks of treatment with atorvastatin (10 mg) or placebo. Dosage was increased to 20 mg if LDL cholesterol (LDL-C) levels remained >3.4 mmol/L (130 mg/dL) at week 4. At week 26, subjects received 10 mg of atorvastatin for an additional 26 weeks. Efficacy variables included percent changes in LDL-C, total cholesterol, triglycerides, HDL cholesterol, and apolipoprotein B from baseline to week 26. Atorvastatin caused a highly significant reduction in LDL-C compared with placebo (-40% vs -0.4%, respectively; P<.001). Percent changes at week 26 also significantly favored atorvastatin for total cholesterol (-32% vs -1.5%; P<.001), triglycerides (-12% vs +1.0%; P=0.03), and apolipoprotein B (-34% vs +0.7%; P<.001), with a significantly greater increase in HDL cholesterol with atorvastatin compared with placebo (+2.8% vs -1.8%; P=.02). Atorvastatin was as well-tolerated as placebo. Treatment with atorvastatin for 12 months was effective and safe for pediatric subjects with known familial hypercholesterolemia or severe hypercholesterolemia.",2003.0,0,0 2285,12915931,Clopidogrel is associated with better in-hospital and 30-day outcomes than ticlopidine after coronary stenting.,Philippe L L'Allier; Herbert D Aronow; Fernando A Cura; Deepak L Bhatt; Abdulhay Albirini; Jakob P Schneider; Eric J Topol; Stephen G Ellis,"Recent reports of fatal ticlopidine-induced blood dyscrasias have led many interventional cardiologists to administer clopidogrel instead of ticlopidine for coronary stenting. Most studies have demonstrated similar outcomes and a more favourable safety profile supporting this change in practice patterns. To assess the clinical outcomes in patients who received clopidogrel rather than ticlopidine after coronary stenting. Between June 1996 and December 1998, 652 patients received a clopidogrel-based periprocedural regimen (300 mg loading dose followed by 75 mg daily in addition to acetylsalicylic acid 325 mg daily) and 1717 patients received a ticlopidine-based regimen (500 mg loading dose followed by 250 mg bid in addition to acetylsalicylic acid 325 mg daily). In-hospital and 30-day outcomes were assessed in the two groups. At 30 days, unadjusted mortality was 0.3% in the clopidogrel group versus 1.5% in the ticlopidine group, and myocardial infarction (MI) was also reduced in the clopidogrel group (4.0% versus 6.5%). No difference was found in the rate of repeat revascularization (1.4% versus 1.2%). The combination of death/MI/repeat revascularization at 30 days was reduced by 32%, an absolute difference of 2.9% (6.2% versus 9.1%). On multivariate analysis, clopidogrel was found to be an independent predictor of freedom from nonfatal MI (odds ratio [OR] 0.64, 95% CI 0.41 to 0.99, P=0.04), the composite of death or MI (OR 0.62, 95% CI 0.40 to 0.95, P=0.03) and the composite of death/MI/revascularization (OR 0.69, 95% CI 0.48 to 1.00, P=0.05). After coronary stenting, in a large, nonrandomized, consecutive patient experience, clopidogrel appears to be associated with more favourable clinical outcomes than ticlopidine, without increasing the risk of bleeding or peripheral vascular complications.",2003.0,0,0 2286,12918548,The future of lipid-lowering therapy: the big picture.,J J P Kastelein,"Several lipid-lowering intervention studies published in 2002 shed light on the current status and the future of cardiovascular risk reduction by drug therapy. The Heart Protection Study has demonstrated that simvastatin reduces heart attack, stroke and revascularisation risk by about one-third irrespective of total cholesterol, LDL cholesterol, patient's age or sex, or the nature of pre-existing cardiovascular disease. Coronary heart disease death and myocardial infarction risk reduction in elderly patients by pravastatin in the PROSPER study was similar to the benefit of statins in middle-aged populations in other studies. The ALLHAT-LLT study has failed to demonstrate a benefit of pravastatin on all-cause mortality, CHD death or nonfatal myocardial infarction, illustrating that too modest cholesterol lowering does not result in clinical benefit under all circumstances. The cholesterol absorption inhibitor ezetimibe has demonstrated significant LDL and total cholesterol lowering, and induced an additional 21% LDL cholesterol lowering when added to ongoing statin therapy. The cholesteryl ester transfer protein inhibitor JJT-705 produced a dose-dependent increase in HDL cholesterol concentrations of up to 34% and improved the total cholesterol/HDL cholesterol ratio in healthy individuals while having very mild side effects. Cholesterol absorption inhibitors and HDL cholesterol enhancers may become useful tools to achieve further improvements in cardiovascular risk reduction in the future.",2003.0,0,0 2287,12918888,The reality of treating dyslipidaemia in patients with coronary heart disease: a primary care survey.,D J Wright; A D Grayson; M Jackson; C Dainty,"Management of hyperlipidaemia in patients with ischaemic heart disease is suboptimal despite the proven benefit of statin therapy. Significant improvement in management has been shown in the EUROASPIRE II study. It is unclear, however, whether such changes have also occurred in primary care. We aimed to evaluate the use of statin therapy by performing a cross-sectional survey of 300 patients with CHD aged >30 years from three general practices. A total of 249 (83%) of the 300 patients had their cholesterol measured and 141 (47%) were on statin therapy; 129 (43% of total) achieved a target cholesterol of <5 mmol/l, of whom 85 (64%) were on statin therapy. Of the remaining 120 patients whose cholesterol exceeded 5 mmol/l, 56 (47%) were on statin therapy Thus 60% (85/141) of those on statin therapy achieved adequate control compared with 40% (44/108) without statins (p<0.008). Those patients with CHD diagnosed on objective evidence were more likely to receive statin therapy (55.5%). Many patients with CHD are still not receiving appropriate secondary prevention. Those on statin therapy are more likely to achieve target levels <5 mmol/l. The average doses of statins vary and are lower than the evidence-based doses used in previous large-scale studies, which may help explain the persistence of failed treatment.",2003.0,0,0 2288,12925055,"Effects of atorvastatin on glucose homeostasis, postprandial triglyceride response and C-reactive protein in subjects with impaired fasting glucose.",A Costa; R Casamitjana; E Casals; L Alvarez; J Morales; X Masramón; G Hernández; R Gomis; I Conget,"To investigate the effects of atorvastatin on glucose homeostasis, the basal and postprandial lipid profiles and the CRP levels (C reactive protein) in subjects with impaired fasting glucose (IFG). Thirty-three subjects (22 men and 11 women) were included in our study. All displayed an IFG (fasting plasma glucose between 6.1 and 7.0 mmol/l) on at least two occasions during the last 6 months prior the study. They were randomly assigned to receive either 40 mg atorvastatin/day (n=16) or placebo (n=17) over 16 weeks, in a double-blind design. Before and after the end of the study all participants underwent on three consecutive days: a 75-g oral glucose tolerance test, a frequent sampling intravenous glucose tolerance test with Minimal Model analysis and a meal tolerance test (glucose, insulin and triglycerides). CRP was measured before and after the treatment period. CRP decreased significantly in the atorvastatin-treated group compared with the placebo group (percent change respect initial values; -42.3 %[-21.5 to - 63.1] and -9.6%[15.0 to -34.0], respectively, p<0.01). Atorvastatin treatment did not produce any change in oral glucose tolerance categories or induce any change in glucose and insulin response in OGTT. The statin produced a trend towards a significant improvement in insulin sensitivity as expressed by a change in Si from baseline to the end of treatment. Atorvastatin reduced the postprandial response of triglycerides to the meal test compared with placebo (19-26 % across the meal test, p<0.05) correlating with the amelioration observed in Si (-0.34, p<0.05; percentage changes). Our results suggest that the use of statins in subjects with IFG seems to include other potentially beneficial actions in addition to their cholesterol-lowering effects.",2003.0,0,0 2289,12925453,"Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial.",Jacqueline Saw; Steven R Steinhubl; Peter B Berger; Dean J Kereiakes; Victor L Serebruany; Danielle Brennan; Eric J Topol; Clopidogrel for the Reduction of Events During Observation Investigators,"Statins primarily metabolized by cytochrome P450 3A4 (CYP3A4) reportedly reduce clopidogrel's metabolism to active metabolite, thus attenuating its inhibition of platelet aggregation ex vivo. However, the clinical impact of this interaction has not been evaluated. Clopidogrel for the Reduction of Events During Observation (CREDO) was a double-blind, placebo-controlled, randomized trial comparing pretreatment (300 mg) and 1-year (75 mg/d) clopidogrel therapy (clopidogrel) with no pretreatment and 1-month clopidogrel therapy (75 mg/d) (control) after a planned percutaneous coronary intervention. All patients received aspirin. The 1-year primary end point was a composite of death, myocardial infarction, and stroke. We performed a post hoc analysis to evaluate the clinical efficacy of concomitant clopidogrel and statin administration, categorizing baseline statin use to those predominantly CYP3A4-metabolized (atorvastatin, lovastatin, simvastatin, and cerivastatin) (CYP3A4-MET) or others (pravastatin and fluvastatin) (non-CYP3A4-MET). Of the 2116 patients enrolled, 1001 received a CYP3A4-MET and 158 a non-CYP3A4-MET statin. For the overall study population, the primary end point was significantly reduced in the clopidogrel group (8.5% versus 11.5%, RRR 26.9%; P=0.025). This clopidogrel benefit was similar with statin use, irrespective of treatment with a CYP3A4-MET (7.6% clopidogrel, 11.8% control, RRR 36.4%, 95% CI 3.9 to 57.9; P=0.03) or non-CYP3A4-MET statin (5.4% clopidogrel, 13.6% control, RRR 60.6%, 95% CI -23.9 to 87.4; P=0.11). Patients given atorvastatin or pravastatin had similar 1-year event rates. Additionally, concomitant therapy with statins had no impact on major or minor bleeding rates. Although ex vivo testing has suggested a potential negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel, this was not clinically observed statistically in a post hoc analysis of a placebo-controlled study.",2003.0,0,0 2290,12928279,The association between statin use and age related maculopathy.,G McGwin; C Owsley; C A Curcio; R J Crain,"To evaluate the association between age related maculopathy (ARM) and statin use. A nested case-control study among patients at the Veterans Affairs Medical Center in Birmingham, Alabama, with newly diagnosed ARM (cases) between 1997 to 2001 were selected and age matched to non-ARM controls. 550 incident cases of ARM were identified and matched to 5500 controls. Overall, cases were 70% (OR 0.30, 95% CI 0.21 to 0.45) less likely to have received and filled a statin prescription relative to the controls. This association was present among both current and past (OR 0.34, 95% CI 0.21 to 0.53 and OR 0.26, 95% CI 0.14 to 0.47, respectively) statin users. When considering use of statin and/or non-statin lipid lowering medications, a significant risk reduction was observed for statin only users (OR 0.30, 95% CI 0.20 to 0.45) and combined statin and non-statin users (OR 0.20, 95% CI 0.06 to 0.64); there was no significant association for non-statin only users (OR 0.47, 95% CI 0.20 to 1.13). The results of this study suggest that subjects with ARM were significantly less likely to have filled a statin prescription. Future clinical research initiatives should include a clinical trial to provide direct evidence of the effectiveness of statins in lowering the incidence and progression of ARM.",2003.0,0,0 2291,12932588,Prospective serial evaluation of myocardial perfusion and lipids during the first six months of pravastatin therapy: coronary artery disease regression single photon emission computed tomography monitoring trial.,Ronald G Schwartz; Thomas A Pearson; Vijay G Kalaria; Maria L Mackin; Daniel J Williford; Ashish Awasthi; Abrar Shah; Adam Rains; Joseph J Guido,"This study was designed to assess prospectively changes in serum lipid profile and myocardial perfusion with serial radionuclide single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) during the first six months of pravastatin therapy. Morbid coronary events occur despite statin therapy and lipid-lowering in patients with coronary artery disease (CAD). A reliable strategy to identify responders with effective treatment from nonresponders on statin therapy before clinical events is needed. Rest and stress SPECT MPI and lipids were assessed serially in 25 patients (36% women) with CAD and dyslipidemia during the first six months of pravastatin therapy. Total cholesterol, low-density lipoprotein cholesterol, and triglycerides declined (26%, 32%, and 30%, respectively) by six weeks and remained reduced at six months. Mean stress perfusion defect (summed stress score [SSS]) was severe (13.3 +/- 6.0) at baseline, showed no change at six weeks, and improved significantly at six months (10.3 +/- 7.3, p < 0.01). The six-month study SSS improved in 11 (48%) patients, was unchanged in 10 (43%) patients, and worsened in 2 (9%) patients. Changes in lipid levels did not reliably predict changes in myocardial perfusion at six weeks or six months in this small pilot study. Serial SPECT MPI demonstrated improved stress myocardial perfusion in 48% of patients treated for six months with pravastatin. Time course of improved myocardial perfusion during pravastatin therapy is delayed compared to lipids. Direction and magnitude of changes in the myocardial perfusion vary and do not correlate closely with improvements in lipids.",2003.0,0,0 2292,12932601,Changes in coronary plaque color and morphology by lipid-lowering therapy with atorvastatin: serial evaluation by coronary angioscopy.,Masamichi Takano; Kyoichi Mizuno; Shinya Yokoyama; Koji Seimiya; Fumiyuki Ishibashi; Kentaro Okamatsu; Ryota Uemura,"Changes in coronary plaque color and morphology by statin therapy were evaluated using coronary angioscopy. Coronary plaque stabilization by statin therapy has not been clarified in humans. Thirty-one patients with coronary artery disease were divided into either the comparison group (n = 16) or the atorvastatin group (n = 15). Before treatment and 12 months after, the color and complexity of 145 coronary plaques were determined according to angioscopic findings. The yellow score of the plaque was defined as 0 (white), 1 (light yellow), 2 (yellow), or 3 (dark yellow), and its disrupted score was defined as 0 (smooth surface) or 1 (irregular surface) and as 0 (without thrombus) or 1 (with thrombus). In each patient, the mean yellow score and mean disrupted score were calculated. Mean low-density lipoprotein cholesterol (LDL-C) decreased by 45% in the atorvastatin group, whereas an increase of 9% was seen in the comparison group. The mean yellow score decreased from 2.03 to 1.13 in the atorvastatin group, whereas it increased from 1.67 to 1.99 in the comparison group. There was a good correlation between the change in the mean yellow score and the change in LDL-C levels (r = 0.81, p < 0.0001). The change in the mean yellow score and mean disrupted score differed significantly between the two groups (p = 0.002 and p = 0.03, respectively). This is the first report clarifying detailed changes in coronary plaque by statin in humans. This study indicated that lipid-lowering therapy changes plaque color and morphology and should then lead to coronary plaque stabilization.",2003.0,0,0 2293,12932603,Long-term statin use and psychological well-being.,Yinong Young-Xu; K Arnold Chan; James K Liao; Shmuel Ravid; Charles M Blatt,"We sought to study the effect of long-term statin use on psychometric measures in an adult population with underlying coronary artery disease (CAD). Previous studies have suggested associations between cholesterol lowering and psychological well-being. Study subjects were recruited from an outpatient cardiology clinic. Psychological well-being was assessed at baseline and annually during follow-up. The exposure of interest was long-term statin use and the outcomes of interest were depression, anxiety, and hostility. We estimated the odds ratios (ORs) and 95% confidence intervals (CI) that represented the strength of association between statin use (vs. no use of any cholesterol-lowering drug) and the risk of having abnormal depression, anxiety, and hostility scores. Study subjects had an average follow-up of four years and maximum of seven years. Comparing the 140 patients who had continuous use of statins with the 231 patients who did not use any cholesterol-lowering drugs, statin use was associated with lower risk of abnormal depression scores (OR 0.63, 95% CI 0.43 to 0.93), anxiety (OR 0.69, 95% CI 0.47 to 0.99), and hostility (OR 0.77, 95% CI 0.58 to 0.93) after adjustment for the propensity for statin use and potential confounders. The beneficial psychological effects of the statins appeared to be independent of the drugs' cholesterol-lowering effects. Long-term use of statins among patients with CAD appeared to be associated with reduced risk of anxiety, depression, and hostility.",2003.0,0,0 2294,12934785,Niacin as a component of combination therapy for dyslipidemia.,Michael Miller,"Dyslipidemia is one of the most important modifiable risk factors for coronary disease. Despite the availability of highly effective lipid-modifying agents, many patients still do not reach lipid targets established by national guidelines. Niacin has been known to be an effective treatment of dyslipidemia for almost half a century. Niacin substantially increases high-density lipoprotein cholesterol (HDL-C) levels while lowering levels of low-density lipoprotein cholesterol (LDL-C), triglycerides, and lipoprotein(a). In addition, niacin converts small LDL particles into more buoyant, less atherogenic LDL particles. Combined with other agents, niacin offers an important treatment option for patients with dyslipidemia. In particular, niacin complements LDL-C-lowering drugs; it is the most effective agent available for increasing HDL-C levels while lowering levels of LDL-C and triglycerides and improving other lipid risk factors such as lipoprotein(a). Combining niacin with statins or bile acid sequestrant therapy is safe and effective for improving lipid levels and decreasing coronary risk. Differences in niacin formulations dictate tolerability profiles and should be considered when selecting niacin as part of lipid therapy. Furthermore, adverse effects on glucose and insulin sensitivity should be considered when selecting candidates for niacin therapy. Adding niacin to lipid-lowering regimens is a valuable option for physicians treating patients with dyslipidemia and should be considered in appropriate patients.",2003.0,0,0 2295,12938249,Hypercholesterolemia. The evidence supports use of statins.,Wilbert S Aronow,"Using statins to treat older men and women with coronary artery disease (CAD) and hypercholesterolemia reduces the risk of all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, Intermittent claudication, and congestive heart failure. The target serum low-density lipoprotein (LDL) cholesterol level is < 100 mg in older patients with CAD, prior stroke, peripheral arterial disease, extracranial carotid arterial disease, abdominal aortic aneurysm, diabetes meilitus, and the metabolic syndrome. Statins are also effective in reducing cardiovascular events in older persons with hypercholesterolemia without cardiovascular disease. Consider using statins in older persons without cardiovascular disease but with a serum LDL cholesterol > or = 130 mg/dL, or a serum high-density lipoprotein cholesterol < 50 mg/dL. Data from the Heart Protection Study favor treating patients at high risk for vascular events with statins regardless of age or initial serum lipids.",2003.0,0,0 2296,12939228,Differences in medical care and disease outcomes among black and white women with heart disease.,Ashish K Jha; Paul D Varosy; Alka M Kanaya; Donald B Hunninghake; Mark A Hlatky; David D Waters; Curt D Furberg; Michael G Shlipak,"The risk of cardiovascular mortality is higher among black women than white women, and the reasons for this disparity are largely unexplored. We sought to evaluate differences in medical care and clinical outcomes among black and white women with established coronary artery disease. Among the 2699 women enrolled in the Heart and Estrogen/progestin Replacement Study (HERS), we used Cox proportional hazards models to determine the association of race with risk of coronary heart disease (CHD) events independent of major cardiovascular risk factors or medical therapies. During an average of 4.1 years of follow-up, CHD events were twice as likely in black compared with white women (6.4 versus 3.1 per 100 person-years, hazard ratio, 2.1; 95% confidence interval, 1.5 to 2.8; P<0.001). Black women had higher rates of hypertension, diabetes, and hypercholesterolemia, yet were less likely to receive aspirin or statins. Black women less often had optimal blood pressure (56% versus 63%; P=0.01) and LDL cholesterol (30% versus 38%; P=0.04) control at baseline and during follow-up. After adjusting for these and other differences, black women still had >50% higher CHD event risk (hazard ratio, 1.52; 95% confidence interval, 1.1 to 2.1; P=0.03). In a large cohort of women with heart disease, black women less often received appropriate preventive therapy and adequate risk factor control despite a greater CHD event risk. Interventions to improve appropriate therapy and risk factor control in all women, and especially black women, are needed.",2003.0,0,0 2297,12940609,Effect of fluvastatin and dipyridamole on proteinuria and renal function in childhood IgA nephropathy with mild histological findings and moderate proteinuria.,K Kano; K Nishikura; Y Yamada; O Arisaka,"In recent reports, some kinds of HMG-CoA reductase inhibitors were able to decrease proteinuria and to improve renal function. Here we aimed to clarify the effect of fluvastatin (an HMG-CoA reductase inhibitor) on proteinuria and renal function in children with mild IgA nephropathy. We conducted a prospective controlled study of 30 children who had been recently diagnosed with normocholesterolemic IgA nephropathy following the detection of a minor lesion or of focal mesangial proliferation and moderate proteinuria. The 30 patients were randomly assigned to receive both of 20 mg of fluvastatin and 5 mg/kg of dipyridamole (group 1), or 5 mg/kg of dipyridamole only (group 2) for 1 year. By the end of the trial, urinary protein, hematuria, BUN and serum creatinine levels had significantly decreased in the patients of group 1 as compared to baseline. Serum total cholesterol, triglyceride and LDL cholesterol levels had significantly decreased, while serum total protein and albumin, and creatinine clearance had significantly increased in group 1 as compared to baseline and group 2. The urinary protein level had significantly decreased in the group 2 patients as compared to baseline, but only slightly. The results of this study suggest that fluvastatin and dipyridamole treatment yields an antiproteinuric effect and leads to the amelioration of renal function in moderately proteinuric patients with mild histological IgA nephropathy.",2003.0,0,0 2298,12941576,Treatment of Alzheimer's disease: current status and new perspectives.,Elio Scarpini; Philip Scheltens; Howard Feldman,"Alzheimer's disease (AD) is the most common neurodegenerative disorder and the most prevalent cause of dementia with ageing. Pharmacological treatment of AD is based on the use of acetylcholinesterase inhibitors, which have beneficial effects on cognitive, functional, and behavioural symptoms of the disease, but their role in AD pathogenesis is unknown. Other pharmacological therapies are becoming available--including the recently approved drug memantine, an NMDA channel blocker indicated for advanced AD. Here, we review clinical features of the available cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) including their pharmacological properties, the evidence for switching from one agent to another, ""head to head"" studies, and the emerging evidence for the use of memantine in AD. New therapeutic approaches--including those more closely targeted to the pathogenesis of the disease--will also be reviewed. These potentially disease modifying treatments include amyloid-beta-peptide vaccination, secretase inhibitors, cholesterol-lowering drugs, metal chelators, and anti-inflammatory agents.",2003.0,0,0 2299,12941579,New and emerging treatment options for multiple sclerosis.,Chris H Polman; Bernard M J Uitdehaag,"The use of interferon beta and glatiramer acetate for the treatment of multiple sclerosis (MS) has, to some extent, changed the course of the disease. The annual relapse rate of patients treated with these drugs is lower than that in placebo-treated patients, and more treated patients remain relapse-free compared with untreated patients. In addition, these compounds reduce the development of new lesions, as detected by MRI. The limited effectiveness of approved treatments for MS, as well as reports of adverse events and toxicity, emphasise the need for the development of new therapies with improved efficacy and fewer side-effects. Clinical observations, increased understanding of the underlying pathophysiology of the disease, and advances in biotechnology have led to several new therapeutic approaches to the treatment of MS that are currently under investigation. WHERE NEXT? Mitoxantrone has recently been shown to produce benefit when used to treat patients with progressive MS; it may also be an effective second-line treatment for patients who do not respond to interferon beta or glatiramer acetate. Over the past few years, several studies have drawn attention to the potential of natalizumab, alemtuzumab, statins, and oestrogens as effective treatments for MS. These drugs are at different stages of clinical development and additional clinical data are needed to support their use and devise dosage regimens. However, they are important and attractive candidates for several reasons: they counteract a fundamental and well-defined pathophysiological process; they have a less cumbersome route of administration than interferon beta and glatiramer acetate; or they have a remarkable safety record.",2003.0,0,0 2300,12943890,Effect of atorvastatin on myocardial contractile reserve assessed by tissue Doppler imaging in moderately hypercholesterolemic patients without heart disease.,Manolis Bountioukos; Vittoria Rizzello; Boudewijn J Krenning; Jeroen J Bax; Miklos D Kertai; Eleni C Vourvouri; Arend F L Schinkel; Elena Biagini; Eric Boersma; Jos R T C Roelandt; Don Poldermans,"An improvement in myocardial longitudinal systolic velocities, assessed by pulsed-wave tissue Doppler imaging during low-dose dobutamine infusion, was observed at 6-month follow-up after 6 months of treatment with atorvastatin. Our findings indicate a favorable effect of atorvastatin on contractile reserve, possibly through an enhancement of flow-dependent coronary dilatation during stress.",2003.0,0,0 2301,12944570,Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients.,Howard J Eisen; E Murat Tuzcu; Richard Dorent; Jon Kobashigawa; Donna Mancini; Hannah A Valantine-von Kaeppler; Randall C Starling; Keld Sørensen; Manfred Hummel; Joan M Lind; Kamal H Abeywickrama; Peter Bernhardt; RAD B253 Study Group,"Everolimus, a novel proliferation inhibitor and immunosuppressive agent, may suppress cardiac-allograft vasculopathy. We conducted a randomized, double-blind, clinical trial comparing everolimus with azathioprine in recipients of a first heart transplant. A total of 634 patients were randomly assigned to receive 1.5 mg of everolimus per day (209 patients), 3.0 mg of everolimus per day (211 patients), or 1.0 to 3.0 mg of azathioprine per kilogram of body weight per day (214 patients), in combination with cyclosporine, corticosteroids, and statins. The primary efficacy end point was a composite of death, graft loss or retransplantation, loss to follow-up, biopsy-proved acute rejection of grade 3A, or rejection with hemodynamic compromise. At six months, the percentage of patients who had reached the primary efficacy end point was significantly smaller in the group given 3.0 mg of everolimus (27.0 percent, P<0.001) and the group given 1.5 mg of everolimus (36.4 percent, P=0.03) than in the azathioprine group (46.7 percent). Intravascular ultrasonography showed that the average increase in maximal intimal thickness 12 months after transplantation was significantly smaller in the two everolimus groups than in the azathioprine group. The incidence of vasculopathy was also significantly lower in the 1.5-mg group (35.7 percent, P=0.045) and the 3.0-mg group (30.4 percent, P=0.01) than in the azathioprine group (52.8 percent). The rates of cytomegalovirus infection were significantly lower in the 1.5-mg group (7.7 percent, P<0.001) and the 3.0-mg group (7.6 percent, P<0.001) than in the azathioprine group (21.5 percent). Rates of bacterial infection were significantly higher in the 3.0-mg group than in the azathioprine group. Serum creatinine levels were also significantly higher in the two everolimus groups than in the azathioprine group. Everolimus was more efficacious than azathioprine in reducing the severity and incidence of cardiac-allograft vasculopathy, suggesting that everolimus therapy may alleviate this serious problem.",2003.0,0,0 2302,12945474,An analysis of first authorizations for lipid-lowering drugs in Belgium.,D Devroey; W Betz,"In Belgium lipid-lowering drugs are reimbursed in primary and secondary prevention when after a non-specified diet of at least three months total cholesterol (TC) remains higher than 250 mg/dl or triglycerides (TG) remain higher than 200 mg/dl. Low-density lipoprotein cholesterol (LDL-C) is only taken into account for the reimbursement of fibrates when it remains higher than 160 mg/dl in secondary prevention. The aim of this study was to evaluate the changes in fasting lipoproteins levels among patients who wait for the reimbursement of a lipid-lowering drug. Additionally, the parameters influencing the physicians' choice to prescribe a statin or a fibrate were analysed. In total 286 first authorizations for the reimbursement of lipid-lowering drugs were recorded during February and March of 2002 at two regional health insurance offices. We studied a mixed primary and secondary prevention population. The mean age at the initiation of the treatment was 61 years (SD = 12). Mean fasting TC was 285 mg/dl before the diet and 286 mg/dl after the diet. Fasting TC and TG did not decrease with the diet for respectively 51% and 54% of the patients. High TC and an improvement of TG during the diet were the only two factors correlated with the prescription of a statin instead of a fibrate. Half of the patients receiving lipid-lowering drugs in Belgium were not able to decrease their TC with diet before the initiation of the treatment. Cardiovascular risk factors were not taken into account for the reimbursement of statins. Belgian reimbursement criteria should be adapted.",2003.0,0,0 2303,12952839,Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease.,Emile R Mohler; William R Hiatt; Mark A Creager,"Cholesterol modification reduces cardiovascular events in patients with atherosclerosis, including those with peripheral arterial disease. The purpose of this study was to determine whether cholesterol lowering with atorvastatin improves walking performance in patients with intermittent claudication. This randomized, double-blind, parallel-design study included 354 persons with claudication attributable to peripheral arterial disease. Patients were treated with placebo, atorvastatin (10 mg per day), or atorvastatin (80 mg per day) for 12 months. The outcome measures included change in treadmill exercise time and patient-reported measures of physical activity and quality of life based on questionnaires. Maximal walking time after 12 months of treatment with atorvastatin did not change significantly. However, there was improvement in pain-free walking time after 12 months of treatment for the 80-mg (P=0.025) group compared with placebo. A physical activity questionnaire demonstrated improvement in ambulatory ability for the 10- and 80-mg groups (P=0.011), whereas 2 quality of life instruments, the Walking Impairment Questionnaire and Short Form 36 Questionnaire, did not show significant change. Atorvastatin improves pain-free walking distance and community-based physical activity in patients with intermittent claudication. When treated with atorvastatin, patients with peripheral arterial disease may experience improvement in symptoms to complement the anticipated reduction in cardiovascular events reported in other studies of statins.",2003.0,0,0 2304,12953339,"Comparative effects of atorvastatin, simvastatin, and fenofibrate on serum homocysteine levels in patients with primary hyperlipidemia.",Haralampos J Milionis; John Papakostas; Anna Kakafika; George Chasiotis; Konstantine Seferiadis; Moses S Elisaf,"Hyperhomocysteinemia is regarded as an independent risk factor for cardiovascular disease. Lipid-lowering agents, such as fibrates, can modify homocysteine levels. However, less is known about the effect of statin therapy on homocysteine. The authors compared the effects of atorvastatin (40 mg/day), simvastatin (40 mg/day), and micronized fenofibrate (200 mg/day) on the serum concentrations of total homocysteine, vitamin B12, and folic acid in patients with primary hyperlipidemia. A total of 128 patients with primary hyperlipidemia (total cholesterol > 240 mg/dL and triglycerides < 350 mg/dL) were assigned to atorvastatin, simvastatin, or fenofibrate. Serum lipid and metabolic parameters were measured at baseline and at 6 and 12 weeks of treatment. Homocysteine correlated positively with serum creatinine and uric acid levels and inversely with serum folic acid levels. All treatment modalities reduced total, low-density lipoprotein (LDL) cholesterol, and triglyceride concentrations. High-density lipoprotein (HDL) cholesterol levels significantly increased only in the fenofibrate-treated patients (47.9 +/- 12.5 vs. 50.7 +/- 12.6 vs. 51.2 +/- 12.8 mg/dL, p < 0.01). Atorvastatin and fenofibrate treatment resulted in a significant reduction of serum uric acid levels (5.3 +/- 1.6 vs. 4.9 +/- 1.4 vs. 4.8 +/- 1.4 mg/dL, p < 0.0001 for atorvastatin; 5.6 +/- 1.6 vs. 4.3 +/- 1.4 vs. 4.4 +/- 1.4 mg/dL, p < 0.0001 for fenofibrate). Homocysteine levels were significantly increased only by fenofibrate (10.3 +/- 3.3 vs. 14.1 +/- 3.8 vs. 14.2 +/- 3.6 microU/L, p < 0.001) but did not change from baseline following statin treatment. Neither statins nor fenofibrate had any effect on serum vitamin B12 and folic acid levels. In contrast to fenofibrate, therapeutic dosages of atorvastatin and simvastatin have a neutral effect on serum homocysteine levels, which is in favor of their ""cardioprotective"" properties.",2003.0,0,0 2305,12954916,Behavioral implications of lowering cholesterol levels: a double-blind pilot study.,Tom Ormiston; Owen M Wolkowitz; Victor I Reus; Francesca Manfredi,"The treatment of hypercholesterolemia may be associated with greater noncardiac mortality. This current pilot study sought to determine which behaviors, if any, are associated with decreases in cholesterol level. Twelve subjects received one of two cholesterol-reducing drugs or placebo. Cholesterol and behavioral ratings were measured at baseline, 4, and 52 weeks with standardized scales. Cholesterol levels markedly declined with concomitant significant increases in impulsivity ratings at 4 weeks. At 52 weeks, the increase in impulsivity ratings was no longer apparent, but depression ratings showed a significant improvement. This pilot study, although limited in size, raises the possibility that cholesterol-lowering drugs are associated with mild, time-limited increases in impulsivity and with mild, time-delayed improvements in depression ratings.",2003.0,0,0 2306,12957096,Dyslipidaemia.,Paul Durrington,"The lowering of serum cholesterol is increasingly recognised as essential in the prevention of coronary heart disease and other atherosclerotic disease. The success of statin trials and the need to deploy these drugs effectively in the population has led increasingly to the identification of many people whose serum cholesterol, triglycerides, and HDL-cholesterol require clinical assessment, and frequently treatment. Lipid disorders are mainly straightforward, but some are complex or resistant to simple treatment strategies. I have reviewed the clinical manifestations of disordered lipid metabolism (dyslipidaemia) and its management.",2003.0,0,0 2307,12957104,Comments on the MRC/BHF Heart Protection Study.,John Abramson,,2003.0,0,0 2308,12957331,CSF taurine level is influenced by plasma cholesterol and the CYP2D6 phenotype.,Conny Nordin; Marja Liisa Dahl; Thomas Eklundh; Mats Eriksson; Stefan Sjöberg,"Eight healthy male volunteers, lumbar-punctured before and during simvastatin treatment, were phenotyped for CYP2D6 analysis of the debrisoquine metabolic ratio (the ratio between the urinary recovery of debrisoquine and its 4-hydroxy metabolite) after a single oral dose of debrisoquine. The mean cerebrospinal fluid concentrations of cholesterol and taurine did not differ before and during treatment. During (but not before) treatment taurine in the CSF correlated with the debrisoquine metabolic ratio (r=-0.93; P=0.0007) Our results might indicate an influence of CYP2D6 on the level of taurine in the CSF that was secondary to the change in plasma cholesterol.",2003.0,0,0 2309,12957768,,,,,0,0 2310,12959299,Stress responses after treatment of hypercholesterolaemia with simvastatin.,A M Nugent; D Neely; I Young; I McDowell; M O'Kane; N Bell; C F Stanford; D P Nicholls,"In order to determine whether treatment of hyperlipidaemia with simvastatin impairs exercise stress responses and so may contribute to an excess of suicides and violent deaths, the effects of simvastatin 20 mg daily and placebo on exercise physiology were compared in 19 patients. After 6 weeks of treatment there was no evidence of reduced exercise capacity, or of reduced cortisol or catecholamine responses. It is concluded that treatment of hyperlipidaemia with an inhibitor of HMG-CoA reductase does not significantly modify stress responses, and so the explanation for a possible increase in non-cardiac mortality must be sought elsewhere.",2003.0,0,0 2311,12963641,Oxygen free radical release in human failing myocardium is associated with increased activity of rac1-GTPase and represents a target for statin treatment.,Christoph Maack; Tanja Kartes; Heiko Kilter; Hans-Joachim Schäfers; Georg Nickenig; Michael Böhm; Ulrich Laufs,"Reactive oxygen species (ROS) contribute to the development of heart failure. A potential source of myocardial ROS is the NADPH oxidase, which is regulated by the small GTP-binding protein rac1. Isoprenylation of rac1 can be inhibited by statin therapy. Thus, we examined ROS and rac1 in human failing myocardium and tested their regulation by statins in vivo. In human left ventricular myocardium from patients with ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM), NADPH oxidase activity was increased 1.5-fold compared with nonfailing controls (P<0.05, n=8). In failing myocardium, increased oxidative stress determined by measurements of lipid peroxidation and aconitase activity was associated with increased translocation of rac1 from the cytosol to the membrane. Pull-down assays revealed a 3-fold increase of rac1-GTPase activity in ICM and DCM. In parallel, membrane expression of the NADPH oxidase subunit p47phox, but not p67phox, was upregulated in failing compared with nonfailing myocardium. In right atrial myocardium from patients undergoing cardiac surgery who were prospectively treated with atorvastatin or pravastatin (40 mg/d, 4 weeks), rac1-GTPase activity was decreased to 67.9+/-12% and 65.6+/-13.8% compared with patients without statin (P<0.05, n=8). Both atorvastatin and pravastatin significantly reduced angiotensin II-stimulated but not basal NADPH oxidase activity. Failing myocardium of patients with DCM and ICM is characterized by upregulation of NADPH oxidase-mediated ROS release associated with increased rac1 activity. Oral statin treatment inhibits myocardial rac1-GTPase activity. These data suggest that extrahepatic effects of statins can be observed in humans and may be beneficial for patients with chronic heart failure.",2003.0,0,0 2312,12967330,Testosterone as a protective factor against atherosclerosis--immunomodulation and influence upon plaque development and stability.,C J Malkin; P J Pugh; R D Jones; T H Jones; K S Channer,"Inflammation plays a central pathogenic role in the initiation and progression of coronary atheroma and its clinical consequences. Cytokines are the mediators of cellular inflammation and promote local inflammation in the arterial wall, which may lead to vascular smooth muscle apoptosis, degradation of the fibrin cap and plaque rupture. Platelet adhesion and thrombus formation then occur, resulting clinically in unstable angina or myocardial infarction. Recent studies have suggested that cytokines are pathogenic, contributing directly to the disease process. 'Anti-cytokine' therapy may, therefore, be of benefit in preventing or slowing the progression of cardiovascular disease. Both oestrogens and testosterone have been shown to have immune-modulating effects; testosterone in particular appears to suppress activation of pro-inflammatory cytokines. Men with low testosterone levels are at increased risk of coronary artery disease. An anti-inflammatory effect of normal physiological levels of sex hormones may, therefore, be important in atheroprotection. In this Article, we discuss some of the mechanisms involved in atherosclerotic coronary artery disease and the putative link between testosterone deficiency and atheroma formation. We present the hypothesis that the immune-modulating properties of testosterone may be important in inhibiting atheroma formation and progression to acute coronary syndrome.",2003.0,0,0 2313,12967531,Ezetimibe plus atorvastatin lowers cholesterol.,Wendy S Madigosky; Kevin Y Kane,,2003.0,0,0 2314,12968198,Congestive heart failure: guidelines for the primary care physician.,Ira Galin; David A Baran,"Heart failure is a common medical condition affecting nearly 5 million people each year in the United States, of whom 500,000 are newly diagnosed. The impact of this disease on society and the health care system is immense. Inpatient and outpatient costs are approximately $40 billion annually, almost $500 million of which is spent on heart failure medications alone. Beyond the problem of financial costs, however, it is imperative for us as health care professionals to improve our ability to prevent disease progression, decrease morbidity and mortality, and optimize patients quality of life. The use of a broad spectrum of treatments is reviewed in the context of a patient case study. Primary data justifying the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, digoxin, as well as beta blockers and spironolactone, is reviewed, with special reference to the stage of heart failure.",2003.0,0,0 2315,12968995,Statins and the risk of idiopathic venous thromboembolism.,Joel G Ray; Muhammad M Mamdani,,2003.0,0,0 2316,12970329,"Angiotensin II receptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-kappa B, in mononuclear cells of normal subjects: evidence of an antiinflammatory action.",Paresh Dandona; Vikramjeet Kumar; Ahmad Aljada; Husam Ghanim; Tufail Syed; Debborah Hofmayer; Priya Mohanty; Devjit Tripathy; Rajesh Garg,"In view of the pro-oxidant and proinflammatory effects of angiotensin II, we have tested the hypothesis that valsartan, an angiotensin receptor blocker, may exert a suppressive action on reactive oxygen species (ROS) generation, nuclear factor kappa B (NF-kappa B) in mononuclear cells. Four groups of eight normal subjects were given 1) 160 mg daily of valsartan, 2) 80 mg daily of simvastatin, 3) 40 mg quinapril, or 4) no treatment. Fasting blood samples were obtained before treatment and at d 1, 8, and 14 (7 d after the cessation of the drug). After valsartan, ROS generation by polymorphonuclear cells and mononuclear cells fell significantly by more than 40% (P < 0.01). NF-kappa B binding activity and the expression of total cellular p65, a protein component of NF-kappa B, fell significantly (P < 0.01). The expression of inhibitor kappa B (I kappa B) increased significantly (P < 0.05). Plasma C-reactive protein (CRP) concentration fell significantly (P < 0.01). All indices, except I kappa B, reverted toward baseline, 7 d after the cessation of the drug. I kappa B persisted in an elevated state. Neither quinapril nor simvastatin given for 7 d produced a suppression of ROS generation, intranuclear NF-kappa B, p65, or CRP, and these two agents did not alter cellular I kappa B either. The untreated controls also did not demonstrate a change in their ROS generation or NF-kappa B binding activity or plasma CRP concentration. We conclude that valsartan at a modest dose exerts a profound and rapid ROS and inflammation-suppressive effect that may be relevant to its potential beneficial effects in atherosclerosis, diabetes, and congestive cardiac failure. In contrast, quinapril and simvastatin produced no similar effect over the period of 1 wk. Our observations may also have implications to clinical situations in which a rapid antiinflammatory effect is required.",2003.0,0,0 2317,12970413,New inhibitors of scrapie-associated prion protein formation in a library of 2000 drugs and natural products.,David A Kocisko; Gerald S Baron; Richard Rubenstein; Jiancao Chen; Salomon Kuizon; Byron Caughey,"Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases associated with the accumulation of a disease-specific form of prion protein (PrP) in the brain. One approach to TSE therapeutics is the inhibition of PrP accumulation. Indeed, many inhibitors of the accumulation of PrP associated with scrapie (PrP(Sc)) in scrapie-infected mouse neuroblastoma cells (ScN(2)a) also have antiscrapie activity in rodents. To expedite the search for potential TSE therapeutic agents, we have developed a high-throughput screening assay for PrP(Sc) inhibitors using ScN(2)a cells in a 96-well format. A library of 2000 drugs and natural products was screened in ScN(2)a cells infected with scrapie strain RML (Chandler) or 22L. Forty compounds were found to have concentrations causing 50% inhibition (IC(50)s) of PrP(Sc) accumulation of 3 times the upper limit of normal (ULN) were experienced by 0.5% (n = 47) of atorvastatin-treated patients. A persistent elevation in creatine phosphokinase (CPK) (>10 x ULN) was observed in only 1 atorvastatin-treated patient and was not associated with myopathy. The incidence of treatment-associated myalgia was low in the atorvastatin (1.9% [n = 181]), placebo (0.8% [n = 14]), and other statin (2.0% [n = 105]) groups, and was not related to the atorvastatin dose. No cases of rhabdomyolysis or myopathy were reported. Thus, the overall incidence of treatment-associated adverse events observed with atorvastatin did not increase in the 10- to 80-mg dose range, and was similar to that observed with placebo and in patients treated with other statins. Specific analysis of musculoskeletal and hepatic adverse events showed that these occurred infrequently and rarely resulted in treatment discontinuation.",2003.0,0,0 2319,12972108,Statins and safety: applying the results of randomized trials to clinical practice.,David Waters,,2003.0,0,0 2320,12972114,Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at six months and at one year after treatment.,Wilbert S Aronow; Devraj Nayak; Steven Woodworth; Chul Ahn,"Simvastatin significantly increased treadmill exercise time until onset of intermittent claudication from baseline by 54 seconds (a 24% increase, p <0.0001) at 6 months after treatment and by 95 seconds (a 42% increase, p <0.0001) at 1 year after treatment. At 6 months and 1 year after treatment with placebo, treadmill exercise time until onset of intermittent claudication was not significantly different from baseline exercise time.",2003.0,0,0 2321,12975259,High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study.,Scott Kinlay; Gregory G Schwartz; Anders G Olsson; Nader Rifai; Sally J Leslie; William J Sasiela; Michael Szarek; Peter Libby; Peter Ganz; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study Investigators,"Inflammation promotes acute coronary syndromes and ensuing clinical complications. Although statins reduce inflammatory markers in asymptomatic adults or in patients with stable angina, the effect of statins on the markedly heightened inflammation in patients with acute coronary syndromes is unknown. We measured C-reactive protein (CRP), serum amyloid A (SAA), and interleukin 6 (IL-6) in 2402 subjects enrolled the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study. Subjects with unstable angina or non-Q-wave myocardial infarction were randomized to atorvastatin 80 mg/d or placebo within 24 to 96 hours of hospital admission and treated for 16 weeks. The effect of treatment on inflammatory markers was assessed by ANCOVA after adjustment for presenting syndrome, country, and initial level of marker. All 3 markers were markedly elevated at randomization and declined over the 16 weeks in both treatment groups. Compared with placebo, atorvastatin significantly reduced CRP, -83% (95% CI, -84%, -81%) versus -74% (95% CI, -75%, -71%) (P<0.0001) and SAA, -80% (95% CI, -82%, -78%) versus -77% (-79%, -75%) (P=0.0006) but not IL-6, -55% (95% CI, -57%, -53%) versus -53% (95% CI, -55%, -51%) (P=0.3). Reductions in CRP and SAA were observed in patients with unstable angina and non-Q-wave myocardial infarction, with initial LDL cholesterol <3.2 or > or =3.2 mmol/L (125 mg/dL), age > or =65 or <65 years, and in men and women. By 16 weeks, CRP was 34% lower with atorvastatin than with placebo. High-dose atorvastatin potentiated the decline in inflammation in patients with acute coronary syndromes. This supports the value of early statin therapy in these patients.",2003.0,0,0 2322,12975438,The central role of platelet activation in determining the severity of acute coronary syndromes.,S Kennon; C P Price; P G Mills; M Macey; J Cooper; H Clarke; A D Timmis,,2003.0,0,0 2323,12975445,Plaque stabilisation in acute coronary syndromes: clinical considerations.,Adam D Timmis,,2003.0,0,0 2324,13129994,Antibiotic therapy for coronary artery disease: can a WIZARD change it all?,Sorin V Pislaru; Frans Van de Werf,,2003.0,0,0 2325,1341189,[An evaluation of the efficacy and safety of pravastatin in patients with primary hypercholesterolemia. A Brazilian open multicenter study].,S D Giannini,"To evaluate the efficacy and safety of pravastatin in patients with primary hypercholesterolemia In an open-label multicenter uncontrolled study under the usual conditions of clinical practice 1,850 patients with primary hypercholesterolemia were submitted, after one month of placebo control and low fat/low cholesterol diet, to 12 weeks of treatment with pravastatin 10mg o.d. Significant reductions higher than 25% were obtained in plasma levels of total cholesterol and low density lipoprotein (LDL) cholesterol associated with an increase > 10% in the HDL cholesterol plasma concentration in 51% of the patients. The individual results were classified as satisfactory (higher than 20% decrease) in 70% of the studied population. The compliance of pravastatin was excellent, since 118 patients (6.4%) developed adverse reactions, but interruption of the treatment was necessary in only 18 (0.9%); 9 patients due to muscular pain, 3 by gastrointestinal symptoms, 2 by cutaneous reactions and 4 due to general complaints. The clinical conditions of diabetes, obesity, hypertension did not modify the efficacy of the drug. Previous unsatisfactory hypolipidemic treatment did not alter the results of the efficacy. The satisfactory results in efficacy and safety and the facility of the pravastatin use, make this drug as a first line agent in the hypolipidemic treatment.",1992.0,0,0 2326,1345159,Prevention of cardiovascular disease.,A Haines; D Patterson; M Rayner; K Hyland,"1. Major risk factors for coronary heart disease (CHD) are smoking, blood pressure and blood cholesterol and they interact in a multiplicative fashion. Family history of premature coronary heart disease and lack of exercise also contribute. Obesity increases risk probably mainly by its effect on blood cholesterol and blood pressure. Heavy alcohol consumption is a risk factor for stroke. 2. Prevention may be opportunistic or in specially organized clinics, the latter being less likely to result in the attendance of high risk individuals. 3. Worthwhile reductions in cigarette smoking can be achieved by brief advice and follow-up. Literature on smoking and other aspects of prevention is available from the district health education department. 4. Risk scores can be used to calculate the risk of coronary heart disease. They can help to indicate the advisability of measurement of blood cholesterol and to focus limited resources on those at highest risk by helping to define a 'special care group'. 5. Indications for measuring blood cholesterol are: a family history of premature coronary heart disease or hyperlipidaemia, personal history of coronary heart disease, clinical evidence of raised lipids (xanthelasma, corneal arcus under 50, xanthomas at any age), a high risk of coronary heart disease according to a risk score. Many would also include those under treatment for hypertension and diabetes. 6. Dietary advice can moderately reduce blood cholesterol. The proportion of calories from fat should be reduced from the current average of around 40% to a maximum of 33%. Dietary advice should be tailored to the patient's current diet. An increase in vegetables and fruit can be generally advocated. 7. Regular exercise has a worthwhile role to play in prevention. Rapid walking, jogging and swimming may all be suitable, as may be heavy gardening and housework. 8. A small proportion of patients may require lipid-lowering drugs. These include resins (cholestyramine and colestipol), fibrates (eg bezafibrate and gemfibrozil) and more recently HMG CoA inhibitors (eg simvastatin). The HMG CoA inhibitors produce large falls in cholesterol and may become first line drugs in future. Because of the current controversy about the effect of lipid-lowering drugs on total mortality, many believe that they should be reserved for those at the highest risk, for example patients with familial hypercholesterolaemia or with pre-existing coronary heart disease and a high plasma cholesterol (> 7.8 mmol/L). 9. The special care group defined by the practice should be offered regular follow-up.(ABSTRACT TRUNCATED AT 400 WORDS)",1992.0,0,0 2327,14499232,Effects of exercise training on conduit and resistance vessel function in treated and untreated hypercholesterolaemic subjects.,Jennifer H Walsh; Gerald Yong; Craig Cheetham; Gerald F Watts; Gerard J O'Driscoll; Roger R Taylor; Daniel J Green,"Despite the importance of both lipid metabolism and physical activity to cardiovascular health, few studies have examined the effect of exercise training on vascular function in hypercholesterolaemic humans. A randomized, cross-over design investigated the effect of 8 weeks of combined aerobic and resistance exercise training on conduit and resistance vessel function in 11 untreated subjects with hypercholesterolaemia and 11 subjects taking lipid-lowering medication. High-resolution vascular ultrasonography following forearm ischaemia and glyceryl trinitrate administration determined conduit vessel endothelium-dependent and independent function. Strain-gauge plethysmography, with intra-aerial infusions of acetylcholine, sodium nitroprusside and N(G)-monomethyl-L-arginine, determined resistance vessel function. Flow-mediated dilation and the forearm blood flow response to acetylcholine improved significantly following training in the treated subgroup (both P<0.05) but not the untreated, although the blood flow response to N(G)-monomethyl-L-arginine was augmented following training in the untreated subjects (P<0.05), indicating greater basal nitric oxide bioactivity. Training did not alter responsiveness to glyceryl trinitrate or sodium nitroprusside. Combined aerobic and resistance training improves endothelium-dependent conduit and resistance vessel function in hypercholesterolaemic subjects taking lipid-lowering medications and basal nitric oxide bioactivity in untreated hypercholesterolaemic subjects. Exercise training may provide additional cardiovascular benefits for hypercholesterolaemic patients including those taking lipid-lowering medication.",2003.0,0,0 2328,14500332,Antiarrhythmic drug target choices and screening.,Michael C Sanguinetti; Paul B Bennett,"Most antiarrhythmic drugs are ion channel blockers, and to date, those tested in large randomized placebo-controlled clinical trials have shown no decrease in mortality outcome. This apparent lack of survival benefit may result from the significant liabilities associated with these agents that offset any long-term benefit. Despite the current success of implantable defibrillators and the future promise of gene therapy, there is still a pressing need for new antiarrhythmic drugs. An improved understanding of cardiac ion channels and novel approaches to target selection and compound screening will provide new opportunities for drug discovery in the near future. Here, we briefly review the multiple mechanisms of arrhythmia, the history of drug failures, and the possibilities that evolving technologies may provide in the search for more efficacious and safer antiarrhythmic drugs.",2003.0,0,0 2329,14501025,A position paper: based on observational data indicating an increased rate of altered blood chemistry requiring withdrawal from the Alzheimer's Disease Cholesterol-Lowering Treatment Trial (ADCLT).,D Larry Sparks; Jean Lopez; Don Connor; Marwan Sabbagh; Jim Seward; Patrick Browne; Alzheimer's Disease Cholesterol-Lowering Treatment Team,"Recruitment for the inaugural double-blind placebo-controlled trial investigating a cholesterol-lowering treatment for benefit in Alzheimer's disease (AD) (ADCLT) ended after obtaining 98 informed consents. Suspension of recruitment of the ADCLT occurred in concert with initiation of two separate multicenter trials testing similar hypotheses. Although occurring at very low rates (<2%), altered-chemistry adverse events requiring discontinuation of therapy (withdrawal AEs) are not unexpected with use of cholesterol-lowering statins. We suggest that exceptionally close monitoring for altered chemistry among individuals with AD should be undertaken in future statin treatment trials, as limited data from the ADCLT indicate that chemically based withdrawal AEs could be more prevalent among female AD patients. There was no apparent correlation between the occurrence of withdrawal-AE incidence and lower body mass among the female AD trial subjects and, therefore, probably was not a dose-related resultant. This might indicate that cognitively intact elderly women at risk for heart disease and those with clinically documented AD should not be presumed to be pharmocodynamically equivalent. Lipid profiles obtained at screening in the ADCLT are consistent with a possible difference between patients with current AD and those at risk for heart disease. Elevated cholesterol, increased cholesterol/high-density lipid (HDL) ratios, and elevated triglycerides are routinely observed among those at risk for heart disease; however, among ADCLT study participants, only cholesterol levels were increased while cholesterol/HDL ratio and triglyceride levels remained within normal limits.",2003.0,0,0 2330,14503013,The risk of dementia in relation to statins and other lipid lowering agents.,Kenneth Rockwood; Sultan Darvesh,"Recent epidemiological reports suggest that statins, and possibly other lipid lowering agents, might be protective for Alzheimer disease, and for other types of dementia. Importantly, however, epidemiological reports of this type are susceptible to indication bias, i.e. people who elect to take lipid-lowering agents might be healthier than those who do not, so that it may be these other health factors which explain their lower risk of dementia. Limited clinical trials data support the notion that statins, in particular, have important effects on cerebral cholesterol metabolism, but the link to clinical effects in dementia has yet to be established, and the mechanisms by which lipid lowering agents might confer protective effects is unclear. Dedicated clinical trials are now under way, and their results are awaited with great interest.",2003.0,0,0 2331,14503906,1: Epidemiology and prevention of type 2 diabetes and the metabolic syndrome.,Jonathan E Shaw; Donald J Chisholm,"The prevalence of type 2 diabetes in Australia has doubled over the past 20 years; more than 7% of Australian adults now have diabetes. An additional 16% of Australian adults have lesser abnormalities of glucose tolerance. Insulin resistance and increased cardiovascular risk occur in both these groups (the metabolic syndrome). 50% of cases of type 2 diabetes are undiagnosed; screening is indicated in everyone aged over 55 and in younger people with risk factors such as obesity, hypertension, family history or certain ethnic backgrounds. Dietary modification and increased physical activity have been shown to dramatically reduce the incidence of type 2 diabetes in those at high risk. General practitioners should target individuals at high risk, but this needs to be reinforced by community-wide preventive action. National prevention programs are needed, but GPs can contribute through screening and lifestyle advice.",2003.0,0,0 2332,14504184,,,,,0,0 2333,14505289,Translating tomographic plaque imaging into treatment: interventional lipidology.,Harvey S Hecht,"In the context of the beneficial effects of statins, irrespective of the low-density lipoprotein cholesterol level (LDL-C) in the Heart Protection Study and the relatively poor event reduction (24%-37%) in the LDL-C reduction trials, electron beam tomography plaque imaging has provided the necessary data to support a reorientation of traditional treatment paradigms. The prognostic superiority of calcified plaque quantitation to conventional risk factor assessment and the poor correlation between pretreatment standard lipid values and amount of plaque in individual patients, as well as between post treatment lipid changes and changes in calcified plaque burden, suggest the following: (1) significant calcified plaque shifts the asymptomatic patient from primary to secondary prevention status; (2) ""abnormal"" lipid values in individual patients are best defined by the level at which atherosclerosis develops; (3) non LDL-C disorders contribute to CAD and should be identified and treated; (4) plaque burden, rather than plasma lipid values, should be the target of therapy; and (5) adequacy of therapy is best evaluated with serial plaque imaging. Other treatment applications of plaque imaging include triage of patients for stress testing and evaluation of stress test results.",2003.0,0,0 2334,14506118,"Evaluation of prolonged antithrombotic pretreatment (""cooling-off"" strategy) before intervention in patients with unstable coronary syndromes: a randomized controlled trial.",Franz-Josef Neumann; Adnan Kastrati; Gisela Pogatsa-Murray; Julinda Mehilli; Hildegard Bollwein; Hans-Peter Bestehorn; Claus Schmitt; Melchior Seyfarth; Josef Dirschinger; Albert Schömig,"In unstable coronary syndromes, catheter intervention is frequently preceded by antithrombotic treatment to reduce periprocedural risk; however, evidence from clinical trials to support antithrombotic pretreatment is sparse. To test the hypothesis that prolonged antithrombotic pretreatment improves the outcome of catheter intervention in patients with acute unstable coronary syndromes compared with early intervention. Randomized controlled trial conducted from February 27, 2000, to April 8, 2002, and including patients admitted to 2 German tertiary care centers with symptoms of unstable angina plus either ST-segment depression or elevation of cardiac troponin T levels. Patients were randomly allocated to antithrombotic pretreatment for 3 to 5 days or to early intervention after pretreatment for less than 6 hours. In both groups, antithrombotic pretreatment consisted of intravenous unfractionated heparin (60-U/kg bolus followed by infusion adjusted to maintain partial thromboplastin time of 60 to 85 seconds), aspirin (500-mg intravenous bolus followed by 100-mg twice-daily oral dose), oral clopidogrel (600-mg loading dose followed by 75-mg twice-daily dose), and intravenous tirofiban (10- microg/kg bolus followed by continuous infusion of 0.10 microg/kg per min). Composite 30-day incidence of large nonfatal myocardial infarction or death from any cause. Of the 410 patients enrolled, 207 were allocated to receive prolonged antithrombotic pretreatment and 203 to receive early intervention. Elevated levels of cardiac troponin T were present in 274 patients (67%), while 268 (65%) had ST-segment depression. The antithrombotic pretreatment and the early intervention groups were well matched with respect to major baseline characteristics and definitive treatment (catheter revascularization: 133 [64.3%] vs 143 [70.4%], respectively; coronary artery bypass graft surgery: 16 [7.7%] vs 16 [7.9%]). The primary end point was reached in 11.6% (3 deaths, 21 infarctions) of the group receiving prolonged antithrombotic pretreatment and in 5.9% (no deaths, 12 infarctions) of the group receiving early intervention (relative risk, 1.96 [95% confidence interval, 1.01-3.82]; P =.04). This outcome was attributable to events occurring before catheterization; after catheterization, both groups incurred 11 events each (P =.92). In patients with unstable coronary syndromes, deferral of intervention for prolonged antithrombotic pretreatment does not improve the outcome compared with immediate intervention accompanied by intense antiplatelet treatment.",2003.0,0,0 2335,14509100,Impact of the new National Cholesterol Education Program (NCEP) guidelines on patient management.,Anne Peters Harmel; Kathy Berra,"To update nurse practitioners (NPs) on the latest National Cholesterol Education Program (NCEP) guidelines for the management of high blood cholesterol in adults. The 2001 NCEP Adult Treatment Panel (ATP) III guidelines and supporting scientific reviews and reports of clinical trials related to the evidence upon which the guidelines are based. The many new features of the ATP III guidelines include an increased emphasis on the patient with multiple risk factors in order to identify appropriate candidates for primary prevention and on more stringent classifications of elevated lipid/lipoprotein levels. However, elevated levels of low-density lipoprotein (LDL) cholesterol continue to be the focus for both primary and secondary prevention, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are clearly the drugs of choice for decreasing LDL cholesterol in most patients. Because NPs play key roles in optimizing treatment management, it is important that they become familiar with, and be prepared to help implement, these latest guidelines. By embracing the global risk assessment approach of ATP III and aggressively treating all at-risk patients, NPs can take a proactive role in helping to halt the progression of coronary heart disease and its consequences.",2003.0,0,0 2336,14511903,What's different about older people.,Peter Crome,"Older people can be regarded as a marginalised group within society from a number of perspectives including that of health. When it comes to the use of medication older people have suffered from a double whammy. Not only are they more at risk from the adverse effects of drugs but also their involvement in clinical trials has been limited so that rational prescribing both to maximise benefit and to reduce risk has been problematic. Their special problems have been recognised formerly by the Department of Health in its NSF for Older People [National Service Framework for Older People. Department of Health, London (2001a)], [Medicines and Older People. Implementing medicines-related aspects of the NSF for Older People. Department of Health (2001b)]. Early studies focussed on compliance, the avoidance of poly-pharmacy and the high prevalence of adverse effects of drugs and the reasons for this. Studies in long-stay patients showed dramatic differences in pharmacokinetics between such older people and young healthy volunteers. Initially such differences were ascribed to age alone and the overall message became ""start low and go slow"". Studies in healthy older people then revealed that age differences in drug metabolism were, as a rule, not so marked although clearance of renally excreted drugs was reduced in line with the age associated decline in renal function. Including older people in clinical trials poses challenges. Many traditional trialists do not have ready access to older people, co-morbidity and poly-pharmacy are common and most people feel reluctant to ask older people to take part in complex and potentially hazardous trials. Concern about compliance is unwarranted. Adverse events may be more serious. Thus in a younger patient postural hypotension may make a subject unsteady but in an older subject the unsteadiness may lead to a fall, the fall to a fracture, and the fracture to poor recovery. The choice of end-points is crucial. Although reduction of clinical events is clearly important, effects on quality of life become more important as natural life expectancy reduces. Although regulatory bodies state that they now evidence of effectiveness in older people before registration there are still many examples of arbitrary and illogical upper age limits in clinical trials.",2003.0,0,0 2337,14515113,Building a better quality measure: are some patients with 'poor quality' actually getting good care?,Eve A Kerr; Dylan M Smith; Mary M Hogan; Timothy P Hofer; Sarah L Krein; Martin Bermann; Rodney A Hayward,"National performance measures monitor the proportion of diabetic patients with low-density lipoprotein (LDL) levels >/=130 mg/dL, but such simple intermediate outcomes measure poor control, not necessarily poor care. ""Tightly linked"" quality measures define good quality either by a good intermediate outcome (LDL <130 mg/dL) or by evidence of appropriate responses to poor control (eg, starting or optimizing medications for high LDL or not doing so in the face of contraindications). We examined hyperlipidemia therapy for patients with diabetes to determine the relative accuracy of quality assessment using simple intermediate outcome versus tightly linked quality measures. Retrospective longitudinal cohort. A total of 1154 diabetic patients with an LDL test done between October 1, 1998, and March 31, 1999, in 2 large VA facilities. LDL levels, medication treatment, and explanations for poor quality. Although 27% (307 of 1154) of patients had an LDL >/=130 mg/dL using the simple intermediate outcome measure, only 13% (148 of 1154) were classified as having substandard quality using the tightly linked measure. Among the 159 reclassified to adequate quality, 117 had lipid-lowering medication started or increased within 6 months of an LDL >/=130 mg/dL, 8 were already on high-dose medication, 12 had a repeat LDL <130 mg/dL, and 22 had contraindications to treatment. Simple intermediate outcome measures can be an inaccurate reflection of true quality of care, and many patients classified as having substandard quality by ""poor control"" might actually be receiving good quality of care.",2003.0,0,0 2338,14516878,"Effects of baseline level of triglycerides on changes in lipid levels from combined fluvastatin + fibrate (bezafibrate, fenofibrate, or gemfibrozil).",Michel Farnier; Thomas Salko; Jonathan L Isaacsohn; August J Troendle; Sylvie Dejager; Leonard Gonasun,"This analysis was conducted to evaluate the effect of baseline triglyceride levels on lipid and lipoprotein changes after treatment with the combination of fluvastatin and fibrates. The analysis involved pooling data from 10 studies that included 1,018 patients with either mixed hyperlipidemia or primary hypercholesterolemia. Patients received a combination of fluvastatin and a fibrate (bezafibrate, fenofibrate, or gemfibrozil) from 16 to 108 weeks. The combination of fluvastatin and a fibrate improved lipid profiles, with reductions in triglycerides, low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol that were dependent on baseline triglyceride levels. The greatest triglyceride reductions were observed in patients with high baseline triglyceride levels (> or =400 mg/dl) (41%, p <0.0001). The greatest LDL cholesterol and non-HDL cholesterol reductions occurred in patients with normal baseline triglyceride levels (<150 mg/dl) (35% and 33%, respectively; p <0.0001). The combined fluvastatin-fibrate therapy was well tolerated. Two patients (0.2%) (1 patient on fluvastatin 80 mg + gemfibrozil 1,200 mg and 1 patient on fluvastatin 20 mg + fenofibrate 200 mg) had creatine kinase levels > or =10 times the upper limit of normal, 11 patients (1.1%) had an elevation in alanine transaminase >3 times the upper limit of normal, and 7 patients (0.7%) had elevations in aspartate transaminase >3 times the upper limit of normal. Combined fluvastatin-fibrate therapy takes advantage of the complementary effects of the 2 agents, with the extent of triglyceride, LDL cholesterol, and non-HDL cholesterol lowering dependent on baseline triglyceride levels. The combination of fluvastatin and fibrates was well tolerated with no major safety concerns.",2003.0,0,0 2339,14517149,Epidemic obesity and the metabolic syndrome.,Steven Haffner; Heinrich Taegtmeyer,,2003.0,0,0 2340,14517152,"Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part II.",Thomas F Lüscher; Mark A Creager; Joshua A Beckman; Francesco Cosentino,,2003.0,0,0 2341,14518081,[Comparison of utilization of cardiovascular drugs in the Czech Republic and in Wales].,K Górecká; J Vlcek; R Walker,"To compare and describe the trends in the consumption of selected groups of cardiovascular drugs in several districts of the Czech Republic and counties of Wales in the period of 1997-2000. A retrospective analysis of prescription data from General Medical Insurance Company (three districts in the Czech Republic) and data from the Health Solutions Wales (3 counties of Wales). The data were analyzed during seven half-year intervals from January 1997 till June 2000. The authors investigated the consumption of antihypertensives, diuretics, beta-blockers, calcium channel blockers, ACE inhibitors, hypolipidemic drugs, digoxin and acetylsalicylic acid classified according to ATC classification. The drug consumption was expressed at defined daily doses (DDD) and standardized per 1,000 insured individuals and day for the Czech districts and per 1,000 inhabitants and day for the Welsh counties (DID). The total consumption of the cardiovascular drugs under study in the last half-year of the investigated period of time (1/00) proved to be highest in CZ2 (40.2 DID), the value being by 40% higher than in CZ1 (348.6 DID) and by 11% higher than in CZ3 (386.9% DID). The rates of consumption in the Welsh counties during this period of time were 338.8 DID (W1), 307.9 DID (W2) and 298.0 DID (W3), respectively. Diuretics proved to be used at the highest rate in both countries. The consumption of thiazides and loop diuretics in the Czech districts during 1/00 represented 67.6% and 16.7% of the all diuretic consumption on the average, whereas the corresponding values in Wales were 42.3% for thiazide preparations and 46.7% for the loop diuretics. An increase in the consumption of new drugs such as ACE inhibitors, calcium channel blockers of 2nd generation and statins was noted in both countries. The statins represented 33.5% of total prescription of hypolipidemic drugs in the Czech districts, whereas their consumption in the Welsh districts represented 88.1% consumption of these drugs. The most significant differences were found in the consumption of diuretics and hypolipidemic drugs. The results of consumption studies could highlight the differences in drug utilization and thereby stimulate discussion on optimization of drug selection.",2003.0,0,0 2342,14518613,The challenges of treating peripheral arterial disease.,Christian F A Kügler; Gottfried Rudofsky,"Today, peripheral arterial disease (PAD) patients need effective medical care for an extended period of their lifetime. Therefore, different treatment modalities have to be tied sequentially into an effective therapeutic chain. First, preventive measures have to be reinforced and risk factors tightly controlled. Furthermore, antiplatelet agents have to be applied in every PAD patient to reduce the risk of cardiac and cerebral ischemic events, restenosis or reocclusion after revascularization, and possibly also progression of the PAD itself. Angiotensin-converting enzyme (ACE) inhibitors should be entertained in high-risk groups such as PAD patients with diabetes. In the claudicant, exercise therapy should be strongly encouraged and vasoactive drugs considered for those who are not good candidates for either exercise training or revascularization. In patients with disabling claudication or critical limb ischemia, revascularization procedures are highly effective. Especially for high-grade stenoses or short arterial occlusions, percutaneous transluminal angioplasty (PTA) should be the method of first choice followed by the best surgical procedure later on. To achieve good long-term efficacy, a close follow-up including objective tests of both the arterial lesion and hemodynamic status, surveillance of secondary preventive measures and risk factor control is mandatory.",2003.0,0,0 2343,14522569,Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function--a flow cytometry study.,Horst Neubauer; Bülent Günesdogan; Christoph Hanefeld; Martin Spiecker; Andreas Mügge,"Clopidogrel is a pro-drug which is converted to an active, unstable drug by cytochrome P450 (CYP). The active drug irreversibly blocks one specific platelet adenosine 5'-diphosphate (ADP) receptor (P2Y12). It has been recently suggested that the most abundant human CYP isoform, 3A4, activates clopidogrel. Since certain lipophilic statins (i.e. simvastatin, atorvastatin, lovastatin) are a substrate of CYP3A4, we were interested in potential drug interactions between clopidogrel and statins. In patients with coronary artery disease (n=47) in whom clopidogrel treatment was initiated for balloon angioplasty and stent implantation, blood samples were taken at 0, 5 and 48 h after oral administration of clopidogrel (loading dose 300 mg, followed by 75 mg daily). ADP-stimulated (1, 10, 100 micromol/l) expression of P-selectin (CD62P) on platelets was measured by flow cytometry, and used as a marker for the antiplatelet effect of clopidogrel. Pre-treatment with statins (atorvastatin, simvastatin) reduced significantly (10 micromol/l ADP stimulation) the inhibitory effects of clopidogrel during the loading phase (relative reduction after 5 h 29.3%) and, to a lesser extent during the maintenance phase (relative reduction after 48 h 16.6%). In addition we found a considerable individual heterogeneity in the response and three patients (6%) were identified in whom clopidogrel exerted almost no effect. Certain statins which are substrates of the CYP3A4 isoform competitively inhibit the metabolic activation of clopidogrel. As a result the relative clopidogrel induced platelet inhibition (P-selectin-expression) is diminished--but still there is a relative clopidogrel effect of more than 80% in the maintenance phase. It may be reasonable to test the therapeutic efficacy of clopidogrel in those patients who require long-term treatment.",2003.0,0,0 2344,14525878,Taking simvastatin in the morning compared with in the evening: randomised controlled trial.,Alan Wallace; David Chinn; Greg Rubin,,2003.0,0,0 2345,14528286,Small-molecule cyclin-dependent kinase modulators.,Adrian M Senderowicz,"Aberrations in cell cycle progression occur in the majority of human malignancies. The main pathway affected is the retinoblastoma (Rb) pathway. The tumor suppressor gene Rb is an important component in the G(1)/S transition and its function is abnormal in most human neoplasms. Loss in Rb function occurs by the hyperactivation of the cyclin-dependent kinases (cdk's). Therefore, modulation of cdk's may have an important use for the therapy and prevention of human neoplasms. Efforts to obtain small-molecule cdk modulators yielded two classes of modulators: direct and indirect modulators. Direct cdk modulators are small molecules that specifically target the ATP binding site of cdk's. Examples for this group include flavopiridol, roscovitine and BMS-387032. In contrast, indirect cdk modulators affect cdk function due to modulation of upstream pathways required for cdk activation. Some examples include perifosine, lovastatin, and UCN-01. The first example of a direct small-molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. Clinical trials with this agent were performed with at least three different schedules of administration: 1-, 24- and 72-h infusions. The main toxicities for infusions >/=24-h are secretory diarrhea and proinflammatory syndrome. In addition, patients receiving shorter infusions have nausea/vomiting and neutropenia. A phase II trial of patients with advanced non-small-cell lung carcinoma using the 72-h infusion every 2 weeks was recently completed. The median overall survival for the 20 patients who received treatment was 7.5 months, a survival similar to that obtained in a randomized trial of four chemotherapy regimens containing platinum analogues in combination with taxanes or gemcitabine, or with gefitinib, a recently approved EGFR inhibitor for the treatment of advanced lung cancer. Based on these encouraging results, a phase III trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of direct small-molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca(2+)-dependent PKCs, promotes apoptosis, arrests cell cycle progression at G(1)/S, and abrogates checkpoints upon DNA damage. The first phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72-h continuous infusion every 4 weeks (in second and subsequent cycles UCN-01 is administered as a 36-h infusion). Other shorter schedules (i.e. 3 h) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia, and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, phase I trials with two novel small-molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. In summary, novel small-molecule cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies.",2003.0,0,0 2346,14529367,Physiological approaches to the prediction of drug-drug interactions in study populations.,J Y Chien; M A Mohutsky; S A Wrighton,"The prediction of metabolic drug-drug interactions should include quantitative attributes, such as variability in the study populations, and the results should be presented in terms of probability and uncertainty. The simple algebraic equations used to calculate one mean value for the extent of drug-drug interaction are adequate for qualitative or semi-quantitative risk assessment. However, truly quantitative predictions continue to fail. The success of drug-drug interaction predictions requires understanding of the relationship between drug disposition and quantifiable influential factors on the change in systemic exposure. The complex interplay of influential factors, including variability estimates, on successful prediction of drug interaction have not been systematically examined. Therefore, physiologically relevant models of metabolic drug-drug interaction will likely play increasingly important roles in improving quantitative predictions and in the assessment of the influential factors underlying the interactions. The physiologically-based approach, with stochastic considerations, offers a powerful alternative to the empirical calculation of mean values. In addition to quantitative estimation of the interaction for assessing probability of risk, a reasonably validated predictive model is useful for prospective optimization of study designs. As a consequence, the definitive clinical trial would yield more meaningful information to support dosing recommendations. This review focuses on illustrating the importance of an integrated approach to building useful models for prediction of metabolism-based drug-drug interactions in human subjects.",2003.0,0,0 2347,14529370,Prediction of human drug metabolizing enzyme induction.,Dayna C Mankowski; Sean Ekins,"New chemical entities are routinely screened in vitro and in vivo for their ability to induce cytochrome P450s (CYP), other drug-metabolizing enzymes and possibly transporters in an attempt to more accurately predict clinical parameters such as drug-drug interactions and clearance in humans. Some of these potential therapeutic agents can cause induction of the metabolism of another molecule or auto-induction thereby increasing their own metabolism and elimination, as well as potentially any molecules metabolized by the same enzyme(s). Key CYPs in the 1A, 2B, 2C, and 3A families have all been shown to be inducible. It would be clearly advantageous to know the potential for a compound to induce drug metabolizing enzymes or transporters prior to clinical development, and many in vitro systems have been developed for this purpose. Newer computational technologies are also being applied in order to attempt to predict induction from the molecular structure alone before a molecule is even synthesized or tested. This review will cover the various in vitro and in silico methods developed for prediction of key inducers of CYPs and other proteins, as well as the limitations of such technologies and applications in the future.",2003.0,0,0 2348,14529594,Estrogen plus progestin may increase incidence of dementia.,Nicole S Culhane,,2003.0,0,0 2349,14550919,Pravastatin at 10 mg/day does not decrease plasma levels of either amyloid-beta (Abeta) 40 or Abeta 42 in humans.,Kazuhiro Ishii; Takahiko Tokuda; Teruhiko Matsushima; Fuyuki Miya; Shin'ichi Shoji; Shu-ichi Ikeda; Akira Tamaoka,"It has been assumed that statins work as a preventative drug for Alzheimer's disease (AD). Although some epidemiological observations raise doubts to the effectiveness of statins for AD, many in vitro and clinical studies insist on the effectiveness of statins decreasing amyloid-beta (Abeta) levels in medium or blood. To explore the effect of pravastatin on Abeta production, we followed the longitudinal plasma levels of both Abeta 40 and Abeta 42 during the allocation of pravastatin in 46 patients with hyperlipidemia. We found no correlation between plasma cholesterol levels or the decreasing values of total cholesterol and those of Abeta 40 or Abeta 42. Patients having Apolipoprotein E4 (ApoE4) had higher low-density lipoprotein levels and lower Abeta 40 levels in plasma, suggesting ApoE4 seems to influence plasma Abeta levels via cholesterol metabolism.",2003.0,0,0 2350,14551064,Is concordance the primrose path to health?,Robin E Ferner,,2003.0,0,0 2351,14557343,Aldosterone blockade in patients with systolic left ventricular dysfunction.,Bertram Pitt,,2003.0,0,0 2352,14558433,Pharmacological comparison of the statins.,Ulrich Klotz,"The statins (3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors) represent drugs of first choice for treatment of hypercholesterolemia. The safety and efficacy of atorvastatin (CAS 134523-00-5), simvastatin (CAS 79902-63-9), lovastatin (CAS 75330-75-7), pravastatin (CAS 81093-37-0) and fluvastatin (CAS 93957-54-1) has been well documented. Statins decrease dose-dependently low-density lipoprotein (LDL) cholesterol as well as coronary events and total mortality. Clinical outcome data indicate that for simvastatin the lowest number of treated patients is needed to prevent one major coronary event (NNT 15). Based on an approximately 30% reduction of LDL (valid surrogate parameter) atorvastatin (5 mg/day) and simvastatin (10 mg/day) are the most potent agents whereas 40 mg of lovastatin or pravastatin and 60 mg of fluvastatin are needed to reach this ""therapeutic target"". While all statins share the same mode of action their pharmacokinetic properties and their susceptibility to drug interactions differ slightly. Agents inhibiting CYP3A4 (e.g. grapefruit juice, itraconazole, cyclosporine) should be discouraged if a patient is on atorvastatin, lovastatin or simvastatin. Likewise, fluconazole interferes with the CYP2C9-mediated hepatic elimination of fluvastatin. Moreover, coadministration of gemfibrozil should be avoided because it seems to increase the very low risk for statin-induced rhabdomyolysis. Several statins are available and their equieffective doses have been defined. Selection of a particular drug should be primarily based on clinical outcome data. However, costs and in certain situations the pharmacokinetic profile including the interaction potential of the statins should be taken into account.",2003.0,0,0 2353,14561376,Report from the 55th Annual Meeting of the American Academy of Neurology (AAN).,Sten Fredrikson,,2003.0,0,0 2354,14563343,Effect of pravastatin on LDL particle concentration as determined by NMR spectroscopy: a substudy of a randomized placebo controlled trial.,Gavin J Blake; Michelle A Albert; Nader Rifai; Paul M Ridker,"Recent data suggests that LDL particle concentration, as determined by Nuclear Magnetic Resonance (NMR) spectroscopy, may be associated with cardiovascular risk. We sought to determine the effect of randomization to pravastatin therapy on LDL particle concentration-NMR, among a primary prevention population. LDL particle concentration-NMR, LDL size-NMR, and standard chemical lipid parameters were measured at baseline and after 12 weeks among 500 individuals without overt coronary disease randomly allocated to pravastatin 40mg (n=256) or placebo (n=244). Randomization to pravastatin therapy caused a 19% reduction in median LDL particle concentration-NMR at 12 weeks, as compared to a 4.2% increase among those randomized to placebo (P<0.001 for pravastatin group compared to placebo). Pravastatin therapy caused a median 24.9% reduction in LDL cholesterol measured chemically compared to a 0.9% increase in the placebo group (P<0.001). Pravastatin therapy did not cause a significant change in median LDL size-NMR (0.5% increase in pravastatin group vs 0.0% in placebo group; P=0.25). The change in LDL particle concentration with pravastatin correlated inversely with baseline LDL size (r=-0.24; P<0.001) such that the largest reduction in LDL particle concentration-NMR was among those with the smallest LDL size-NMR at baseline (median% change =21.4% for tertile 1 of LDL size, 19.9% for tertile 2, and 16.5% for tertile 3; P=0.03). In contrast, pravastatin-induced changes in LDL cholesterol did not correlate with baseline LDL size-NMR (r=-0.05; P=0.47). Among individuals without overt hyperlipidemia or known coronary artery disease, randomized allocation to pravastatin (40mg) therapy for 12 weeks caused a reduction in LDL particle concentration-NMR, the magnitude of which was dependent on baseline LDL size-NMR.",2003.0,0,0 2355,14564305,Pharmaceutical advertising versus research spending: are profits more important than patients?,Debabrata Mukherjee; Eric J Topol,,2003.0,0,0 2356,14564313,"Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS).",Mitsuhiro Yokoyama; Hideki Origasa; JELIS Investigators,"The principle aim of the current study is to test the hypothesis that the long-term use of highly purified EPA (eicosapentaenoic acid: 1800 mg/day), in addition to HMG-CoA reductase inhibitor, is effective in preventing cardiovascular events in Japanese patients with hypercholesterolemia. Epidemiological and clinical evidence suggest that intake of long-chain polyunsaturated n-3 fatty acids (PUFAs), which are abundant in fish, might have a significant role in the prevention of coronary artery disease, as marine PUFAs have multiple biological functions through lipid-dependent and lipid-independent mechanisms. The Japan EPA Lipid Intervention Study (JELIS) is a prospective, randomized, open-label, blinded end point trial including both primary and secondary prevention strata, with a maximum follow-up of 5 years. Its main purpose is to examine the clinical effectiveness of EPA oil given as an additional treatment to patients taking HMG-CoA reductase inhibitors for hypercholesterolemia. A primary end point is major coronary events: sudden cardiac death, fatal and nonfatal myocardial infarction, and unstable angina pectoris including hospitalization for documented ischemic episodes, and events of angioplasty/stenting or coronary artery bypass grafting. Secondary end points include all-cause mortality, stroke, peripheral artery disease, and cancer. Baseline study composition comprises 15,000 participants (4204 men and 10,796 women) in the primary prevention stratum and 3645 (1656 men and 1989 women) in the secondary stratum. The minimum age is 40 years for men, women are required to be postmenopausal, and all patients must be < or =75 years of age. The mean age of participants is 61 years, and 69% are female. The schedule for plasma fatty acid composition measurement is as follows: at baseline, at 6 month, and yearly thereafter. The mean baseline total and low-density lipoprotein cholesterol levels were 275 mg/dL (7.1 mmol/L) and 180 mg/dL (4.6 mmol/L). Results are expected in 2005. JELIS is a large clinical trial that will evaluate whether EPA can make an additional improvement in mortality and morbidity of coronary artery disease beyond that of HMG-CoA reductase inhibitor treatment.",2003.0,0,0 2357,14564329,,,,,0,0 2358,14568745,Stroke.,Charles Warlow; Cathie Sudlow; Martin Dennis; Joanna Wardlaw; Peter Sandercock,"Stroke is a major public-health burden worldwide. Prevention programmes are essential to reduce the incidence of stroke and to prevent the all but inevitable stroke epidemic, which will hit less developed countries particularly hard as their populations age and adopt lifestyles of the more developed countries. Efficient, effective, and rapid diagnosis of stroke and transient ischaemic attack is crucial. The diagnosis of the exact type and cause of stroke, which requires brain imaging as well as traditional clinical skills, is also important when it will influence management. The treatment of acute stroke, the prevention and management of the many complications of stroke, and the prevention of recurrent stroke and other serious vascular events are all improving rapidly. However, stroke management will only be most effective when delivered in the context of an organised, expert, educated, and enthusiastic stroke service that can react quickly to the needs of patients at all stages from onset to recovery.",2003.0,0,0 2359,14568856,Effects of statins on nonlipid serum markers associated with cardiovascular disease: a systematic review.,Ethan M Balk; Joseph Lau; Leonidas C Goudas; Harmon S Jordan; Bruce Kupelnick; Linda U Kim; Richard H Karas,"Statins reduce cardiovascular events to a greater extent than can be explained by their effect on lipids. Several studies have attempted to elucidate mechanisms by which statins reduce cardiovascular risk. To summarize the effects of statins on nonlipid serum markers and to correlate statins' effect on serum markers with lipid levels and cardiovascular outcomes. MEDLINE (1980 to 2003) search limited to English-language articles. Studies reporting original data in at least 10 participants on the effect of statins on outcomes of interest, excluding studies of cerivastatin, drug combinations, and patients with organ transplants. Study design, sample size, treatment, and outcome data extracted on the basis of preestablished criteria. When appropriate, meta-analysis was performed by using a random-effects model. All statins are effective at lowering C-reactive protein levels, and the effect is not dose-dependent. Studies do not demonstrate a correlation between statins' effects on C-reactive protein levels and on lipids or cardiovascular outcomes. Statins do not affect fibrinogen levels, and limited data suggest little effect on lipid oxidation, tissue plasminogen activator, or plasminogen activator inhibitor. Platelet aggregation data are inconclusive. Among nonlipid serum markers examined, only C-reactive protein levels are statistically significantly affected by statins. These findings suggest that statin-mediated anti-inflammatory effects may contribute to the ability of statins to reduce risk for cardiovascular disease. Overall, however, available data are insufficient to support recommendations for using nonlipid serum markers in decisions regarding statin therapy for individual patients.",2003.0,1,1 2360,14568892,Effects of statins on platelet inhibition by a high loading dose of clopidogrel.,Iris Müller; Felicitas Besta; Christian Schulz; Zhongyan Li; Steffen Massberg; Meinrad Gawaz,"Recent studies suggested that some HMG-CoA reductase blockers might inhibit the antiplatelet activity of clopidogrel. Therefore, we analyzed how various statins together with a high loading dose of clopidogrel (600 mg) affect platelet aggregation. Seventy-seven patients with stable angina scheduled for elective coronary stenting were studied. Patients were randomized to receive atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin (each 20 mg), cerivastatin (0.3 mg), or placebo, plus a high loading dose of 600 mg of clopidogrel. ADP-induced platelet aggregation (5 and 20 micromol/L) was determined before and 2 and 4 hours after first clopidogrel administration. All patients were taking aspirin (100 mg/d) regularly. We found that none of the statins significantly influenced inhibition of platelet aggregation by clopidogrel. Concomitant use of statins with clopidogrel does not significantly inhibit antiplatelet activity, at least when clopidogrel is administered at a high loading dose of 600 mg.",2003.0,0,0 2361,14573737,Clinical practice. Gout.,Robert A Terkeltaub,,2003.0,0,0 2362,14576420,Race and medicine.,Constance Holden,,2003.0,0,0 2363,14579811,Rosuvastatin calcium.,Jeremy Quirk; Mark Thornton; Peter Kirkpatrick,,2003.0,0,0 2364,14579987,Current perspectives on statins.,Trinath Kumar Mishra; Satyanarayan Routray,"As the epidemic of coronary artery disease rages on round the globe, research is always on to find suitable drugs to reverse the trend. While aspirin, beta-blockers and ACE inhibitors have been shown to reduce coronary mortality and morbidity, statins are rapidly coming to fore as another important cog in the wheel of primary and secondary prevention of coronary artery disease. Newer trial like Heart Protection Study suggests benefit of statin for high risk individuals, irrespective of initial serum cholesterol concentrations. This may be of great relevance in the Indian context taking into consideration the vast majority of coronary artery disease patients having normal to mildly elevated serum cholesterol in contrast to their western counterparts.",2003.0,0,0 2365,14581396,Human epicardial adipose tissue is a source of inflammatory mediators.,Tomasz Mazurek; LiFeng Zhang; Andrew Zalewski; John D Mannion; James T Diehl; Hwyda Arafat; Lea Sarov-Blat; Shawn O'Brien; Elizabeth A Keiper; Anthony G Johnson; Jack Martin; Barry J Goldstein; Yi Shi,"Inflammatory mediators that originate in vascular and extravascular tissues promote coronary lesion formation. Adipose tissue may function as an endocrine organ that contributes to an inflammatory burden in patients at risk of cardiovascular complications. In this study, we sought to compare expression of inflammatory mediators in epicardial and subcutaneous adipose stores in patients with critical CAD. Paired samples of epicardial and subcutaneous adipose tissues were harvested at the outset of elective CABG surgery (n=42; age 65+/-10 years). Local expression of chemokine (monocyte chemotactic protein [MCP]-1) and inflammatory cytokines (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) was analyzed by TaqMan real-time reverse transcription-polymerase chain reaction (mRNA) and by ELISA (protein release over 3 hours). Significantly higher levels of IL-1beta, IL-6, MCP-1, and TNF-alpha mRNA and protein were observed in epicardial adipose stores. Proinflammatory properties of epicardial adipose tissue were noted irrespective of clinical variables (diabetes, body mass index, and chronic use of statins or ACE inhibitors/angiotensin II receptor blockers) or plasma concentrations of circulating biomarkers. In a subset of samples (n=11), global gene expression was explored by DNA microarray hybridization and confirmed the presence of a broad inflammatory reaction in epicardial adipose tissue in patients with coronary artery disease. The above findings were paralleled by the presence of inflammatory cell infiltrates in epicardial adipose stores. Epicardial adipose tissue is a source of several inflammatory mediators in high-risk cardiac patients. Plasma inflammatory biomarkers may not adequately reflect local tissue inflammation. Current therapies do not appear to eliminate local inflammatory signals in epicardial adipose tissue.",2003.0,0,0 2366,14582446,Is there a 'treatment gap' in acute coronary syndromes?,Brian R Krause; Roger S Newton,,2003.0,0,0 2367,14582452,Prospects for prevention and treatment of vascular cognitive impairment.,Silvia Di Legge; Vladimir Hachinski,"With the aging population and rising prevalence of vascular disease in developed and developing countries, increasing numbers of individuals are at risk of cognitive impairment. Despite the potential of the therapeutics that are currently under investigation, none have yet fulfilled their promise for the prevention and treatment of dementia. The term vascular cognitive impairment (VCI) describes individuals with significant cognitive impairment arising from vascular disease. Risk factors predisposing to stroke correlate with brain changes, cognitive loss and Alzheimer's disease pathology. The volume of the infarcts and white matter changes, silent lacunar infarcts, and global and regional brain atrophy may be imaged non-invasively, targeted as surrogates of the dementia processes and considered parameters to be targeted for interventional strategies. As the greatest chance to prevent cognitive impairment and its progression is by intervening in the early stages or prior to any change, the development of preventative therapeutics is an important strategy. Non-invasive magnetic resonance imaging techniques may help to identify a subgroup of patients in whom infarct prevention, via risk factor control, may be of paramount importance. As the pathophysiology of dementia becomes more fully understood by coupling neuropsychological with neuroimaging, genetic and pathological features, there is the potential for the establishment of diagnostic criteria of the early phase of VCI and the testing of novel interventional strategies.",2003.0,0,0 2368,14582453,Diabetes mellitus: a cardiovascular disease.,Riccardo Candido; Piyush Srivastava; Mark E Cooper; Louise M Burrell,"Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with diabetes mellitus (DM). The pathophysiology of CVD in diabetes involves traditional and novel cardiac risk factors, including hypertension, dyslipidemia, smoking, genetic factors, hyperglycemia, insulin resistance/hyperinsulinemia, metabolic abnormalities, oxidative/glycoxidative stress, inflammation, endothelial dysfunction, a procoagulant state and myocardial fibrosis. Specific vascular, myopathic and neuropathic alterations have been suggested to be responsible for the excessive cardiovascular morbidity and mortality in diabetes. These alterations manifest themselves clinically as coronary heart disease, congestive heart failure and/or sudden cardiac death. In order to contain the emerging epidemic of CVD in DM, diabetic patients should ideally have excellent glycemic control, a low normal blood pressure and low levels of low-density lipoprotein cholesterol, and be taking an angiotensin-converting enzyme inhibitor and aspirin, which may go some way to containing the emerging epidemic of CVD in DM.",2003.0,0,0 2369,14582454,Acyl-coenzyme A:cholesterol acyltransferase inhibitors for controlling hypercholesterolemia and atherosclerosis.,Akira Miyazaki; Masakazu Sakai; Yuichiro Sakamoto; Seikoh Horiuchi,"Acyl-coenzyme A:cholesterol acyltransferase (ACAT; Sterol O-acyltransferase/SOAT) is an intracellular enzyme that catalyzes the formation of cholesteryl esters from cholesterol and fatty acyl-coenzyme A. ACAT inhibitors reduce plasma cholesterol levels by suppressing absorption of dietary cholesterol and by suppressing the assembly and secretion of apolipoprotein B-containing lipoproteins such as very low density lipoprotein in liver and chylomicron in intestine. Moreover, ACAT inhibitors prevent the conversion of macrophages into foam cells in the arterial walls. Thus, ACAT inhibitors are under investigation for controlling hypercholesterolemia and the development of atherosclerosis. Some potent ACAT inhibitors have been tested for their efficacy and safety in humans.",2003.0,0,0 2370,14583366,Adherence with statin therapy in secondary prevention of coronary heart disease in veterans administration male population.,Branko Kopjar; Anne E B Sales; Sandra L Piñeros; Haili Sun; Yu-Fang Li; Ashley N Hedeen,"This retrospective cohort study enrolled 8,768 male Veterans Administration patients with coronary heart disease who were prescribed statins from July 1, 1999, to June 30, 2000. After 18 months of follow-up, 71% of the patients had been dispensed >or=80% of the medication. Our population's persistence in using statins was higher than in other open-population cohorts but lower than in randomized controlled trials.",2003.0,0,0 2371,14583367,Pharmacoeconomic evaluation of the effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes.,Gregory G Schwartz; Peter Ganz; David Waters; Steve Arikian,"An economic analysis was conducted using clinical outcomes in the MIRACL trial that evaluated high-dose atorvastatin versus placebo for 16 weeks after acute coronary syndrome. The direct cost of atorvastatin was largely offset by the associated decrease in cardiovascular events. The net incremental cost of atorvastatin treatment was 157 dollars/patient with a cost-effectiveness ratio of 4,086 dollars/event avoided.",2003.0,0,0 2372,14583368,Effect of pretreatment vitamin D levels on in vivo effects of atorvastatin on bone metabolism in patients with heterozygous familial hypercholesterolemia.,Kouji Kajinami; Noboru Takekoshi; Shinobu Matsui; Seiyu Kanemitsu; Shinji Okubo; Sugako Kanayama; Naohiro Yamashita; Ryoko Sato,"To find the clinical variables associated with atorvastatin's effects on bone metabolism markers, 35 patients with heterozygous familial hypercholesterolemia were treated with atorvastatin for 24 weeks, and the levels of bone formation markers (bone-specific alkaline phosphatase and osteocalcin) and resorption marker (urine collagen type-1 cross-linked N-telopeptide) were determined. Pretreatment vitamin D levels showed significant and positive associations with changes in 2 bone formation markers. The serial changes in 3 markers were favorable-increased bone formation markers and unchanged bone resorption marker-but the changes occurred only in patients with pretreatment vitamin D levels >50 pg/ml.",2003.0,0,0 2373,14601690,Effect of a high saturated fat and no-starch diet on serum lipid subfractions in patients with documented atherosclerotic cardiovascular disease.,James H Hays; Angela DiSabatino; Robert T Gorman; Simi Vincent; Michael E Stillabower,"To determine whether a diet of high saturated fat and avoidance of starch (HSF-SA) results in weight loss without adverse effects on serum lipids in obese nondiabetic patients. Twenty-three patients with atherosclerotic cardiovascular disease participated in a prospective 6-week trial at the Christiana Care Medical Center in Newark, Del, between August 2000 and September 2001. All patients were obese (mean +/- SD body mass index [BMI], 39.0+/-7.3 kg/m2) and had been treated with statins before entry in the trial. Fifteen obese patients with polycystic ovary syndrome (BMI, 36.1+/-9.7 kg/m2) and 8 obese patients with reactive hypoglycemia (BMI, 46.8+/-10 kg/m2) were monitored during an HSF-SA diet for 24 and 52 weeks, respectively, between 1997 and 2000. In patients with atherosclerotic cardiovascular disease, mean +/- SD total body weight (TBW) decreased 5.2%+/-2.5% (P<.001) as did body fat percentage (P=.02). Nuclear magnetic resonance spectroscopic analysis of lipids showed decreases in total triglycerides (P<.001), very low-density lipoprotein (VLDL) triglycerides (P<.001), VLDL size (P<.001), large VLDL concentration (P<.001), and medium VLDL concentration (P<.001). High-density lipoprotein (HDL) and LDL concentrations were unchanged, but HDL size (P=.01) and LDL size (P=.02) increased. Patients with polycystic ovary syndrome lost 14.3%+/-20.3% of TBW (P=.008) and patients with reactive hypoglycemia lost 19.9%+/-8.7% of TBW (P<.001) at 24 and 52 weeks, respectively, without adverse effects on serum lipids. An HSF-SA diet results in weight loss after 6 weeks without adverse effects on serum lipid levels verified by nuclear magnetic resonance, and further weight loss with a lipid-neutral effect may persist for up to 52 weeks.",2003.0,0,0 2374,14602771,Effects of bezafibrate and simvastatin on endothelial activation and lipid peroxidation in hypercholesterolemia: evidence of different vascular protection by different lipid-lowering treatments.,Giovambattista Desideri; Giuseppe Croce; Marzia Tucci; Gabriella Passacquale; Simona Broccoletti; Letizia Valeri; Anna Santucci; Claudio Ferri,"Hypercholesterolemia is combined with enhanced lipid peroxidation, which can promote atherogenesis by inducing endothelial adhesion molecule expression. Statins may protect vascular endothelium in hypercholesterolemia by reducing enhanced plasma levels of low-density lipoprotein and decreasing oxidative stress. Herein, we describe increased circulating levels of soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin and total 8-iso-prostaglandin F(2 alpha) (8-iso-PGF(2 alpha)) concentrations, as indexes of endothelial activation and lipid peroxidation, respectively, in 67 hypercholesterolemic patients compared with 32 normocholesterolemic subjects. Significant cholesterol reductions were achieved in hypercholesterolemic patients after 6 months under either simvastatin (40 mg/d) or bezafibrate (800 mg/d) treatment, given according to a randomized double-blind trial. Simvastatin but not bezafibrate simultaneously reduced soluble adhesin and total 8-iso-PGF(2 alpha) concentrations also. Vitamin E supplementation (400 IU/d) further reduced indexes of endothelial activation and lipid peroxidation in simvastatin-treated patients and significantly reduced the above indexes in bezafibrate-treated patients. Changes in circulating soluble adhesion molecule levels were directly correlated with changes in total 8-iso-PGF(2 alpha) concentrations in simvastatin-treated patients also receiving vitamin E supplementation. All together, our data demonstrated that hypercholesterolemia was combined with endothelial activation and lipid peroxidation, which were efficaciously counteracted by simvastatin but not bezafibrate treatment. Thus, a different vascular protection can be achieved by different lipid-lowering treatments.",2003.0,0,0 2375,14604738,"Pharmacology and therapeutics of ezetimibe (SCH 58235), a cholesterol-absorption inhibitor.",LilyAnn Jeu; Judy W M Cheng,"Ezetimibe is the first of a new class of antihyperlipidemic agents, the cholesterol-absorption inhibitors. It is indicated for monotherapy or in combination with 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins) in patients with primary hypercholesterolemia, in combination with simvastatin or atorvastatin in patients with homozygous familial hypercholesterolemia, and as monotherapy in patients with homozygous familial sitosterolemia. This article reviews available data on the clinical pharmacology, clinical efficacy, and tolerability of ezetimibe. A literature review was conducted using the search terms ezetimibe and SCH 58235 to identify articles and abstracts indexed in MEDLINE and the Iowa Drug Information Service from 1966 to February 2003. The reference lists of the identified articles were reviewed for additional publications. In adults, ezetimibe 10 mg PO given once daily has been reported to reduce intestinal cholesterol absorption by 54% from baseline in association with a compensatory increase in endogenous cholesterol synthesis. Within 2 weeks of its initiation, ezetimibe monotherapy produced a 17% to 20% reduction from baseline in low-density lipoprotein cholesterol (LDL-C); in combination with statins, ezetimibe produced a reduction in LDL-C of up to 40% over the same period. Based on studies performed to date, ezetimibe appears to be well tolerated, with a safety profile similar to that of placebo. Because ezetimibe is eliminated primarily by glucuronidation and not by cytochrome P450 (CYP) oxidation, it is subject to minimal drug interactions involving the CYP enzyme system. Ezetimibe is an option for monotherapy in patients with mild hypercholesterolemia or in those requiring adjunctive drug therapy for reduction of LDL-C levels. It may be useful in patients at risk for adverse events (eg, liver toxicity, myopathy) from other hypocholesterolemic agents. Additive LDL-C-lowering effects of ezetimibe may allow use of lower doses of conventional agents (eg, statins, fibric acid derivatives, niacin) to achieve an equivalent effect, thereby reducing the potential for adverse events and drug interactions. However, because trials have lasted no longer than 12 weeks, the long-term effect of ezetimibe on cardiovascular morbidity and mortality remains to be determined.",2003.0,0,0 2376,14604742,A retrospective analysis of the effect of noncompliance on time to first major adverse cardiac event in LIPS.,Emmanuel Lesaffre; Dora Kocmanová; Pedro A Lemos; Clemens M C Disco; Patrick W Serruys,"In the main publication for LIPS (Lescol Intervention Prevention Study), a 22% relative risk (RR) reduction for major adverse cardiac events (MACE) was found among those who used fluvastatin after a successful first percutaneous coronary intervention (PCI). However, intent-to-treat (ITT) analysis of clinical studies generally provides an observed treatment effect that is likely to underestimate what the treatment effect would be if compliance were perfect, because compliance in a clinical trial is invariably <100% during long-term follow-up. The aim of this study was to analyze the relationship between compliance and treatment effect in LIPS. In LIPS, patients who had undergone a successful first PCI were randomized to receive fluvastatin 40 mg BID or placebo BID for 3 to 5 years. The primary end point was survival time free of MACE (ie, cardiac death, nonfatal myocardial infarction, or reintervention procedure), and a Cox proportional hazards regression model with time-dependent covariates was used to predict the effect that fluvastatin would have had if trial medication had been continued. Logistic regression was used to determine factors influencing discontinuation of trial medication. A total of 1677 patients were enrolled in LIPS: 844 in the fluvastatin group and 833 in the placebo group. In the fluvastatin group, 294 patients (34.8%) discontinued taking trial medication and 73 (8.6%) switched to another lipid-lowering medication, compared with 353 (42.4%) and 187 (22.4%) patients in the placebo group, respectively. The risk factor-adjusted RR of MACE with fluvastatin treatment was 0.74 (P = 0.004; 95% CI, 0.61-0.91). When also adjusted for noncompliance, the RR for fluvastatin versus placebo was 0.68 (P = 0.002; 95% CI, 0.53-0.86). Discontinuing fluvastatin without switching to another lipid-lowering medication increased the risk of MACE compared with that of patients who stayed on fluvastatin (RR = 2.27; P < 0.001; 95% CI, 1.60-3.23) and the increase in the risk of MACE was greater than that associated with discontinuing placebo (P = 0.032). The present study found a 32% RR reduction for experiencing MACE during fluvastatin treatment after a successful PCI in LIPS, when analysis allowed for noncompliance. This suggests that the ITT analysis discussed in the main LIPS publication underestimated the benefit of fluvastatin treatment. Our survival model also provided tentative evidence that discontinuing lipid-lowering medication might lead to a potentially harmful rebound effect in this patient group.",2003.0,0,0 2377,14605034,The effect of successful heart transplant treatment of heart failure on central sleep apnea.,Darren R Mansfield; Peter Solin; Teanau Roebuck; Peter Bergin; David M Kaye; Matthew T Naughton,"Central sleep apnea (CSA) associated with Cheyne-Stokes respiration in patients with congestive heart failure (CHF) is thought to be an acquired pattern of respiratory control instability related, at least in part, to elevated sympathetic nervous system activity. The effect of restoring heart function to normal with heart transplantation in patients with CHF and CSA has only been reported within weeks of the transplant and with varying results. The purpose of the study was to evaluate the impact of successful heart transplant on sympathetic nervous system activity and CSA severity in patients with CHF. Controlled prospective trial. University hospital. Twenty-two patients with CHF (13 patients with CSA, and 9 patients with no sleep-disordered breathing [SDB]). Polysomnography, left ventricular ejection fraction (LVEF), and overnight urinary norepinephrine excretion (UNE) were measured before and > 6 months after successful heart transplantation. In the CSA group, there was a fall in apnea-hypopnea index (AHI) [mean +/- SD, 28 +/- 15 to 7 +/- 6/h; p < 0.001] and UNE (48.1 +/- 30.9 to 6.1 +/- 4.8 nmol/mmol creatinine, p < 0.001) associated with normalization of LVEF (19.2 +/- 9.3% to 53.7 +/- 6.1%, p < 0.001) at 13.2 +/- 8.3 months following heart transplantation. Of the CSA group following transplantation, seven patients had no SDB (AHI < 5/h), three patients had persistent CSA (AHI, 12.3 +/- 0.9/h) and four patients acquired obstructive sleep apnea (OSA) [AHI, 11.2 +/- 7.4/h]. In comparison, none of the control group acquired CSA or OSA after transplantation. We conclude that CSA may persist despite normalization of heart function and sympathetic nerve activity.",2003.0,0,0 2378,14606112,Formalized therapeutic guideline for hyperlipidemic severe acute pancreatitis.,En-Qiang Mao; Yao-Qing Tang; Sheng-Dao Zhang,"To investigate a formalized therapeutic guideline for hyperlipidemic severe acute pancreatitis (HL-SAP). Thirty-two consecutive patients with severe acute pancreatitis were included in the clinical trial. All of them met the following five criteria for admission to the study, namely the Atlanta classification and stratification system for the clinical diagnosis of SAP, APACHEII score more than 8, time interval for therapeutic intervention less than 72 hours after onset of the disease, serum triglyceride (TG) level 6.8 mmol/l or over, and exclusion of other etiologies. They were divided into severe acute pancreatitis group (SAP, 22 patients) and fulminant severe acute pancreatitis group (FSAP, 10 patients). Besides the conventional therapeutic measures, Penta-association therapy was also applied in the two groups, which consisted of blood purification (adsorption of triglyceride and hemofiltration), antihyperlipidemic agents (fluvastatin or lipanthyl), low molecular weight heparin (fragmin), insulin, topical application of Pixiao (a traditional Chinese medicine) over the whole abdomen. Serum triglyceride, pro-inflammatory cytokines and anti-inflammatory cytokines were determined before blood purification (PF), at the end of blood purification (AFE) and on the 7th day after onset of the disease (AF7) respectively. Simultaneously, severity of the diseases was assessed by the APACHE II system. PROGNOSIS was evaluated by non-operation cure rate, absorption rate of pseudocyst, time interval pseudocyst absorption, hospital stay and survival rate. Serum triglyceride level (mmol/L), TNFalpha (U/ml) concentration and APACHE II score were significantly decreased (P<0.05) at AFE and AF7, as compared with PF. However, serum IL-10 concentration (pg/ml) was increased significantly (P<0.001) at AFE, and decreased significantly (P<0.05) at AF7 when compared with PF. The First surgical intervention time was 55.8+/-42.6 days in SAP group (5 patients) and 12.2+/-6.6 days in FSAP group (7 patients), there was a significant difference between the two groups (P=0.02). The number of operations in the two groups was 1.33+/-0.5 vs 3.5+/-1.2 (P=0.0037), respectively. Non-operation cure rate, absorption rate of pseudocyst, hospital stay and survival rate in SAP group and FSAP group were 100% (22/22) vs 11.1% (1/9), 77.3% (17/22) vs 11.1% (1/9), 54.2+/-35.9 vs 99.1+/-49.5 days (P=0.008) and 100%(22/22) vs 66.7% (6/9) (P=0.0044). The time for absorption of pseudocyst was 135.1+/-137.5 days in SAP group. Penta-association therapy is an effective guideline in the treatment of hyperlipidemic severe acute pancreatitis at its early stage (within 72 hours).",2003.0,0,0 2379,14609996,Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial.,Paul M Ridker; JUPITER Study Group,,2003.0,0,0 2380,14611010,Cardiovascular disease and lipids. Issues and evidence for the management of dyslipidaemia in primary care.,F D Hobbs,"The commonest manifestations of cardiovascular disease, namely coronary heart disease (CHD) and stroke, represent the two most common causes of death in the world today. Furthermore, cardiovascular diseases have the highest healthcare utilisation costs in most countries. Both primary and secondary prevention management strategies are essential. Although more than 200 risk factors for CHD have now been identified, the single most powerful predictor of CHD risk is abnormal lipid levels. The relative risk influences of the various lipid sub-fractions are described, with particular emphasis on LDL cholesterol, which represents the principal target for treatment in most management guidelines. Unfortunately, there remains considerable evidence of continued under-management of patients with elevated cholesterol and cardiovascular risk who are eligible for secondary prevention. The barriers contributing to such physician under-performance are numerous. The more recent recognition of the importance of identifying patients at enhanced risk, but without established disease (primary prevention), will require greatly familiarity with the clinical use of CHD risk scoring systems, most of which are based upon the Framingham equation. Special reference is made to groups at particular risk of CHD. In summary, the application of the enormous evidence-base for interventions in cardiovascular disease, especially over the treatment of elevated cholesterol, pose a huge challenge to primary and secondary care in most healthcare systems.",2003.0,0,0 2381,14613259,"New approaches to prevention of thrombosis in the antiphospholipid syndrome: hopes, trials, and tribulations.",Robert A S Roubey,,2003.0,0,0 2382,14613355,Combination therapy.,Margo A Denke,"Adult Treatment Panel III (ATP III) guidelines recommend specific treatment targets for low-density lipoprotein cholesterol (LDL-C) levels according to an individual.s short-term and long-term risk for coronary heart disease (CHD). Therapeutic lifestyle changes are recommended for all patients at any level of risk for CHD. Although most patients will achieve some LDL-C lowering with lifestyle modification, ATP III recognizes that a majority of patients with dyslipidemia will require drug therapy to reach their LDL goal. Surveys of physicians. practices suggest that only a small percentage of patients enrolled in an active treatment program actually achieve their LDL-C target. In addition, other surveys suggest that not all patients who are treatment candidates are receiving assessment. From a medication perspective, either up-titration of statin dose or the use of drug combinations should further enhance the likelihood of achieving target lipid levels. Combination therapies that target both the endogenous and exogenous pathways of cholesterol synthesis are particularly attractive. This paper reviews the pharmacotherapeutic effects of combination therapy, summarizes the strengths and weaknesses of current lipid-lowering drug combinations, and identifies the potential contribution of the novel cholesterol absorption inhibitor, ezetimibe, to the LDL-C treatment algorithm.",2003.0,0,0 2383,14623791,Indications for coronary artery bypass surgery and percutaneous coronary intervention in chronic stable angina: review of the evidence and methodological considerations.,Charanjit S Rihal; Dominic L Raco; Bernard J Gersh; Salim Yusuf,,2003.0,0,0 2384,14626470,Changing medication use in managed care: a critical review of the available evidence.,Sallie-Anne Pearson; Dennis Ross-Degnan; Ann Payson; Stephen B Soumerai,"To review the effectiveness of strategies to improve the quality and efficiency of medication use in managed care organizations (MCOs). Systematic review of published intervention studies. Studies were identified by using computerized and manual literature searches and personal contacts, and were categorized by intervention type and adequacy of research design according to commonly accepted criteria. Reported significance and magnitude of the changes in key outcomes were used to summarize the effects of studies with adequate research designs. The searches identified 105 studies, 70 of which were reported since 1996. Overall, 46% of the studies met the minimum criteria for methodologic adequacy (n = 48). Consistently effective interventions included dissemination of educational materials with drug samples, participatory clinical guideline development, group or one-to-one educational outreach, and enhanced patient-specific feedback. Disease management (primarily for depression and diabetes) showed promise in improving short-term outcomes. Dissemination of educational materials and aggregated feedback alone were ineffective. Interventions in staff-model health maintenance organizations were more effective than those conducted in group-model health maintenance organizations. High-quality studies of interventions to improve drug use in MCOs are increasing in frequency. There is evidence for the effectiveness of several strategies to change drug use, but little is known about longer-term clinical outcomes. Few well-designed, published studies have assessed the efficacy or safety of financial incentives for physicians, tiered copayments for patients, or formularies--despite their widespread use.",2003.0,0,0 2385,14627172,Ezetimibe: a new addition to lipid-lowering therapy.,A S Wierzbicki,,2003.0,0,0 2386,14627186,EUROPA shows role for ACE inhibition in low-risk CHD.,Olwen Glynn Owen,,2003.0,0,0 2387,14636780,Functional roles and therapeutic targeting of gelatinase B and chemokines in multiple sclerosis.,Ghislain Opdenakker; Inge Nelissen; Jo Van Damme,"Multiple sclerosis (MS) is a demyelinating disease of the CNS of unknown cause. Pathogenetic mechanisms, such as chemotaxis, subsequent activation of autoreactive lymphocytes, and skewing of the extracellular proteinase balance, are targets for new therapies. Matrix metalloproteinase gelatinase B (MMP-9) is upregulated in MS and was recently shown to degrade interferon beta, one of the drugs used to treat MS. Consequently, the effect of endogenously produced interferon beta or parenterally given interferon beta may be increased by gelatinase B inhibitors. Blockage of chemotaxis or cell adhesion molecule engagement, and inhibition of hydroxymethyl-glutaryl-coenzyme-A reductase to lower expression of gelatinase B, may become effective treatments of MS, alone or in combination with interferon beta. This may allow interferon beta to be used at lower doses and prevent side-effects.",2003.0,0,0 2388,14638524,"Should evidence-based proof of drug efficacy be extrapolated to a ""class of agents""?",Curt D Furberg; Bruce M Psaty,,2003.0,0,0 2389,14638526,Clinician guide to angiogenesis.,Neil P Fam; Subodh Verma; Michael Kutryk; Duncan J Stewart,,2003.0,0,0 2390,14644934,What do we gain from the sixth coronary heart disease drug?,Rebecca N Warburton,,2003.0,0,0 2391,14645303,Ethical aspects of recommending lifestyle interventions to patients.,Robert M Veatch,,2003.0,0,0 2392,14650474,"The Heart Protection Study: high-risk patients benefit from statins, regardless of LDL-C level.",Hitinder S Gurm; Byron Hoogwerf,"The landmark Heart Protection Study (Lancet 2002; 360:7-22) found benefit in treating subjects at high risk of a coronary event with simvastatin 40 mg daily, regardless of baseline low-density lipoprotein cholesterol level and in all subgroups, including women and the elderly. The study found no benefit of simvastatin therapy in preventing noncardiac events (eg, dementia, osteoporotic fractures), and no negative effects, such as an increase in cancer, respiratory disease, or suicide.",2003.0,0,0 2393,14652963,New anabolic agents in the treatment of osteoporosis.,Stephen Hough,,2003.0,0,0 2394,14657430,The effect of incentive-based formularies on prescription-drug utilization and spending.,Haiden A Huskamp; Patricia A Deverka; Arnold M Epstein; Robert S Epstein; Kimberly A McGuigan; Richard G Frank,"Many employers and health plans have adopted incentive-based formularies in an attempt to control prescription-drug costs. We used claims data to compare the utilization of and spending on drugs in two employer-sponsored health plans that implemented changes in formulary administration with those in comparison groups of enrollees covered by the same insurers. One plan simultaneously switched from a one-tier to a three-tier formulary and increased all enrollee copayments for medications. The second switched from a two-tier to a three-tier formulary, changing only the copayments for tier-3 drugs. We examined the utilization of angiotensin-converting-enzyme (ACE) inhibitors, proton-pump inhibitors, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Enrollees covered by the employer that implemented more dramatic changes experienced slower growth than the comparison group in the probability of the use of a drug and a major shift in spending from the plan to the enrollee. Among the enrollees who were initially taking tier-3 statins, more enrollees in the intervention group than in the comparison group switched to tier-1 or tier-2 medications (49 percent vs. 17 percent, P<0.001) or stopped taking statins entirely (21 percent vs. 11 percent, P=0.04). Patterns were similar for ACE inhibitors and proton-pump inhibitors. The enrollees covered by the employer that implemented more moderate changes were more likely than the comparison enrollees to switch to tier-1 or tier-2 medications but not to stop taking a given class of medications altogether. Different changes in formulary administration may have dramatically different effects on utilization and spending and may in some instances lead enrollees to discontinue therapy. The associated changes in copayments can substantially alter out-of-pocket spending by enrollees, the continuation of the use of medications, and possibly the quality of care.",2003.0,0,0 2395,7475814,Statins prevent coronary heart disease.,M F Oliver,,1995.0,0,0 2396,7478073,[Effects of simvastatin on blood levels of lipoprotein (a)].,F Galetta; T Sampietro; G Basta; G Giannasi; A Bionda,"The efficacy of Simvastatin to reduce plasma cholesterol is well documented. Other molecule within the lipo-lipoprotein family, such as, particularly, lipoprotein (a) -Lp(a)-, have been recently found to have a predictive and/or causative role in atherosclerosis. Based on the above consideration, we studied 20 patients (7 females and 13 males), mean age 52.4 +/- 14.2 years, affected by primary hypercholesterolemia to evaluate the effect of simvastatin on Lp(a), in addition to the classic lipidic parameters. Five weeks after suspension of lipid-lowering drugs and on a normal caloric-fat diet, were given 20 mg simvastatin/day for 12 months. Clinical and laboratory parameters, cholesterol (CH), triglycerides (TG), high density and low density lipoprotein cholesterol (HDL-CH and LDH-CH) measured enzymatically, apoproteins A1, B measured radial immunodiffusion technique and Lp(a) measured as apoprotein(a) with immunoradiometric assay and were evaluated before therapy and after 12 months of therapy. Simvastatin determined a significant reduction in total cholesterol and cholesterol-LDL (CH 327.7 +/- 44.4 vs 255.5 +/- 37.3, p < 0.0001; LDL-CH 257.1 +/- 60.9 vs 183.8 +/- 46.9, p < 0.0001) and a significant increase in HDL-CH (36.7 +/- 5.9 vs 40.2 +/- 5.7, p < 0.005); no variation was observed in triglycerides (TG) levels. Simvastatin therapy further determined a significant increase in Lp(a) plasma levels (43.8 +/- 25.6 vs 50.5 +/- 28.0, p < 0.02). The our data, in agreement with those documenting the beneficial effect of Simvastatin in greatly decreasing CH and LDL-CH, but point out the need for further studies concerning the long-ter effect of simvastatin on Lp(a), in order to fully establish its role in the secondary prevention of atherosclerosis.",1995.0,0,0 2397,7478355,Management of patients with dyslipidaemia.,J Mann; A Chisholm; M Crooke; R Jackson; J Neutze; D North; B Swinburn; H White; J Wilcox,,1995.0,0,0 2398,7482835,The efficacy and safety of fluvastatin in hypercholesterolemia in renal transplant recipients.,A J Ghods; I Milanian; H Arghani; G Ghadiri,,1995.0,0,0 2399,7484829,"Design, rational, and baseline characteristics of the Prospective Pravastatin Pooling (PPP) project--a combined analysis of three large-scale randomized trials: Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), Cholesterol and Recurrent Events (CARE), and West of Scotland Coronary Prevention Study (WOSCOPS).",,"The Prospective Pravastatin Pooling (PPP) project is a pooled evaluation of 3 large, placebo-controlled, randomized trials of cholesterol-lowering treatment with pravastatin. It is designed to more reliably evaluate the effect of treatment on coronary and all-cause mortality and on total coronary artery disease (CAD) events for specific populations of interest, including women and the elderly. The trials--Long-Term Intervention With Pravastatin in Ischemic Disease trial, the Cholesterol and Recurrent Events trial, and the West of Scotland Coronary Prevention Study--each have common design features, including drug, dose, and duration. The project prospectively defines the objectives, end points, and analytic plans in a protocol developed before results are known of any individual trial. More than 2,000 (or 10%) of the participants in the pooled data set are women, 1,841 are aged > or = 70 years at trial entry, and > 6,000 have a total cholesterol < 5.5 mmol/L (213 mg/dl). The mean low-density lipoprotein cholesterol level is 4.2 mmol/L (162 mg/dl). The mean blood pressure level is 134/81 mm Hg and 20% are current smokers. Half of the PPP participants have had a prior myocardial infarction. More than 7% have a history of diabetes and 26% have a history of hypertension. PPP is projected to have data on about 1,100 CAD deaths, 500 non-CAD deaths, and > 1,000 cancers by study completion.(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0 2400,7484908,"Combination of lovastatin, enalapril, and colchicine does not prevent restenosis after percutaneous transluminal coronary angioplasty.",M Freed; R D Safian; W W O'Neill; M Safian; D Jones; C L Grines,,1995.0,0,0 2401,7485045,Estrogen replacement therapy and progression of intimal-medial thickness in the carotid arteries of postmenopausal women. ACAPS Investigators. Asymptomatic Carotid Atherosclerosis Progression Study.,M A Espeland; W Applegate; C D Furberg; D Lefkowitz; L Rice; D Hunninghake,"The effect of estrogen replacement therapy (ERT) on 3-year changes in carotid intimal-medial thickness (IMT) was explored using serial B-mode ultrasound measurements collected during 1989-1993 as part of the Asymptomatic Carotid Atherosclerotic Progression Study (ACAPS). Eligibility included increased IMT and elevated low density lipoprotein cholesterol. Of the 186 postmenopausal ACAPS women randomly assigned to receive either placebo or lovastatin, 34% reported use of ERT. Users tended to be younger than nonusers by an average of 3 years, to have more favorable high and low density lipoprotein cholesterol levels, and to be more likely to have had hysterectomies. Baseline blood pressure, body mass index, and cross-sectional IMT were similar among ERT users and nonusers. In the placebo group, IMT tended to progress among ERT nonusers but to regress among ERT users: Mean covariate-adjusted progression rates were 0.015 +/- 0.007 mm/year versus -0.012 +/- 0.012 mm/year, respectively (p = 0.05). This difference appeared to be independent of lipoprotein concentrations. Lovastatin was associated with an approximately 25% lowering of low density lipoprotein cholesterol among both ERT users and nonusers and had a marked impact on IMT progression (p = 0.004) in these women. ERT appeared to have little additional effect on IMT in women assigned to lovastatin. ERT may reduce or halt the progression of early atherosclerosis in women not receiving active lipid-lowering medication.",1995.0,0,0 2402,7488443,Angiographic trials of lipid-lowering therapy: end of an era?,G R Thompson,,1995.0,0,0 2403,7489845,Cholesterol-lowering therapy may retard the progression of diabetic nephropathy.,K S Lam; I K Cheng; E D Janus; R W Pang,"There is experimental evidence to suggest that hypercholesterolaemia may play a pathogenetic role in progressive glomerular injury. We investigated the effect of cholesterol-lowering therapy on the progression of diabetic nephropathy in 34 patients with non-insulin-dependent diabetes mellitus. Patients were randomly assigned in a single-blind fashion to treatment with either lovastatin, an HMG CoA reductase inhibitor (n = 16; mean dose 30.0 +/- 12.6 mg/day) or placebo (n = 18) for 2 years. Renal function was assessed by serially measuring the serum creatinine, glomerular filtration rate (using Cr51-EDTA), and 24-h urinary protein excretion. Lovastatin treatment was associated with significant reductions in total cholesterol (p < 0.001), LDL-cholesterol (p < 0.001) and apo B (p < 0.01), the reductions at 24 months being 26, 30 and 18%, respectively. Beneficial effects on serum triglyceride, HDL-cholesterol and apo A1 levels were also observed. Lp(a) showed no significant change in both groups. Glomerular filtration rate deteriorated significantly in the placebo group after 24 months (p < 0.025) but showed no significant change in the lovastatin-treated patients. The increase in serum creatinine was statistically significant (p < 0.02) in placebo-treated patients at 12 and 24 months, and in the lovastatin group after 24 months. Twenty-four hour urinary protein excretion increased in both groups (p < 0.05). Lovastatin treatment was not associated with significant elevations in liver or muscle enzymes. We conclude that effective normalisation of hypercholesterolaemia may retard the progression of diabetic nephropathy.",1995.0,0,0 2404,7494938,[The pharmacological treatment of hypercholesterolemia].,F Pérez Jiménez,"Hypercholesterolaemia therapy should begin with implementation of a suitable diet in order to achieve optimum weight and reduce the intake of saturated fats. Often, however, a dietary regime is not sufficient to decrease cholesterol levels in hypercholesterolaemic patients and drugs must also be used. Some of the pharmacological options available act principally on LDL cholesterol, whereas others have more effect on triglyceride rich particle. HMGCoaA reductase inhibitors exert the greatest effect on plasmatic LDL cholesterol levels and are therefore recommended in cases of moderate or severe hypercholesterolaemia, particularly in the secondary prevention of ischaemic cardiopathy. Comparing the three statin drugs, lovastatin, pravastatin and simvastatin, the latter has recently been shown in study 4S to be effective in reducing global and coronary mortality in patients with a history of coronary heart disease. In addition to their action on LDL cholesterol, these drugs also increase HDL cholesterol, reduce triglycerides and have a beneficial effect on some of the fundamental mechanisms involved in the development of arteriosclerosis. Ion-exchange resins moderately reduce cholesterol levels, thus are used in young people or in combination with other drugs when a further reduction of LDL cholesterol is required. Their main drawback, however, is that they can often cause digestive intolerance. Primary prevention trials have shown that fibrates also reduce mortality by coronary heart disease but have no effect on global mortality. They are well tolerated and are used in the treatment of mixed hyperlipaemia. Other products, such as probucol and oestrogens, are also used but only under specific circumstances.",1995.0,0,0 2405,7494939,[The Scandinavian Simvastatin Survival Study: the clinical consequences].,M L Larsen,"In the recently reported Scandinavian Simvastatin Survival Study (4S), 4,444 men and women between 35 and 70 years of age who had coronary heart disease and plasma total cholesterol concentrations of 212 to 310 mg per deciliter (5.5 to 8.0 mmol/l) received simvastatin or placebo for 5.4 years; in the treatment group, mortality from coronary heart disease was 42 percent lower and mortality from all causes was 30 percent lower. Further analysis of the relation between the risk of major coronary events and baseline cholesterol levels in patients randomised to placebo or simvastatin therapy in the study showed that simvastatin significantly reduced the risk of major coronary events in all quartiles of baseline total, high-density-lipoprotein, and low-density-lipoprotein cholesterol, by a similar amount in each quartile. Clearly, cholesterol-modifying interventions can substantially improve the outlook for patients with coronary heart disease and should be considered in identification and treatment of patients with established coronary heart disease. The available data from secondary intervention trials indicates that all patients with documented ischemic heart disease should be offered a reliable assessment of plasma total cholesterol. However, since the impact of simvastatin on CHD seems to begin after about one year of therapy it would be reasonable to exclude very old persons and patients with serious disease with a limited life-expectancy. As a consequence of the 4S data it should be recommended that all the patients in question, who after lifestyle modifications and non-pharmacological risk factor modification still have total cholesterol levels above 200 mg per deciliter (5.2 mmol) should be offered treatment with a HMG-CoA reductase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0 2406,7500065,A strategy to arrest and reverse coronary artery disease: a 5-year longitudinal study of a single physician's practice.,C B Esselstyn; S G Ellis; S V Medendorp; T D Crowe,"Animal experiments and epidemiological studies have suggested that coronary disease could be prevented, arrested, or even reversed by maintaining total serum cholesterol levels below 150 mg/dL (3.88 mmol/L). In 1985, we began to study how effective one physician could be in helping patients achieve this cholesterol level and what the associated effect of achieving and maintaining this cholesterol level has on coronary disease. The study included 22 patients with angiographically documented, severe coronary artery disease that was not immediately life threatening. These patients took cholesterol-lowering drugs and followed a diet that derived no more than 10% of its calories from fat. Disease progression was measured by coronary angiography and quantified with the percent diameter stenosis and minimal lumen diameter methods. Serum cholesterol was measured biweekly for 5 years and monthly thereafter. Of the 22 participants, 5 dropped out within 2 years, and 17 maintained the diet, 11 of whom completed a mean of 5.5 years of follow-up. All 11 of these participants reduced their cholesterol level from a mean baseline of 246 mg/dL (6.36 mmol/L) to below 150 mg/dL (3.88 mmol/L). Lesion analysis by percent stenosis showed that of 25 lesions, 11 regressed and 14 remained stable. Mean arterial stenosis decreased from 53.4% to 46.2% (estimated decrease = 7%; 95% confidence interval [CI], 3.3 to 10.7, P < .05). Analysis by minimal lumen diameter of 25 lesions found that 6 regressed, 14 remained stable, and 5 progressed. Mean lumen diameter increased from 1.3 mm to 1.4 mm (estimated increase = 0.08 mm; 95% CI, -0.06 to 0.22, P = NS). Disease was clinically arrested in all 11 participants, and none had new infarctions. Among the 11 remaining patients after 10 years, six continued the diet and had no further coronary events, whereas the five dropouts who resumed their prestudy diet reported 10 coronary events. A physician can influence patients in the decision to adopt a very low-fat diet that, combined with lipid-lowering drugs, can reduce cholesterol levels to below 150 mg/dL and uniformly result in the arrest or reversal of coronary artery disease.",2001.0,0,0 2407,7500507,Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a).,V M Maher; B G Brown; S M Marcovina; L A Hillger; X Q Zhao; J J Albers,"To determine if lowering elevated low-density lipoprotein cholesterol (LDL-C) levels offsets the adverse effect of raised lipoprotein(a) (Lp[a]) levels on coronary artery disease (CAC) in men. Randomized, double-blind, placebo-controlled trial of lipid lowering for CAD. Post hoc analysis of the Familial Atherosclerosis Treatment Study. A total of 146 men aged 62 years or younger with CAD and apolipoprotein B levels of at least 125 mg/dL. Patients received a Step II Diet and lovastatin (40 mg daily) plus colestipol (30 g daily), niacin (4 g daily) plus colestipol, or placebo (plus colestipol if LDL-C > 90th percentile) for 2.5 years. They were grouped by their LDL-C responses: ""minimal"" if LDL-C decreased by 10% or less from baseline (mean [SD] change, +6% [13%]) and ""substantial"" if LDL-C decreased more than 10% (mean [SD] change, -40% [16%]). Impact of lowering elevated LDL-C on the cardiac event rate (death, myocardial infarction, and revascularization for refractory ischemia) and CAD change associated with elevated Lp(a). In multivariate analyses, the best correlate of baseline CAD severity was Lp(a) (r = 0.30; P < .001). For 36 patients with minimal LDL-C reduction, CAD progression correlated only with in-treatment Lp(a) levels (r = 0.45; P < .01), but for 84 patients with substantial LDL-C reduction, disease regressed and its change correlated with in-treatment LDL-C (r = 0.24; P < .05) but not with Lp(a) (r = -0.05). Lipoprotein(a) levels were not significantly altered in either group. For 40 patients with Lp(a) at the 90th percentile or higher, events were frequent (39%) if reduction of LDL-C was minimal, but were few (9%) if reduction was substantial (relative risk, 0.23; 95% confidence interval, 0.06 to 0.99). In men with CAD and elevated LDL-C, Lp(a) levels were dominant correlates of baseline disease severity, its progression, and event rate over 2.5 years. However, with substantial LDL-C reductions, persistent elevations of Lp(a) were no longer atherogenic or clinically threatening. This provides a possible direction for treatment in such patients with elevated Lp(a) and LDL-C.",1995.0,0,0 2408,7502550,Simvastatin added to ursodeoxycholic acid does not enhance disappearance of gallstone fragments after shock wave therapy.,M Sackmann; R Koelbl; J Pauletzki; P Cremer; U G Klueppelberg; C von Ritter; G Sauter; J Holl; D Seidel; G Paumgartner,"Inhibitors of the HMG-CoA reductase have been shown to further reduce the biliary cholesterol saturation in patients treated with oral bile acids for cholesterol gallbladder stones. It was the aim of our study to evaluate the efficacy of simvastatin in addition to ursodeoxycholic acid in the dissolution of gallstone fragments after shock wave lithotripsy and adjuvant bile acid dissolution therapy. Eighteen patients with a single radiolucent gallbladder stone and a serum cholesterol of more than 250 mg/dl were randomly assigned to receive either ursodeoxycholic acid alone (750 mg per day, group A, n = 9) or in combination with simvastatin (20 mg per day, group B, n = 9) for the dissolution of the gallstone fragments generated by extracorporeal shock wave lithotripsy. The two groups were well matched regarding their baseline characteristics. At the primary end point of the study 6 months after lithotripsy, there was no difference between the groups in the rate of gallstone disappearance with 4 of 9 patients being stone free in each group. As evaluated by life table analysis, even further follow-up showed no significant difference between the groups (P = 0.8). In group B, serum cholesterol levels decreased by 22% at 3 months (P = 0.01 vs. baseline) and by 24% at six months (P = 0.02) during treatment while no significant change was observed in group A. With both regiments, no adverse effects were observed. While simvastatin added to ursodeoxycholic acid resulted in a decrease of elevated serum cholesterol levels in gallstone patients, it did not enhance stone disappearance after shock wave lithotripsy and adjuvant bile acid dissolution therapy.",1995.0,0,0 2409,7503003,Noninvasive tracking of coronary atherosclerosis by electron beam computed tomography: rationale and design of the Felodipine Atherosclerosis Prevention Study (FAPS).,N D Wong; W Teng; D Abrahamson; R Willner; N Henein; S S Franklin; M L Kashyap; B Rosenzweig; G Kukes; R C Detrano,"The Felodipine Atherosclerosis Prevention Study is designed to evaluate the efficacy of the calcium antagonist felodipine ER and combined felodipine/simvastatin therapy on retarding the progression of atherosclerosis, estimated by serial changes in coronary calcium evaluated by noninvasive electron beam computed tomography. Subjects include 180 men and women aged 40 to 69 and 50 to 69 years, respectively, with moderate type IIa dyslipidemia, with either cardiovascular disease or risk factors. All subjects receive simvastatin lipid-lowering therapy, and are randomized either to felodipine or placebo for a treatment period of 2 years. Monitoring of blood chemistry, measures of lipids and apolipoproteins, blood pressure, evaluation of symptoms, and interim clinical event monitoring are done at routine follow-up visits. Baseline and 2-year follow-up electron beam computed tomography, measuring changes in total calcium score, area, and mass, evaluate the effects of intervention on the progression of calcified atherosclerosis. The results from the Felodipine Atherosclerosis Prevention Study will provide valuable information about the effect of felodipine alone and in combination with simvastatin on progression of calcified atherosclerosis evaluated noninvasively.",1995.0,0,0 2410,7517829,Analysis of angiographic trial data in women.,R J Havel,"There are few angiographic trials of cholesterol lowering in women. Two trials have included a sufficient number of women for meaningful assessment of lesion change, as determined by quantitative coronary angiography. In the University of California, San Francisco Specialized Center of Research in Arteriosclerosis (UCSF SCOR) trial, 72 patients (57% women) with familial hypercholesterolaemia (90% of whom had no overt coronary heart disease) were randomised to receive either diet and intensive drug therapy (combinations of colestipol, nicotinic acid and lovastatin) or diet and modest doses of colestipol, according to baseline low density lipoprotein cholesterol level. Coronary angiograms were obtained at 2-year intervals. Change in percentage area of stenosis (the primary end-point) in women receiving intensive drug treatment was -2.06% compared with +1.07% for the controls (p = 0.05). For the intensively treated men, corresponding values were -0.88% compared with +0.41% for the controls (difference not significant). In a recently completed trial in Canada, 269 men and 62 women with established coronary heart disease were randomised to receive either diet alone, or diet and lovastatin (up to 80 mg daily). In men, the increase in percentage diameter of stenosis was reduced by 43% (p = 0.05), and in women by 40% (not significant). By contrast, new lesions appeared in 4% of women assigned to intensive drug treatment, compared with 45% of those randomised to diet (p < 0.001). In men, new lesions appeared in 18% and 29% of patients, respectively (p = 0.047). These data suggest that coronary artery lesions in women respond at least as well as those in men to cholesterol lowering.",1994.0,0,0 2411,7517835,"Efficacy and safety of fluvastatin, a new HMG CoA reductase inhibitor, in elderly hypercholesterolaemic women.",G Baggio; O De Candia; P L Forte; F Mello; A Andriolli; S Donazzan; G Valerio; M Milani; G Crepaldi,"This multicentre open 6-week study evaluated the efficacy, safety and tolerability of fluvastatin, the first fully synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, in elderly women with type IIa hypercholesterolaemia. After a 4-week single-blind placebo period, 22 elderly women (mean age 68 +/- 5 years) with primary hypercholesterolaemia [low density lipoprotein (LDL) cholesterol > 160 mg/dl] were enrolled in the trial. Fluvastatin 40 mg was administered once in the evening. At baseline, and after 3 and 6 weeks of treatment, total cholesterol, LDL cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins B (apo B) and A-I (apo A-I) were measured. Safety and tolerability were assessed by monitoring routine laboratory parameters and by recording spontaneously reported side effects. The mean (+/- SD) baseline total cholesterol, LDL cholesterol, triglyceride, HDL cholesterol, apo B and apo A-I levels were 325 +/- 43, 236 +/- 43, 128 +/- 56, 61 +/- 16, 221 +/- 60 and 164 +/- 28 mg/dl, respectively. After 6 weeks, fluvastatin significantly (p < 0.001, ANOVA test) reduced total cholesterol, LDL cholesterol and apo B levels by 22%, 29% and 23%, respectively. These significant reductions were already reached at week 3 (total cholesterol, -21%; LDL cholesterol, -27%). The total cholesterol: HDL cholesterol ratio was reduced by 22% at week 3 and by 21% at week 6 (from 5.3 to 4.2). 78% of the patients showed a reduction > or = 20% for LDL cholesterol. Triglycerides were reduced by 16% (not significant).(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2412,7517836,Efficacy and safety of fluvastatin in women with primary hypercholesterolaemia.,T K Peters; E N Muratti; M Mehra,"Women with primary hypercholesterolaemia are often considered for lipid-lowering drug therapy at a later age than men. With regard to the prevention of cardiovascular morbidity, women can expect to receive the same benefits from lipid-lowering treatment as men. Thus, it is of interest to evaluate the efficacy, safety and tolerability of the new lipid-lowering agent fluvastatin in women. A retrospective analysis was made on the basis of data from controlled clinical trials in which 1815 patients were treated with fluvastatin at a daily dose of > or = 20 mg, and 783 patients received placebo. 782 of the fluvastatin-treated patients (43.1%) and 315 patients on placebo (40.2%) were women. Within these groups, 577 patients (73.8%) treated with fluvastatin and 183 patients receiving placebo (78.4%) were at least 50 years of age. The effect of fluvastatin 40 mg/day on low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol was more favourable in women than in men. In women, the change from baseline was -26.7% for LDL cholesterol and 5.3% for HDL cholesterol. In men, the equivalent changes from baseline were -23.8% and 4.0%, respectively. All changes from baseline were highly significant (p < 0.001). Fluvastatin lowered triglycerides to a similar extent in women and men (7.1% vs 6.9%, respectively). More women than men experienced a confirmed increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) when receiving fluvastatin.(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2413,7521386,Rapid quantitation of mRNA species in ethidium bromide-stained gels of competitive RT-PCR products.,A Gebhardt; A Peters; D Gerding; A Niendorf,"A rapid method for quantifying the low-abundant mRNAs of the low density lipoprotein receptor and the 3-hydroxy-3-methylglutaryl coenzyme A reductase by competitive polymerase chain reaction is presented. This approach requires neither special labeling nor blotting procedures. For each analysis, a defined amount of total cellular RNA is co-reverse transcribed and co-amplified with a titration series of in vitro synthesized competitor RNA that carries an internal deletion. The equivalence point, which defines the amount of specific RNA in the sample, can be scored in ethidium bromide-stained agarose or polyacrylamide gels of the reaction products. As an example, responses to pravastatin, a competitive inhibitor of the HMG-CoA reductase, in a human tumor cell line were analyzed with this new technique. As a control, the expression of the unregulated gene, glyceraldehyde-3-phosphate dehydrogenase was measured in parallel using the same methodology. The results obtained were compared with those obtained by conventional Northern blotting.",1994.0,0,0 2414,7555484,Treatment of hypercholesterolemia in NIDDM with policosanol.,O Torres; A J Agramonte; J Illnait; R Más Ferreiro; L Fernández; J C Fernández,"To determine whether elevated levels of cholesterol and low-density lipoprotein (LDL) cholesterol in non-insulin-dependent diabetes mellitus (NIDDM) patients could be decreased by policosanol, a new cholesterol-lowering drug. NIDDM predisposes patients to coronary artery disease (CAD) through the direct action of hyperglycemia on the arteries as well as the dyslipidemia induced by NIDDM. This double-blind placebo-controlled trial was performed in 29 patients with NIDDM and hypercholesterolemia. After stable glycemic control was achieved by diet and/or oral hypoglycemic drugs, patients were instructed to follow a cholesterol-lowering diet for 6 weeks. Patients who met entry criteria received, under double-blind conditions, policosanol (5 mg) or placebo tablets twice a day for 12 weeks. Policosanol (10 mg/day) significantly reduced total cholesterol by 17.5% and LDL cholesterol by 21.8% compared with baseline and placebo. Furthermore, high-density lipoprotein (HDL) cholesterol was raised by 11.3% (not significant), and triglycerides showed a statistically nonsignificant decrease of 6.6%. These changes in lipid profile were similar to those induced by policosanol in nondiabetic patients with type II hyperlipoproteinemia. Glycemic control was unaffected by treatment. No clinically or biochemically adverse effects attributable to treatment were observed. Only one patient (placebo) withdrew from the trial because of an adverse experience (erythema). We concluded that policosanol is effective and safe in patients with NIDDM and hypercholesterolemia.",1995.0,0,0 2415,7555549,Metformin.,Z T Bloomgarden,,1995.0,0,0 2416,7562885,"Changes in plasma lipids, lipoproteins and apolipoproteins in hypercholesterolaemic patients treated with pravastatin.",P Lijnen; H Celis; J P Desager; R Fagard,"Plasma lipids, lipoproteins and apolipoproteins were studied before and during 6 months of pravastatin administration in patients with hypecholesterolaemia. After a 1 month placebo run-in period, the patients were treated double-blind either with placebo (n = 25) or with pravastatin (n = 25) for 6 months. Placebo or pravastatin 10 mg during the first month, 20 mg during the second month and 40 mg during the additional 4 months was administered once daily in the evening. Compared with the placebo group the plasma concentration of total cholesterol and phospholipids, free cholesterol and cholesterol esters as well as the plasma LDL-cholesterol and LDL-phospholipids were decreased during 6 months of pravastation therapy. No changes in plasma VLDL-, HDL-, HDL2-, or HDL3-cholesterol, -phospholipids or -triglycerides were observed in the pravastatin-treated patients. A decrease in the plasma level of apolipoprotein B and of LDL-apo B, but not of VLDL-apo B, was observed during pravastatin therapy; the plasma apolipoprotein AI and AII levels as well as HDL2- and HDL3-apo AI and apo AII levels remained, however, unchanged. Plasma lipoprotein Lp(a) did not change during pravastatin therapy whereas the plasma lecithin cholesterol acyltransferase activity (LCAT) increased. In conclusion, treatment of hypercholesterolaemic patients with pravastatin results in a decrease in the plasma concentration of total and free cholesterol, LDL-cholesterol, apolipoprotein B, LDL-apo B, phospholipids and cholesterol esters and in an increase in plasma LCAT activity. Plasma Lp(a), HDL-cholesterol and triglyceride levels remained, however, unchanged.",1995.0,0,0 2417,7563487,Treatment of hyperlipidemia in women.,J M Walsh; D Grady,"To assess the evidence that lipid lowering prevents coronary heart disease (CHD) events in women. English-language literature assessing the effects of cholesterol lowering with dietary and/or drug interventions as primary or secondary prevention on CHD events in women. Coronary heart disease and total mortality were the primary outcomes assessed. Angiographic regression of coronary atherosclerosis was a secondary outcome. STUDY SELECTION, DATA EXTRACTION, AND DATA SYNTHESIS: All nine of the identified studies that met the criteria were included. Relative risks for CHD and total mortality were calculated from available data. Summary relative risks were calculated using meta-analytic techniques. There is no evidence from primary prevention trials that cholesterol lowering affects total mortality in healthy women, although the available data are limited. Limited evidence suggests that treatment of hypercholesterolemia in women with coronary disease may decrease CHD mortality. Future research should address the role of dietary and other nondrug treatment of hypercholesterolemia in women at high risk for CHD.",1995.0,0,0 2418,7566020,Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.,J Shepherd; S M Cobbe; I Ford; C G Isles; A R Lorimer; P W MacFarlane; J H McKillop; C J Packard,"Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease. We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points. Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051). Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.",1995.0,1,1 2419,7566029,Lowering cholesterol with drugs and diet.,T R Pedersen,,1995.0,0,0 2420,7566298,"Comparison of Lp(a) concentrations and some potential effects in hemodialysis, CAPD, transplantation, and control groups, and review of the literature.",M H Gault; L L Longerich; L Purchase; J Harnett; C Breckenridge,"Apolipoprotein (a)-Lp(a)-is reported to be an independent risk factor for coronary artery disease and for hemodialysis (HD) access occlusion. Homology with plasminogen may predispose to thrombosis. High concentrations usually have been reported in patients on HD and on continuous ambulatory peritoneal dialysis (CAPD), but near-normal values in many kidney transplants (TP). We used Pharmacia immunoradiometric assay in 52 patients on HD, 58 on CAPD, 94 after TP, and 56 controls. The Lp(a) mean levels for CAPD, HD, TP, and control groups were 738, 647, 348, and 368 U/l and the medians were 542, 537, 96 and 143 U/l, respectively. The means and medians for CAPD and HD were significantly greater than those for TP and controls (p < 0.003 for means and < 0.005 for medians). We found no significant difference between: (1) Lp(a) means or medians comparing HD and CAPD or TP and controls; (2) Lp(a) means for the 33 patients with insulin-dependent diabetes mellitus and the 171 without; (3) number of occlusions of HD fistulae or grafts in patients with high Lp(a) values and without; (4) mean Lp(a) for CAPD patients on gemfibrozil and also for TP patients on 3-hydroxy-methylglutaryl coenzyme 1 reductase inhibitors, or diet alone, before and after treatment, and (5) mean Lp(a) values for HD and CAPD patients with and without myocardial infarction. Lp(a) did not correlate significantly with fractional shortening or left ventricular end systolic or diastolic diameter by echocardiogram or with ejection fraction. For TP patients, Lp(a) and serum creatinine correlated (p = 0.004), and mean Lp(a) for 71 TP on ciclosporin A exceeded that for the other 23 patients (p < 0.03). Lp(a) fell in 13 of 14 patients after TP (mean fall 77%). The dominant Apo(a) isoform in 10 of 13 patients on CAPD or HD with high Lp(a) values was the equivalent of S2 (Utermann). Lp(a) in HD or CAPD is often elevated and regulated by both genetic and renal failure factors, but falls after TP with return of renal function and mainly genetic regulation. Lp(a) was not a risk factor for coronary artery disease in HD or CAPD patients and did not fall significantly with two drugs or diet.",1995.0,0,0 2421,7568903,"Atherosclerosis, oxidative stress, and antioxidant protection in endothelium-derived relaxing factor action.",J F Keaney; J A Vita,"The vascular endothelium plays a central role in the regulation of vascular function. In particular, the local release of endothelium-derived relaxing factor (EDRF) regulates vascular tone and prevents platelet adhesion to the vascular wall. Impairment of EDRF action develops early in atherosclerosis and, in part, contributes to platelet deposition and vasospasm involved in the clinical expression of coronary artery disease. Recent evidence suggests that an imbalance between vascular oxidative stress and antioxidant protection is involved in the development of this vascular dysfunction. In this report, the relation between oxidative stress, atherosclerosis, and abnormal EDRF action is reviewed with particular attention to the effects of antioxidant supplementation in animal models of atherosclerosis and hypercholesterolemia.",2001.0,0,0 2422,7570232,Pharmaco-economic assessment of the HMG-CoA reductase inhibitors.,A J Smart; L Walters,"To perform a comparative pharmaco-economic assessment of two HMG-CoA reductase inhibitors. A cost-effectiveness analysis was employed using comparative efficacy data from selected clinical trials. A comprehensive international literature search formed the basis for this selection. Criteria for inclusion of clinical trial results in the analysis were set a priori. Acquisition costs used were the recommended reimbursement prices as at September 1994. Two outcome measures are reported: (i) the comparative cost-effectiveness in lowering blood lipid concentrations; and (ii) the comparative cost-effectiveness of the medicines when used to achieve a predetermined therapeutic goal. The average cost per 1% decrease in total cholesterol is 21.9% higher on 10 mg pravastatin daily than on 10 mg simvastatin daily. Similarly the average cost per 1% decrease in low-density lipoprotein (LDL) cholesterol is 23.1% higher on 10 mg pravastatin than on 10 mg simvastatin daily. This difference is consistent throughout the dosage range. The use of incremental doses of simvastatin monotherapy in order to reach a predetermined therapeutic goal (LDL < or = 4.14 mmol/l) is more cost-effective than an equivalent pravastatin dosage regimen. Total treatment costs for simvastatin-treated patients are 3.5% less than for pravastatin-treated patients. More patients on simvastatin are successfully treated; the difference in overall treatment costs per successfully treated patient is 27.9% in favour of simvastatin. Sensitivity analysis shows these results to be stable under extreme scenarios. This analysis employed objective comparative efficacy data obtained from peer-reviewed sources to compare the economic and clinical outcomes of simvastatin and pravastatin in the treatment of hypercholesterolaemia. The acquisition cost of simvastatin is 10.3-22.8% higher than an equivalent milligram dose of pravastatin, depending on the dosage used. However, because of the greater milligram potency of simvastatin, it is a more cost-effective alternative. Simvastatin therefore provides better value for money than pravastatin in lowering lipid levels in clinical practice.",1994.0,0,0 2423,7570971,Effect of fluvastatin on lipoprotein profiles in treating renal transplant recipients with dyslipoproteinemia.,P K Li; T W Mak; T H Chan; A Wang; C W Lam; K N Lai,"A single, blinded placebo-drug trial was conducted to study the efficacy and safety of fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, in treating dyslipoproteinemia in 16 renal transplant recipients who had been on an immunosuppressive regimen that included cyclosporine (CsA). They were studied for 32 consecutive weeks, with 4 weeks of baseline treatment, 4 weeks of placebo, 12 weeks of treatment with fluvastatin 20 mg daily, and 12 weeks of fluvastatin 40 mg daily. Blood samples were obtained every 4 weeks for measurement of the lipoprotein profiles, which included total cholesterol (TC), triglyceride, low density lipoprotein (LDL)-, high density lipoprotein (HDL)-, HDL2-, HDL3- and very low density lipoprotein-cholesterol (C), apolipoprotein (Apo) A-1, Apo B, and lipoprotein(a). Fifteen patients completed the trial. After 12 weeks of treatment, fluvastatin 20 mg significantly reduced TC by 13.4% (from 6.7 +/- 0.5 [mean +/- SEM] to 5.8 +/- 0.2 mmol/L), LDL-C by 22% (from 4.1 +/- 0.3 to 3.2 +/- 0.2 mmol/L), and Apo B by 13.2% (from 159.6 +/- 8.8 to 138.6 +/- 9.2 mg/dl) (P < 0.005). The subsequent 12-week treatment of fluvastatin 40 mg significantly reduced TC by 16.4% to 5.6 +/- 0.3 mmol/L, LDL-C by 29.3% to 2.9 +/- 0.2 mmol/L, and Apo B by 18.2% to 130.6 +/- 5.5 mg/dl (P < 0.00005). There was no significant change in levels of other lipoproteins, including lipoprotein (a). There were no significant changes in the whole blood trough CsA concentrations, renal and liver function tests, and serum creatine phosphokinase level during treatment when compared with baseline and placebo. No patient complained of myalgia or failed to complete the study due to side effects of the drug. Fluvastatin appears to be safe and effective in treating dyslipoproteinemia in renal transplant recipients who are maintained on CsA.",1995.0,0,0 2424,7573090,Efficacy and safety of pravastatin in the treatment of patients with type I or type II diabetes mellitus and hypercholesterolemia.,P Raskin; O P Ganda; S Schwartz; D Willard; J Rosenstock; P A Lodewick; M D Cressman; B Phillipson; B Weiner; M E McGovern,"Patients with type I and type II diabetes mellitus have an increased risk of coronary heart disease. In many diabetics, hypercholesterolemia is present and further exacerbates this risk. We investigated the efficacy and safety of pravastatin in the treatment of patients with type I or type II diabetes mellitus and hypercholesterolemia. In this 24-week, multi-center, double-blind, placebo-controlled study, 94 patients (45 men, 49 women), 18 to 70 years of age, with type I or type II diabetes mellitus and hypercholesterolemia (fasting plasma low-density lipoprotein cholesterol [LDL-C] levels > 150 mg/dL and above the 75th percentile for the US population by age and gender) were randomized to receive pravastatin 20 mg hs or matching placebo. Two patients were randomized to treatment with drug for every 1 randomized to placebo. The dose could be doubled after 10 weeks, and cholestyramine or colestipol could be added after 18 weeks, as needed, to attempt to lower the LDL-C levels to below the 50th percentile for the US population. Significant reductions in LDL-C (-27.6%), total cholesterol (-22.1%), very-low-density lipoprotein cholesterol (-22.6%), and triglycerides (-12.8%) (P < or = 0.001 versus placebo for all reductions), and significant increases in high-density lipoprotein cholesterol (4.4%) (P < or = 0.05 versus placebo) were noted in the pravastatin treatment group (average dose 29.5 mg) at 16 weeks. The beneficial lipid-lowering effects of pravastatin were maintained throughout the 24 weeks of the study. Pravastatin was well tolerated, and the frequency of side effects was similar in the pravastatin and placebo groups. No clinically significant changes in the control of diabetes, as assessed by fasting blood glucose levels and glycosylated hemoglobin measurements, were seen during this study. The results of this study demonstrate that pravastatin is well tolerated and effective in lowering total cholesterol and LDL-C in patients with type I or type II diabetes mellitus and hypercholesterolemia.",1995.0,0,0 2425,7575771,Long-term efficacy and tolerability of simvastatin in a large cohort of elderly hypercholesterolemic patients.,P J Lansberg; Y B Mitchel; D Shapiro; J J Kastelein; R Altman; G Jerums; K Bolzano; S Giannini; J Davignon; P DeWailly,"The long-term efficacy and tolerability of simvastatin, a 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase inhibitor, was assessed during a 24-month follow-up period in 168 elderly hypercholesterolemic patients. After completing a 4 week double blind dose ranging study with simvastatin, 47 males and 122 females over 62 years of age with type II hyperlipidemia, a total cholesterol level above 6.5 mmol/l and clinically manifest cardiovascular disease were included in this extended study. A total of 159 patients completed the 12-month follow-up period and 141 patients were monitored over the full 24 months. All patients were started on 10 mg simvastatin once daily and the dosage was increased until the target levels of low density lipoprotein (LDL) cholesterol between 2.3 mmol/l (90 mg/dl) and 3.6 mmol/l (140 mg/dl) were reached. Fifty percent of patients reached the targeted LDL cholesterol goal of < 3.6 mmol/l (140 mg/dl) during the study. At study completion, 65 patients (39%) were taking 40 mg simvastatin per day, 56 patients (33%) 20 mg, 42 patients (25%) 10 mg and 5 patients (3%) only used 5 mg per day. Sixteen patients (9%) received concomitant lipid lowering therapy. Over 2 years, the mean decrease in LDL cholesterol ranged from 36% to 38%, the median decrease in triglycerides was 12% to 19% and the mean increase in high density lipoprotein (HDL) cholesterol ranged from 9% to 10%, respectively. Seven patients discontinued simvastatin because of adverse clinical or laboratory events, but only in two (1.1%) was this considered to be drug-related. Side-effects were mild and most frequently gastrointestinal in nature. Mean changes in asparate aminotransferase (AST) were not significantly different from zero and mean changes in alanine aminotransferase (ALT) and creatine phosphokinase (CPK) showed a small increase. We conclude that simvastatin is an efficacious and well-tolerated treatment for hypercholesterolemia in elderly individuals for extended periods.",1995.0,0,0 2426,7578166,Cholesterol-lowering therapy after heart transplantation: a 12-month randomized trial.,P W Pflugfelder; M Huff; R Oskalns; L Rudas; W J Kostuk,"Hypercholesterolemia, a common problem after heart transplantation, may be important in the genesis and progression of allograft coronary artery disease. The current study was performed to compare the efficacy of gemfibrozil, simvastatin, and cholestyramine for cholesterol lowering in heart transplant recipients. In this prospective 1-year study, 48 heart transplant recipients with moderate hypercholesterolemia were randomized to therapy with gemfibrozil 600 mg twice daily (n = 17), simvastatin 10 mg daily (n = 13), and cholestyramine 4 gm twice daily (n = 18). Detailed lipoprotein analysis was performed at baseline and after 3, 6, and 12 months of treatment. Total cholesterol and low-density lipoprotein cholesterol were reduced 19% and 29%, respectively, after 3 months of simvastatin therapy (p < 0.0001) with a sustained reduction in total cholesterol (25%) and low-density lipoprotein cholesterol (39%) at 1 year. Gemfibrozil and cholestyramine treatment did not result in a reduction in cholesterol levels. Apolipoprotein B levels were reduced by 29% at the end of 1 year with simvastatin but not with the other treatments. Serum triglyceride levels were reduced significantly by treatment with gemfibrozil (up to 36%, p < 0.01) but not by the other treatments. High-density lipoprotein cholesterol initially rose in patients treated with simvastatin and gemfibrozil; however, this effect did not persist to 12 months. However, the ratio of low-density lipoprotein/high-density lipoprotein was favorably affected by simvastatin, with a 38% reduction by 12 months (p < 0.0001) but not by the other treatments. Over the course of 1 year, 14 patients dropped out of the study: four from the gemfibrozil arm and ten from the cholestyramine arm. Gastrointestinal intolerance was the most common reason for study termination (8 of 14). All patients in the simvastatin treatment arm completed 12 months of therapy. No biochemical abnormalities resulted from any therapy, and no therapy caused significant alteration in cyclosporine blood levels. Of the three therapies studied, simvastatin was found to be the most efficacious and well tolerated for cholesterol lowering in patients after heart transplantation.",1995.0,0,0 2427,7583826,Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors.,W R Garnett,"Drug-drug, drug-food, and drug-disease interactions involving hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are reviewed. The four available HMG-CoA reductase inhibitors-lovastatin, simvastatin, pravastatin, and fluvastatin-have different potentials for drug interactions, probably because of their different pharmacokinetic characteristics. Interactions of some of these cholesterol-lowering agents with cyclosporine, erythromycin, high-dose niacin, or gemfibrozil may produce myopathy with or without rhabdomyolysis. Interactions with other commonly prescribed agents, such as bile acid sequestrants, coumarin anticoagulants, and cardiovascular drugs, may alter the pharmacokinetics of either drug, but the clinical significance is generally minor. Food may affect plasma lovastatin concentrations, systemic pravastatin bioavailability, and the maximum serum concentration (Cmax) and time to achieve Cmax for fluvastatin. Hepatic dysfunction may influence the pharmacokinetics of pravastatin; all HMG-CoA reductase inhibitors are contraindicated in patients with liver disease or unexplained elevations in serum aminotransferases. Severe renal insufficiency may necessitate dosage modification in lovastatin recipients. Renal dysfunction seems to affect the pharmacokinetics of pravastatin, simvastatin, and fluvastatin only minimally, but caution is still warranted. Although the HMG-CoA reductase inhibitors rarely have severe adverse effects, they may interact, in some cases dangerously, with other drugs, with food, and with disease states.",1995.0,0,0 2428,7585842,"Effect of low-dose simvastatin on cholesterol levels, oxidative susceptibility, and antioxidant levels of low-density lipoproteins in patients with hypercholesterolemia: a pilot study.",H Yoshida; T Ishikawa; M Ayaori; H Shige; H Hosoai; E Nishio; K Tomiyasu; T Yamashita; M Suzukawa; M Nishiwaki,"In this pilot study, 12 patients (6 men, 6 postmenopausal women) with hypercholesterolemia were treated with low-dose (5 mg/d) simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, for 4 weeks. Low-density lipoprotein (LDL) samples were isolated at the beginning (week 0) and at the end (week 4) of the treatment regimen. Simvastatin caused significant decreases of total cholesterol (-18.1%), LDL cholesterol (-27.6%), and apolipoprotein B (-21.8%), and significantly reduced total cholesterol, free cholesterol, cholesterol esters, phospholipids, and protein in LDL without significantly changing the component ratios and fatty acid levels of LDL. However, simvastatin therapy had no major effects on either antioxidant levels in LDL or the oxidative susceptibility of LDL. We conclude that low-dose simvastatin significantly reduces LDL cholesterol levels without increasing the oxidative susceptibility of LDL or decreasing the antioxidant levels of LDL, and thus may reduce the risk of coronary artery disease.",1995.0,0,0 2429,7585861,Cost-effectiveness analysis of lipid-modifying therapy in Canada: comparison of HMG-CoA reductase inhibitors in the primary prevention of coronary heart disease.,B Jolain; D Pettitt,,1995.0,0,0 2430,7586300,Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction.,L Lacoste; J Y Lam; J Hung; G Letchacovski; C B Solymoss; D Waters,"Hypercholesterolemia is a risk factor for coronary disease, and platelet reactivity is increased with hypercholesterolemia, suggesting a prethrombotic risk. The aim of this study was to measure mural platelet thrombus formation on an injured arterial wall in a model simulating vessel stenosis and plaque rupture in hypercholesterolemic coronary disease patients before and after cholesterol reduction. Thirty-two patients with stable coronary disease were studied. Platelet thrombus formation and serum lipids were measured in 16 hypercholesterolemic patients (cholesterol > 5.2 mmol/L) before and after a mean of 2.5 months of pravastatin therapy (40 mg/d) and in 16 normocholesterolemic control patients. Thrombus formation was assessed by exposing porcine aortic media to the patient's flowing venous blood for 3 minutes at a shear rate of 754 or 2546 s-1 at 37 degrees C in an ex vivo superfusion chamber. Quantitative morphometric platelet thrombus formation at baseline was higher in the hypercholesterolemic patients at both the high and low shear rates: 4.8 +/- 1.0 and 3.3 +/- 0.7 micron 2/mm, respectively, compared with normocholesterolemic patients: 2.1 +/- 0.5 and 1.6 +/- 0.4 micron 2/mm (both P < .05). In the hypercholesterolemic patients, pravastatin decreased total cholesterol from 6.5 +/- 0.2 to 4.5 +/- 0.2 mmol/L and LDL cholesterol from 4.5 +/- 0.2 to 2.8 +/- 0.1 mmol/L (both P < .05). Platelet thrombus formation at high and low shear rates decreased to 2.0 +/- 0.3 and 1.3 +/- 0.3 micron 2/mm, respectively (both P < .05). Thus, hypercholesterolemia is associated with an enhanced platelet thrombus formation on an injured artery, increasing the propensity for acute thrombosis. Platelet thrombus formation at both high and low shear rates decreased as total and LDL cholesterol levels were reduced with pravastatin. Cholesterol lowering may therefore reduce the risk of acute coronary events in part by reducing the thrombogenic risk.",1995.0,0,0 2431,7586338,Effects of cholesterol lowering on the progression of coronary atherosclerosis in women. A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) substudy.,D Waters; L Higginson; P Gladstone; S J Boccuzzi; T Cook; J Lespérance,"Although coronary disease is the leading cause of death in women and its clinical features differ from those in men, very few women have been included in angiographic trials of cholesterol lowering. Sixty-two women with diffuse but not necessarily severe coronary atherosclerosis documented on a recent angiogram and with fasting serum cholesterol between 220 and 300 mg/dL were enrolled in a double-blind, placebo-controlled trial. More than one half had a history of hypertension, approximately one quarter were diabetics, and one third were current smokers. All women received dietary counseling. Lovastatin or placebo was begun at 20 mg/d and was titrated if necessary to 40 and then to 80 mg during the first 16 weeks to attain a fasting LDL cholesterol < or = 130 mg/dL. The mean lovastatin dose was 34 mg/d. Total and LDL cholesterol decreased by 24% and 32%, respectively, in lovastatin-treated women but by < 3% in women receiving placebo. Coronary arteriography was repeated after 2 years in 54 women (87%), and their 394 lesions were measured ""blindly"" on pairs of film with an automated computerized quantitative system. Progression, defined as a worsening in minimum diameter of one or more stenoses by > or = 0.4 mm, occurred in 7 of 25 lovastatin-treated women and 17 of 29 placebo-treated women (28% versus 59%, P = .031). New coronary lesions developed in 1 lovastatin-treated woman and 13 placebo-treated women (4% versus 45%, P < .001). The outcome for each of the angiographic end points was not significantly different between the women and the 245 men who completed the trial. Lovastatin slows the progression of coronary atherosclerosis and prevents the development of new coronary lesions in women.",1995.0,0,0 2432,7586340,Reduction in cardiovascular events during pravastatin therapy. Pooled analysis of clinical events of the Pravastatin Atherosclerosis Intervention Program.,R P Byington; J W Jukema; J T Salonen; B Pitt; A V Bruschke; H Hoen; C D Furberg; G B Mancini,"It has been documented that the HMG coenzyme A reductase inhibitors, or statins, can decrease cardiovascular events and mortality in patients with clinical coronary disease and moderately to severely elevated lipid levels. Additional data are required to demonstrate a reduction of vascular events in coronary patients with less than severely elevated lipid levels and in subgroups of this population. Clinical data from four atherosclerosis regression trials that evaluated pravastatin were pooled for a predetermined analysis of the effect of that agent on the risk of coronary events. All trials were double-masked, placebo-controlled designs that used pravastatin as monotherapy for 2 to 3 years. The 1981 participants in the trials had evidence of atherosclerosis and mildly to moderately elevated lipid levels. For fatal or nonfatal myocardial infarction, there was a 62% reduction in events attributable to pravastatin (P = .001). This effect was evident in younger and older patients, men and women, and patients with and without histories of hypertension and prior infarction. There was a 46% reduction in all-cause mortality (P = .17), which, although not statistically significant, is consistent with the results of other statin trials. There also was a 62% reduction in the risk of fatal or nonfatal stroke (P = .054). These pooled results provide strong evidence that pravastatin reduces the risk of cardiovascular events in patients with atherosclerotic disease and mildly to moderately elevated lipid levels. The benefit for reducing myocardial infarction is evident in older and younger patients, men and women, and patients with and without histories of hypertension and prior infarction.",1995.0,0,0 2433,7588915,Coronary artery disease: prevention of progression and prevention of events.,M L Simoons; J Vos; J W Deckers; P J de Feyter,,1995.0,0,0 2434,7589011,Simvastatin decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: pathophysiological and therapeutic implications.,G F Watts; M H Cummings; M Umpleby; J R Quiney; R Naoumova; G R Thompson; P H Sönksen,"We studied six patients with heterozygous familial hypercholesterolaemia (FH) before and after 8 weeks of treatment with simvastatin (40 mg day-1), an inhibitor of 3-hydroxy-3-methyl-glutaryl-Coenzyme A. Simvastatin decreased plasma low-density lipoprotein (LDL) cholesterol by 43% (P = 0.002), triglycerides by 15% [corrected] (P = 0.05) and mevalonic acid (a measure of in vivo cholesterol synthesis) by 20% (P = 0.002); high-density lipoprotein cholesterol increased by 17% (P = 0.02). The hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) was measured directly using a primed, constant intravenous infusion of 1-[13C]-leucine with monitoring of the isotopic enrichment of apoB by gas chromatography-mass spectrometry; fractional secretion rate (FSR) was derived using a monoexponential function. Simvastatin decreased the FSR, ASR and pool size of VLDL apoB by 17% (14.3 (SEM 3.6)) vs. (11.9 (SEM 3.5) pools day-1, P = 0.10), 83% (51.4 (SEM 17.9) vs. (8.6 (SEM 1.4), P = 0.007 mg kg-1 day-1) and 65% (234.2 (SEM 30.4) vs. 82.6 (SEM 24.0) mg, P = 0.02), respectively. The change in the ASR of VLDL apoB was significantly correlated with the change in plasma LDL cholesterol concentration (P = 0.04), but not with the change of triglyceride or mevalonic acid. We conclude that the hepatic secretion of VLDL apoB in FH is decreased by simvastatin, which may partly explain the fall in plasma cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0 2435,7589044,Does lowering of cholesterol levels influence functional properties of large arteries?,M Kool; F Lustermans; H Kragten; H Struijker Boudier; A Hoeks; R Reneman; H Rila; I Hoogendam; L Van Bortel,"Hypercholesterolaemia is a risk factor for atherosclerosis and induces endothelial dysfunction. Endothelial dysfunction may increase vascular tone and arterial stiffness and as a consequence may decrease arterial distensibility (DC) and arterial compliance (CC). It is hypothesized that lipid-lowering therapy may enhance DC and CC. Therefore, the present study investigates the effect of lipid-lowering therapy with pravastatin on the haemodynamics, DC and CC of the elastic common carotid artery (CCA), and the muscular femoral (FA) and brachial (BA) arteries in patients with primary hypercholesterolaemia. After an 8-week placebo run-in period with a low-cholesterol diet, 19 patients with total cholesterol concentrations of between 6.5 and 9.0 mmol.l-1 and triglyceride concentrations < 4 mmol.l-1 entered a double-blind placebo controlled crossover study. Patients received pravastatin 40 mg o.d. or placebo, each for 8 weeks. Throughout the study the lipid-lowering diet was continued. With pravastatin, total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides were decreased (total cholesterol 26%, LDL-C 35%, triglycerides 16%), while high-density lipoprotein cholesterol (HDL-C) was not changed. Other laboratory values remained within the normal range. Blood pressure, heart rate, cardiac function and systemic vascular resistance were not influenced by pravastatin. Compared to placebo, diameter, distensibility and compliance of all arteries were not statistically significantly changed with pravastatin. These data suggest that, in patients with mild to moderate primary hypercholesterolaemia, short-term lowering of plasma cholesterol does not alter the haemodynamics and vessel wall properties of large arteries.",1995.0,0,0 2436,7594023,Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. PLAC I investigation.,B Pitt; G B Mancini; S G Ellis; H S Rosman; J S Park; M E McGovern,"This study was designed to evaluate the effect of pravastatin on progression of coronary atherosclerosis and ischemic events in patients with coronary artery disease and mild to moderate hyperlipidemia. Few clinical trial data support the use of lipid-lowering therapy in patients with coronary artery disease and mild to moderate elevations in cholesterol levels. Four hundred eight patients (mean age 57 years) with coronary artery disease and low density lipoprotein (LDL) cholesterol > or = 130 mg/dl (3.36 mmol/liter) but < 190 mg/dl ([4.91 mmol/liter]) despite diet were randomized in a 3-year study to receive pravastatin or placebo. Atherosclerosis progression was evaluated by quantitative coronary arteriography. Baseline mean LDL cholesterol was 164 mg/dl (4.24 mmol/liter). Pravastatin decreased total and LDL cholesterol and triglyceride levels by 19%, 28% and 8%, respectively, and increased high density lipoprotein cholesterol by 7% (p < or = 0.001 vs. placebo for all lipid variables). Progression of atherosclerosis was reduced by 40% for minimal vessel diameter (p = 0.04), particularly in lesions < 50% stenosis at baseline. There was a consistent although not statistically significant effect on mean diameter and percent diameter stenosis. There were also fewer new lesions in those assigned pravastatin (p < or = 0.03). Myocardial infarction was reduced during active treatment (8 in the pravastatin group, 17 in the placebo group; log-rank test, p < or = 0.05; 60% risk reduction), with the benefit beginning to emerge after 1 year. In patients with coronary artery disease and mild to moderate cholesterol elevations, pravastatin reduces progression of coronary atherosclerosis and myocardial infarction. The time course of event reduction increases the potential for a relatively rapid decrease in the clinical manifestations of coronary artery disease with lipid lowering.",1995.0,1,1 2437,7598133,Lovastatin-associated sleep and mood disturbances.,J A Tobert,,1995.0,0,0 2438,7605354,Effect of apolipoprotein E and A-IV phenotypes on the low density lipoprotein response to HMG CoA reductase inhibitor therapy.,J M Ordovas; J Lopez-Miranda; F Perez-Jimenez; C Rodriguez; J S Park; T Cole; E J Schaefer,"Our purpose was to assess the effect of apolipoprotein (apo) E and apo A-IV isoform variation on low density lipoprotein (LDL) cholesterol lowering response to the HMG CoA reductase inhibitor, pravastatin. Plasma samples were obtained from participants (apo E, n = 97; apo A-IV, n = 144) in the PLAC-I (Pravastatin Limitation of Atherosclerosis in Coronary Arteries Study-1). The mean LDL cholesterol reduction in these subjects who were randomized to pravastatin 40 mg/day was 28%. Subjects with the APOE*2 allele (n = 12) had significantly (P = 0.04) greater reductions at 36% than subjects homozygous for the APOE*3 allele (n = 66, 27%) or those with the APOE*4 allele (n = 19, 26%). No significant effect of apo A-IV phenotype on LDL cholesterol lowering in response to pravastatin was noted. A meta-analysis utilizing published data from 4 previously published studies as well as our own data with a total sample size of 625 subjects was carried out. This analysis indicates that the presence of the APOE*2 allele was associated with a significantly greater (P < 0.05) LDL-cholesterol lowering response at 37% than those subjects homozygous for the APOE*3 allele at 35%, while those with the APOE*4 allele had a significantly lower response (P < 0.05), at 33%. These data are consistent with the concept that apo E phenotype modulates the LDL cholesterol lowering response observed with the use of HMG CoA reductase inhibitors.",1995.0,0,0 2439,7605391,"Effects of simvastatin on plasma lipoprotein subfractions, cholesterol esterification rate, and cholesteryl ester transfer protein in type II hyperlipoproteinemia.",Y Homma; H Ozawa; T Kobayashi; H Yamaguchi; H Sakane; H Nakamura,"We investigated the effects of simvastatin on plasma levels of lipoprotein subfractions, cholesterol esterification rates and activities of cholesteryl ester transfer protein in 28 patients with type II hyperlipoproteinemia (i.e., nonfamilial hyperlipoproteinemia type IIa and type IIb, and heterozygous familial hypercholesterolemia (FH)). Plasma levels of VLDL-cholesterol (C) and VLDL-triglyceride (TG) were significantly reduced overall by 12.9 +/- 58.0% (mean +/- S.D.; P < 0.05) and 4.2 +/- 54.2% (P < 0.05) respectively, but not in FH. Plasma levels of IDL-C and IDLT-G were decreased overall by 23.2 +/- 47.5% (P < 0.001) and 12.3 +/- 49.7% (P < 0.05), respectively, again mainly due to decreases seen in nonfamilial type II hyperlipoproteinemia. Plasma levels of LDL1 (1.019 < d < 1.045)-C and LDL1-TG were significantly reduced by 33.1 +/- 12.9% (P < 0.001) and 23.3 +/- 24.7% (P < 0.001), respectively. Plasma levels of LDL2 (1.045 < d < 1.063)-C were significantly reduced by 22.9 +/- 18.1% (P < 0.001) overall but not in FH. Gradient PAGE showed no consistent changes in the distribution of LDL particles. Thus, plasma levels of all apo B-containing lipoprotein subfractions were reduced by simvastatin, but its effects varied among the three subgroups. Cholesterol esterification rates were suppressed by 9.3 +/- 19.7% (P < 0.01) and activities of cholesteryl ester transfer protein were reduced by 30.6 +/- 21.5% (P < 0.001). Changes in CETP activity and in plasma levels of cholesterol in lipoprotein subfractions were not correlated. Thus, the changes in distribution of lipoprotein subfractions were not due mainly to CETP suppression.",1995.0,0,0 2440,7606066,Efficacy and pharmacokinetics of simvastatin in heart transplant recipients.,C Campana; I Iacona; M B Regazzi; A Gavazzi; G Perani; V Raddato; C Montemartini; M Viganò,"To evaluate the efficacy and safety of simvastatin administered to a group of heart transplant patients receiving triple-drug immunosuppressive therapy. We also assessed the potential pharmacokinetic interaction between simvastatin and cyclosporine by comparing mean plasma concentrations of simvastatin beta-hydroxy acid, the major metabolite of the drug, in a group of heart transplant patients treated with cyclosporine and in a control group of patients who had not received heart transplants. Both groups received long-term (> 6 wk) simvastatin therapy. We monitored hyperlipidemia in 20 hypercholesterolemic heart transplant patients receiving simvastatin 10 mg/d and triple-drug immunosuppressive therapy. Changes in laboratory results before and after 4 months of simvastatin therapy were considered. The same laboratory data were monitored in a control group of 20 nonhypercholesterolemic heart transplant patients who were not treated with simvastatin but were receiving triple-drug immunosuppressive therapy. Plasma concentrations of simvastatin beta-hydroxy acid were measured in 14 hypercholesterolemic patients, 7 of whom had received heart transplants and 7 who had not. The Division of Cardiology and the First Medical Clinic for the clinical study, as well as the Department of Pharmacology for the pharmacokinetic analysis. Forty heart transplant patients and 7 hypercholesterolemic nontransplant patients. Effectiveness of simvastatin was determined by comparing cholesterol and lipoprotein plasma concentrations in 20 patients who underwent heart transplant and were treated with simvastatin for 4 months. The safety of the drug was determined by analyzing changes in laboratory results in the treated group and in the control group, both those who had received heart transplants and those who had received immunosuppressive therapy. After 4 months of simvastatin therapy, total cholesterol decreased by 12.5% and low-density lipoprotein cholesterol decreased by 21.3%. The only statistically significant laboratory change was an increase of 28.7% in the alanine aminotransferase concentrations. Plasma concentrations of simvastatin beta-hydroxy acid were higher in heart transplant patients than in those who had not received heart transplants, the control group. Low-dosage simvastatin treatment seems to be safe and sufficiently effective to decrease cholesterol concentrations. Concomitant treatment with immunosuppressive therapy (primarily cyclosporine) in heart transplant patients appeared to cause a reduced metabolic clearance of simvastatin from the plasma. More extensive studies on the interaction between simvastatin and cyclosporine are needed to understand the marked variability found in the response to simvastatin.",1995.0,0,0 2441,7606882,Reduction of intermediate density lipoprotein by pravastatin in hemo- and peritoneal dialysis patients.,Y Nishizawa; T Shoji; M Emoto; K Kawasaki; T Konishi; T Tabata; T Inoue; H Morii,"Elevated plasma intermediate density lipoprotein (IDL) is one of the features of uremic dyslipidemia which is potentially atherogenic. We examined the effects of pravastatin, an HMG-CoA reductase inhibitor, on IDL levels as well as other lipoprotein parameters in 19 uremic patients treated with hemodialysis (HD, n = 11) or continuous ambulatory peritoneal dialysis (CAPD, n = 8). The patients were administered 5 mg/day pravastatin for the initial 4 weeks and 10 mg/day for the subsequent 12 weeks. In the analysis of the total subjects, IDL-cholesterol was reduced by 31% as well as low density lipoprotein (LDL)-cholesterol. Cholesterol in very low density lipoprotein (VLDL) also decreased whereas that in high density lipoprotein (HDL) did not. Significant decrease of serum triglycerides was due mainly to reduced IDL- and LDL-triglycerides. Apolipoprotein (apo) A-I did not change, whereas apo A-II, B, C-II, C-III, E, and B/A-I ratio were significantly lowered. Pravastatin did not affect measured activity of lecithin: cholesterol acyltransferase, post-heparin plasma lipoprotein lipase or hepatic triglyceride lipase. HD and CAPD patients responded almost equally to the treatment. IDL elevation was present independent of serum total cholesterol, and it was lowered by pravastatin even in non-hypercholesterolemic subjects. There was no critical adverse effect besides transient and asymptomatic increase of serum creatine kinase level. We conclude that pravastatin can be a safe and effective approach to the management of dyslipidemia in uremic patients who have an elevated level of IDL.",1995.0,0,0 2442,7608323,No pharmacokinetic or pharmacodynamic interaction between rivastatin and warfarin.,R Schall; F O Müller; H K Hundt; W Ritter; L Duursema; G Groenewoud; M V Middle,"Twenty-one healthy, male volunteers completed this double-blind, randomized, two-period, crossover study to determine the possible pharmacodynamic and pharmacokinetic interaction of the concomitant administration of rivastatin and warfarin sodium in healthy volunteers. The study comprised 2 treatment periods of 8 days each, with a medication-free period of 14 days between the 2 treatment periods. According to the randomization, the volunteers received either 300 micrograms of rivastatin or matching placebo once daily during the treatment periods. On day 4 of each treatment period, the volunteers also received a single oral dose of 25 mg of warfarin sodium together with rivastatin or matching placebo. The effect of rivastatin on both the pharmacokinetics and pharmacodynamics (prothrombin time and clotting factor VII activity) of warfarin sodium, and the effect of warfarin sodium on the pharmacokinetics of rivastatin were investigated. Blood sample assays included the analysis of both R- and S-warfarin, because it is known that the enantiomers differ in anticoagulant potency. The study results indicate that the concomitant administration of rivastatin and warfarin does not affect the pharmacokinetics of R- and S-warfarin, or the pharmacodynamics of warfarin. Furthermore, the administration of warfarin sodium does not affect the pharmacokinetics of rivastatin.",1995.0,0,0 2443,7611141,Exercise thallium-201 single photon emission computed tomography for evaluation of coronary artery bypass graft patency.,N M Lakkis; J J Mahmarian; M S Verani,"Thallium-201 single photon emission computed tomography (SPECT) is superior to planar imaging for localizing native coronary stenoses, but has not yet been studied for assessing graft patency late after coronary artery bypass graft surgery (CABG). Accordingly, we studied 50 patients (40 males), aged 58 +/- 9 years (mean +/- SD), who presented for evaluation of angina (30 patients), atypical chest pain (20 patients), and other symptoms (9 patients), late after CABG (51 +/- 47 months). Patients with prior myocardial infarction were excluded. The mean ejection fraction was 58 +/- 17%. All patients underwent coronary angiography within 3 weeks of symptom-limited exercise thallium-201 SPECT. There were 119 grafts, of which 48 had > 50% stenosis by angiography. Thallium-201 SPECT detected 40 of these 48 (83%) stenosed grafts. The sensitivity of thallium-201 SPECT for detecting any graft stenosis was higher than that of the exercise electrocardiogram in patients with typical recurrent angina (84% vs 24%, p < 0.0001), as well as in those with atypical symptoms (70% vs 50%, p = 0.0039). The sensitivity of thallium-201 SPECT for correctly localizing the graft stenosis site was 82% for the left anterior descending, 92% for the right coronary, and 75% for the circumflex coronary artery. In conclusion, exercise thallium-201 SPECT is an excellent method to detect and localize graft stenosis late after CABG; it is far superior to the exercise electrocardiogram alone, both in patients with and without typical recurrent angina.",1995.0,0,0 2444,7611143,Luminal loss and site of restenosis after Palmaz-Schatz coronary stent implantation.,Y Ikari; K Hara; T Tamura; F Saeki; T Yamaguchi,"Restenosis has frequently been observed at the articulation of the Palmaz-Schatz stent. However, the precise mechanism for this remains poorly understood. We measured the luminal diameter in 5 segments within the stent in 67 lesions of 63 patients with successful stenting. Luminal diameter at all 5 sites was significantly reduced 6 months after stent implantation (3.2 +/- 0.5 vs 2.4 +/- 0.7 mm, p < 0.05). Angiographic restenosis rate was 18%. Restenosis involving the articulation was found in 75% of the lesions, and that involving the articulation or edges in 83%. The diameter at the articulation was significantly smaller both immediately (3.0 +/- 0.5 mm vs 3.3 +/- 0.5 mm, p < 0.05) and 6 months after (2.1 +/- 0.8 mm vs 2.5 +/- 0.7 mm, p < 0.05) stenting than the diameter of other stent segments. The loss index was significantly greater at the proximal and distal edges than at the bodies of the stent (0.98 vs 0.60, p < 0.05). The edges of the Palmaz-Schatz stent tend to dilate more than the body of the stent during normal inflation. Although this anchoring system protects against dislodgment or migration of the stent, it may cause more injury. The articulation has 2 anchoring edges within only a 1 mm diameter. Thus, restenosis at the articulation may be ascribed to residual stenosis, increased intimal proliferation due to more severe injury, and delayed late vessel remodeling from lack of mechanical support. These characteristics may be attributed to stent design, and design improvement of the articulation may lead to more favorable results after stent implantation.",1995.0,0,0 2445,7611158,Comparison of lovastatin (20 mg) and nicotinic acid (1.2 g) with either drug alone for type II hyperlipoproteinemia.,J L Vacek; G Dittmeier; T Chiarelli; J White; H H Bell,"Our study indicates that the combination of nicotinic acid (1.2 g/day) and lovastatin (20 mg/day) is more effective than either drug alone in reducing total and LDL cholesterol. Although HDL cholesterol was not significantly improved by these doses of agents over the duration of this study, LDL/HDL and HDL/total cholesterol ratios were improved due to the beneficial actions on total and LDL cholesterol. No serious side effects or changes in serum chemistries were observed, and the combination was well tolerated.",1995.0,0,0 2446,7611159,Escape phenomenon of low-density lipoprotein cholesterol during lovastatin treatment.,A Rubinstein; M Weintraub,"The main issue is whether briefly stopping treatment of the hypercholesterolemic patient will accelerate the atherosclerotic process. This is possible, but such a strategy is preferable only in a subgroup of patients who cannot bear the economic burden of increasing the dosage of statins. In addition, stopping and restarting the drug at different stages lessens the likelihood of more adverse effects occurring when the dosage is increased.",1995.0,0,0 2447,7611249,Reduction of lipoprotein(a) following treatment with lovastatin in patients with unremitting nephrotic syndrome.,C D Brown; N Azrolan; L Thomas; K G Roberts; A Bostom; Z H Zhao; E A Friedman,"Pharmocologic treatment of the hyperlipidemia associated with the nephrotic syndrome with lovastatin has been previously shown to be safe and effective. However, there is no information on the effect of lovastatin treatment on plasma lipoprotein(a) [Lp(a)] levels in patients with the nephrotic syndrome. We administered lovastatin (40 to 80 mg/day) to 20 adult patients with unremitting nephrotic syndrome for 8 weeks to assess its effect on plasma Lp(a) and other plasma lipid concentrations. Apoprotein(a) (apo(a)) phenotype was determined in all patients. Patients were grouped according to their plasma Lp(a) levels. Those with elevated plasma Lp(a) (> or = 30 mg/dL) were placed in group I and those with normal Lp(a) levels (< 30 mg/dL) were placed in group II. Mean total cholesterol and LDL cholesterol were similarly and significantly reduced in groups I and II (-35.9% and -43.3%, P < 0.0005, P < 0.0005 group I, and -31.0% and -42.0%, P < 0.02, P < 0.03 group II, respectively). The median reduction in plasma Lp(a) was -32% (P < 0.003) in nephrotic patients in group I, whereas the median decline in plasma Lp(a) levels in nephrotic patients in group II was only -8.0% (P = 0.052). The overall frequency of the high molecular weight (M(r)) apo(a) phenotype S4 was 70% in nephrotic patients. There was no correlation between plasma Lp(a) and apo(a) phenotype. Treatment with lovastatin results in a favorable response in terms of total and low-density lipoprotein cholesterol lowering in patients with the nephrotic syndrome; however, plasma Lp(a) levels are uniformly and significantly reduced only in nephrotic patients with elevated baseline plasma Lp(a) concentrations. There was no correlation between plasma Lp(a) concentration and other lipid and biochemical parameters.",1995.0,0,0 2448,7614520,Effects of simvastatin versus gemfibrozil on lipids and glucose control in patients with non-insulin-dependent diabetes mellitus. NIDDM Study Group.,A E Sweany; D R Shapiro; A C Tate; R B Goldberg; E A Stein,"The objective of this study was to compare the lipid-altering efficacy and safety of simvastatin with that of gemfibrozil in hypercholesterolemic patients with non-insulin-dependent diabetes mellitus (NIDDM). The study was a 24-week, double-blind, randomized, multicenter trial conducted at clinics and hospitals in the United States, Austria, Germany, Brazil, and New Zealand. The study population included 168 men and women aged 34 to 78 years with NIDDM and primary hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C] level at screening was > or = 4.9 mmol/L with no other risk factor or > or = 4.1 mmol/L with one or more other risk factors). All patients had been under moderate-to-good diabetic control (hemoglobin A1c [HbA1c] < or = 10.0%) for at least 6 months with diet alone, oral hypoglycemic agents, or insulin therapy. Patients meeting eligibility criteria were randomized to receive either simvastatin 10 mg (titrated up to 40 mg to achieve an LDL-C level < 3.4 mmol/L) once in the evening or gemfibrozil 600 mg twice daily. There were 81 patients in the simvastatin group and 87 patients in the gemfibrozil group. After 17 weeks of treatment, simvastatin significantly reduced levels of total cholesterol, LDL-C, and very-low-density lipoprotein cholesterol (VLDL-C) by approximately 25%, 33%, and 20%, respectively (P < or = 0.001), and triglycerides by about 9% (P < or = 0.05). The drug increased high-density lipoprotein cholesterol (HDL-C) levels by about 6% (P < 0.01). Gemfibrozil significantly reduced total cholesterol, VLDL-C, and triglyceride levels by approximately 8%, 38%, and 27%, respectively (P < 0.001); it significantly increased HDL-C values by about 12% (P < 0.001). Gemfibrozil lowered LDL-C levels by 4% but not significantly. The decreases in total cholesterol and LDL-C were significantly greater (P < 0.001) in the simvastatin group, and decreases in VLDL-C and triglycerides were significantly greater in the gemfibrozil group (P < 0.01). The changes in HDL-C were not significantly different between groups. LDL-C values of < 3.4 mmol/L were achieved in 60% of the simvastatin patients and 14% of the gemfibrozil patients. There were no significant between-group differences in fasting serum glucose or HbA1c at any time point. Glycemic profiles (performed at baseline and after 17 weeks of treatment) and glucose area under the curve (at baseline and after 17 weeks of treatment) were not significantly different between treatment groups. Both drugs were generally well tolerated.(ABSTRACT TRUNCATED AT 400 WORDS)",1995.0,0,0 2449,7618632,Effect of lovastatin administered every other day on serum low-density lipoprotein cholesterol > 160 mg/dl.,J P Rindone; R Achacoso; R Bledsoe,"We undertook a pilot study examining the efficacy of lovastatin 20 mg every other day in patients with hypercholesterolemia, and found lovastatin to be effective in lowering low-density lipoprotein (LDL) levels in patients with serum LDL > 160 mg/dl.",1995.0,0,0 2450,7619678,Effects of treatment with simvastatin and pravastatin on cognitive function in patients with hypercholesterolaemia.,N Cutler; J Sramek; A Veroff; G Block; L Stauffer; C Lines,"The effects of equi-efficacious doses of the cholesterol-lowering drugs simvastatin (20 mg day-1) and pravastatin (40 mg day-1) on tests of cognitive function were investigated in a double-blind, placebo-controlled, 2-period (4 weeks per period), incomplete block, crossover study of 36 patients (24 per treatment) with hypercholesterolaemia. After 4 weeks neither of the active treatments differed significantly from placebo on any cognitive measure.",1995.0,0,0 2451,7619944,Depression-induced absenteeism in relation to antihyperlipidemic treatment: a study using GAZEL cohort data.,E Boumendil; P Tubert-Bitter,"We examined the relation between overall 1-year exposure to diet and drugs prescribed for hyperlipidemia and the occurrence of medically certified absence from work with depression during the year of exposure (N = 289). The 17,244 persons studied are middle-aged employees of a national company who volunteered as cohort participants. Depression was more prevalent among those exposed to an antihyperlipidemic diet (N = 1,614) than among those unexposed. After stratification by sex and professional status, we found a prevalence ratio (PR) of 1.83 [95% confidence interval (CI) = 1.30-2.58]. Exposure to simvastatin (N = 376) produced comparable results, with a prevalence ratio of 2.18 (95% CI = 1.18-4.03). For subjects who were not cases in the year of exposure assessment, the hypolipidemic treatments are not associated with depression-induced absenteeism the following year. Our results point to a possible role of prescribed diet and simvastatin in depression-related absenteeism.",1995.0,0,0 2452,7621303,Complementary effects of pravastatin and nicotinic acid in the treatment of combined hyperlipidaemia in diabetic and non-diabetic patients.,C Tsalamandris; S Panagiotopoulos; A Sinha; M E Cooper; G Jerums,"Given that treatment with a single drug is frequently unsuccessful in patients with combined hyperlipidaemia, there is a rationale for the study of regimens using drugs that have complementary therapeutic profiles. We therefore set out to compare the efficacy of a combined pravastatin and nicotinic acid regimen with higher dose monotherapy using either drug in patients with non-insulin-dependent diabetes and in non-diabetic patients with combined hyperlipidaemia. Forty-four patients with total-cholesterol levels of 6.5 mmol/l or higher and triglyceride levels of 2.5 mmol/l or above were randomly assigned to receive either pravastatin alone (40mg/day) or nicotinic acid alone (1500mg/day) for 12 weeks. At the end of this period, the participants received a combination of pravastatin (20mg/day) and nicotinic acid (1000mg/day) for a further 12 weeks. The lipid parameters measured included levels of total cholesterol, triglycerides, low-density-lipoprotein (LDL) cholesterol and high-density-lipoprotein (HDL) cholesterol. Thirty-three patients (22 without and 11 with diabetes) completed the protocol. Monotherapy with pravastatin was more effective than that with nicotinic acid in reducing levels of total cholesterol (-24.9 versus -9.8%, P<0.001) and LDL cholesterol (-32.1 versus -16.9%, P < 0.01), similar in reducing levels of triglyceride (-28.0 versus -31.8%, NS) and tended to be less effective in elevating levels of HDL cholesterol (+16.4 versus +30.8%, P = 0.06). Combination therapy was more effective than pravastatin monotherapy in reducing levels of triglyceride (-39.3 versus -28.0%, P < 0.05) and elevating those of HDL cholesterol (+35.6 versus +16.4%, P < 0.001) and was equally effective in reducing total-cholesterol (-22.3 versus -24.9%, NS) and LDL-cholesterol (-27.1 versus -32.1%, NS) levels. Combination therapy was more effective than nicotinic acid monotherapy in reducing levels of total cholesterol (-23.8 versus -9.8%, P < 0.001), triglyceride (-39.4 versus -31.8%, P < 0.05) and LDL cholesterol (-35.7 versus -16.9%, P < 0.05) and equally effective in elevating HDL-cholesterol levels (+33.6 versus +30.8%, NS). Diabetic and non-diabetic participants responded similarly to combination therapy. Eleven patients (25%) were withdrawn from the study: nine as a result of nicotinic acid intolerance (flushing and nausea) and one through pravastatin intolerance (nausea); one patient died of a myocardial infarction. Combination therapy elevated glycosylated haemoglobin A1c levels in non-diabetic patients (5.5 to 5.8%, P < 0.001); in diabetic patients, however, the observed rise (7.4 to 7.9%) was not statistically significant. Fasting plasma glucose levels, liver function tests and levels of creatine kinase or uric acid were unaffected by either monotherapy or by combination therapy, with the exception of an elevation of the glucose level in diabetic patients receiving nicotinic acid monotherapy. Pravastatin and nicotinic acid in lower-dose combination are more effective than pravastatin alone in reducing levels of triglyceride and elevating those of HDL cholesterol and are more effective than nicotinic acid alone in reducing total-cholesterol triglyceride and LDL-cholesterol levels. Combination therapy is equally effective in type-II diabetic and non-diabetic people. The complementary effects of the combination therapy on lipid levels suggest that this regimen should be considered as a therapeutic option in patients with combined hyperlipidaemia who tolerate the side effects of nicotinic acid.",1994.0,0,0 2453,7628131,Effect of simvastatin on Lp(a) concentrations.,S Haffner; T Orchard; E Stein; D Schmidt; P LaBelle,"The effect of HMG-CoA reductase inhibitors on Lp(a) concentrations is controversial, with some studies showing an increase and others showing no effect on Lp(a) concentrations. Many of these studies have been limited by small sample size and the lack of a prospective design. We evaluated the effect of four treatments: (1) placebo, (2) simvastatin 10 mg PO QPM, (3) simvastatin 20 mg PO QAM, and (4) simvastatin 20 mg PO QPM on Lp(a) concentrations in a prospective, randomized, controlled clinical trial of 24 weeks in 343 subjects in 28 clinical sites in the United States. Simvastatin was not associated with a change in Lp(a) concentrations relative to placebo. These results were not affected by controlling for race, initial Lp(a) level, or urinary albumin excretion. Simvastatin significantly reduced low-density lipoprotein (LDL) cholesterol levels (10 mg PO QPM: -27.6%; 20 mg PO QAM: -28.1%; and 20 mg PO QPM: -34.3%, all p < 0.001). It was concluded that in a large, randomized, controlled trial, simvastatin does not affect Lp(a) levels but markedly lowers LDL cholesterol levels.",1995.0,0,0 2454,7631459,[The Scandinavian Simvastatin Survival Study (4S): old wine in new bottles].,K N Seidelin,,1995.0,0,0 2455,7636533,"Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study.",J N Bavinck; L M Tieben; F J Van der Woude; A M Tegzess; J Hermans; J ter Schegget; B J Vermeer,"The purpose of this study was to investigate the effect of acitretin on the development of keratotic skin lesions, and on squamous cell carcinomas and basal cell carcinomas in a group of renal transplant recipients. Forty-four renal transplant recipients with more than 10 keratotic skin lesions on the hands and forearms were enrolled onto a randomized, double-blind, placebo-controlled trial to test the possible skin cancer-preventing effect of a 6-month treatment with acitretin 30 mg/d. No deterioration in renal function occurred in any of the 38 assessable patients treated. During the 6-month treatment period, two of 19 patients (11%) in the acitretin group reported a total of two new squamous cell carcinomas, compared with nine of 19 patients (47%) in the placebo group who developed a total of 18 new carcinomas (chi 2 = 6.27, P = .01). The relative decrease in the number of keratotic skin lesions in the acitretin group was 13.4%, as compared with a relative increase in the placebo group of 28.2% (difference, 41.6%; 95% confidence interval, 11.5 to 71.7). Most patients treated with acitretin had mild mucocutaneous side effects, but these were easily manageable. Some patients experienced mild hair loss. With the exception of three patients, no increase in serum cholesterol or triglyceride above pretreatment levels was observed, and liver function remained unchanged in all patients. Acitretin 30 mg/d over 6 months had significantly more effect than placebo in the prevention of squamous cell carcinomas and reduced the occurrence of keratotic skin lesions in a group of renal transplant recipients with severe lesions. This effect was most pronounced in patients with a history of squamous cell carcinomas and basal cell carcinomas.",1995.0,0,0 2456,7637480,Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication.,E S Stroes; H A Koomans; T W de Bruin; T J Rabelink,"To study whether vascular dysfunction in hypercholesterolaemia is reversible, we investigated patients without overt arterial disease who were taking maintenance treatment for hypercholesterolaemia. Medication was stopped for 2 weeks, reinstituted for 12 weeks, and again stopped for 6 weeks. During both maintenance treatment and the 12 weeks of step-up medication the lipid profile was improved but did not return to normal. Dose-response curves for serotonin-induced vasodilatation, an index of nitric oxide-dependent vasodilatation, showed a comparable and significant rightward shift after a medication-free period of 2 and 6 weeks compared with control subjects, indicating endothelial dysfunction, which was already maximum after 2 weeks. After 12 weeks of lipid-lowering medication, the difference in endothelial function between controls and patients had disappeared. Co-infusion of L-arginine, the substrate for nitric oxide synthase, returned the impaired serotonin response during hypercholesterolaemia to normal, but had no effect on this response in controls or in patients while on lipid-lowering medication. Neither endothelium-independent vasorelaxation, assessed by sodium nitroprusside infusion, nor vasoconstriction induced by the nitric oxide blocker L-NMMA, were different between controls and patients, whether the latter were on or off lipid-lowering medication. Our results show an L-arginine-sensitive, impaired nitric-oxide-mediated vascular relaxation of forearm resistance vessels in hypercholesterolaemia which is reproducible, and reversible after short-term lipid-lowering therapy. Demonstration of such changes in this readily accessible vascular bed will allow larger trials assessing vascular function during lipid-lowering therapy to be done.",1995.0,0,0 2457,7637722,Effect of pravastatin on outcomes after cardiac transplantation.,J A Kobashigawa; S Katznelson; H Laks; J A Johnson; L Yeatman; X M Wang; D Chia; P I Terasaki; A Sabad; G A Cogert,"Hypercholesterolemia is common after cardiac transplantation and may contribute to the development of coronary vasculopathy. Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to be effective and safe in lowering cholesterol levels after cardiac transplantation. Cell-culture studies using inhibitors of HMG-CoA reductase have suggested an immunosuppressive effect. Early after transplantation, we randomly assigned consecutive patients to receive either pravastatin (47 patients) or no HMG-CoA reductase inhibitor (50 patients). Twelve months after transplantation, the pravastatin group had lower mean (+/- SD) cholesterol levels than the control group (193 +/- 36 vs. 248 +/- 49 mg per deciliter, P < 0.001), less frequent cardiac rejection accompanied by hemodynamic compromise (3 vs. 14 patients, P = 0.005), better survival (94 percent vs. 78 percent, P = 0.025), and a lower incidence of coronary vasculopathy in the transplant as determined by angiography and at autopsy (3 vs. 10 patients, P = 0.049). There was no difference between the two groups in the incidence of mild or moderate episodes of cardiac rejection. In a subgroup of study patients, intracoronary ultrasound measurements at base line and one year after transplantation showed less progression in the pravastatin group in maximal intimal thickness (0.11 +/- 0.09 mm, vs. 0.23 +/- 0.16 mm in the control group; P = 0.002) and in the intimal index (0.05 +/- 0.03 vs. 0.10 +/- 0.10, P = 0.031). In a subgroup of patients, the cytotoxicity of natural killer cells was lower in the pravastatin group than in the control group (9.8 percent vs. 22.2 percent specific lysis, P = 0.014). After cardiac transplantation, pravastatin had beneficial effects on cholesterol levels, the incidence of rejection causing hemodynamic compromise, one-year survival, and the incidence of coronary vasculopathy.",1995.0,0,0 2458,7638696,Pravastatin versus simvastatin--what happens in the real world?,S Levenstein,,1995.0,0,0 2459,7643027,Clinical evaluation of pravastatin in the treatment of type II hyperlipidemia in patients with non-insulin-dependent diabetes mellitus.,C Deerochanawong; S Serirat,"The study was conducted on 30 NIDDM patients with type II hyperlipoproteinemia. They consisted of 13 males and 17 females with the mean (+/- S.D.) age of 60.6 +/- 7.6 year. They were treated with a daily dose of 10 mg pravastatin given orally twice a day for 16 weeks. Their mean (+/- S.D.) serum TC, LDL-C, TG and HDL-C levels at week 0 were 259.7 +/- 22.6, 177.4 +/- 20.3, 173.9 +/- 62.3 and 44.0 +/- 9.9 mg/dl respectively. After receiving pravastatin the maximal reduction of TC, LDL-C and TG was 22.9, 31.2 and 17.1 per cent with statistical significant difference from the baseline. The maximal increment of HDL-C was 11.9 per cent, also showing statistical significant difference from the baseline. Plasma glucose, serum fructosamine and glycated hemoglobin were not affected by pravastatin. There were no significant changes in the patients' body weight and other biochemical parameters except for one case who had transient slight increase in transaminase during pravastatin treatment. These results indicate that pravastatin is an effective and safe drug in diabetic patients with hypercholesterolemia.",1995.0,0,0 2460,7646575,Clinical efficacy of pravastatin for hyperlipidemia in patients with type 2 diabetes mellitus.,M Tawata; I Miwa; K Tsuchiya; M Ozawa; H Shindo; M Wakasugi; T Onaya,"The efficacy of pravastatin (CAS 81131-70-6) on serum lipid levels in 91 type 2 diabetic patients with mean glycosylated hemoglobin of 8.5% was investigated up to 12 weeks. Oral administration of 10 to 20 mg/d of pravastatin significantly decreased total cholesterol by 18.4 +/- 1.5% after 4 weeks. When analyzed separately in type IIa and IIb hyperlipidemia, the reduction of total cholesterol by pravastatin was more prominent in the former. Low-density lipoprotein cholesterol were also significantly decreased 22.2 +/- 2.7% after 4 weeks. The effect of pravastatin in reducing triglyceride was more prominent in patients with higher triglyceride compared to those with lower triglyceride before the administration of the drug. High-density lipoprotein cholesterol showed a slight but significant increase by 4.2 +/- 1.9% after 4 weeks. Among the apolipoproteins examined, apolipoprotein B was significantly decreased after 4 weeks. Atherogenic index and apolipoprotein B/apolipoprotein A-I ratio were also significantly decreased after 4 weeks. The efficacy of pravastatin was also observed after 12 weeks to the same extent as after 4 weeks. No major side effects or abnormalities of laboratory parameters have been observed. These data lead to the conclusion that pravastatin is useful for the treatment of hyperlipidemia in type 2 diabetic patients with poor glycemic control without major adverse effects.",1995.0,0,0 2461,7648234,Combined bezafibrate and simvastatin treatment for mixed hyperlipidaemia.,A Kehely; M MacMahon; M Barbir; R Wray; B J Hunt; R J Prescott; G R Thompson,"The safety and efficacy of combined bezafibrate-simvastatin therapy was evaluated in 49 patients with diet-resistant mixed hyperlipidaemia (type IIb). After a two-month placebo phase, patients were randomized to receive either Bezafibrate Slow Release (SR) 400 mg mane or simvastatin 20 mg nocte followed by three months combination therapy. Total cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol were measured at monthly intervals. Apolipoproteins (apo) A1 and B, lipoprotein (a) [Lp(a)] and fibrinogen were measured before and after each treatment. Simvastatin was more effective than Bezafibrate SR in reducing total cholesterol (2.0 vs. 1.1 mmol/l, p = 0.003) and lowering LDL cholesterol (1.7 vs. 0.4 mmol/l, p = 0.0001) whereas Bezafibrate SR was more effective in reducing triglycerides (by 41% vs. 17%, p = 0.001) and fibrinogen (by 23% vs. 3%, p = 0.004). Compared with simvastatin monotherapy, combined drug therapy induced further reductions in triglycerides (by 26%, p = 0.0003) and apoB (by 11 mg/dl, p = 0.03) and an increase in apoA1 (by 21 mg/dl, p = 0.0008). Symptomatic and biochemical adverse events did not occur more frequently on combined drug therapy than on monotherapy. The combination of bezafibrate and simvastatin was more effective in controlling mixed hyperlipidaemia than either drug alone and did not provoke more adverse events.",1995.0,0,0 2462,7652773,Effects of simvastatin in hyperlipidemic renal transplant patients receiving cyclosporine.,M A Rehman; M H al-Sulaiman; D H Mousa; F A al-Hawas; A H Abdalla; Z Rassoul; A A al-Khader,,1995.0,0,0 2463,7652779,Effect of pravastatin in the treatment of hypercholesterolemia after renal transplantation under cyclosporine and prednisone.,A M Castelao; J M Grinyó; M J Castiñeiras; C Fiol; S Gilvernet; D Seron; J Torras; J M Cruzado; J Alsina,,1995.0,0,0 2464,7652781,Vitamin E in kidney transplantation: effect of treatment with simvastatin in hypercholesterolemia.,C Cantarell; J Bonal; C Sierra; C Pastor; R Lauzurica; L Capdevila,,1995.0,0,0 2465,7652960,[Real results of The Scandinavian Simvastatin Survival Study (4S)].,B Ostergaard Kristensen,,1995.0,0,0 2466,7652961,[The Scandinavian Simvastatin Survival Study (4S): hasty conclusions].,U Ravnskov,,1995.0,0,0 2467,7653179,Effect of systemic treatment with cholesterol-lowering drugs on the skin barrier function in humans.,D Ramsing; E Agner; J Malinowski; J Meibom; T Agner,"The intercellular lipids of stratum corneum are predominantly formed by cholesterol, ceramides and free fatty acids. Cholesterol synthesis is inhibited by statins, cholesterol-lowering drugs (lovastatin, pravastatin, simvastatin). The present study was undertaken to examine the effect of these drugs on skin barrier function. Knowledge about the effect on epidermis of systemic inhibition of cholesterol synthesis may improve our understanding of the skin barrier function. Seventeen statin-treated subjects were compared to controls. All were patch-tested with sodium lauryl sulphate (SLS), and the skin was evaluated after 24 h and after 7 days by measurement of transepidermal water loss (TEWL), erythema and visual scoring. After 24 h as well as after one week erythema was significantly less pronounced in the statin-treated group than in controls (p < 0.001). No significant differences in TEWL were found between the groups at any time. The results imply a decreased bioavailability of SLS in the statin-treated group, while no evidence for an altered permeability barrier to water was found.",1995.0,0,0 2468,7653447,Design features and baseline characteristics of the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) Study: a randomized trial in patients with previous acute myocardial infarction and/or unstable angina pectoris.,,"LIPID is a multicenter, double-blind, randomized, placebo-controlled trial comparing the effects of pravastatin, 40 mg/day, with placebo, given for > or = 5 years, in patients aged 31 to 75 years with a total cholesterol level at baseline of 4.0 to 7.0 mmol/L (155 to 270 mg/dl), and with a history of acute myocardial infarction (AMI) or hospitalization for unstable angina pectoris (UAP). Each group receives dietary advice according to National Heart Foundation guidelines. Individual care of each patient is otherwise left to the discretion of the patient's usual doctor. The study has a primary outcome of coronary mortality, and is designed to detect an 18% reduction with 80% power. From April 1990 to September 1992, 11,106 patients were registered, and following the run-in phase, 9,014 were randomized: 5,754 (64%) after a qualifying event of AMI and 3,260 (36%) after hospitalization for UAP. The randomized population includes relatively large numbers in subgroups not assessed reliably in earlier trials: 1,511 women, 3,516 patients aged > or = 65 years, 777 diabetics, and 3,829 patients with serum cholesterol < or = 5.5 mmol/L (213 mg/dl) at baseline. With a projected 700 fatal coronary events, the trial should be able to detect important reductions in coronary mortality and contribute substantially to prospective meta-analyses to detect effects on total mortality. The spectrum of patients being assessed will improve the reliability of evidence for the benefits and risks of cholesterol-lowering therapies in patients with lower cholesterol levels and in other important subgroups.",1995.0,0,1 2469,7653448,Effects of pravastatin with niacin or magnesium on lipid levels and postprandial lipemia.,J H O'Keefe; W S Harris; J Nelson; S L Windsor,"This study was designed to evaluate the therapeutic effectiveness of 3 different pharmacologic lipid-lowering regimens in the treatment of patients with clustered lipid risk factors. Sixty-five patients with low high-density lipoprotein (HDL) levels and hypertriglyceridemia were randomized to 1 of 3 treatment arms: pravastatin/niacin, pravastatin/magnesium, or pravastatin/placebo. After 18 weeks, patients in the pravastatin/niacin group had a -41% change in the total cholesterol/HDL ratio compared with -13% in the pravastatin/magnesium arm and -16% in the pravastatin/placebo group. The HDL2 and HDL3 subfractions, as well as the apolipoprotein A-I levels, were increased significantly only in the pravastatin/niacin arm. The levels of small dense low-density lipoprotein (LDL) cholesterol (LDL3) were decreased to a greater extent in the pravastatin/niacin arm (-43%) than in either the pravastatin/magnesium (-13%) or the pravastatin/placebo (-20%) arm. Only the pravastatin/niacin regimen significantly diminished postprandial lipemia (-32% change in the remnant particle triglyceride concentration and decreased very-low-density lipoprotein remnant levels). Thus, in this group of patients with clustered risk factors, the combination of pravastatin and niacin resulted in significant improvements in HDL and triglyceride levels, total cholesterol to HDL ratio, small dense LDL levels, and postprandial lipemia. Pravastatin alone or in combination with magnesium resulted in less significant changes that were largely limited to LDL cholesterol reduction.",2001.0,0,0 2470,7653449,Screening experience and baseline characteristics in the West of Scotland Coronary Prevention Study. The WOSCOPS Study Group. West of Scotland Coronary Prevention Study.,,"The West of Scotland Coronary Prevention Study (WOSCOPS) is a randomized, double-blind, placebo-controlled trial of pravastatin in a primary prevention context. The primary end point of the trial is definite coronary artery disease (CAD) death and/or nonfatal acute myocardial infarction. This study describes the baseline characteristics of the trial recruits and of the subjects who were screened during the recruitment process; 6,595 men, aged 45 to 64 years, with raised cholesterol levels, were randomized in equal numbers to placebo or pravastatin after initial screening of approximately 81,000 subjects in the West of Scotland. With the exception of cholesterol levels and history of CAD, the recruits had a similar risk factor profile and demographic distribution to the group of screenees from which they were selected. Compared with previous primary prevention studies of cholesterol-lowering drugs, the WOSCOPS recruits are, on average, 7 to 9 years older than subjects in other trials and have average total cholesterol levels 0.5 mmol/L (19.4 mg/dl) lower than those in the Helsinki Heart Study and the Lipid Research Clinics-Coronary Primary Prevention Trial. The study has achieved its initial goal of accumulating > 30,000 patient-years of randomized follow-up. Recruits had their final trial visits in the first half of 1995 and the main results will be available in the fourth quarter of 1995.",1995.0,0,0 2471,7656097,Replacing lovastatin with pravastatin: effect on serum lipids and costs.,L Korman; L Borysiuk,"The effects on costs and lipid levels of replacing lovastatin therapy with pravastatin were studied. Beginning in April 1992, outpatients receiving lovastatin were switched to pravastatin. Physicians were asked but not required to initiate the pravastatin sodium treatment at half the daily lovastatin dose in milligrams. In October 1993, the dosages of lovastatin and pravastatin and the corresponding lipid-profile results were recorded for each patient for whom lovastatin had been replaced by pravastatin. The drug acquisition cost per year of therapy was calculated for each patient's most recent dosage of lovastatin and pravastatin as of April 1993. The costs used in the analysis were the most recent available (March 1995). Lovastatin therapy was changed to pravastatin in a total of 168 patients. Of the 168 patients, 145 (86%) were prescribed an initial daily pravastatin sodium dose that was at least 50% lower in milligrams than that of lovastatin. All of the 168 patients who received pravastatin had two usable total-cholesterol measurements during lovastatin therapy, and 148 (88%) had at least one such measurement during pravastatin therapy. Among patients with usable serum-lipid data, there was no significant difference between any of the mean serum lipid concentration (total cholesterol, low-density-lipoprotein cholesterol, or high-density-lipoprotein cholesterol) before and after the conversion. The annual cost of lovastatin for the 148 patients would be $71,693 for the most recent dosages; the corresponding cost for pravastatin would be $56,875 (21% lower). The replacement of lovastatin with pravastatin sodium was associated with a 21% cost reduction but no significant change in mean serum lipid concentrations.",1995.0,0,0 2472,7657845,Surrogate biochemical markers: precise measurement for strategic drug and biologics development.,J W Lee; J D Hulse; W A Colburn,"More efficient drug and biologics development is necessary for future success of pharmaceutical and biotechnology companies. One way to achieve this objective is to use rationally selected surrogate markers to improve the early decision-making process. Using typical clinical chemistry methods to measure biochemical markers may not ensure adequate precision and reproducibility. In contrast, using analytical methods that meet good laboratory practices along with rational selection and validation of biochemical markers can give those who use them a competitive advantage over those who do not by providing meaningful data for earlier decision making.",1995.0,0,0 2473,7658290,Treatment and liver transplantation for cholesterol ester storage disease.,L Leone; P F Ippoliti; R Antonicelli; F Balli; B Gridelli,,1995.0,0,0 2474,7661873,"Cholesterol absorption and synthesis during pravastatin, gemfibrozil and their combination.",H T Vanhanen; T A Miettinen,"The study evaluates cholesterol metabolism off and on treatment with pravastatin (P), gemfibrozil (G) and their combination (PG) in 38 middle-age hyperlipidemic primary care patients with serum cholesterol > 6 mmol/l and serum triglycerides < 4 mmol/l after a low-fat low-cholesterol diet. The subjects were randomized to P (40 mg/g), G (1200 mg/day), PG (40 + 1200 mg/day) or placebo for 12 weeks. We analyzed serum lipids, apolipoproteins A-I, B and E, serum cholesterol precursors (markers of cholesterol synthesis), serum plant sterols and cholestanol (markers of cholesterol absorption) and cholesterol metabolism by the sterol balance technique and cholesterol absorption efficiency. P alone or in combination with G lowered apoprotein E concentration, and serum cholesterol levels by inhibiting cholesterol synthesis measured by the precursor/cholesterol proportions with inconsistent change in fecal output of cholesterol. G alone decreased bile acid synthesis and increased biliary cholesterol secretion which were associated with reduced cholesterol absorption efficiency and the serum plant sterol and cholestanol proportions, and increased synthesis of cholesterol as measured both by the sterol balance technique and the precursor sterol proportions. A combination of PG also lowered LDL cholesterol similarly but triglyceride-rich lipoproteins significantly more than P alone, and otherwise inhibited the changes caused by G in cholesterol metabolism except that the precursor sterol proportions still indicated reduced cholesterol synthesis. Overall, the changes of the cholesterol precursor proportions were negatively related to that of cholesterol absorption efficiency and positively to that of cholesterol synthesis. The respective plant sterol and cholestanol values correlated oppositely to cholesterol absorption efficiency and synthesis. Serum precursor sterols reflected changes in cholesterol synthesis more sensitively than the sterol balance technique, even though only the latter method can quantitate cholesterol synthesis.",1995.0,0,0 2475,7661884,Autoantibodies against malondialdehyde-modified LDL are elevated in subjects with an LDL subclass pattern B.,H Jansen; H Ghanem; J H Kuypers; J C Birkenhäger,"Small low density lipoproteins (LDL) are more susceptible to in vitro oxidation than larger LDL. To study whether this leads to more oxidation of small LDL in vivo, we determined the level of autoantibodies against malondialdehyde-modified LDL (MDA-LDL) in subjects with small or large LDL (LDL subclass pattern B or A) by ELISA. The study group consisted of 92 subjects with coronary heart disease without severe hypercholesterolemia (mean total plasma cholesterol 5.9 +/- 0.8 mM), 46 with an LDL subclass pattern A and 46 with an LDL subclass pattern B. In the subjects with LDL subclass pattern B the titre of autoantibodies of the IgM class against MDA-LDL was 29% higher than in the subjects with LDL subclass pattern A (P < 0.0001). The concentration of the anti-MDA-LDL autoantibodies of the IgM class was 58% higher in the patients with the pattern B than in the patients with the pattern A (P < 0.0001). There was no statistically significant difference in the titre or concentration of autoantibodies of the IgG class between subjects with LDL subclass patterns A and B. Besides plasma triglyceride and HDL cholesterol, the titre and concentration of the IgM autoantibodies were found to be independent predictors of the LDL subclass pattern. These results show that small LDL are associated with higher autoantibody levels than large LDL. Based on the assumption that the level of autoantibodies against MDA-LDL represents the rate of LDL oxidation in vivo, we conclude that in vivo small LDL is more readily oxidised than larger LDL.(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0 2476,7662446,Long-term safety of statin-fibrate combination treatment in the management of hypercholesterolaemia in patients with coronary artery disease.,M D Feher; J Foxton; D Banks; A F Lant; R Wray,"To evaluate the long-term safety profile of treatment with a statin-fibrate combination in a cohort of patients with documented coronary artery disease. Retrospective cohort analytical study. District general hospital. 102 (81 male and 21 female) hypercholesterolaemic (total cholesterol concentration > 6.5 mmol/l) patients with documented coronary artery disease and who had been treated with a statin-fibrate combination for over 1 year. Coronary artery disease was confirmed by angiography in 93 patients and by a positive (Bruce protocol) exercise test in the remainder. Fifty eight patients had a history of previous coronary bypass graft surgery. Twice daily lipid lowering treatment was given, with the fibrate administered in the morning (either bezafibrate 400 mg (n = 101) or fenofibrate 200 mg (n = 1)) and the statin in the evening (either simvastatin 10 mg (n = 23), 20 mg (n = 72), or 40 mg (n = 2) or pravastatin 10 mg (n = 1) or 20 mg (n = 4)). Treatment continued for 1 (n = 9), 2 (n = 58), or 3 (n = 35) years. Selected laboratory variables (total cholesterol concentration and liver (aspartate transaminase (AST)) and muscle enzyme (creatine kinase (CK)) activities) and documented symptomatology. A mean (SD) total cholesterol concentration of 5.2 (0.8) mmol/l was achieved after combined treatment for 1 year which was maintained at annual follow up. Over a maximum 3 year follow up no patient reported myalgic symptoms and none had a measured CK activity > 10 times above nomal. Four men on a simvastatin-bezafibrate combination had a CK activity rise to less than three times normal. Fourteen patients with a negative history of alcohol excess (consumption < 21 units/week) had borderline raised AST values. Statin-fibrate combination treatment for up to 3 years in a cohort of patients with coronary artery disease was not associated with serious disturbances in biochemical markers of muscle or liver function.",1995.0,0,0 2477,7663036,Psyllium in hypercholesterolemia.,E K Chan; D J Schroeder,"In summary, within a controlled study situation, psyllium seems to be effective in lowering total and LDL cholesterol by 4-8% and 6-13%, respectively. Compared with conventional antilipidemic agents such as lovastatin, which lowers total cholesterol 30%, LDL cholesterol 40%, and triglycerides 20%, the effect of psyllium on lipids is minimal, and its use as a form of drug therapy in patients with moderate-to-severe hypercholesterolemia is not recommended. As an adjunct to AHA step 1 diet therapy, however, psyllium can be useful. The NCEP recently has stressed diet therapy as a first-line primary intervention in patients not a high risk from multiple risk factors or very high LDL cholesterol concentrations. Men ( < or = 45 y) and premenopausal women with no other risk factors and moderately high LDL cholesterol concentrations (4.1-5.7 mmol/l) are at relatively low risk for coronary events in the near future, and would therefore be suitable for diet therapy combined with adjunctive psyllium therapy. Psyllium is well tolerated with minor transient adverse effects (abdominal distention, excessive gas, flatulence) and has a good compliance record ( > or = 90%). It would be a useful adjunct to dietary intervention in low-risk patients with mild-to-moderate hypercholesterolemia. Further research is needed to evaluate psyllium's effect in women and its efficacy in long-term use.",1995.0,0,0 2478,7664501,Economics of lipid lowering with HMG CoA reductase inhibitors.,D R Illingworth,,1995.0,0,0 2479,7664504,"Update on the treatment of hypercholesterolemia, with a focus on HMG-CoA reductase inhibitors and combination regimens.",H N Ginsberg,"Numerous studies involving patients with hypercholesterolemia have demonstrated that reduction of lipid levels markedly reduces morbidity and mortality from cardiovascular disease. Diet alone may enable patients without established disease to attain target lipid levels, but pharmacotherapy generally is necessary for those with coronary artery disease. Choice of a suitable agent for monotherapy--a bile acid resin, niacin, or an HMG-CoA reductase inhibitor--may be determined by patient phenotype. For resistant cases, therapy combining an HMG-CoA reductase inhibitor with another agent generally is effective and well tolerated.",1995.0,0,0 2480,7665720,The effect of lovastatin on early restenosis.,Y Beigel; N Zafrir; Y Teplitzky; Y Neuman; D Gavish; M Wurzel; M Fainaru,"The effect of lovastatin given before percutaneous coronary angioplasty (PTCA) on early restenosis was investigated in men with mild to moderate hypercholesterolemia. Thirty-four hypercholesterolemic patients (serum LDL cholesterol 130-200 mg/dL) undergoing their first PTCA completed a 6-month prospective, double-blind, placebo-controlled trial. Eighteen received lovastatin 20 mg/day (Lo group) and 16 placebo (P1 group), beginning 10 to 21 days before PTCA. All underwent a thallium-201 quantitative exercise test 5 to 7 days after PTCA. Endpoints for restenosis were either 50% narrowing of the dilated artery on coronary angiography, performed in symptomatic patients or, in asymptomatic patients, the appearance of newly developed reversible filling defects in the vascular territory of the dilated artery on a second thallium scan done 6 months after PTCA. The hypocholesterolemic change observed in the Lo group was not accompanied by a reduction in early restenosis risk. The authors conclude that effective hypocholesterolemic therapy before PTCA does not affect early restenosis rate in men with mild to moderate hypercholesterolemia.",1995.0,0,0 2481,7667166,Dyslipidemias in patients with diabetes mellitus: classification and risks and benefits of therapy.,J C Oki,"To characterize the lipid and lipoprotein abnormalities in patients with diabetes mellitus and evaluate the risks and benefits of marketed pharmacologic therapies, a MEDLINE search of the National Library of Medicine data base was performed of studies published from January 1966 to March 1994. Clinical trials assessing effects on lipids and lipoproteins, and adverse effects of marketed lipid-lowering agents were extracted. Reviews and other relevant articles were included if they provided information regarding lipid and lipoprotein metabolism or guidelines on the treatment of dyslipidemias in patients with diabetes mellitus. An extensive review of clofibrate was not included. The most common dyslipidemia in patients with poorly controlled insulin-dependent diabetes mellitus (IDDM) is combined elevated triglyceride and cholesterol levels, with reduced high-density lipoprotein (HDL) cholesterol (mixed hyperlipidemia). Hypertriglyceridemia combined with a reduced HDL cholesterol is the most common dyslipidemia in patients with noninsulin-dependent diabetes mellitus, but essentially any pattern of dyslipidemia may be present. Small and dense low-density lipoprotein (LDL), glycosylation of lipoproteins, and increased oxidized lipoproteins may be present in patients with diabetes mellitus; all contribute to accelerated atherosclerotic cardiovascular disease. Insulin therapy generally corrects quantitative lipid abnormalities in patients with IDDM, so drug treatment is seldom indicated. Diet, exercise, and insulin or oral sulfonylureas will improve hypertriglyceridemia and low HDL concentrations, but do not always return them to normal. Drug therapy is indicated when nonpharmacologic measures are inadequate. It is administered based on the effects of each agent on lipids and lipoproteins, patient age, adverse effect profile, patient tolerability, and drug-disease and drug-drug interactions. A fibric acid derivative is the drug of choice for marked hypertriglyceridemia in patients with diabetes mellitus. Niacin can worsen glycemic control, but it may be required in severe hypertriglyceridemia, hypercholesterolemia, or mixed hyperlipidemia. Bile-acid binding resins may accentuate hypertriglyceridemia but may be useful in selected patients with marked hypercholesterolemia and normal triglycerides. Hydroxymethylglutaryl coenzyme A reduced inhibitors are preferred in patients with elevated LDL cholesterol and mild hypertriglyceridemia. Patients with marked lipid abnormalities or mixed hyperlipidemias may require carefully dosed combinations of lipid-lowering drugs.",1995.0,0,0 2482,7669080,Regression of transplant coronary artery disease during chronic HELP therapy: a case study.,J W Park; M Vermeltfoort; P Braun; E May; M Merz,"This report concerns a heart transplant patient with hypercholesterolemia who showed rapid development of a severe transplant coronary artery disease. The patient received 10 mg pravastatine per day. Quantitative coronary angiography analyses of 4 serial angiograms clearly demonstrated that in the first 2.5 years following surgery, there was a rapid simultaneous progression in both the transplant coronary disease, involving the entire coronary system, and the development of segmental stenotic lesions. During one year of weekly heparin-mediated extracorporeal LDL-cholesterol precipitation (HELP) therapy in addition to diet and pravastatine therapy, the serum low density lipoprotein (LDL), lipoprotein (a) (Lp(a)), and fibrinogen levels could be reduced from 185 +/- 45 mg/dl, 138 mg/dl and 248 mg/dl, respectively, to interval values of 136 +/- 17 mg/dl, 48 +/- 15 mg/dl, and 185 +/- 44 mg/dl, respectively [interval value = (the concentration after HELP + the concentration before the next HELP treatment):2]. This therapy halted further progression of coronary diameter throughout the whole coronary system and brought about marked regression of segmental obstructive lesions.",1995.0,0,0 2483,7669084,Postprandial vitamin A and squalene clearances and cholesterol synthesis off and on lovastatin treatment in type III hyperlipoproteinemia.,H Gylling; H Relas; T A Miettinen,"Postprandial fat clearance and absorption, fecal elimination and synthesis of cholesterol, bile acid synthesis, and cholesterol precursors and plant sterols in serum were studied in five patients with type III dyslipoproteinemia off and on lovastatin. The basal values were related to those in nontreated normolipidemic control subjects with apolipoprotein E3/3 phenotype (apo E3 controls, n = 16). On regular home diets, cholesterol precursor concentrations and cholesterol precursor/cholesterol ratios were high in the type III group. However, cholesterol absorption efficiency, bile acid and cholesterol synthesis measured with sterol balance technique and the precursor sterol/plant sterol ratios in serum were similar to the control values, suggesting that cholesterol absorption and metabolism was normal in these subjects. Lovastatin normalized the increased lipoprotein concentrations and reduced biliary cholesterol secretion, absolute absorption of cholesterol, precursor sterol/cholesterol and precursor sterol/plant sterol ratios in serum, fecal neutral and total sterol outputs and cholesterol synthesis. Lovastatin had no effect on cholesterol absorption efficiency or bile acid synthesis. Despite normalization of the triglyceride-rich lipoprotein levels by lovastatin, the postprandial vitamin A and squalene peak concentrations and the areas under the curves remained above the control ranges. The findings show that in type III hyperlipidemia, the precursor sterol/cholesterol ratios do not predict cholesterol synthesis. The latter, bile acid synthesis, precursor sterol/plant sterol ratios in serum, and cholesterol absorption are normal under basal conditions. The normalization of increased lipids by lovastatin is mainly due to reduced synthesis and absolute absorption of cholesterol, while the retarded postprandial fat clearance was not normalized by the drug.",1995.0,0,0 2484,7670749,Triglyceride-rich lipoproteins and the progression of coronary artery disease.,H N Hodis; W J Mack,"A growing body of evidence from serial coronary angiographic studies indicates that triglyceride-rich lipoproteins are an important factor in the progression of coronary artery disease. Compelling evidence also suggests that triglyceride-rich lipoproteins may be most important in the progression of mild-moderate lesions, the very lesions that are likely to be responsible for clinical coronary events.",1995.0,0,0 2485,7670752,Lipoprotein (a) and coronary heart disease.,V M Maher; B G Brown,"The role of lipoprotein (a) in the atherosclerotic process is continually being unraveled, and many of its potential proatherogenic and prothrombotic features have already been elucidated. Whereas most studies have demonstrated a strong association between lipoprotein (a) and the presence and severity of coronary heart disease, other groups have failed to observe such a relationship, which does question the importance of this particle in promoting atherosclerosis. Evidence from a study of human coronary atherosclerosis appears to demonstrate that the pathogenicity of lipoprotein (a) is modulated by concomitant LDL-cholesterol levels. Such a modulation of the pathogenicity of lipoprotein (a) may underlie the conflicting results regarding its association with coronary heart disease. This article will examine this possibility, and will also outline the potential mechanisms through which lipoprotein (a) may interact with LDL to exert its adverse effects. As a consequence of its interaction with LDL, alternative strategies for treating high levels of lipoprotein (a) will be discussed.",1995.0,0,0 2486,7670753,Hyperlipidaemia and atherosclerotic cerebrovascular disease.,A Postiglione; C Napoli,"Controversies exist concerning the role of hypercholesterolaemia as a risk factor for nonhaemorrhagic stroke because intracranial arteries seem to be more resistant than coronary arteries to cholesterol-induced endothelial damage. Only very high levels of serum cholesterol seem to be a significant risk factor. It is possible that coronary heart disease may occur earlier in life than cerebrovascular atherosclerosis, and it could then become the cause of stroke. In our view, the causal relationship between very low levels of serum cholesterol and haemorrhagic stroke is unlikely, and cholesterol-lowering treatment appears to be safe. New studies should consider the particular metabolic aspects of intracranial arteries and the independent role of lipoprotein (a), apolipoprotein E phenotypes and other molecular and genetic mechanisms involved in atherosclerotic cerebrovascular disease.",1995.0,0,0 2487,7671358,Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries.,R Salonen; K Nyyssönen; E Porkkala; J Rummukainen; R Belder; J S Park; J T Salonen,"The atherosclerotic progression-reducing effect of LDL cholesterol (LDL-C) lowering has been established in subjects with severe atherosclerotic disease but not in persons with elevated LDL cholesterols without severe atherosclerosis. KAPS (Kuopio Atherosclerosis Prevention Study) is the first population-based trial in the primary prevention of carotid and femoral atherosclerosis. The eligibility requirements were serum LDL-C > or = 4.0 mmol/L and total cholesterol < 7.5 mmol/L. Out of a geographically defined population, 447 men aged 44 to 65 years (mean, 57) were randomized to pravastatin (40 mg/d) or placebo for 3 years. Less than 10% of the subjects had prior myocardial infarction. Thirty-nine men discontinued study medication; however, efficacy data were available for 424 men. The primary outcome was the rate of carotid atherosclerotic progression, measured as the linear slope over annual ultrasound examinations in the average of the maximum carotid intima-media thickness (IMT) of the far wall of up to four arterial segments (the right and left distal common carotid artery and the right and left carotid bulb). For the carotid arteries, at the overall mean baseline IMT of 1.66 mm, the rate of progression of carotid atherosclerosis was 45% (95% CI, 16 to 69%) less in the pravastatin (0.017 mm/y) than the placebo (0.031 mm/y) group (P = .005). In the common carotid artery there was a treatment effect of 66% (95% CI, 30 to 95%; pravastatin 0.010 mm/y; placebo 0.029 mm/y; P < .002) at the overall mean baseline IMT of 1.35 mm. A treatment effect of 30% (95% CI, -1% to 54%) was found for the carotid bulb (pravastatin, 0.028; placebo, 0.040; P = .056) at the overall mean baseline IMT of 2.0 mm. The treatment effect was larger in subjects with higher baseline IMT values, in smokers and in those with low plasma vitamin E levels. There was no significant treatment effect on atherosclerotic progression in the femoral arteries. These data establish the antiatherogenic effect of LDL-C lowering by pravastatin in hypercholesterolemic men in a primary prevention setting and suggest a greater effect in smokers than in nonsmokers.",1995.0,1,1 2488,7674695,Clinical perspectives on primary and secondary prevention of coronary atherosclerosis.,P C Deedwania,"Several clinical trials have provided compelling evidence in support of the benefits of lipid-lowering therapy for primary and secondary prevention of atherosclerosis. The results of primary prevention trials have demonstrated that coronary morbidity can be reduced and survival improved with effective lipid-lowering regimens. There has been concern, however, regarding harmful effects (e.g., increased rate of suicide and increased risk of gastrointestinal cancer) of cholesterol-lowering therapies in primary prevention trials. These concerns are not well supported by strong evidence, and there has been lack of a dose-response relationship. It is generally believed that for 1% reduction in serum cholesterol, there is a 2% reduction in the risk of coronary events. The results of numerous secondary prevention trials have clearly demonstrated the benefit of lipid-lowering therapies in reducing the risk of future cardiac events and cardiac mortality in patients with preexistent coronary artery disease. Several studies have shown that treatment regimens effective in reducing LDL cholesterol levels lead to regression of atherosclerotic plaques as well as retard the progression of the disease process. Interestingly, some of these studies have also shown that when measured angiographically, the luminal diameter at the site of stenotic lesions might improve only by an average of 2% to 3%; however, this small degree of improvement is associated with a remarkable reduction by 35% to 25% in the risk of future coronary events. These findings further corroborate the hypothesis about the importance of a lipid-rich cap of the vulnerable plaques and suggest that the reduction in lipid levels is associated with the efflux of lipids from the plaque, thus converting it from a vulnerable to a stable state. The most recent data from the 4S trial have unequivocally demonstrated the benefits of treatment with HMG coenzyme-A reductase inhibitors in reducing the risk of future coronary events and improving the overall survival in patients with established CHD. Although there is still ongoing controversy regarding the precise course of action for primary prevention of CHD, the results of a large number of studies provide overwhelming evidence in support of aggressive lipid-lowering therapy for secondary prevention of CHD. Based on the findings of these studies, it seems prudent that clinicians become actively involved in the evaluation and management of lipid abnormalities and other risk factors in patients with CHD.",1995.0,0,0 2489,7677557,Efficacy and safety of pravastatin in African Americans with primary hypercholesterolemia.,T A Jacobson; M M Chin; C L Curry; V Miller; V Papademetriou; R C Schlant; J C LaRosa,"Coronary artery disease strikes early and may prove particularly severe in persons of African-American descent. Therefore, we studied the lipid-lowering efficacy and safety of pravastatin sodium (20 mg/d), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in 245 African-American patients with primary hypercholesterolemia. After 4 weeks on an American Heart Association phase I low-fat diet, patients were randomized in a double-blind manner to either pravastatin or placebo in a 3:1 ratio. After 12 weeks of pravastatin treatment, low-density lipoprotein cholesterol levels declined 25.8%, total cholesterol levels 20.3%, and triglyceride levels 6.2%, while high-density lipoprotein cholesterol levels remained essentially unchanged. Overall, 72% of pravastatin-treated patients achieved reductions in low-density lipoprotein cholesterol level in excess of 20%, and 44% attained declines in excess of 30% (both P < .01 vs placebo). Pravastatin was generally well tolerated in this population, with one patient (0.5%) exhibiting a reversible myopathy with creatine kinase elevations to 10 times the upper limit of normal. No substantial elevations of aminotransferase levels of two to three times the upper limit of normal occurred in either the pravastatin or the placebo group. Drug compliance was high, exceeding 90%. Pravastatin appears to be an effective and safe lipid-lowering agent and is the first 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor to be studied extensively in this underrepresented population.",1995.0,0,0 2490,7695166,Pravastatin (mevalotin) restenosis trial after percutaneous transluminal coronary angioplasty. Cholesterol reduction rate determines the restenosis rate.,Y Yui; C Kawai; S Hosoda,"There is no consensus on lipids and restenosis after percutaneous transluminal coronary angioplasty (PTCA). We evaluated whether prevastatin could prevent restenosis after PTCA. In this study, pravastatin therapy was started one month before PTCA. The follow-up angiography was done three months later. Total cholesterol reduction rates [one index of reduction rate is calculated between 1 M (month) before PTCA and at PTCA, and another done between 1 M before PTCA and at follow-up angiography] proved to be good predictors of restenosis rate after PTCA; The greater the cholesterol reduction rate, the lower the rate of restenosis. The residual stenosis after PTCA correlated with the restenosis rate. The restenosis rate in the pravastatin group was lower than that in the control group, but the difference was not statistically significant. However, in the subgroup with pre-PTCA restenosis of 99% or more, the restenosis rate in the pravastatin group was significantly lower than that of the control group. Pravastatin seems to prevent intimal hyperplasia through the reduction of cholesterol level and to reduce restenosis. Many macrophages are present in the highly stenosed or occluded coronary arteries, and the reduction of the number and the activity of macrophages may prevent the restenosis. Pravastatin also has an antithrombotic action. In such regions, the occlusion by the thrombus formation is also considered to play a key role in restenosis in addition to the intimal hyperplasia. Thus, pravastatin may be useful especially for PTCA against highly stenosed or occluded coronary arteries.",1995.0,0,0 2491,7695184,Types of change in coronary stenosis severity and their relative importance in overall progression and regression of coronary disease. Observations from the FATS Trial. Familial Atherosclerosis Treatment Study.,B G Brown; L Hillger; X Q Zhao; D Poulin; J J Albers,,1995.0,0,0 2492,7695185,Prevention of post-PTCA restenosis.,D P Faxon; J W Currier,"Significant improvements in the success of angioplasty combined with a major reduction in complications have led to widespread use of the technique in the treatment of symptomatic patients with coronary disease. Restenosis, however, remains the most significant limitation of angioplasty, occurring in 20-50% of patients following a successful procedure. Over the past 10 years, more than 40 large randomized pharmacological trials have attempted to address this problem. Currently no single agent has clearly been shown to reduce restenosis. As a consequence of intensive research, improved understanding of the pathophysiology of restenosis as well as the design of clinical studies necessary to study the process has resulted. Recent experimental studies suggest that vascular remodeling may be as important as intimal hyperplasia, and future trials will need to address this aspect of the restenosis process. Current approaches to preventing restenosis include the use of combined drug therapy to attack several pathophysiological processes, local delivery of drug at the site of the injury to maximize drug effect, and the use of highly specific drugs including local gene therapy.",1995.0,0,0 2493,7695217,Beneficial effect of cholesterol-lowering therapy on endothelium-dependent coronary vasodilation in patients with hypercholesterolemia.,K Egashira; A Takeshita,,1995.0,0,0 2494,7696283,The role of cytochrome P450 in developmental pharmacology.,A S Rogers,"Numerous sources of human heterogeneity affect biotransformation of compounds. Cytochrome P450, the primary oxidative pathway of drug metabolism, is the dominant phase I oxidative system metabolizing, to some degree, most of the drugs used clinically in humans. The P450 pathway is a major site of drug-drug, drug-diet, and drug-disease/condition interactions. Functional variability in this system can have pronounced consequences in suboptimal therapeutic response or enhanced toxicity. Methods for cataloguing specific P450 enzymes are being developed and their identification will promote rational drug development, more efficient clinical trial evaluation, and improved therapeutic approaches to patients requiring special consideration. These methods will facilitate the study of the impact of pubertal development on function in this system.",1994.0,0,0 2495,7697684,Cost-effectiveness analysis of lipid-modifying therapy in Canada: comparison of HMG-CoA reductase inhibitors in the primary prevention of coronary heart disease.,L L Martens; R Guibert,"This study estimated the cost-effectiveness of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors available in Canada for the primary prevention of coronary heart disease (CHD). A model of the cost-effectiveness of therapy used to modify low-density lipoprotein (LDL) cholesterol and high-density lipoprotein cholesterol levels was developed in the primary prevention of CHD based on risk functions from the Framingham Heart Study and Canadian data on coronary risk factors and the cost of treating the leading manifestations of CHD. Relative to no treatment, discounted gains in life expectancy range from 0.174 year for fluvastatin 40 mg to 0.215 year for simvastatin 10 mg. Costs per year-of-life-saved range from $38,800 for fluvastatin 40 mg to $56,200 for pravastatin 20 mg. In the incremental analysis relative to fluvastatin 40 mg, additional gains in life expectancy range from 0.011 year for pravastatin 20 mg to 0.041 year for simvastatin 10 mg, and incremental cost-effectiveness ratios range from $88,200 for simvastatin, 10 mg to $330,300 for pravastatin 20 mg. Our analysis showed that the cost-effectiveness of cholesterol-lowering therapy is sensitive to pretreatment risk of CHD, as expressed by pretreatment cholesterol levels and the presence of additional risk factors such as hypertension, diabetes, and smoking. The results of the analysis suggest that it is more cost-effective to initiate treatment with fluvastatin than with pravastatin, simvastatin, or lovastatin. Sensitivity analysis showed the results to be stable even if the lipid-lowering effect of fluvastatin is varied by 23% from the original assumption of 25% LDL reduction (ie, from 19.3% to 30.8%). Limitations of the study are recognized and discussed. A head-to-head comparison of these HMG-CoA reductase inhibitors could provide further evidence that therapy initiated with fluvastatin may be the most cost-effective way to treat patients with hypercholesterolemia who are eligible for treatment with HMG-CoA reductase inhibitors.",1994.0,0,0 2496,7697857,Cholesterol reduction yields clinical benefit. A new look at old data.,A L Gould; J E Rossouw; N C Santanello; J F Heyse; C D Furberg,"There has been a continuing debate about the overall benefit of cholesterol lowering. We performed a novel meta-analysis of all randomized trials of more than 2 years' duration (n = 35 trials) to describe how coronary-heart-disease (CHD), non-CHD, and total mortality are related to cholesterol lowering and to type of intervention. The analytic approach was designed to separate the effects of cholesterol lowering itself from the other effects of the different types of intervention used. For every 10 percentage points of cholesterol lowering, CHD mortality was reduced by 13% (P < .002) and total mortality by 10% (P < .03). Cholesterol lowering had no effect on non-CHD mortality. Certain types of intervention had specific effects independent of cholesterol lowering. Fibrates (clofibrates, 7 trials; gemfibrozil, 2 trials) increased non-CHD mortality by about 30% (P < .01) and total mortality by about 17% (P < .02). Hormones (estrogen, 2 trials; dextrothyroxin, 2 trials) increased CHD mortality in men by about 27% (P < .04), non-CHD mortality by about 55% (P < .03), and total mortality by about 33% (P < .01). No specific effects independent of cholesterol lowering were found due to diet (n = 11) or other interventions (resins, 5; niacin, 3; statins, 2; partial ileal bypass, 1). The results suggest that cholesterol lowering itself is beneficial but that specific adverse effects of fibrates and hormones increase the risk of CHD (hormones only), non-CHD, and total mortality.",1995.0,0,0 2497,7698042,Microvascular function.,Z T Bloomgarden,,1995.0,0,0 2498,7698516,Effect of treatment with a hydroxymethylglutaryl coenzyme A reductase inhibitor on fasting and postprandial plasma lipoproteins and cholesteryl ester transfer activity in patients with NIDDM.,D Bhatnagar; P N Durrington; S Kumar; M I Mackness; J Dean; A J Boulton,"Patients with non-insulin-dependent diabetes mellitus (NIDDM) have a greater risk of developing coronary heart disease than would be expected from a similar degree of hyperlipidemia in nondiabetic populations. Accelerated transfer of cholesteryl esters (CET) from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL), a process that is associated with atherosclerosis, may be a possible explanation for this. CET, plasma lipoprotein concentration, and mass in the fasting and postprandial state have been examined in 31 hyperlipidemic patients with NIDDM before and after 8 weeks of treatment with the hydroxymethylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitor pravastatin in a double-blind, placebo-controlled, parallel group study. Body mass index, glycemic control, and blood pressure remained unaltered during the study period. Compared with placebo, pravastatin decreased fasting serum cholesterol (P < 0.001) and LDL cholesterol (P < 0.002) levels. The high basal CET (34.4 +/- 13.1 nmol.ml-1.h-1) was decreased significantly by pravastatin treatment (27.5 +/- 13.7 nmol.ml-1.h-1, P = 0.013). There was a fall in the total cholesterol, free cholesterol, and phospholipid content of the Sf 0-12, 20-60, and 60-400 lipoproteins (all P = 0.001). Lecithin: cholesterol acyl transferase activity was not altered. The postprandial increase in VLDL cholesterol 5 h after a standardized mixed meal was attenuated after pravastatin treatment (P = 0.011). Inhibition of hepatic cholesterol synthesis with an HMG-CoA reductase inhibitor in hyperlipidemic patients with NIDDM decreased serum cholesterol content of triglyceride-rich lipoprotein, thereby decreasing the transfer of cholesteryl ester from HDL to LDL and VLDL.",1995.0,0,0 2499,7700285,,,,,0,0 2500,7701502,[Unfortunate presentation of statin therapy in the mass media].,A Oyri,,1995.0,0,0 2501,7702060,"Effects of nicotinic acid and lovastatin in renal transplant patients: a prospective, randomized, open-labeled crossover trial.",S M Lal; J E Hewett; G F Petroski; J C Van Stone; G Ross,"Lipid abnormalities are seen frequently in renal transplant patients. Cardiovascular disease is an important cause of morbidity and mortality in these patients. We assessed the efficacy and safety of the lipid-lowering drugs, nicotinic acid (short acting) and lovastatin, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Twelve renal transplant patients who had persistent hyperlipidemia despite 6 weeks of dietary treatment participated in this prospective, randomized, open-labeled crossover trial. At 16 weeks, when compared with control values, nicotinic acid (> or = 1.5 g twice a day) significantly reduced the total cholesterol (from 312 +/- 18 [+/- SEM] mg/dL to 229 +/- 19 mg/dL; P = 0.03) and the low-density lipoprotein cholesterol (from 218 +/- 15 mg/dL to 142 +/- 13 mg/dL; P = 0.03) and significantly increased the high-density lipoprotein cholesterol (from 44 +/- 3 mg/dL to 58 +/- 5 mg/dL; P = 0.03). The triglyceride level was reduced from 255 +/- 40 mg/dL to 150 +/- 23 mg/dL (P = 0.09). At 16 weeks, lovastatin therapy (40 mg/d) significantly reduced the total cholesterol (from 285 +/- 13 mg/dL to 233 +/- 10 mg/dL; P = 0.005) and the low-density lipoprotein cholesterol (from 201 +/- 11 mg/dL to 147 +/- 7 mg/dL; P = 0.001). There were no significant changes in the triglyceride and high-density lipoprotein cholesterol levels. Although flushing developed in 67% of patients treated with nicotinic acid, this was not a reason for any of the study dropouts. During this short-term study period no adverse biochemical effects were noted with either of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)",2001.0,0,0 2502,7702230,Effects of alcohol and fluvastatin on lipid metabolism and hepatic function.,J W Smit; H J Wijnne; F Schobben; A Sitsen; T W De Bruin; D W Erkelens,"To determine the effects of fluvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, combined with moderate alcohol consumption on lipid profiles and hepatic function in patients with primary hypercholesterolemia. Randomized, placebo-controlled, crossover study. Lipid clinic of a university hospital. 31 patients with primary hypercholesterolemia (low-density lipoprotein cholesterol levels > or = 4.2 mmol/L) who had previously received a lipid-lowering diet. After a dietary baseline period, 26 patients were randomly assigned to receive 6 weeks of treatment with either 1) fluvastatin, 40 mg/d, added to 20 g of ethanol and diluted to 20% with orange juice or 2) fluvastatin added to orange juice alone. After a 6-week washout period, the two groups crossed over. Plasma fluvastatin levels, lipid levels, and clinical variables were determined at the end of each treatment period. Six patients left the study prematurely. The remaining patients (15 men, 5 women; mean age +/- SD 49.1 +/- 14.5 years; mean body mass index +/- SD 24.5 +/- 2.2 kg/m2) completed the study. Fluvastatin, alone and combined with alcohol, resulted in similar decreases in levels of total cholesterol (22% and 23%, respectively; P < 0.001 when compared with baseline), low-density lipoprotein cholesterol (28% and 29%, respectively; P < 0.001 compared with baseline), and apolipoprotein B (17% and 20%, respectively; P < 0.001 compared with baseline). High-density lipoprotein cholesterol and triglyceride levels were not changed. Fluvastatin with alcohol resulted in a significantly greater area under the plasma concentration curve (23.4 +/- 4.7 compared with 18.2 +/- 3.2 x 10(3) ng.min/mL) and in a greater time to maximum concentration (187.5 +/- 16.6 min compared with 130.9 +/- 7.0 min) than fluvastatin alone. Terminal half-life tended to increase. No important adverse clinical effects were observed. Six weeks of daily, moderate alcohol consumption influenced the metabolism of fluvastatin but did not interfere with its lipid-lowering efficacy and had no adverse effects.",1995.0,0,0 2503,7704289,Short term effects of pravastatin on blood pressure in hypercholesterolaemic hypertensive patients.,C J O'Callaghan; H Krum; E L Conway; W Lam; M A Skiba; L G Howes; W J Louis,"In this study, which was primarily designed to determine the lipid-lowering efficacy of pravastatin in the setting of background antihypertensive therapy with ACE inhibitors and calcium antagonists, we took the opportunity to examine whether pravastatin interacts with antihypertensive therapy to produce additional falls in blood pressure. This may help clarify the mechanism of action of pravastatin's rapid beneficial effects on cardiovascular morbidity. We treated 25 hypertensive hypercholesterolaemic patients with 12 weeks of either pravastatin or placebo in this double blind, placebo controlled parallel group study. Placebo treatment did not alter plasma lipids, whereas 12 weeks' treatment with pravastatin reduced total cholesterol by 27% (from 7.1 +/- 0.27 to 5.2 +/- 0.18, p < 0.001 compared with placebo) and low density lipoprotein cholesterol by 35% (from 4.9 +/- 0.36 to 3.2 +/- 0.17, p < 0.001). There were no changes in systolic or diastolic blood pressure either following 12 weeks' treatment or 3 weeks' withdrawal of pravastatin. Thus, pravastatin remains efficacious as a lipid lowering agent in the presence of antihypertensive therapy but does not enhance the blood pressure lowering action of these drugs. Therefore it is unlikely that blood pressure reduction is the mechanism by which pravastatin mediates its reported short term effects on cardiovascular morbidity.",1994.0,0,0 2504,7706943,Physiologic mechanisms of action of lovastatin in nephrotic syndrome.,C A Aguilar-Salinas; P H Barrett; J Kelber; J Delmez; G Schonfeld,"The effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the metabolism of apolipoprotein (apo) B-containing lipoproteins appear to differ according to the predominant lipoprotein profiles present and the condition being treated. In familial hypercholesterolemia, with isolated low density lipoprotein (LDL) elevations, the LDL-apoB elimination rate is increased by up-regulated LDL-receptors. In familial combined hyperlipidemia where very low density lipoprotein (VLDL) and LDL both may be increased and enhanced production of LDL-apoB may be present, HMG-CoA reductase inhibitors seem to diminish increased LDL-apoB production. The drug-induced decreases in LDL-apoB production could be due to decreased production of precursor VLDL-apoB or due to decreased conversion of VLDL-apoB to LDL-apoB after enhanced removal of VLDL by up-regulated LDL-receptors. To distinguish between these possibilities, we assessed the effects of HMG-CoA reductase inhibitors in another condition in which there is both apoB overproduction and accumulation of VLDL and LDL in plasma, the nephrotic syndrome. We used endogenous labeling of apoB with [13C]leucine and a multicompartmental model to calculate the metabolic parameters of apoB-containing lipoproteins. Only subjects with focal segmental glomerular sclerosis (FSGS) were included, as FSGS is a chronic, very slowly progressive form of nephrotic syndrome. A double-blind, randomized, placebo-controlled, crossover design was used. Treatment periods of 6 weeks were separated by a 2-week washout period. Of the four men studied, three had high triglyceride levels and four had high cholesterol levels. Lovastatin (20 mg/day) significantly decreased cholesterol (27.6 +/- 6%), LDL-cholesterol (27.6 +/- 9%) and plasma apoB (17.9 +/- 2.9%) (P < 0.01 for all). During the placebo period, calculation of kinetic parameters revealed VLDL-, intermediate density lipoprotein (IDL)-, and LDL-apoB overproduction and decreased VLDL-apoB fractional catabolic rate. Lovastatin significantly decreased LDL-apoB production rate in all cases (34.1 +/- 14%, P = 0.03). The decreased LDL-apoB was mainly due to a channelling of LDL precursors away from conversion to LDL (conversion of VLDL to LDL decreased from 80.6 +/- 8.3% to 55.9 +/- 17.2%, P = 0.05). Thus, lovastatin decreased LDL-cholesterol in nephrotic subjects mainly by inhibiting LDL-apoB production from VLDL.",1995.0,0,0 2505,7710266,Familial xanthomatous hypercholesterolemia: abnormal exogenous lipid metabolism evidenced by the vitamin A test.,F Assadollahi; E Cavallero; J C Buxtorf; B Jacotot; J L Beaumont,"Familial xanthomatous hypercholesterolemia is a metabolic disorder associated with high LDL levels attributed to a familial defect in LDL receptor activity. We have previously shown that hyperlipoproteinemia of WHHL rabbits, considered to be a model for heritable hypercholesterolemia, was at least partly of exogenous origin. We have though studied retinyl palmitate (RP) levels 12 h after a standardized mixed meal as a simple test to detect abnormalities of intestinal-derived lipoprotein clearance in 22 familial hypercholesterolemic patients with xanthomatosis (13 of them treated by simvastatin, an HMGCoA reductase inhibitor, and 9 not treated), as compared to a control group (n = 12). Total and LDL cholesterol, plasma triglyceride and apo B levels were significantly higher in patients when compared to controls. Mean RP levels appeared higher in familial hypercholesterolemic patients, when compared to controls, with 6 among 22 patients showing clearly high vitamin A levels and 4 borderline values, whereas high triglyceride levels (> 2 g/l) were detected in only 1 patient. No patients within the group with high vitamin A levels showed an apo E2/E2 phenotype. Vitamin A levels correlated with plasma triglycerides in the whole group of subjects (r = 0.50, p < 0.05). No difference was observed in vitamin A distribution between treated and untreated hypercholesterolemic patients. Our results indicate that the clearance of RP-labeled intestinal lipoproteins is delayed in some xanthomatous familial hypercholesterolemic patients as compared with that of controls. These findings suggest that familial xanthomatous hypercholesterolemia may be heterogenous concerning physiopathological mechanisms inducing hyperlipidemia.",1994.0,0,0 2506,7711417,Treatment of patients with familial defective apolipoprotein B-100 with pravastatin and gemfibrozil: a two-period cross-over study.,P S Hansen; H Meinertz; L U Gerdes; I C Klausen; O Faergeman,"Thirty patients with familial defective apolipoprotein B-100 were treated in a two-period (8 weeks each) cross-over study with pravastatin and gemfibrozil. Cholesterol, LDL cholesterol, and apo B were reduced by 20-25% (P < 10(-4)) by pravastatin and by 4-6% by gemfibrozil (pravastatin vs. gemfibrozil: P < 10(-4)). Response to pravastatin was variable and not correlated to gender, age, or apo E genotype. Gemfibrozil lowered triglycerides by 25% (P < 10(-4)) and raised HDL cholesterol by 11%. The effects of pravastatin on these two interrelated variables were significantly smaller. Both drugs increased Lp(a) significantly by about 10%. The LDL cholesterol lowering effect of pravastatin in patients with FDB is similar to that observed in patients with familial hypercholesterolemia.",1994.0,0,0 2507,7712482,"Suppression of the proliferation of Ras-transformed cells by fluoromevalonate, an inhibitor of mevalonate metabolism.",J A Cuthbert; P E Lipsky,"Mevalonate is the precursor of a number of different products potentially required for the growth of cells, including the prenylated oncoprotein Ras. To determine whether inhibition of mevalonate metabolism would selectively block proliferation of Ras-transformed cells, 6-fluoromevalonate (Fmev), an inhibitor of diphosphomevalonate decarboxylase, was used to block the synthesis of prenyl-derived lipids and prenylated proteins in interleukin-3 (IL-3)-dependent FDC-P1 cells (control FDC-P1 cells) and FDC-P1 cells transformed with oncogenic Ras (RasDC cells) that proliferated in the absence of IL-3. Fmev completely inhibited synthesis of prenyl-derived lipids and prenylated proteins and blocked proliferation of FDC-P1 and RasDC cells. Restoration of the proliferation of Fmev-blocked FDC-P1 cells required both an exogenous source of cholesterol and prevention of the accumulation of mevalonate and the mevalonate phosphates with lovastatin. In contrast, ongoing IL-3-independent proliferation of Fmev-blocked RasDC cells was not completely restored by providing exogenous cholesterol and preventing the accumulation of inhibitory mevalonate product(s). However, these cells proliferated when cultures were supplemented with IL-3 together with exogenous cholesterol and lovastatin, implying that Fmev had prevented Ras-dependent, IL-3-independent growth. Fmev markedly diminished total cellular Ras in RasDC cells. In contrast, lovastatin depleted membrane-associated Ras and increased cytosolic Ras but did not diminish total cellular Ras. These data indicate that Fmev depletes total cellular Ras and specifically inhibits the autonomous growth of Ras-transformed cells.",1995.0,0,0 2508,7715916,Ocular drug safety and HMG-CoA-reductase inhibitors.,J Schmidt; C Schmitt; O Hockwin; U Paulus; K von Bergmann,"150 patients suffering from primary hypercholesterolemia were divided into three different groups receiving (1) lovastatin, (2) simvastatin, or (3) fenofibrate as controls. The aim of the study was to detect possible drug-induced ocular side effects, especially in the lens. The study period was 2 years. Ophthalmological examination and Scheimpflug photography were performed at the beginning and every 6 months. Increases or decreases in the visual acuity were distributed very similarly in the three groups. Definite evidence of side effects was not found, nor was there evidence of deleterious effects on refraction. The intraocular pressure revealed intraindividual fluctuations without clinical significance. Many changes were observed in the lens, all were minimal, including those of the extreme lens periphery which had no effect on visual acuity. The present study shows the great value of Scheimpflug photography with densitometric image analyses because of its objectivity when compared with other methods. Our observations provide good evidence that lovastatin and simvastatin have no undesirable toxic effects on the lens and other ocular tissues, compared with fenofibrate.",1994.0,0,0 2509,7717016,[Therapy of hypercholesterolemia after heart transplantation with the HMG-CoA reductase inhibitor simvastatin in long-term follow-up].,K Wenke; J Thiery; B Meiser; N Arndtz; D Seidel; B Reichart,"The problem of hypercholesterolemia following heart transplantation (HTx) is often underestimated. Up to now there is no concept of therapy allowing an optimal adjustment of lipid parameters. Therapeutical trials using ion exchange resins, derivates of nicotinic acids and fibrates were not successful due to Cyclosporin A interaction, hepatotoxicity and limited efficacy of the applied substances. In a prospective, randomized and controlled trial, we investigated the effects of monotherapy with the HMG-CoA-reductase inhibitor Simvastatin in heart transplant recipients. The study included 70 patients (Simvastatin n = 37, control group n = 33). Eight patients died within the first 3 month postoperatively following HTx. Purpose of the study was adjustment of LDL-cholesterol-values in the Simvastatin-treated group to < 110 mg/dl. Following 24 months of treatment a mean LDL-cholesterol-plasma level of 110 mg/dl was obtained. The corresponding mean value of the control group was 150 mg/dl. The difference between both groups was significant (p < .001). In the same period the mean HDL-cholesterol values increased by approximately 15% in both groups. The ratio of LDL-/HDL-cholesterol was significantly lower in the Simvastatin treated group (2.28) than in the control group (2.94) (p < .01). There was no significant difference in Lp(a)-values. No adverse effects were observed within the following period of 24 months, particularly no increase in the frequency of rejection episodes. The drug induced hypercholesterolemia following HTx could be treated safely and effectively by low-dose Simvastatin.",1995.0,0,0 2510,7722549,Descriptive study of lipid-modulating drug use in a French professional population.,E F Boumendil,"The objectives of this cross-sectional study presented as the first stage of a cohort follow-up pharmacoepidemiological study of lipid modulators, are to determine the extent and pattern of use of antihyperlipidemics and concomitant drugs and to compare antihyperlipidemic subgroups. The study population are the 17,244 respondents to the 1991 questionnaire in which questions on drug utilization were asked for the first time. It comprises 40.5% of the men and 32% of the women of the population originally targeted in 1989, i.e. the entire workforce of a national company within an age range of 35-45 years for men and 35-50 years for women. Self-reported health events and drug use over the previous year were measured. Overall 1 year prevalence of use of lipid lowering drugs was 7.7% (9.5% in men and 2.7% in women). Most antihyperlipidemics were fibrates (n = 878), with fenofibrate ranking above ciprofibrate, as opposed to HMG-CoA reductase inhibitors (n = 436), principally simvastatin. Only 60% of antihyperlipidemic drug users were following a prescribed lipid-lowering diet; over half were taking other drugs concomitantly, most often b-blockers. The simvastatin group differs from the fibrate group by an excess of prevalent thyroid disease. The link between simvastatin and thyroid disease may be indication-related. In conclusion, the relevant features of this study are the extensive use of antihyperlipidemics, frequently, without concomitant diet, and the marked preference for antihyperlipidemics for which long term safety is unknown. Extent of use and choices of antihyperlipidemics are corroborated by estimations in the general middle-aged population.",1994.0,0,0 2511,7725511,Renal transplantation and dyslipidemia: characterization of a population and treatment with diet and low dose lovastatin.,P Downey; A Maiz; A Vaccarezza; C Pinto; F Retamal; L Martínez,,1995.0,0,0 2512,7728297,In-vitro effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on non-hepatic LDL receptor activity: evidence of lack of stimulatory effect of pravastatin.,J Pedreño; J L Sánchez; D Zambón; E Ros,"It is speculated that, as a result of its tissue selectivity, pravastatin may be a safer drug than the lipophilic 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors in combination therapy involving drugs with potential muscle toxicity. Several studies have shown specific inhibitory activity on hepatic cholesterogenesis and a potent induction of hepatic low-density lipoprotein (LDL) receptors. However, data about its effect on stimulation of LDL receptor activity on non-hepatic cells are not available. Several experiments were carried out in order to assess the in-vitro effect of HMG-CoA reductase inhibitors on the activity of LDL receptors of human non-hepatic cells. Lymphocytes from both normolipidemic controls and patients with heterozygous familial hypercholesterolemia along with human fibroblasts were cultured in both the presence and absence of pravastatin and lovastatin. Pravastatin, at concentrations of 0.25-50 mumol/l, did not enhance the LDL receptor activity of lymphocytes derived from both patients with familial hypercholesterolemia and normolipidemic controls. In contrast, lovastatin, at concentrations of 0.25 mumol/l, increased the LDL receptor activity in both control lymphocytes and lymphocytes from patients with familial hypercholesterolemia by 121% and 148%, respectively. Fibroblast LDL receptor activity was not altered by pravastatin at a concentration of 50 mumol/l, whereas lovastatin at the same concentration increased the LDL uptake by 153%. From in-vitro experiments of LDL receptor activity stimulation, we conclude that pravastatin has little effect on non-hepatic cells.(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2513,7729012,Angiographic and clinical progression in unstable angina. From clinical observations to clinical trials.,P Théroux,,1995.0,0,0 2514,7730777,Simvastatin decreases mortality.,A F Shaughnessy; D C Slawson,,1995.0,0,0 2515,7730896,Reproducibility of carotid vessel wall thickness measurements. The Rotterdam Study.,M L Bots; P G Mulder; A Hofman; G A van Es; D E Grobbee,"We studied the reproducibility of measurement of ultrasonographically assessed common carotid intima-media thickness and assessed whether measurement error of intima-media thickness occurred randomly or was associated with potential determinants of atherosclerosis. Eighty participants of the Rotterdam Study underwent a second ultrasound scan of both carotid arteries within 3 months of the first scan. The replicate measurements involved the posterior intima-media thickness of the distal common carotid artery. Mean differences (SD) in intima-media thickness of the right common carotid artery between paired measurements of sonographers, readers and visits were -0.004 mm (0.10), 0.066 mm (0.07), and -0.013 mm (0.13), respectively. Similar results were obtained for the left common carotid artery. Measurement error of intima-media thickness, i.e. the absolute difference in measurements between two subsequent visits, increased significantly with increasing common carotid intima-media thickness. This association disappeared after logarithmical transformation of the intima-media thickness data. Age, sex, smoking, body mass index, serum lipids, fibrinogen, and systolic and diastolic blood pressure were not significantly associated with the measurement error of intima-media thickness. Our findings indicate that measurements of common carotid intima-media thickness are highly reproducible. Measurement error of intima-media thickness is small and appears to be proportional with the level of intima-media thickness and is not significantly associated with most risk factors for atherosclerotic vessel wall disease.",1994.0,0,0 2516,7733005,Effect of serum lipid concentrations on restenosis after successful de novo percutaneous transluminal coronary angioplasty in patients with total cholesterol 160 to 240 mg/dl and triglycerides < 350 mg/dl.,V Dzavik; K K Teo; S Yokoyama; R Modi; A Dinwoodie; J R Burton; W J Tymchak; T J Montague,,1995.0,0,0 2517,7734010,Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group.,C D Furberg; H P Adams; W B Applegate; R P Byington; M A Espeland; T Hartwell; D B Hunninghake; D S Lefkowitz; J Probstfield; W A Riley,"HMG CoA reductase inhibitors (or statins), a new class of lipid-lowering compounds, have raised expectations for more widespread use than that of the older lipid-lowering drugs. Not only are they more effective in lowering LDL cholesterol, but they are better tolerated as well. No data exist concerning the effect of statins on early carotid atherosclerosis and clinical events in men and women who have moderately elevated LDL cholesterol levels but are free of symptomatic cardiovascular disease. Lovastatin (20 to 40 mg/d) or its placebo was evaluated in a double-blind, randomized clinical trial with factorial design along with warfarin (1 mg/d) or its placebo. This report is limited to the lovastatin component of the trial. Daily aspirin (81 mg/d) was recommended for everyone. Enrollment included 919 asymptomatic men and women, 40 to 79 years old, with early carotid atherosclerosis as defined by B-mode ultrasonography and LDL cholesterol between the 60th and 90th percentiles. The 3-year change in mean maximum intimal-medial thickness (IMT) in 12 walls of the carotid arteries was the primary outcome; change in single maximum IMT and incidence of major cardiovascular events were secondary outcomes. LDL cholesterol fell 28%, from 156.6 mg/dL at baseline to 113.1 mg/dL at 6 months (P < .0001), in the lovastatin groups and was largely unchanged in the lovastatin-placebo groups. Among participants not on warfarin, regression of the mean maximum IMT was seen after 12 months in the lovastatin group compared with the placebo group; the 3-year difference was statistically significant (P = .001). A larger favorable effect of lovastatin was observed for the change in single maximum IMT but was not statistically significant (P = .12). Five lovastatin-treated participants suffered major cardiovascular events--coronary heart disease mortality, nonfatal myocardial infarction, or stroke--versus 14 in the lovastatin-placebo groups (P = .04). One lovastatin-treated participant died, compared with eight on lovastatin-placebo (P = .02). In men and women with moderately elevated LDL cholesterol, lovastatin reverses progression of IMT in the carotid arteries and appears to reduce the risk of major cardiovascular events and mortality. Results from ongoing large-scale clinical trials may further establish the clinical benefit of statins.",2001.0,1,1 2518,7735713,An update on lipid-lowering therapy.,J D Barth; G B Mancini,"New information on the effects of lipid-lowering drugs is reviewed with an emphasis on special groups that benefit from specific drug therapy. Although it has been shown that the diet may further enhance the effectiveness of lipid-lowering drugs, compliance to diet and drugs remains an important issue and the large individual variations in dietary responses should be studied more extensively. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are safe and effective in different populations such as in women, elderly people and in special cases of secondary hyperlipidaemia. More widespread implementation of screening programmes to identify suitable patients for lipid-lowering therapy may help prevent the excess utilization of health care resources.",1995.0,0,0 2519,7735716,Diet and drug therapy for lipoprotein (a).,L Berglund,"Lipoprotein (a) has been implicated with an increased risk of atherosclerosis and cardiovascular disease. Recently, considerable progress has been made toward understanding the importance of genetics in the regulation of plasma levels of lipoprotein (a). However, the issue as to whether lipoprotein (a) levels should be treated is still debated and furthermore the possibilities to influence lipoprotein (a) levels remain limited. The potential clinical importance of lipoprotein (a) has stimulated interest in the dietary and pharmacologic agents that affect this lipoprotein. At present, only a few of the existing therapeutic tools, such as nicotinic acid and estrogens, have been found to consistently affect lipoprotein (a).",1995.0,0,0 2520,7737266,"Heterozygous familial hypercholesterolaemia is associated with pathological exercise-induced leakage of muscle proteins, which is not aggravated by simvastatin therapy.",J W Smit; P R Bär; R A Geerdink; D W Erkelens,"The objective of this study was to assess the relationship between therapy with the HMG-CoA reductase inhibitor simvastatin and muscle damage and the possible causal role of hypercholesterolaemia. The exercise-induced release of muscle proteins as a parameter of muscle damage was studied in two equicholesterolaemic groups of male patients with heterozygous familial hypercholesterolaemia (FH); one group without treatment, the second group on simvastatin. To assess the role of cholesterol, a third group of healthy male volunteers was studied as well. The study took place at the Lipid Clinic of an 800-bed University Hospital. One group of 21 male patients with heterozygous FH did not receive treatment, except for a lipid-lowering diet. A second group of 13 male FH patients were treated with 40 mg simvastatin day-1 for at least 1 year and matched for cholesterol levels with the first group. A third group consisted of 25 normocholesterolaemic male controls. All subjects underwent a 45 min lean body mass (LBM) standardized ergometer muscle provocation test (2 Watt/kg LBM). Levels of creatine kinase (CK) and myoglobin (Mb) were assessed before and 1 and 8 h after exercise and compared with baseline levels. The exercise-induced release of muscle proteins is reflected by peak CK and Mb levels expressed as a percentage of baseline levels. The exercise-induced increase in Mb and CK levels did not differ between untreated and simvastatin-treated FH patients.(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0 2521,7741833,Efficacy and safety of controlled-release niacin in dyslipoproteinemic veterans.,D R Gray; T Morgan; S D Chretien; M L Kashyap,"To evaluate the safety and efficacy of controlled-release niacin in patients with hyperlipoproteinemia. A retrospective cohort study. A Department of Veterans Affairs Medical Center. A consecutive sample of 969 predominantly elderly male veterans treated for dyslipoproteinemia with controlled-release niacin between October 1988 and October 1991. Primary outcomes were lipid levels and lipoprotein cholesterol response, alternations in levels of hepatic enzymes and blood chemistry test results, and characterization of niacin-induced hepatotoxicity abstracted from the patient's medical, laboratory, and pharmacy records. 93% (896 of 969) of the cohort was evaluable. Patients (age, 61.7 years [9.4 years], mean [SD]) were treated for 1 to 36 months (13.0 months [9.7 months]) with an average maintenance dose of 1.67 g/d (0.8 g/d). Niacin was discontinued in 48.5% (435 of 896) of the patients primarily because of adverse effects. Poor glycemic control led to discontinuation in 40.6% (43 of 106) of the patients with diabetes mellitus. The lipoprotein response was dose-related and favorable (levels of total cholesterol, -19.1%; low-density lipoprotein cholesterol, -24.0%; high-density lipoprotein cholesterol, +5.7%; and triglycerides, -32.5%). Statistically but not clinically meaningful dose-related increases were seen in levels of liver enzymes and serum glucose (aspartate aminotransferase, +29%; alanine aminotransferase, +23%; alkaline phosphatase, +25%; and glucose, +7%; P = 0.0001). Twenty of 896 (2.2%) and 42 of 896 (4.7%) patients met biochemical criteria for probable and for possible or probable niacin-induced hepatotoxicity, respectively. Predisposing factors included high dose, alcohol use, preexisting liver disease, and concurrent oral sulfonylurea therapy. Controlled-release niacin is effective in treating dyslipoproteinemia in selected middle-aged and elderly veterans, but approximately one half of patients discontinued the drug because of adverse effects or other causes including noncompliance. Niacin should be avoided in patients with hepatic dysfunction or a history of liver disease, patients with diabetes mellitus, and patients who abuse alcohol. Because controlled-release niacin seems to be more potent than crystalline niacin, product substitution without dose adjustment should be avoided.",1994.0,0,0 2522,7742151,A comparison of the effects of simvastatin and pravastatin monotherapy on muscle histology and permeability in hypercholesterolaemic patients.,J Contermans; J W Smit; P R Bär; D W Erkelens,"1. In this double-blind, placebo controlled, prospective study, it was assessed whether simvastatin or pravastatin monotherapy have adverse effects on muscle histology and muscle membrane permeability in hypercholesterolaemic patients. 2. Twenty-four patients, seven females and 17 males, with primary hypercholesterolaemia (LDL cholesterol levels > or = 4.14 mmol l-1) were selected from the outpatient lipid clinic of a 650 bed academic medical centre. 3. After a 6-week lipid lowering diet and placebo period, patients were randomized into two groups of 12 subjects with similar characteristics, to receive either simvastatin or pravastatin in dosages of 10-40 mg day-1 for three periods of 6 weeks. After each 3-week period the dose was adjusted to LDL cholesterol to aim for equipotent dosage. 4. All subjects performed a 45 min, lean body mass standardized bicycle ergometer test, before and after 18 weeks of treatment. As parameter for muscle damage, the exercise-induced rise of the muscle proteins, creatine kinase (CK) and myoglobin (Mb), relative to pre-exercise levels, were determined 1 and 8 h after the test. Forty-eight hours after each test a biopsy was taken from the quadriceps muscle and histology was judged by three independent observers. 5. Eighteen weeks of monotherapy with simvastatin and pravastatin did not affect the exercise induced release of CK and Mb, neither were any differences observed in muscle histology before and after treatment with either of the drugs. 6. Although simvastatin doses were lower than pravastatin, reductions in total- and LDL-cholesterol were greater in the simvastatin treated patients than in the pravastatin treated group.(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0 2523,7743614,Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS).,J W Jukema; A V Bruschke; A J van Boven; J H Reiber; E T Bal; A H Zwinderman; H Jansen; G J Boerma; F M van Rappard; K I Lie,"Intensive lowering of serum cholesterol may retard progression of coronary atherosclerosis in selected groups of patients. However, few data are available on the potential benefit of serum cholesterol reduction in the broad range of patients with coronary atherosclerosis and normal to moderately elevated serum cholesterol levels who undergo various forms of treatment. The Regression Growth Evaluation Statin Study (REGRESS) addresses this group of patients. REGRESS is a double-blind, placebo-controlled multicenter study to assess the effects of 2 years of treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin on progression and regression of coronary atherosclerosis in 885 male patients with a serum cholesterol level between 4 and 8 mmol/L (155 and 310 mg/dL) by quantitative coronary arteriography. Primary end points were (1) change in average mean segment diameter per patient and (2) change in average minimum obstruction diameter per patient. Clinical events were also analyzed. Of the 885 patients, 778 (88%) had an evaluable final angiogram. Mean segment diameter decreased 0.10 mm in the placebo group versus 0.06 mm in the pravastatin group (P = .019): The mean difference between treatment groups was 0.04 mm, with a 95% CI of 0.01 to 0.07 mm. The median minimum obstruction diameter decreased 0.09 mm in the placebo group versus 0.03 mm in the pravastatin group (P = .001): The difference of the medians between the treatment groups was 0.06 mm, with a CI of 0.02 to 0.08 mm. At the end of the follow-up period, 89% (CI, 86% to 92%) of the pravastatin patients and 81% (CI, 77% to 85%) of the placebo patients were without new cardiovascular events (P = .002). In symptomatic men with significant coronary atherosclerosis and normal to moderately elevated serum cholesterol, less progression of coronary atherosclerosis and fewer new cardiovascular events were observed in the group of patients treated with pravastatin than in the placebo group.",1995.0,1,1 2524,7743787,A randomized trial to assess effectiveness and cost in clinical practice: rationale and design of the Cholesterol Reduction Intervention Study (CRIS).,G Oster; G M Borok; J Menzin; J F Heys; R S Epstein; V Quinn; V V Benson; R J Dudl; A Epstein,"To compare the effectiveness and costs of two alternative approaches to the treatment of hypercholesterolemia, a prospective randomized trial is being undertaken at Southern California Kaiser Permanente, a large health maintenance organization. Six hundred and twelve patients with postdiet LDL cholesterol (LDL-C) levels in the range of 190-230 mg/dl (or 160-230 mg/dl for those with coronary heart disease or two or more coronary risk factors) were randomized to a stepped-care regimen (initial treatment with niacin followed by other agents if needed) or to initial use of lovastatin, an HMG-CoA reductase inhibitor. All patients are being followed for 1 year. The study seeks to approximate conditions of typical clinical practice: provider compliance with these plans of treatment is encouraged but not enforced and patients pay for medication as they customarily would. Principal outcomes of interest include the proportion of participants who achieve goal LDL-C at one year, the mean change in total cholesterol and LDL-C levels between baseline and the end of follow-up, and the costs of cholesterol-lowering therapy.",1995.0,0,0 2525,7743788,An empirical evaluation of the placebo run-in.,C E Davis; W B Applegate; D J Gordon; R C Curtis; M McCormick,"A prerandomization placebo run-in period is often used in an attempt to exclude potential clinical trial participants who are likely to be poor adheres. It is assumed that potential participants who are poor adherers during the run-in will be less likely to take medication during the trial. This assumption was tested in the Cholesterol Reduction in Seniors Program (CRISP), by prescribing placebo for a 3-week period, but not using the results of the run-in as an entry criterion. The CRISP study was a pilot study designed to compare the effects on lipids and the safety of two doses of lovastatin and placebo in persons 65 years of age and older. After general entry criteria were satisfied, each participant was prescribed placebo for a 3-week period. At the end of the 3-week period, all participants were randomized to one of the three treatment groups, regardless of their adherence to the placebo. Of the 431 participants in the study, 66 (15%) who took less than 80% of the prescribed placebo or who failed to return their unused placebo pills were classified as poor run-in adherers. Poor run-in adherence was associated with lower educational attainment. At 3 and 6 months of follow-up mean adherence was 89.3% and 83.4% among all participants. Exclusion of poor run-in adherers would have increased these means to 90.9% and 85.5%, respectively. Treatment effect as measured by fall in LDL cholesterol would have increased by 2.9 mg/dl in the 40 mg/day dose group at 3 months of follow-up with the addition of a placebo run-in. We conclude that a placebo run-in would have had little effect on the outcome of the CRISP study and would have substantially increased recruitment difficulties. Lower educated persons were more likely to be excluded by a placebo run-in, but the effect of the run-in on follow-up adherence was stronger in less educated participants. More research about the role of a placebo run-in is needed in order to determine the appropriate role of this method in clinical trials.",1995.0,0,0 2526,7746058,Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S),,"We examined the relation between the risk of major coronary events (coronary death and non-fatal myocardial infarction) and baseline cholesterol levels in patients with coronary heart disease, randomised to placebo or simvastatin therapy in the Scandinavian Simvastatin Survival Study (4S). The relative risk reduction in the simvastatin group was 35% (95% CI 15-50) in the lowest quartile of baseline low-density-lipoprotein cholesterol and 36% (19-49) in the highest. Simvastatin significantly reduced the risk of major coronary events in all quartiles of baseline total, high-density-lipoprotein, and low-density-lipoprotein cholesterol, by a similar amount in each quartile.",1995.0,0,0 2527,7746199,Lowering cholesterol levels in patients with coronary heart disease. The LIPID Study Management Committee.,,,1995.0,0,0 2528,7751423,Gastrointestinal absorption of pravastatin in healthy subjects.,J Triscari; D O'Donnell; M Zinny; H Y Pan,"The bioavailability of pravastatin, a hypocholesterolmic agent, may be enhanced by decreasing its exposure to stomach contents, where it may be converted nonenzymatically to a relatively inactive metabolite. The pharmacokinetics of pravastatin and its metabolite were determined after infusion of pravastatin directly into the stomach (locus for greatest bioavailability for the metabolite), duodenum (greatest bioavailability for pravastatin), jejunum, or ileum. An enterically coated formulation of pravastatin may increase its bioavailability.",1995.0,0,0 2529,7751822,Serum lathosterol levels in human subjects reflect changes in whole body cholesterol synthesis induced by lovastatin but not dietary cholesterol.,W C Duane,"We measured serum lathosterol levels and whole body cholesterol synthesis by sterol balance in 12 human subjects on a metabolic ward in four randomly allocated, 6-7 week periods: 1) lovastatin (40 mg b.i.d.) + low cholesterol diet (mean 246 mg/day); 2) lovastatin + high cholesterol diet (mean 1071 mg/day); 3) low cholesterol diet alone; and 4) high cholesterol diet alone. Whole body cholesterol synthesis was significantly reduced both by lovastatin (P = 0.0004) and by high dietary cholesterol (P = 0.0005). Serum total lathosterol (micrograms/dl) was reduced by lovastatin (P < 0.0001), but was not significantly altered (and actually tended to increase) during consumption of the high cholesterol diet, presumably because eggs contained appreciable lathosterol as demonstrated by direct analysis. Results were similar for total versus free lathosterol and for lathosterol expressed as micrograms/dl serum versus micrograms/100 mg cholesterol. We conclude that serum lathosterol does not reflect changes in cholesterol synthesis induced by dietary cholesterol. Studies using serum lathosterol as an indicator of cholesterol synthesis must be carefully controlled for dietary cholesterol.",1995.0,0,0 2530,7752281,The successful recruitment of elderly black subjects in a clinical trial: the CRISP experience. Cholesterol Reduction in Seniors Program.,D B Stoy; R C Curtis; K S Dameworth; A A Dowdy; J Hegland; J A Levin; B G Sousoulas,"This article describes the recruitment of elderly black subjects into the Cholesterol Reduction in Seniors Program (CRISP), a federal, multi-center, randomized, double-masked feasibility study of cholesterol intervention in the elderly. The study tested the feasibility of recruiting significant numbers of hypercholesterolemic black men, black women, and white women over the age of 65, groups previously underrepresented in federal trials. The study involved dietary modification and drug intervention with either 20 mg or 40 mg of lovastatin or placebo. Maximum follow-up was 18 months. Over the 12-month screening and recruitment period, 431 subjects (108% of the recruitment goal) were randomized. A total of 311 (72% of the study cohort) was female; 105 subjects (24% of the total cohort) were minorities. Media sources were most effective in recruiting white subjects. Church screening was an effective strategy in the black community, although such an approach required considerable resources s and time. The CRISP feasibility study demonstrated that a large cohort of elderly black subjects could be recruited in a cholesterol intervention trial, although the use of community-based approaches required substantial resources and staff time.",1995.0,0,0 2531,7752405,Cardiovascular disease.,J M Gore; J E Dalen,The Thrombolysis in Myocardial Ischemia trial randomized patients with unstable angina or non-Q-wave myocardial infarction and found that thrombolytic therapy was not beneficial and may be harmful. Drug treatment of hypercholesterolemia improves survival in patients with established coronary artery disease.,1995.0,0,0 2532,7758262,The effects of lipid lowering drugs on metabolic control and lipoprotein composition in type 2 diabetic patients with mild hyperlipidaemia.,M W Stewart; R G Dyer; K G Alberti; M F Laker,"Patients with Type 2 diabetes are at increased risk from macrovascular disease whether or not they are hyperlipidaemic. Several factors may contribute to this increased risk including abnormalities of lipoprotein composition. The aim of our study was to determine the effects of lipid lowering drugs on lipoprotein composition (lipoprotein fractions were separated by sequential flotation ultracentrifugation) and insulin sensitivity (measured by a modified Harano technique) in 44 patients with mild hyperlipidaemia. All patients had total cholesterol concentrations between 5.2 and 6.5 mmol l-1 and total triglyceride concentrations < 3.0 mmol l-1, and were randomized by minimization to receive treatment for 12 weeks with bezafibrate, acipimox, simvastatin or placebo. Total cholesterol concentrations were decreased by simvastatin, 5.7 +/- 0.4 to 3.7 +/- 0.6 mmol l-1 (p < 0.05), due mainly to reduced LDL-cholesterol levels (-1.25 mmol l-1; p < 0.05), and bezafibrate 5.7 +/- 0.6 to 4.6 +/- 0.4 mmol l-1 (p < 0.05). The LDL:HDL-cholesterol ratio was reduced in the simvastatin group 2.0 +/- 0.5 to 1.2 +/- 0.3 (p < 0.005). There was no effect of the drugs on glycated haemoglobin or insulin sensitivity. In conclusion bezafibrate and simvastatin improve the lipid profile in Type 2 diabetic patients without adversely affecting diabetic control.",1995.0,0,0 2533,7760966,Long-term experience (6 years) with simvastatin in patients with heterozygous familial hypercholesterolaemia.,R E Knops; A A Kroon; M J Mol; P M Stuyt; A F Stalenhoef,"To study the long-term efficacy and safety of the cholesterol synthesis inhibitor, simvastatin, in the treatment of familial hypercholesterolaemia. This is an open long-term follow-up of patients treated for 5 years or more in the Nijmegen University lipid clinic. Forty-four patients with heterozygous familial hypercholesterolaemia (mean baseline serum cholesterol level 11.5 mmol/l) were treated with simvastatin alone (monotherapy group) in doses ranging from 20 to 80 mg/day, or in combination with other lipid-lowering agents (combination-therapy group). Over the intervention period of 6 years the mean overall reduction of the serum cholesterol level was 37.8% for the total group, 37.7% for the monotherapy group and 42.6% for the combination-therapy group. The reduction of the low-density lipoprotein (LDL)-cholesterol in the three groups was 45.0, 44.6 and 50.3%, respectively. The serum triglyceride concentration was reduced by 14.0, 20.5 and 12.5%, respectively. The increase in the high-density lipoprotein (HDL)-cholesterol level was 14.4, 16.2 and 14.0%, respectively. One patient died from a myocardial infarction and 2 patients had a non-fatal cardiac event. Two patients stopped taking medication due to side-effects (dizziness and insomnia). Biochemical adverse effects were confined to elevations of the alanine aminotransferase level and the creatine phosphokinase level and did not lead to discontinuation of therapy. Simvastatin proves to be a safe and effective lipid-lowering drug during long-term treatment.",1995.0,0,0 2534,7761664,Effects of treatment with Simvastatin in elderly patients with primary hypercholesterolemia.,R Terranova; S Luca,"Atherosclerosis and its complications are the main cause of death and disability in affluent nations, especially in the elderly population. Lipids and lipoproteins play an important role in its pathogenesis. The authors treated a group of elderly patients with Simvastatin (20 mg/day for 1 year), a HMG CoA reductase inhibitor and observed a significant reduction in total cholesterol (p < 0.001). LDL (p < 0.001) and beta apolipoproteins (p < 0.05). They also achieved regression of the atherosclerotic plaque in 5 patients and arrested the atherosclerotic process in 8. The authors intend to conduct further studies in this field to better define the action of Simvastin on the atherosclerotic plaque.",1993.0,0,0 2535,7762089,[Therapeutic trial of simvastatin versus fenofibrate in primary hypercholesterolemia].,S Turki; A Mekaouer; A Kaabachi; B Ftouhi; R Mebazaa; F Ben Khalifa,,1994.0,0,0 2536,7762498,Changes in plasma lipid and apolipoprotein levels between heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) treatments.,D M Lane; P Alaupovic; C Knight-Gibson; V S Dudley; L O Laughlin,"Heparin-induced extracorporeal low-density lipoprotein (LDL) precipitation (HELP) treatments selectively remove LDL with minimal effects on high-density lipoproteins (HDL), but limited data are available on effects between treatments. The levels of factors associated with increased coronary artery disease risk (atherogenic) among treatments may have therapeutic significance, especially for combined HELP and lipid-lowering drug therapy. Hypercholesterolemic and combined hyperlipidemic patients resistant to diet/drug therapy were treated with biweekly HELP therapy. Hypercholesterolemic patients received either lovastatin or no drug, whereas combined hyperlipidemic patients received gemfibrozil. Plasma lipid (total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol) and apolipoprotein A-I, A-II, B, C-III, and E levels were measured before treatment, then immediately, and 2, 4, 7, and 14 days after treatments (n = 28). Atherogenic factor (LDL cholesterol, total cholesterol, apolipoprotein B) levels decreased > 50% with treatment, gradually increasing over 14 days to pretreatment levels. Factors associated with reduced coronary artery disease risk (HDL cholesterol and apolipoproteins A-I and A-II) decreased 8% to 16% but recovered by 2 days. Components of triglyceride-rich lipoproteins (triglycerides and apolipoproteins C-III and E) decreased 38% to 55% with variable post-treatment recoveries. Lovastatin reduced pretreatment levels of atherogenic and triglyceride-rich lipoprotein components and slowed post-treatment increases compared with no drug therapy. Gemfibrozil produced changes similar to lovastatin. Drug therapy had little effect on factors associated with reduced coronary artery disease risk. HELP apheresis produced large reductions in plasma atherogenic factor levels with gradual return to pretreatment levels over 14 days, whereas antiatherogenic factors were minimally reduced and recovered rapidly.(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0 2537,7762499,Protocol for a prospective collaborative overview of all current and planned randomized trials of cholesterol treatment regimens. Cholesterol Treatment Trialists' (CTT) Collaboration.,,"The Cholesterol Treatment Trialists' Collaboration aims to provide reliable information about the effects on mortality and morbidity of treatments that modify blood lipid levels for a wide range of patient populations and risk groups. This protocol prospectively defines study eligibility, the main questions to be addressed, and statistical methods to be used. Additionally, by establishing a register of ongoing and planned trials prior to any trial results being known, this systematic overview attempts to avoid the methodologic problems and potential data-dependency of a retrospective project. The collaboration expects to have individual patient data on > 60,000 subjects by the year 2000, including 12,000 women and 20,000 elderly subjects, and should have good power to examine any effects on non-coronary artery disease events. Overall, there should be about 1,900 non-coronary artery disease deaths and > 2,000 total cancer events.",1995.0,0,0 2538,7765570,Atherosclerosis patents: clues to the next drug generation.,K E Suckling,,1994.0,0,0 2539,7768495,"The effects of the 3-hydroxy, 3-methylglutaryl coenzyme A reductase inhibitor pravastatin on bile composition and nucleation of cholesterol crystals in cholesterol gallstone disease.",J W Smit; K J van Erpecum; W Renooij; M F Stolk; P Edgar; H Doornewaard; G P Vanberge-Henegouwen,"3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce biliary cholesterol saturation index (CSI) in duodenal bile in hypercholesterolemic patients and might be useful for gallstone dissolution. However, preliminary data suggest that these drugs are not effective in this respect. We therefore studied 33 patients with radiolucent gallstones in an opacifying gallbladder who were scheduled for elective cholecystectomy. Patients were treated with 40 mg pravastatin day-1 or placebo during the 3 weeks before surgery. Six patients could not be evaluated. Baseline characteristics (age, sex, body mass index, serum cholesterol, and the solitary/multiple gallstone ratio) were similar in both groups. Serum cholesterol fell by 39% in the pravastatin group (P < .001) and remained unchanged in the placebo group. Biliary cholesterol (9.5 +/- 1.3 vs. 14.3 +/- 1.5 mmol/L, P = .026), and phospholipid concentrations (24.8 +/- 3.9 vs. 36.7 +/- 3.9 mmol/L, P = .043) were lower in the pravastatin group. Although bile salt concentrations were lower in the pravastatin group (114 +/- 21 vs. 152 +/- 15 mmol/L), this difference was not significant. CSI was not different between both groups (142 +/- 27% [pravastatin] vs. 113 +/- 6% [placebo], P = NS). Cholesterol crystals were present in fresh bile in 7 of 13 patients in the pravastatin group and in 11 of 14 controls (P = NS). Nucleation time was comparable between the 2 groups (13 +/- 3 vs. 9 +/- 3 days, P = NS). Bile salt species and molecular species of phospholipids determined with high-performance liquid chromatography did not differ either between both groups.(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0 2540,7771954,"[Randomized, double-blind comparative study between pravastatin and lovastatin. Evaluation of efficacy and safety].",S D Giannini; M C Bertolami; J Schölz; A A Faludi; N Forti; J Diament,"To verify eventual difference observed in the efficacy and safety of lovastatin (L) when compared to pravastatin (P), considering increasing doses up to the maximum and recommended ones in clinical practice. Forty-eight hypercholesterolemic patients (LDL-C > 160 mg/dl after a placebo seven-day period) were studied and randomly assigned to constitute groups of 24 patients (GL and GP groups). The patients from GL group received L 20 mg/day and those from GP group P 10 mg/day, in a double-blind fashion. Six and 12 weeks later, the those were doubled. At the end of the placebo period and at weeks 6, 12 and 18 they were evaluated for clinical data and laboratorial parameters, such as: lipid profile (TC, TG, HDL-C and LDL-C); enzymes AST, ALT, CPK, gamma-GT, alkalin phosphatase); biochemical data (urea, creatinine, bilirubin, uric acid, glucose); complete blood count and urinalysis. Both drugs have shown significant reductions in TC and LDL-C levels at the lowest clinical doses (L 20 mg/day; P 10 mg/day), which became more marked as doses were gradually increased. However, the responses were always significantly greater for L in all doses employed. No adverse effects requiring treatment discontinuation were observed for both drugs. L showed a higher TC and LDL-C lowering effect than that observed with P, when the doses recommended by the respective manufacturers were compared.",1994.0,0,0 2541,7773032,Lower patients' cholesterol now.,M Oliver; P Poole-Wilson; J Shepherd; M J Tikkanen,,1995.0,0,0 2542,7774989,Effect of gemfibrozil versus lovastatin on increased serum lipoprotein(a) levels of patients with hypercholesterolemia.,J A Ramires; A P Mansur; M C Solimene; R Maranhão; D Chamone; P da Luz; F Pileggi,"The aim of this study was to determine the effect of gemfibrozil, compared with lovastatin, in patients with high levels of lipoprotein(a) and on plasma lipid profile. Twenty-seven nondiabetic patients with high levels of plasma lipids and lipoprotein(a), 19 male and eight female, aged 37-68 (mean +/- S.D. 54.2 +/- 7.5) years, were randomly assigned to 2 weeks of treatment with gemfibrozil 600 mg twice daily (14 pts.) or lovastatin 40-80 mg once daily (13 pts.). Patients had fasting plasma total cholesterol levels > or = 6.2 mmol/l, low-density lipoprotein > 4.14 mmol/l and lipoprotein(a) > 0.62 mmol/l. All patients but one had triglycerides > 2.82 mmol/l. There were no statistical differences between both groups in terms of age, sex, clinical diagnosis and previous medication. After 3 months of treatment, gemfibrozil reduced triglycerides (47.9% vs. 24.5%; P < 0.001), very low density lipoprotein (43.9% vs. 24.6%; P < 0.05), lipoprotein(a) (25.3% vs. 4.9%; P < 0.05) and increased high-density lipoprotein (34.4% vs. 11%; P < 0.01) more than lovastatin. Gemfibrozil and lovastatin reduced comparably total cholesterol (21.4% vs. 29.0%; P = NS) and low-density lipoprotein (26.5% vs. 37.3%; P = NS). The plasma levels of high-density lipoprotein and lipoprotein(a) were unchanged significantly by lovastatin. In conclusion, besides well-known efficacy in hyperlipidemia treatment, gemfibrozil also increased high-density lipoprotein and reduced lipoprotein(a), which may have important epidemiologic implications.",1995.0,0,0 2543,7783286,Tougher on tattoos.,,,1995.0,0,0 2544,7784310,Pharmacology of competitive inhibitors of HMG-CoA reductase.,A Corsini; F M Maggi; A L Catapano,,1995.0,0,0 2545,7788650,[Simvastatin in the treatment of familial hypercholesterolemia].,R Ceska; J Sobra; R Procházková; M Kvasilová,"The association between hypercholesterolemia and premature atherosclerosis is almost universally accepted. Treatment of hyperlipoproteinemias represents a reasonable approach in preventive cardiology. The aim of the study was to prove a hypolipidemic effect of simvastatin, Zocor tablets à 10 mg, produced by MSD, U:S.A. in patients with familial hypercholesterolemia. 29 familial hypercholesterolemia heterozygotes have been treated with increasing dose of simvastatin (10 and 20 mg/day with the evening meal) for three months. All patients have been on AHA step I diet. The basic parameters of lipid and lipoprotein metabolism have been measured, as well the concentrations of apolipoproteins A-I and B, and the level of lipoprotein(a). Concentration of total cholesterol decreased after treatment with 10 and 20 mg of simvastatin by 20%, resp. 26%. The hypolipidemic effect was even more pronounced in LDL-cholesterol level, which was reduced by 24% respectively 34%. On the other hand therapy with simvastatin did not influence HDL-cholesterol at all. Also triglycerides concentration did not changed very significantly after administration of simvastatin (triglycerides levels were reduced by 7% respectively by 18%). Decline of LDL-cholesterol has been accompanied by decrease of apolipoprotein B concentration by 24%, resp. 26%. The concentration of lipoprotein (a) has not been statistically significantly influenced, even its level increased slightly. The body weight of the patients did not changed during the study. Simvastatin treatment has been well tolerated by the patients. Simvastatin, Zocor, seems to be powerful hypolipidemic drug, which is to be used even in the treatment of familial hypercholesterolemia heterozygotes, who are usually very resistant to the therapy. The dose of 10 mg of simvastatin is usually sufficient to influence plasma lipids and lipoproteins. A double dose intensifies the hypolipidemic effect but this additional effect is not so expressive. Zocor is tolerated well by the patients and in safety laboratory we did not notice any important undesirable result.",1995.0,0,0 2546,7788948,Effects of treatment with lovastatin and pravastatin on daytime cognitive performance.,F Gengo; D Cwudzinski; P Kinkel; G Block; L Stauffer; C Lines,"The HMG-CoA reductase inhibitors lovastatin and pravastatin have both proven to be effective and well tolerated in the treatment of hypercholesterolemia. To evaluate whether lovastatin or pravastatin might affect daytime cognitive function, a double-blind, placebo-controlled, two-period, incomplete block, crossover study was performed in 36 patients (24 per treatment) with primary hypercholesterolemia. Patients received placebo, lovastatin (40 mg), or pravastatin (40 mg) for 4 weeks. Following a 1-week washout period, patients were crossed over to either lovastatin, pravastatin, or placebo for an additional 4 weeks. Mental performance tests (digit symbol substitution, choice reaction time, auditory vigilance, selective reminding word recall, finger tapping), visual analogue rating scales, and the Profile of Mood States were administered before test drug administration and after 2 and 4 weeks of each treatment. After 4 weeks, no statistically significant differences between treatments in changes from baseline were observed on any parameter with the exception of digit symbol substitution, for which lovastatin and pravastatin were both significantly better than placebo but did not differ from each other. Low-density lipoprotein cholesterol was reduced 38% by lovastatin and 30% by pravastatin. In summary, neither of these chemically distinct HMG-CoA reductase inhibitors impaired daytime cognitive performance after 4 weeks of treatment in patients with primary hypercholesterolemia.",1995.0,0,0 2547,7791813,"The genotoxicity profile of atorvastatin, a new drug in the treatment of hypercholesterolemia.",V Ciaravino; M L Kropko; C E Rothwell; C A Hovey; J C Theiss,"While HMG-CoA reductase inhibitors such as fluvastatin, lovastatin, pravastatin and simvastatin demonstrate lack of in vitro and in vivo mutagenicity and clastogenicity in bacterial and mammalian cells, long term rodent carcinogenicity studies resulted in an increased incidence in neoplasms at high doses. These effects may be attributable to an exaggeration of the desired biochemical effect of the drug and/or a tumor promoting effect. The genotoxicity of atorvastatin, a newly developed HMG-CoA reductase inhibitor, was evaluated in a variety of test systems. In bacterial mutagenicity tests, the E. coli tester strain WP2(uvrA) and S. typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 were exposed to concentrations of atorvastatin as high as 5000 micrograms/plate both in the absence (S9-) and presence (S9+) of metabolic activation. Atorvastatin was not mutagenic in either E. coli or S. typhimurium. Chinese hamster lung V79 cell cultures were exposed to atorvastatin at concentrations of 50-300 micrograms/ml (S9-) and 100-300 micrograms/ml (S9+) and structural chromosome aberrations were assessed. Mutation at the hgprt locus was assessed at concentrations of 100-300 micrograms/ml (S9-) and 150-275 micrograms/ml (S9+). Atorvastatin was neither mutagenic nor clastogenic in the absence or presence of S9. The lack of in vitro genotoxicity was corroborated in vivo in a mouse micronucleus study in which single oral doses of atorvastatin were administered to male and female CD-1 mice at 1, 2500, or 5000 mg/kg. No biologically significant increases in the frequency of micronucleated polychromatic erythrocytes in bone marrow at 24, 48, or 72 h postdosing were observed. Thus, atorvastatin, as with the other tested HMG-CoA reductase inhibitors, is not genotoxic.",1995.0,0,0 2548,7791863,Paradox of placebo effect.,B A Golomb,,1995.0,0,0 2549,7792841,Prevention and treatment of graft vessel disease after heart transplantation.,B M Meiser; K Wenke; J Thiery; U Brandl; H Mair; F Kur; C Detter; P Uberfuhr; E Kreuzer; D Seidel,,1995.0,0,0 2550,7792848,Is a reduction of graft vessel disease by maximal treatment of hypercholesterolemia after heart transplantation possible?,K Wenke; B Meiser; J Thiery; N Arndtz; W von Scheidt; D Seidel; B Reichart,,1995.0,0,0 2551,7792916,Hyperlipidemia in renal transplant recipients: does it matter and can we treat it?,C A Pollock; J F Mahony; C S Ong; R J Caterson; D A Waugh; L S Ibels,,1995.0,0,0 2552,7793393,Clinical characteristics and mortality of patients screened for entry into the Trandolapril Cardiac Evaluation (TRACE) study.,L Køber; C Torp-Pedersen,"In mortality studies of patients after acute myocardial infarction (AMI), exclusion of patients during selection from the screened population may be important for evaluating the impact of trials, but data on patients excluded from studies are rarely presented. In the Trandolapril Cardiac Evaluation (TRACE) trial of the angiotensin-converting enzyme inhibitor trandolapril versus placebo in patients with left ventricular (LV) systolic dysfunction shortly after AMI, medical history, infarct complication, and survival were accounted for in all patients screened for entry. A total of 7,001 consecutive enzyme-confirmed AMIs were screened for entry in 27 Danish coronary care units. The 1-year mortality of all screened AMI cases was 23% (95% confidence interval 22% to 24%). The target population of the TRACE trial were patients with LV systolic dysfunction (echocardiographically determined wall motion index < or = 1.2, n = 2,606 within 6 days of AMI. The 1-year mortality of this group was 34 +/- 2%. Patients with wall motion index > 1.2 (n = 3,920) had a 1-year mortality of 12 +/- 1%. were excluded. A total of 1,749 were included in the study. The excluded and included groups had a 1-year mortality of 54 +/- 3% and 24 +/- 2%, respectively. The result of the TRACE study will be applicable to two thirds of the patients with LV systolic dysfunction; however, even with this high figure, care should be taken in extrapolating the result to the general population with reduced LV function after AMI since the group excluded from the study had a higher mortality than those who were included.",1995.0,0,0 2553,7793401,An accurate stepwise electrocardiographic algorithm for localization of accessory pathways in patients with Wolff-Parkinson-White syndrome from a comprehensive analysis of delta waves and R/S ratio during sinus rhythm.,C E Chiang; S A Chen; W S Teo; D S Tsai; T J Wu; C C Cheng; C W Chiou; C T Tai; S H Lee; C Y Chen,"Prediction of accessory pathway location before radio-frequency ablation has become increasingly important for patients with Wolff-Parkinson-White syndrome. However, existing electrocardiographic (ECG) criteria for localization of accessory pathways have several limitations, and the polarity of delta waves has not been well defined. In the present study, 369 patients with a single anterogradely conducting accessory pathway who underwent successful radiofrequency ablation were included. The polarity of delta waves was defined and categorized in detail, and various ECG characteristics of the most preexcited QRS complexes were examined and compared with QRS complexes after successful ablation in the initial 182 patients, which included morphology and polarity of delta waves, initial 20, 40, and 60 ms segments of the preexcited QRS complex, R/S ratio in the precordial leads, R/S ratio in the frontal leads, delta wave axis in the frontal plane, polarity of delta waves in the frontal leads, and polarity of delta waves in the precordial leads. The polarity of the initial 40 ms segment of the most preexcited QRS complexes in each of the frontal leads, and the polarity of the initial 60 ms segment of the most preexcited QRS complex in each of the precordial leads proved to be the best representatives of delta wave polarity in the respective leads.(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0 2554,7793402,Long-term efficacy of amiodarone for the maintenance of normal sinus rhythm in patients with refractory atrial fibrillation or flutter.,S H Chun; P T Sager; W G Stevenson; K Nademanee; H R Middlekauff; B N Singh,"The purpose of this study was to examine the efficacy and safety of amiodarone to maintain sinus rhythm in patients with refractory atrial fibrillation or flutter. One hundred ten patients with atrial fibrillation or flutter, refractory to > or = 1 class I antiarrhythmic agents (mean +/- SD 2.5 +/- 1.5, median 2), were given low-dose amiodarone (mean maintenance dose 268 +/- 100 mg/day) to determine its efficacy to maintain normal sinus rhythm after chemical or electrical cardioversion. Fifty-three patients had chronic and 57 patients had paroxysmal atrial fibrillation or flutter. Mean age of the study population was 60 +/- 13 years, and the mean follow-up was 36 +/- 38 months (range 31 days to 137 months). Actuarial rates for maintenance of sinus rhythm were 0.87, 0.70, and 0.55 at 1, 3, and 5 years, respectively. Twenty-one patients (19%) with arrhythmia recurrence had an increase in amiodarone dose, and after a mean additional follow-up of 2.5 years, 86% remained in normal sinus rhythm. The only observed predictor of atrial fibrillation or flutter recurrence was paroxysmal arrhythmia (40% recurrence vs 9% in patients with chronic atrial fibrillation or flutter; p < 0.001). Actuarial rates for withdrawal because of adverse effects were 0.08, 0.22, and 0.30 at 1, 3, and 5 years, respectively. The most frequent adverse effects necessitating withdrawal were skin discoloration (4.5%), pulmonary fibrosis (3.6%; none fatal), and thyroid toxicity (2.7%). No deaths occurred during the study period. In conclusion, amiodarone sinus rhythm in patients with atrial fibrillation or flutter, with a relatively low incidence of adverse effects necessitating withdrawal.",1995.0,0,0 2555,7793403,Examination of mechano-electrical feedback in the transplanted human heart.,K A Ellenbogen; B S Stambler; M A Wood; P K Mohanty,"Several investigators have demonstrated that changes in atrial or ventricular pressure and size may modulate changes in electrophysiologic properties. The coupling of mechanical and electrical changes in the heart has been termed mechano-electrical feedback and is believed to play a role in arrhythmias observed with mitral valve disease, congestive heart failure, and left ventricular hypertrophy. To avoid confounding influences of the autonomic nervous system on electrophysiologic measurements, we measured right atrial and ventricular pacing thresholds with temporary epicardial pacing wires, right ventricular monophasic action potential duration at 90% repolarization during right ventricular pacing at 600 and 400 ms, donor heart rate, systolic, diastolic, and mean arterial and central venous pressures in 22 patients after orthotopic heart transplantation. Each variable was measured at baseline, in the resting supine state, and during graded lower body negative pressure of -10, -20, and -30 mm Hg. All levels of lower body negative pressure resulted in a significant decrease in mean right atrial pressure up to 5 +/- 6 mm Hg at maximal lower body negative pressure, and a significant decrease in mean arterial pressure occurred only at -20 and -30 mm Hg. Lower body negative pressure did not result in a significant change in any electrophysiologic variable despite significant changes in right atrial pressure. Thus, in the denervated transplanted human heart, unloading of the right heart results in no or small changes in atrial or ventricular pacing thresholds and ventricular monophasic action potential duration.",1995.0,0,0 2556,7793410,Late angiographic follow-up after Palmaz-Schatz stent implantation.,J B Foley; J White; P Teefy; D G Almond; R I Brown; I M Penn,,1995.0,0,0 2557,7793412,Exercise training and blood viscosity in patients with ischemic heart disease.,G N Levine; C O'Malley; G J Balady,,1995.0,0,0 2558,7793414,Usefulness of endothelin-1 as a predictor of response to head-up tilt-table testing in children with syncope.,M Mehta; G Wolff; M L Young; M S Mas; A Escobar; H Gelband,,1995.0,0,0 2559,7793415,Developmental changes of alpha 1-adrenergic chronotropic action on human sinus node.,H Saitoh; A Nomura; M Osaka; N Sasabe; H Atarashi; H Hayakawa,"The important role of alpha 1-adrenoceptors in reperfusion ventricular arrhythmia is mentioned in the introduction. However, the present report is concerned with the sinus node. It is speculated that the decreased positive chronotropic action of alpha 1-adrenergic stimulation due to aging may contribute to the development of sick sinus syndrome.",1995.0,0,0 2560,7793418,A prospective study of the seroprevalence of Borrelia burgdorferi infection in patients with severe heart failure.,S W Sonnesyn; S C Diehl; R C Johnson; S H Kubo; J L Goodman,"We conclude that Lyme disease is not a common cause of idiopathic heart failure in the Midwestern United States and that false-positive Lyme disease serologic results are not rare among patients with severe heart failure. Patients with significant cardiac disease who are found to be EIA seropositive should have confirmatory Western blots performed before consideration of treatment. Based on our findings, we cannot recommend either the routine serologic screening of patients with idiopathic cardiomyopathy or aggressive (e.g., parenteral) antibiotic treatment of seropositive patients unless the specific clinical history suggests antecedent Lyme disease.",1995.0,0,0 2561,7798816,Observation on the short and long term response to anti-lipemic drugs in southern Thailand.,S Yipintsoi; T Yipintsoi,"Patients with dyslipidemia were evaluated with regard to the 5 drugs regimen: simvastatin (average dose, 11.8 mg/day), gemfibrozil (dose 963 mg/day), bezafibrate (433 mg/day), fenofibrate (211 mg/day) and acipimox (667 mg/day). The responses to the drug were divided into different time periods and the magnitude of responses were presented either as average changes in per cent from baseline or as proportion of patients (also in %) whose levels changed by a predetermined percentage. These predetermined percentage took into account the variation observed among patients who had more than 3 measurements during baseline. These levels for significant changes were 16 per cent for total cholesterol (TC), 25-30 per cent for high- and low-density lipoprotein (HDL and LDL), and 44 per cent for triglyceride (TG). Our subjects responded to the drugs within the range reported by other investigators except for acipimox which produced no alteration. Sixty to 100 per cent of patients reduced their TC by 16 per cent with an average change in TC of around -16 per cent to -24 per cent. Simvastatin and fenofibrate appeared most effective in altering TC. The HDL increased 10 per cent to 29 per cent depending on the drug but in terms of proportion that responded by an increment greater than 25 per cent, this was seen in only 23 per cent to 45 per cent of the patients. Long term follow-up which was possible only on 42 patients showed 11 who lessened their response and 6 whose response became more marked.(ABSTRACT TRUNCATED AT 250 WORDS)",1993.0,0,0 2562,7798847,Early response of hyperlipidemic subjects to simvastatin.,N Jeamanukoolkit; B Koanantakul; O Dabpetch; P Kakong; S Nontakanun; S Yipintsoi,"Seventy eight patients with hypercholesterolemia from 4 major hospitals were studied with regard to their responses to an adjustable dose of simvastatin, a HMG-CoA reductase inhibitor. They were followed for up to 6 months with 4 sample points during the drug and 2 prior to therapy. The average dose was 10.2 mg/day (S.D. 5.5). Four were controlled on 5 mg and 4 needed 30 mg per day. Thirty seven per cent had elevated serum transaminases but none to greater than twice normal. Only a third of these showed elevation of transaminases during drug therapy alone. The mean total cholesterol (TC) was 304 mg/100 ml and low density lipoprotein (LDL) was 221 mg/100 ml. These fell 70 and 60 per cent respectively and over 90 per cent of the patients reduced their TC and LDL more than the limits defined from previous long term monitoring of patients (i.e. TC fell by more than 17% and LDL by 25%). High density lipoprotein, HDL, started off at 45 mg/100 ml and rose to an average of 115 per cent. Triglyceride, TG, started off at 207 mg/100 ml and fell to about 86 per cent during simvastatin. However, in terms of the proportion of patients who responded greater than the limit previously determined (i.e. more than a 25% change for HDL and 45% for TG), only about 20 per cent significantly responded with elevation of HDL and 13 per cent dropped their TG. The response of TG was more marked at TG greater than 300 mg/100 ml.",1994.0,0,0 2563,7801861,Enhanced low-density lipoprotein cholesterol reduction and cost-effectiveness by low-dose colestipol plus lovastatin combination therapy.,H G Schrott; E A Stein; C A Dujovne; M H Davidson; G B Goris; T H Oliphant; J C Phillips; G G Shawaryn,"A total of 96 patients with moderate elevations of low-density lipoprotein (LDL) cholesterol were randomly assigned to 4 different double-blind treatment regimens: placebo; colestipol 5 g and lovastatin 20 mg/day (C5 + L20); colestipol 10 g and lovastatin 20 mg/day (C10 + L20); and lovastatin 40 mg/day (L40). During 12 weeks of therapy, C10 + L20 achieved the greatest reduction in total cholesterol (-32%) and LDL cholesterol (-48%) levels from baseline. This combination also exhibited significantly greater reductions in LDL cholesterol levels than the C5 + L20 and L40 groups (p < 0.01). The differences in total and LDL cholesterol reduction between the C5 + L20 and L40 groups were not significant. Similar changes and differences between treatments were seen in apolipoprotein B levels. Whereas mean total apolipoprotein A-I levels increased with all treatments (p < 0.05), lipoprotein particles A-I were significantly increased in the C10 + L20 group (p < 0.01) only. Results demonstrate that the combination of low-dose lovastatin (20 mg/day) with low-dose colestipol (5 or 10 g/day) produces LDL cholesterol reductions equal to or greater than higher doses of lovastatin (40 mg/day). In addition, low-dose combinations are > 25% more cost-effective than high-dose monotherapy.",1995.0,0,0 2564,7809382,"Effects of acute exercise on the changes of lipid profiles and peroxides, prostanoids, and platelet activation in hypercholesterolemic patients before and after treatment.",M F Chen; H C Hsu; Y T Lee,"The effects of acute exercise on the changes of plasma lipid profiles and peroxides, prostanoids and platelet activation in hypercholesterolemic patients before and after pravastatin 5 mg twice daily treatment for 4 weeks was studied in 30 (M/F = 21/9, age = 52 +/- 7, Mean +/- SD) patients with plasma total cholesterol level > 240 mg/dl. Pravastatin significantly reduced plasma total and low density lipoprotein cholesterol levels as expected. All patients before and after treatment and 30 healthy controls performed a treadmill exercise test using the standard Bruce protocol. The cardiac performance was similar in all groups. Treadmill exercise did not influence lipid levels after plasma volume correction. Hypercholesterolemic patients had significantly higher pre-exercise levels of malondialdehyde, thromboxane beta 2 and beta-thromboglobulin than after treatment or than pre-exercise levels in the control group. Treatment with lipid lowering drug pravastatin lowered the levels of these three parameters. At peak exercise, superoxide dismutase activity and 6-keto-PGF1 alpha were elevated. At 10 min post exercise only malondialdehyde returned to pre-exercise levels. The superoxide dismutase, thromboxane B2 and beta-thromboglobulin remained significantly higher. In the control subjects plasma beta-thromboglobulin and thromboxane 2 returned to pre-exercise levels. These results suggest that hypercholesterolemia may induce lipid peroxidation and platelet activation in resting status. Lowering of plasma cholesterol of pravastatin causes a concomitant decrease in plasma malondialdehyde, thromboxane and beta-thromboglobulin suggesting a decrease in lipid peroxidation and platelet activation. These changes were more pronounced in the hypercholesterolemic patients. Pravastatin treatment attenuated the increase in both malondialdehyde, beta-thromboglobulin and the prostanoids, but not to the level of normal subjects.",1994.0,0,0 2565,7811124,Antithrombotic therapy. An abbreviated reference for clinicians.,R C Becker; J Ansell,"Antithrombotic therapy is a mainstay in the treatment of patients with thromboembolic diseases of the arterial and venous circulatory systems. Continued work and investigation has provided much-needed information directly applicable to meeting high standards of patient care. The American College of Chest Physicians Consensus Conference on Antithrombotic Therapy has been instrumental in developing guidelines. This article is a synopsis of the proposed guidelines, including recent updates and information that will likely influence future recommendations.",1995.0,0,0 2566,7812496,Reoperative approaches for carotid restenosis.,P J Rossi; S I Myers; G P Clagett,,1994.0,0,0 2567,7813167,Clinical investigation on the hypolipidemic effect of simvastatin versus probucol in hemodialysis patients.,F Fiorini; E Patrone; A Castelluccio,"In chronic renal failure hypertriglyceridemia is a well-known complication that persists during hemodialysis treatment: it may be one of the major risk factor for cardiovascular death in these patients. We studied the effects of two lipid lowering drugs; simvastatin (20 mg/day for six months) and probucol (500 mg/day for six months), on lipid profile in 12 hemodialysis patients. Simvastatin therapy reduced plasma total cholesterol by 26% (p > 0.002), LDL-cholesterol by 36% (p > 0.002) and triglycerides by 28% (p > 0.05): plasma HDL-cholesterol and apo-A were raised, but not significantly. Probucol therapy decreased plasma triglycerides by 38% (p > 0.05), total cholesterol by 15% and LDL-cholesterol by 19%: plasma HDL-cholesterol and apo-A were decreased but not significantly. No side effects occurred with either drug. These data suggest that in hemodialysis patients both simvastatin and probucol profoundly affect the lipid profile, as well as the triglyceride levels.",1994.0,0,0 2568,7823749,Validity of the 4S simvastatin trial.,W E Stehbens,,1995.0,0,0 2569,7826828,Efficacy of a low dose-range of fluvastatin (XU 62-320) in the treatment of primary hypercholesterolaemia. A dose-response study in 431 patients. The French-Dutch Fluvastatin Study Group.,B Jacotot; J D Banga; P Pfister; M Mehra,"1. In this randomised, double-blind, placebo-controlled study, the efficacy of four dosages of fluvastatin (2.5, 5, 10 and 20 mg day-1) were assessed in 431 patients with primary hypercholesterolaemia recruited in 17 centres. 2. Following an 8-week dietary stabilisation phase and a 6-week placebo phase, the patients were randomised to receive placebo or fluvastatin 2.5, 5, 10 or 20 mg once daily at night for a period of 6 weeks. 3. Total cholesterol, beta-quant LDL-C, and the beta-quant LDL-C/HDL-C ratio were significantly reduced by all doses of fluvastatin, and HDL-C was significantly increased by the 10 mg and 20 mg doses. Fluvastatin 20 mg day-1 also significantly decreased TG and Lp(a):B levels. 4. Fluvastatin was well tolerated during the study, and relatively few biochemical or haematological abnormalities occurred. 5. Of the dosages tested, 20 mg fluvastatin day-1 is the optimal hypolipidaemic dose.",1994.0,0,0 2570,7830728,Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease.,C B Treasure; J L Klein; W S Weintraub; J D Talley; M E Stillabower; A S Kosinski; J Zhang; S J Boccuzzi; J C Cedarholm; R W Alexander,"Impaired endothelium-mediated relaxation contributes to vasospasm and myocardial ischemia in patients with coronary artery disease. We hypothesized that cholesterol-lowering therapy with the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin could improve endothelium-mediated responses in patients with coronary atherosclerosis. In a randomized, double-blind, placebo-controlled trial, we studied coronary endothelial responses in 23 patients randomly assigned to either lovastatin (40 mg twice daily; 11 patients) or placebo (12 patients) plus a lipid-lowering diet (American Heart Association Step 1 diet). Patients were studied 12 days after randomization and again at 5 1/2 months. These patients had total cholesterol levels ranging from 160 to 300 mg per deciliter (4.1 to 7.8 mmol per liter) and were undergoing coronary angioplasty. At the initial and follow-up studies, patients received serial intracoronary infusions (in a coronary artery not undergoing angioplasty) of acetylcholine to assess endothelium-mediated vasodilatation. The responses of the coronary vessels were analyzed with quantitative angiography. The patients in the placebo and lovastatin groups had similar responses to acetylcholine at a mean of 12 days of therapy (expressed as the percentage of change in diameter in response to acetylcholine doses of 10(-9) M, 10(-8) M, 10(-7) M, and 10(-6) M). In the placebo group, the respective mean (+/- SE) changes were 1 +/- 2, 0 +/- 2, -2 +/- 4, and -19 +/- 4 percent; in the lovastatin group, they were -2 +/- 2, -4 +/- 4, -12 +/- 5, and -16 +/- 7 percent (P = 0.32). (Coronary-artery constriction is reflected by negative numbers). The responses to acetylcholine in the placebo group after a mean of 5.5 months of therapy were -3 +/- 3, -1 +/- 2, -8 +/- 4, and -18 +/- 5 percent, respectively; there was significant improvement in the lovastatin group, which had responses of 3 +/- 3, 3 +/- 3, 0 +/- 2, and 0 +/- 3 percent (P = 0.004). Cholesterol lowering with lovastatin significantly improved endothelium-mediated responses in the coronary arteries of patients with atherosclerosis. Such improvement in the local regulation of coronary arterial tone could potentially relieve ischemic symptoms and signal the stabilization of the atherosclerotic plaque.",1995.0,0,0 2571,7830729,The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.,T J Anderson; I T Meredith; A C Yeung; B Frei; A P Selwyn; P Ganz,"Patients with coronary artery disease and abnormalities of serum lipids often have endothelial vasodilator dysfunction, which may contribute to ischemic cardiac events. Whether cholesterol-lowering or antioxidant therapy can restore endothelium-dependent coronary vasodilation is unknown. We randomly assigned 49 patients (mean serum cholesterol level, 209 +/- 33 mg per deciliter [5.40 +/- 0.85 mmol per liter]) to receive one of three treatments: an American Heart Association Step 1 diet (the diet group, 11 patients); lovastatin and cholestyramine (the low-density lipoprotein [LDL]-lowering group, 21 patients); or lovastatin and probucol (the LDL-lowering-antioxidant group, 17 patients). Endothelium-dependent coronary-artery vasomotion in response to an intracoronary infusion of acetylcholine (10(-8) to 10(-6) M) was assessed at base line and after one year of therapy. Vasoconstrictor responses to these doses of acetylcholine are considered to be abnormal. Treatment resulted in significant reductions in LDL cholesterol levels of 41 +/- 22 percent in the LDL-lowering-antioxidant group and 38 +/- 20 percent in the LDL-lowering group (P < 0.001 vs. the diet group). The maximal changes in coronary-artery diameter with acetylcholine at base line and at follow-up were -19 and -2 percent, respectively, in the LDL-lowering-antioxidant group, -15 and -6 percent in the LDL-lowering group, and -14 and -19 percent in the diet group (P < 0.01 for the LDL-lowering-antioxidant group vs. the diet group; P = 0.08 for the LDL-lowering group vs. the diet group). (The negative numbers indicate vasoconstriction). Thus, the greatest improvement in the vasoconstrictor response was seen in the LDL-lowering-antioxidant group. The improvement in endothelium-dependent vasomotion with cholesterol-lowering and antioxidant therapy may have important implications for the activity of myocardial ischemia and may explain in part the reduced incidence of adverse coronary events that is known to result from cholesterol-lowering therapy.",1995.0,0,0 2572,7830734,Cholesterol reduction in cardiovascular disease. Clinical benefits and possible mechanisms.,G N Levine; J F Keaney; J A Vita,,2001.0,0,0 2573,7832145,Response of high-density lipoproteins to hypolipidemic drugs according to their initial level.,G D Kolovou; Y P Fostinis; H I Bilianou; D V Cokkinos,,1995.0,0,0 2574,7836550,Central nervous system effects of HMG CoA reductase inhibitors: lovastatin and pravastatin on sleep and cognitive performance in patients with hypercholesterolemia.,J B Kostis; R C Rosen; A C Wilson,"Sleep disturbances and decrements of daytime performance have been attributed to HMG-CoA reductase inhibitors. As a rule, lipophilic compounds more readily cross the blood-brain barrier and are more likely to affect central nervous system function. The authors compared the effects of lovastatin (40 mg), a lipophilic compound, to pravastatin (40 mg), a hydrophilic compound, in a 6-week, double-blind, randomized, placebo-controlled, three-way Latin square design, cross-over study on 22 men with hypercholesterolemia. Patients had LDL cholesterol of more than 165 mg/dL and triglyceride of less than 350 mg/dL after 6 weeks of a low-fat (< 30%), low-cholesterol (< 300 mg/day) diet. Compared with placebo, there were no significant effects of lovastatin or pravastatin on the following subjective and polysomnographic sleep measures: changes in total sleep time, time in each sleep stage, sleep efficiency, sleep latency, REM density, REM activity, and number of arousals. Similarly, there were no effects of the two drugs on measures of cognitive performance. A significant increase in the duration of nocturnal tumescence (NPT) was observed after 2 weeks of treatment with both study drugs. This effect was not significant after 6 weeks of treatment. Both lovastatin and pravastatin caused significant (P < .05 compared with placebo) decreases in total cholesterol (by 20.9 and 20.6%, respectively), LDL cholesterol (by 27.8 and 29.9%), and triglycerides (by 13.6 and 3.7%). Subjects' HDL increased by 2.3% with lovastatin (NS) and by 3.1% with pravastatin (P < .05). Lipoprotein(a) increased by 20.5% with lovastatin and by 1.1% with pravastatin; these changes were not significantly different from placebo.(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2575,7846795,[The Scandinavian Simvastatin Survival Study].,O Faergeman; T Haghfelt,,1995.0,0,0 2576,7848022,,,,,0,0 2577,7851467,Postprandial apolipoprotein B100 and B48 metabolism in familial combined hyperlipidaemia before and after reduction of fasting plasma triglycerides.,M Castro Cabezas; D W Erkelens; L A Kock; T W De Bruin,"Hepatic VLDL overproduction in familial combined hyperlipidaemia (FCH) may delay the clearance of atherogenic apolipoprotein (apo) B containing particles. We investigated if normalization of fasting plasma triglycerides (TG) by hypolipidaemic treatment results in improved metabolism of apo B48 and apo B100 in six male subjects with FCH and compared them to six normolipidaemic controls. The FCH patients were studied before (TG, 5.2 +/- 1.2 mmol l-1; mean +/- SEM) and after therapy (TG, 2.1 +/- 0.3 mmol l-1) with either simvastatin (n = 4) or combined therapy with gemfibrozil (n = 2). The postprandial changes of apo B100 and apo B48 were studied after a single oral fat meal (24 h; 50 gram fat m-2). Changes in triglyceride rich particles (TRP; d < 1.006 g ml-1) and remnant fractions (REM; d:1.006-1.019 g ml-1) of apo B were quantitated by scanning silverstained SDS-PAGE (4-15%). Apo B48 in fasting TRP in untreated and treated FCH was 15% and 14% of total apo B, and 6% in controls (P < 0.05). In controls, postprandial B48 increased maximally at 4 h by 81% in TRP and by 137% in REM compared to baseline. In treated FCH, the postprandial apo B48 pattern normalized in TRP compared to the untreated state. Postprandial apo B100 in controls decreased in TRP and REM by 33% and 18% (P < 0.05). In untreated and treated FCH, postprandial apo B100 remained unchanged vs. baseline in TRP and in REM suggesting hypersecretion of VLDL. The elimination of B100--assessed as area under the curve--in TRP (32.5 +/- 3.6 au.h; mean +/- SEM) and REM fractions (33.2 +/- 3.1 au.h), improved significantly after treatment (21.0 +/- 2.8 and 20.4 +/- 3.3 au.h, respectively). The apo B48 clearance in TRP fractions was improved after treatment (4.3 +/- 1.4 au.h vs. 2.9 +/- 1.2 au.h; P = 0.06), but not in REM fractions (2.8 +/- 1.0 au.h vs. 1.8 +/- 0.5 au.h; NS). In conclusion, in FCH subjects with apo B100 hypersecretion and increased fasting plasma apo B48 levels, reduction of fasting plasma TG improved, but did not normalize, TRP apo B48 and B100 metabolism. However, therapy normalized postprandial apo B100 remnant metabolism. Impaired postprandial apo B metabolism may be instrumental in the development of premature atherosclerosis in FCH subjects.",1994.0,0,0 2578,7856175,"The RED-LIP study--pravastatin in primary isolated hypercholesterolemia--an open, prospective, multicenter trial.",H Sinzinger; C Pirich,"The therapeutic effects of the HMG-CoA reductase inhibitor pravastatin on plasma lipids were assessed in an open, prospective, multicenter trial over a treatment period of 3 months. Of a total of 1111 patients, the overall results were calculated from 715 evaluable patients (352 men and 363 women, mean age: 56.1 +/- 11.3 years) with primary isolated hypercholesterolemia (hyperlipoproteinemia type IIa according to Fredrickson) being at high risk for cardiovascular disease according to the classification of the national cholesterol consensus, whose guidelines are distinguishing between three risk levels (low, moderate, and high, respectively) of total-cholesterol (total-c) as well as LDL-c. The treatment period was preceded by a 3-month dietary counselling phase. Treatment with pravastatin significantly reduced total-c (23.8%, p < 0.001), LDL-c (31.9%, p < 0.001) and triglyceride (16.9%, p < 0.001) levels, concomitantly those of HDL-c were significantly raised (15%, p < 0.001). Pravastatin lowered the total-c/HDL-c ratio by nearly 36% from a mean of 8.1 +/- 2.5 to a mean of 5.2 +/- 1.6. At the end 476 patients (66.6%) received the standard dosage of 10 mg/day whereas 140 patients (19.6%) were recorded to take a dose of 20 mg/day. When comparing those patients (n = 456) having maintained consistently a dose of 10 mg pravastatin per day from week 0 to week 12 with patients (n = 113) who received 20 mg/day from week 4 to 12 similar efficacy was observed in both groups (reduction of total-c: 24.5% vs. 22.2%, n.s., reduction of LDL-c: 33.0% vs. 30.0%, n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2579,7856526,"Comparison of gemfibrozil versus simvastatin in familial combined hyperlipidemia and effects on apolipoprotein-B-containing lipoproteins, low-density lipoprotein subfraction profile, and low-density lipoprotein oxidizability.",S J Bredie; T W de Bruin; P N Demacker; J J Kastelein; A F Stalenhoef,"We evaluated in a double-blind, placebo-controlled, randomized trial of 45 well-defined patients with familial combined hyperlipidemia, the effect of gemfibrozil (1,200 mg/day) or simvastatin (20 mg/day) on apolipoprotein-B (apo-B)-containing lipoproteins, low-density lipoprotein (LDL) subfraction profile, and LDL oxidizability. Although both drugs reduced plasma cholesterol and triglyceride concentrations, gemfibrozil reduced plasma triglycerides more effectively and simvastatin reduced plasma cholesterol more effectively. LDL cholesterol was reduced with simvastatin. With both drugs, total serum apo-B concentration decreased. With gemfibrozil, this was due to an exclusive reduction (-46%) of very low/intermediate-density lipoprotein (VLDL + IDL) apo-B, whereas simvastatin decreased apo-B in both VLDL + IDL and LDL (34% and 15%, respectively). Initially, a dense LDL subfraction profile was present in all patients. The decrease in LDL cholesterol with simvastatin was due to a decrease in all isolated LDL subfractions except LDL2; gemfibrozil increased LDL1 and LDL2 cholesterol (p = 0.001) and reduced LDL4 cholesterol, resulting in a more buoyant LDL subfraction profile compared with simvastatin. In both groups, a predominance of small dense LDL remained despite therapy. LDL fatty acid composition showed a shift from oleic acid to linoleic acid after gemfibrozil; arachidonic acid increased after simvastatin. Vitamin E was lower after gemfibrozil. In the measurements of LDL oxidation, only the oxidation rate was significantly reduced with simvastatin. Thus, quantitative and qualitative changes of LDL cholesterol had only a small effect on total in vitro LDL oxidizability in this population with familial combined hyperlipidemia.",1995.0,0,0 2580,7856612,Criteria for use of hypolipidemic agents in adults.,E Morales; S A Spinler; M D Wilson; M M Chin; E Jozefiak,,1994.0,0,0 2581,7857367,Gender and diet interactions with simvastatin treatment.,P M Clifton; M Noakes; P J Nestel,"Twelve men and thirteen women with hypercholesterolaemia participated in a 20-week controlled cross-over trial to assess the interaction between dietary fat intake, gender and an HMGCoA reductase inhibitor, simvastatin. Subjects were matched for total cholesterol, age, body mass index (BMI) and plasma triglyceride. Gender-drug interactions were noted with men demonstrating only a 27% fall in LDL cholesterol with simvastatin when consuming a high fat (40% energy) diet compared to women with a 35% fall. In men, the lowest LDL/HDL ratio was achieved with simvastatin on a low fat diet (22% energy). Gender differences in the effect of simvastatin on HDL were confined to HDL3 cholesterol, although the drug raised HDL2 in both sexes on the low fat diet. Simvastatin was responsible for an 11% increase in HDL3 cholesterol in men particularly when on a low fat diet but did not affect HDL3 in women. An important diet-drug interaction was seen in triglyceride response, with a lowering of 17%-20% only when subjects were on a low fat diet. There was a gender difference in response to dietary fat change with men demonstrating a 19% decrease in triglycerides with dietary fat reduction while on simvastatin, whereas women showed a 9% increase which did not reach significance. Men also responded more favourably to dietary fat reduction with at least two-fold greater falls in plasma cholesterol than was seen in women.(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2582,7858908,Heterogeneity of plasma low-density lipoproteins and atherosclerosis risk.,R M Krauss,"Increased levels of IDL and small, dense LDL are associated with the risk of coronary artery disease. Possible mechanisms include increased susceptibility of small, dense LDL to oxidation, and to other pathologic effects, such as increased retention in the arterial wall. Beneficial effects of a low-fat diet and certain lipid-lowering therapies on the levels and properties of small, dense LDL or their precursors may contribute substantially to the reductions in coronary atherosclerosis observed in several lipid-lowering trials.",1994.0,0,0 2583,7859227,Inhibition of cell signalling pathways.,S P Langdon; J F Smyth,,1995.0,0,0 2584,7859238,Long-term effects of pravastatin on serum lipid levels in elderly patients with hypercholesterolemia.,S Morimoto; E Koh; K Fukuo; J Higaki; H Ikegami; T Miki; T Hata; T Ogihara,"The purpose of this study was to evaluate the long-term efficacy and tolerability of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in elderly patients with hypercholesterolemia. Pravastatin was administered for 12 months at a mean final dose of 9.9 mg/d to 208 elderly patients (mean [+/- SD] age, 70 +/- 7 years) with levels of total serum cholesterol greater than 5.69 mmol/L. The mean total cholesterol level was significantly decreased from 6.85 +/- 0.80 mmol/L to 5.59 +/- 0.70 mmol/L after 3 months, and this decrease was maintained thereafter. A similar change was observed in the mean serum level of low-density lipoprotein cholesterol. Although the mean serum level of high-density lipoprotein cholesterol in all the patients did not change significantly, the level in 34 patients with a value lower than 1.03 mmol/L was significantly increased after 3 months and thereafter. The serum level of triglycerides in all patients was significantly decreased after 3 months and thereafter and the decrease was more marked in 101 patients with levels greater than 1.73 mmol/L. In 168 elderly patients receiving 10 mg/d of pravastatin, there were significant negative correlations between the percent decrease in total cholesterol and both baseline total serum cholesterol level (r = -.354, P < 0.001) and age (r = -.208, P = 0.007). No serious side effects were observed. These results indicate that long-term administration of pravastatin is beneficial in the treatment of hypercholesterolemia in elderly patients.",1994.0,0,0 2585,7859242,Effects of pravastatin treatment on vitamin D metabolites.,M Montagnani; F Loré; G Di Cairano; S Gonnelli; C Ciuoli; A Montagnani; C Gennari,"Hyperlipidemias, and notably hypercholesterolemia, represent important risk factors for atherosclerotic vascular disease. The enzymatic inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a selective and specific key enzyme involved in endogenous cholesterol synthesis, cause a significant mean reduction in low-density lipoprotein (LDL) cholesterol, both in familial and nonfamilial hypercholesterolemic forms. It has been hypothesized that these compounds might interfere with vitamin D endogenous synthesis secondarily to their effects on cholesterol. To verify this hypothesis, we studied 14 hypercholesterolemic patients treated as follows: 4 weeks of low-lipid, fiber-rich diet followed by 8 weeks of pravastatin treatment at the oral evening dose of 20 mg/d and by a 1-month washout period. No significant changes in serum calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were noticed; on the contrary, significant (P < 0.01) reductions in total cholesterol and LDL cholesterol and a significant (P < 0.05) increase in high-density lipoprotein cholesterol were observed. After the final 1-month washout period, all values returned to baseline levels. In conclusion, our study confirms the clinical efficacy of pravastatin on lipid fractions and demonstrates the absence of any interference on the circulating levels of the main vitamin D metabolites.",1994.0,0,0 2586,7859805,Cholesterol malabsorption caused by sitostanol ester feeding and neomycin in pravastatin-treated hypercholesterolaemic patients.,H Vanhanen,"Serum cholesterol values were insufficiently reduced by pravastatin in two different patient populations. Therefore, we studied whether further cholesterol reduction could be achieved by inhibiting both cholesterol synthesis (by pravastatin) and absorption (by neomycin or sitostanol ester). Thus, we measured serum cholesterol, cholesterol precursors (reflecting cholesterol synthesis), cholestanol and plant sterols (reflecting cholesterol absorption and biliary secretion) for up to 6 weeks in pravastatin-treated patients with familial hypercholesterolaemia (FH, n = 13) and with and without ileal bypass during addition of neomycin (1.5 g per day) and in another patient population of non-FH (n = 14) subjects during addition of sitostanol ester (1.5 g per day). Addition of neomycin lowered serum total, LDL and HDL cholesterol by a further 20%, and increased the pravastatin-lowered precursor:cholesterol ratios by 20% (irrespective of ileal bypass). It also reduced by 20% the plant sterol:cholesterol ratio (irrespective of ileal bypass) which was markedly increased by pravastatin alone. Pravastatin and neomycin in combination lowered total, LDL and HDL cholesterol by 45%, 53% and 17%, respectively. This combined regimen reduced the serum lathosterol:cholesterol ratio to about half of the reduction caused by pravastatin, while the elevation of the plant sterols:cholesterol ratio was less with the combination than with pravastatin alone. Changes in serum cholesterol precursor:cholesterol and plant sterol:cholesterol ratios during the combined treatment were smaller in the subgroup with ileal bypass. Addition of sitostanol ester did not lower serum total or LDL cholesterol nor the precursor:cholesterol ratios significantly, while the reduction observed in the plant sterols:cholesterol ratios was similar to that achieved with neomycin addition.(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2587,7863988,"Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II)",J R Crouse; R P Byington; M G Bond; M A Espeland; T E Craven; J W Sprinkle; M E McGovern; C D Furberg,"We randomized 151 coronary patients to placebo or pravastatin and treated them for 3 years. B-mode ultrasound quantification of carotid artery intimal-medial thickness (IMT) was obtained at baseline and sequentially during this period. The primary outcome was the change in the mean of the maximal IMT measurements across time. Effects on individual carotid artery segments (common, bifurcation, and internal carotid) and on clinical events were also investigated. Plasma concentrations of total cholesterol were lower with active treatment than with placebo (4.80 vs 6.07 mmol/L [186 vs 235 mg/dl], respectively) as were concentrations of low-density lipoprotein cholesterol (3.11 vs 4.30 mmol/L [120 vs 167 mg/dl], respectively). Plasma concentrations of high-density lipoprotein2 cholesterol were higher with active treatment (0.16 vs 0.14 mmol/L [6.1 vs 5.5 mg/dl], respectively). Active treatment resulted in a nonsignificant 12% reduction in progression of the mean-maximum IMT (from 0.068 to 0.059 mm/year) and a statistically significant 35% reduction in IMT progression in the common carotid. Active treatment was also associated with a reduction in fatal and nonfatal coronary events [corrected] (p = 0.09) and of any fatal event plus nonfatal myocardial infarction (p = 0.04).",2001.0,1,1 2588,7864934,Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS),,"It has yet to be established whether substantial reduction of plasma lipids will lead to retardation, and to what extent and how quickly, of diffuse and focal coronary atheroma. The Multicentre Anti-Atheroma Study (MAAS) is a randomised double-blind clinical trial of 381 patients with coronary heart disease assigned to treatment with diet and either simvastatin 20 mg daily or placebo for 4 years. Patients on simvastatin had a 23% reduction in serum cholesterol, a 31% reduction in low-density lipoprotein cholesterol, and a 9% increase in high-density lipoprotein cholesterol compared with placebo over 4 years. Quantitative coronary angiography was done at baseline, and after 2 and 4 years. 167 patients (89%) on placebo and 178 (92%) on simvastatin had baseline and follow-up angiograms. In the placebo group there were reductions in mean lumen diameter (-0.08 mm) and in minimum lumen diameter (-0.13 mm). Treatment effects were +0.06 (95% CI 0.02 to 0.10) and +0.08 mm (0.03 to 0.14) for mean and minimum lumen diameter, respectively (combined p = 0.006). Patients on placebo had an increase in mean diameter stenosis of 3.6% and the treatment effect of simvastatin was -2.6% (-4.4 to -0.8). Treatment effects were observed regardless of diameter stenosis at baseline. On a per-patient basis, angiographic progression occurred less often in the simvastatin group, 41 versus 54 patients; and regression was more frequent, 33 versus 20 patients (combined p = 0.02). Significantly more new lesions and new total occlusions developed in the placebo group, 48 versus 28, and 18 versus 8, respectively. There was no difference in clinical outcome. The numbers of patients who died or had a myocardial infarction were 16 and 14 in the placebo and simvastatin groups, respectively. In the placebo group more patients underwent coronary angioplasty or re-vascularisation, 34 versus 23 on simvastatin. The trial showed that 20 mg simvastatin daily over 4 years reduces hyperlipidaemia and slows progression of diffuse and focal coronary atherosclerosis.",1994.0,1,1 2589,7868973,Acute and chronic effects on cholesterol biosynthesis of LDL-apheresis with or without concomitant HMG-CoA reductase inhibitor therapy.,M Pfohl; R P Naoumova; C Klass; W Knisel; B Jakober; T Risler; G R Thompson,"To determine the acute and long-term effects of low density lipoprotein (LDL) reduction on cholesterol biosynthesis, we studied changes in the cholesterol precursors mevalonic acid (MVA) and lathosterol in patients with heterozygous familial hypercholesterolemia undergoing LDL-apheresis. Long-term LDL-apheresis in eight patients resulted in slight but insignificant increases in plasma MVA levels and lathosterol/cholesterol (L/C) ratios over 18 months. In short-term studies, six patients not on drugs and six patients treated with lovastatin or pravastatin had blood taken immediately before and after LDL-apheresis, and afterwards on days 1, 2, 3, 5, and 7. Plasma L/C ratios and MVA concentration did not change significantly on the first day after LDL-apheresis in those not on statin therapy (1.11 +/- 0.08 vs. 1.40 +/- 0.18, and 9.2 +/- 1.3 vs. 9.1 +/- 0.6 ng/ml, respectively) but increased in the statin-treated group (from 0.78 +/- 0.09 to 1.55 +/- 0.21, P = 0.003 and from 5.0 +/- 0.7 to 11.0 +/- 1.6 ng/ml, P = 0.008, respectively). There was no clear correlation between the changes in either of these precursors and the extent of reduction of total cholesterol by LDL-apheresis, but there was a strong inverse correlation with the post-apheresis LDL-cholesterol level (r = -0.77, P = 0.002 for L/C ratio; r = -0.75, P = 0.003 for MVA). Post-apheresis changes in L/C ratio and MVA were mutually correlated (r = 0.68. P = 0.01). We conclude that LDL-apheresis stimulates cholesterol biosynthesis transiently despite concomitant therapy with an HMG-CoA reductase inhibitor, the degree of stimulation being inversely related to the level to which the LDL-cholesterol was reduced.",1994.0,0,0 2590,7871179,"Cost-effectiveness analysis in heart disease, Part III: Ischemia, congestive heart failure, and arrhythmias.",J Kupersmith; M Holmes-Rovner; A Hogan; D Rovner; J Gardiner,"Cost-effectiveness analyses were reviewed in the following diagnostic and treatment categories: acute myocardial infarction (MI) and diagnostic strategies for coronary artery disease (CAD), coronary artery bypass graft (CABG) surgery, percutaneous transluminal coronary angioplasty (PTCA), congestive heart failure (CHF), and arrhythmias. In the case of acute MI, coronary care units, as presently used, are rather expensive but could be made much more efficient with more effective triage and resource utilization; reperfusion via thrombolysis is cost-effective, as are beta-blockers and angiotensin-converting enzyme (ACE) inhibitors post-MI in appropriate patients. Cost-effectiveness of CAD screening tests depends strongly on the prevalence of disease in the population studied. Cost-effectiveness of CABG surgery depends on targeting; eg, it is highly effective for such conditions as left-main and three-vessel disease but not for lesser disease. PTCA appears to be cost-effective in situations where there is clinical consensus for its use, eg, severe ischemia and one-vessel disease, but requires further analysis based on randomized data; coronary stents also appear to be cost-effective. In preliminary analysis, ACE inhibition for CHF dominates, ie, saves both money and lives. Cardiac transplant appears to be cost-effective but requires further study. For arrhythmias, implantable cardioverter defibrillators are cost-effective, especially the transvenous device, in life-threatening situations; radiofrequency ablation is also cost-effective in patients with Wolff-Parkinson-White syndrome apart from asymptomatic individuals; and pacemakers have not been analyzed except in the case of biofascicular block, where results were variable depending on the situation and preceding tests.",1995.0,0,0 2591,7871285,[Moderate hypercholesterolemia and coronary disease: the MAAS study and the 4S study].,C Martinez; V Legrand; H Kulbertus,,1995.0,0,0 2592,7873090,Antihyperlipidaemic agents. Drug interactions of clinical significance.,J A Farmer; A M Gotto,"The available antihyperlipidaemic drugs are generally safe and effective, and major systemic adverse effects are uncommon. However, because of their complex mechanisms of action, careful monitoring is required to identify and correct potential drug interactions. Bile acid sequestrants are the most difficult of these agents to administer concomitantly, because their nonspecific binding results in decreased bioavailability of a number of other drugs, including thiazide diuretics, digitalis preparations, beta-blockers, coumarin anticoagulants, thyroid hormones, fibric acid derivatives and certain oral antihyperglycaemia agents. Although the incidence is low, nicotinic acid may cause hepatic necrosis and so should not be used with drugs that adversely affect hepatic structure or function. With the HMG-CoA reductase inhibitors, relatively new agents for which clinical data are still being accumulated, the major problems appears to be rhabdomyolysis, associated with the concomitant use of cyclosporin, fibric acid derivatives or erythromycin, and mild, intermittent hepatic abnormalities that may be potentiated by other hepatotoxic drugs. Fibrates also have the potential to cause rhabdomyolysis, although generally only in combination with HMG-CoA reductase inhibitors, and are subject to binding by concomitantly administered bile acid sequestrants. The major interaction involving probucol is a possible additive effect with drugs or clinical conditions that alter the prolongation of the QTc interval, increasing the potential for polymorphic ventricular tachycardia.",2001.0,0,0 2593,7875191,Lack of interaction between ramipril and simvastatin.,B H Meyer; H E Scholtz; F O Müller; H G Luus; N de la Rey; M Seibert-Grafe; H G Eckert; H Metzger,"Twenty two healthy males participated in a randomised, placebo-controlled, double blind, cross-over study to investigate the influence of simvastatin on the pharmacokinetics of ramipril and its active metabolite (ramiprilat), and on the ACE-inhibiting effect of ramiprilat. During two study periods, each of 7 days, subjects received daily either simvastatin 20 mg at 19.00 h or placebo; ramipril (5 mg) was given on Day 5 of each of the periods. Plasma concentrations of ramipril and ramiprilat and ACE-activity were measured in sequential blood specimens, and ramipril and ramiprilat concentrations were measured in urine. Blood and urine collections for pharmacokinetic and pharmacodynamic assessment were made up to 72 h after the dose of ramipril. The mean AUC of ramipril for ramipril+placebo (R+P) and ramipril+simvastatin (R+S) was 22.2 and 21.3 ng.h.ml-1, respectively; for ramiprilat the corresponding figures were 61.3 and 57.6 ng.h.ml-1. The urinary excretion of ramipril+metabolites for (R+P) and (R+S) was 25.2 and 24.1% of dose. The maximum percentage inhibition of ACE-activity for (R+P) was 94.6%, and for (R+S) it was 94.1%. It is concluded that concomitant administration of simvastatin and ramipril has no clinically relevant effect on the pharmacokinetics or ACE-inhibition of the latter drug and its metabolites.",1994.0,0,0 2594,7875999,[Can hyperlipidemia after heart transplantation be optimally and safely treated?].,K Wenke; J Thiery; N Arndtz; D Seidel; B Reichart,"""Is there any safe and optimal treatment of hyperlipidemia following heart transplantation?"" The problem of hypercholesterolemia following heart transplantation if often underestimated. Up to now there is no concept of therapy allowing an optimal adjustment of lipid parameters. Therapeutical trials using ion exchange resins, derivatives of nicotinic acids and fibrates were not successful due to cyclosporine A interaction, hepatotoxicity and limited efficacy of the applied substances. In a prospective, randomized and controlled trial we investigated the effects of the HMG-CoA-reductase inhibitor simvastatin in heart transplant recipients. The study included 70 patients (simvastatin n = 37, control group n = 33). 8 patients died within the first three months following heart transplantation. Purpose of the study was the adjustment of the LDL-cholesterol values in the simvastatin treated group to < or = 110 mg/dl. Following 24 months of treatment a mean LDL-cholesterol plasma level of 110 mg/dl was obtained. The corresponding mean value of the control group was 150 mg/dl. The difference between both groups was significant (p < 0.001). In the same period the mean HDL-cholesterol values increased by approx. 15% in both groups (no significant difference [p > 0.05]). The ratio of LDL/HDL-cholesterol was significant lower in the simvastatin treated group (2.28) than in the control group (2.94) (p < 0.05). There was no significant difference in Lp(a) values. No adverse side effects were observed within the observation period of 24 months, particularly no increase in the frequency of rejection episodes. Summarizing the above, we recommend low-dose simvastatin therapy as a safe and optimal treatment of hypercholesterolemia following heart transplantation.",1994.0,0,0 2595,7877544,Efficacy of pravastatin in combination with captopril in hypertensive patients.,C J O'Callaghan; H Krum; E L Conway; W Lam; M A Skiba; L G Howes; W J Louis,"To determine the efficacy of pravastatin in the treatment of primary hypercholesterolaemia in patients being treated with captopril for hypertension. A double-blind parallel group study comparing 12 weeks of pravastatin therapy (20-40 mg/day) with placebo. 25 patients (age, 37-73 years) with mild-to-moderate hypertension and hypercholesterolaemia (total cholesterol level, 5.5-8.8 mmol/L). Pravastatin reduced total cholesterol levels by 22% (from 7.1 +/- 0.29 [SEM] to 5.5 +/- 0.25 mmol/L; P < 0.001) and low-density-lipoprotein cholesterol levels by 32% (from 5.0 +/- 0.32 to 3.4 +/- 0.28 mmol/L; P < 0.001) in four weeks and these levels were maintained for the 12 weeks of therapy. Pre-pravastatin values returned three weeks after stopping therapy. Levels of total cholesterol, cholesterol fractions and triglycerides remained constant or deteriorated in the placebo group. Pravastatin therapy was well tolerated. An integrated coronary risk score showed a 40% reduction in risk. This study indicates that pravastatin (combined with captopril) is an effective cholesterol-lowering drug, but that treatment needs to be maintained.",1995.0,0,0 2596,7879252,Abnormal lipoprotein (a) and lipid profiles in renal allograft recipients: effects of treatment with pravastatin.,W C Lye; K Hughes; S O Leong; C C Tan; E J Lee,,1995.0,0,0 2597,7882060,[Biochemical and functional study of the liver during treatment of familial hyperlipoproteinemia with Mevacor (lovastatin) and Vasosan S (cholestyramine)].,P Kolesár; K Raslová; O Ulicná; V Kupcová; V Mojto,"The aim of our study was the biochemical and functional examination of the liver during the therapy of familiar hyperlipoproteinemia by means of MevacorR (lovostatine) in comparison with the treatment by Vasosan S (cholestyramine). We examined 20 patients treated with a daily dose of MevacorR being 20-40 mg and, 18 patients treated with a daily dose of Vasosan S being 16-32 g for the period of 12 weeks. During the therapy the total cholesterol, LDL-cholesterol, HDL-cholesterol, triacylglycerols, hepatic enzymes (AST, ALT, ALP) activity, functional test of the liver, biological half-time of antipyrine (t 1/2 antipyrine) were investigated at the onset and at the end of the study. We discovered that at the end of the treatments by MevacorR and Vasosan S the hypolipidemic effect increased (cholesterol p < 0.001, LDL cholesterol p < 0.001), and there was difference in the effect on HDL-cholesterol and in that on triacylglycerols. During the treatment we discovered that due to both medicaments the liver enzymes activity increased to a different extent. At the beginning of the study the antipyrine biological half-time statistically increased in both investigated groups, namely in comparison with the control group. At the end of the treatments in both groups the antipyrine half-time was prolonged, however not significantly. Prior to long-term therapy by hypolipidemics the authors recommend biochemical and functional examination of the liver. (Tab. 4, Fig. 8, Ref. 7.)",1994.0,0,0 2598,7883839,Sustained therapy with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors does not impair steroidogenesis by adrenals and gonads.,D Travia; F Tosi; C Negri; G Faccini; P Moghetti; M Muggeo,"Plasma lipoproteins are a major source of cholesterol for steroid hormone synthesis. 3-Hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitors, which reduce both intracellular cholesterol synthesis and serum cholesterol levels, thus have a potential negative impact on steroidogenesis. In this study, we evaluated basal and maximally stimulated adrenocortical and testicular steroidogenesis in 24 hypercholesterolemic male subjects during 6-36 months of statin treatment. One group was evaluated before treatment and after 6 months of treatment. A second group, which received long term treatment, was evaluated after 24-36 months and then 2 months after treatment had been discontinued. Fourteen subjects were given simvastatin, and 12 were given pravastatin, both at the maximum therapeutic dosage of 40 mg/day. During statin therapy, serum cholesterol was lowered by about 30%. Basal serum and urinary cortisol levels as well as serum cortisol response to ACTH were not influenced by statin therapy. Basal serum testosterone and its response to hCG were also unchanged by statin treatment. In addition, steroid hormone urinary metabolites were strikingly similar when patients were given HMG-CoA reductase inhibitors and when they were not. These results indicate that maximum therapeutic doses of statins have no negative impact on adrenocortical and testicular steroidogenesis even when these glands are maximally stimulated.",1995.0,0,0 2599,7885109,[Statin prevents coronary disease. The 4S study changes the therapeutic practice].,A G Olsson,,1995.0,0,0 2600,7885110,[The 4S study is convincing--without explanation].,A Wennmalm,,1995.0,0,0 2601,7886707,"Stroke incidence, case fatality, and mortality in the WHO MONICA project. World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease.",P Thorvaldsen; K Asplund; K Kuulasmaa; A M Rajakangas; M Schroll,"This report compares stroke incidence, case fatality, and mortality rates during the first years of the WHO MONICA Project in 16 European and 2 Asian populations. In the stroke component of the WHO MONICA Project, stroke registers were established with uniform and standardized rules for case ascertainment and validation of events. A total of 13,597 stroke events were registered from 1985 through 1987 in a total background population of 2.9 million people aged 35 to 64 years. Age-standardized stroke incidence rates per 100,000 varied from 101 to 285 in men and from 47 to 198 in women. The combined stroke attack rates for first and recurrent events were approximately 20% higher than incidence rates in most populations and varied to the same extent. Stroke incidence rates were very high among the population of Finnish men tested. The incidence of stroke was, in general, higher among populations in eastern than in western Europe. It was also relatively high in the Chinese population studied, particularly among women. The case-fatality rates at 28 days varied from 15% to 49% among men and from 18% to 57% among women. In half of the populations studied, there were only minor differences between official stroke mortality rates and rates measured on the basis of fatal events registered and validated for the WHO MONICA stroke study. The WHO MONICA Project provides a unique opportunity to perform cross-sectional and longitudinal comparisons of stroke epidemiology in many populations. The present data show how large differences in stroke incidence and case-fatality rates contribute to the more than threefold differences in stroke mortality rates among populations.",1995.0,0,0 2602,7886711,Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study.,G L Burke; G W Evans; W A Riley; A R Sharrett; G Howard; R W Barnes; W Rosamond; R S Crow; P M Rautaharju; G Heiss,"This study was done to assess the relationship between prevalent cardiovascular disease and arterial wall thickness in middle-aged US adults. The association of preexisting coronary heart disease, cerebrovascular disease, and peripheral vascular disease with carotid and popliteal intimal-medial thickness (IMT) (measured by B-mode ultrasound) was assessed in 13,870 black and white men and women, aged 45 to 64, during the Atherosclerosis Risk in Communities (ARIC) Study baseline examination (1987 through 1989). Prevalent disease was determined according to both participant self-report and measurements at the baseline examination (including electrocardiogram, fasting blood glucose, and medication use). Across four race and gender strata, mean carotid far wall IMT was consistently greater in participants with prevalent clinical cardiovascular disease than in disease-free subjects. Similarly, the prevalence of cardiovascular disease was consistently greater in participants with progressively thicker IMT. The greatest differences in carotid IMT associated with prevalent disease were observed for reported symptomatic peripheral vascular disease (0.09 to 0.22 mm greater IMT in the four race-gender groups). These data document the substantially greater arterial wall thickness observed in middle-aged adults with prevalent cardiovascular disease. Both carotid and popliteal arterial IMT were related to clinically manifest cardiovascular disease affecting distant vascular beds, such as the cerebral, peripheral, and coronary artery vascular beds.",1995.0,0,0 2603,7887382,Effects of pravastatin on cardiovascular reactivity to norepinephrine and angiotensin II in patients with hypercholesterolemia and systemic hypertension.,N E Straznicky; L G Howes; W Lam; W J Louis,"This study was conducted to examine the effects of short-term cholesterol reduction on cardiovascular reactivity in mildly hypertensive patients. Seven male and 7 female patients, aged 34 to 68 years, received pravastatin (40 mg/day) or matched placebo for 3 weeks in a randomized, double-blind, crossover study. Cardiovascular reactivity was assessed by measurement of blood pressure (BP) responses to incremental infusions of angiotensin II and norepinephrine, by cold pressor testing and isometric exercise. Compared with placebo, pravastatin caused significant reductions in plasma total and low-density lipoprotein cholesterol levels, which averaged 20% and 31%, respectively (both p < 0.0001), and in diastolic BP responses (expressed as the infusion rate required to raise BP by 20 mm Hg) to both angiotensin II (7.3 +/- 3.0 vs 9.7 +/- 4.7 ng/kg/min, p = 0.05) and norepinephrine (0.15 +/- 0.13 vs 0.38 +/- 0.33 micrograms/kg/min, p = 0.03). Systolic BP responses were similar with both treatments. Body weight, resting BP, and maximal BP responses to physical stressors were similar with each treatment.",1995.0,0,0 2604,7887403,Comparison of lovastatin and bezafibrate on lipoprotein(a) plasma levels in cardiac transplant recipients.,F Perez-Jimenez; L Hidalgo; J L Zambrana; J M Arizon; J A Jimenez-Pereperez; M Concha; A Espino; J Blanco; F Valles; J Lopez-Miranda,Our results suggest that bezafibrate may be useful in the treatment of high Lp(a) levels in heart transplant patients.,1995.0,0,0 2605,7888259,Cholesterol lowering does have a role in secondary prevention.,D A Wood,,1995.0,0,0 2606,7888289,,,,,0,0 2607,7890014,The effect of probucol and vitamin E treatment on the oxidation of low-density lipoprotein and forearm vascular responses in humans.,I F McDowell; G M Brennan; J McEneny; I S Young; D P Nicholls; G E McVeigh; I Bruce; E R Trimble; G D Johnston,"This study investigates the hypothesis that lipid soluble antioxidants may increase the resistance of low-density lipoprotein (LDL) to oxidation and also enhance vascular endothelial responses in humans. In a double-blind parallel group study, 24 hypercholesterolaemic patients already on treatment with simvastatin (20 mg day-1), were randomized to supplementary treatment with probucol (500 mg bd), vitamin E (400 IU daily) or placebo for 8 weeks. Mean serum cholesterol before antioxidant treatment was 7.00 mmol l-1. Resistance of LDL to oxidation by copper was increased by 830% in the probucol group and by 30% in the vitamin E group. However, thiobarbituric acid reacting substances in whole serum were not altered by either antioxidant. Probucol lowered HDL- and LDL-cholesterol levels and increased the QT interval. Forearm vascular responses, as measured by venous occlusion plethysmography, to acetylcholine, glyceryl trinitrate and NG-monomethyl-L-arginine, were not significantly changed by antioxidant treatment. Probucol has a major, and vitamin E a minor, effect on LDL resistance to oxidation but neither compound appears to alter forearm vascular responses in vivo.",1994.0,0,0 2608,7890015,Inhibition of human vascular smooth muscle cell proliferation by lovastatin: the role of isoprenoid intermediates of cholesterol synthesis.,E Munro; M Patel; P Chan; L Betteridge; G Clunn; K Gallagher; A Hughes; M Schachter; J Wolfe; P Sever,"Restenosis remains the largest single obstacle to the long-term success of invasive vascular interventions. Lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce myointimal hyperplasia in animal models of restenosis and in one clinical coronary restenosis trial. We have assessed the effect of lovastatin on the growth of cultured human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses. Lovastatin (2 microM) inhibited proliferation over 14 days in saphenous vein (and graft stenoses) derived vascular smooth muscle cells by 42% and 32% respectively: this was not significantly different. Lovastatin (10 microM) reduced [methyl 3H]-thymidine uptake by 51% in saphenous vein-derived cells. These concentrations were significantly higher than those achieved in plasma during therapeutic dosage. Lovastatin-induced inhibition of vascular smooth muscle cell proliferation and [methyl 3H]-thymidine uptake was completely reversed by adding mevalonate (100 microM) but cholesterol (10-40 micrograms ml-1) had no effect. Isopentenyl adenine (25-50 microM) did not affect the inhibition of [methyl 3H]-thymidine uptake by lovastatin (10 microM), but farnesol (20 microM), another isoprenoid precursor of cholesterol synthesis, reversed the antiproliferative effect.",1994.0,0,0 2609,7898078,Dose-response of simvastatin in primary hypercholesterolemia.,J Tuomilehto; A C Guimaraes; H Kettner; H Lithell; M Pitkänen; D Sailer; L F Van Gaal,"In an 8-week, placebo-controlled multicenter study, the efficacy of dose levels of simvastatin 2.5, 5, 10, 20, and 40 mg was evaluated in 166 patients with hypercholesterolemia, of whom 163 completed the trial. The entry criteria were serum total cholesterol (TCHOL) between 6.2 and 7.8 mM and low-density lipoprotein (LDL) cholesterol between 4.3 and 50 mM on a standard diet and after the 2-week run-in period of placebo treatment. Mean percentage changes in serum lipids in each simvastatin-treated group from baseline were statistically significant. Of treated patients, 0% (placebo), 11% (2.5 mg), 7% (5 mg), 33% (10 mg), 42% (20 mg) and 55% (40 mg) had at least 40% reduction from baseline LDL cholesterol value. After 8 weeks of treatment, 0% (placebo), 11% (2.5 mg), 25% (5 mg), 26% (10 mg), 31% (20 mg), and 55% (40 mg) of patients treated reached a TCHOL level of < or = 5.2 mM. There was a significant linear dose response with regard to the decrease in LDL cholesterol, TCHOL, and triglycerides (TG) and the increase in high-density lipoprotein (HDL) cholesterol after 8 weeks of therapy. No serious clinical or laboratory adverse events related to simvastatin were observed even at higher doses. At each dose level, simvastatin reduced TCHOL and LDL cholesterol. Doses of simvastatin > or = 5 mg moderately increased HDL cholesterol and reduced serum TG. Simvastatin therapy resulted in major improvement in serum lipoprotein profile, particularly at higher doses.",1994.0,0,0 2610,7898227,Familial Hypercholesterolaemia Regression Study: a randomised trial of low-density-lipoprotein apheresis.,G R Thompson; V M Maher; S Matthews; Y Kitano; C Neuwirth; M B Shortt; G Davies; A Rees; A Mir; R J Prescott,"Low-density-lipoprotein (LDL) apheresis has the theoretical advantage over anion-exchange resins and hydroxymethylglutaryl coenzyme A inhibitors of decreasing lipoprotein(a) as well as LDL. To confirm this advantage, patients with heterozygous familial hypercholesterolaemia and coronary artery disease were randomised to receive LDL apheresis fortnightly (with disposable dextran sulphate/cellulose columns) plus simvastatin 40 mg daily, or colestipol 20 g plus simvastatin 40 mg daily. Quantitative coronary angiography was repeated after a mean of 2.1 years in 20 patients undergoing apheresis and in 19 on combination drug therapy. Changes in serum lipoproteins were similar in both groups apart from greater lowering by apheresis of LDL cholesterol (3.2 vs 3.4 mmol/L in drug group, p = 0.03) and lipoprotein(a) (geometric means 14 vs 21 mg/dL, p = 0.03). There were no significant differences in primary angiographic endpoints per patient but lesion-based and segment-based secondary endpoints were biased in favour of the drug group (change in minimum lumen diameter of lesions 0.07 vs -0.004 mm, p = 0.046; change in mean lumen diameter of segments 0.02 vs -0.06 mm, p = 0.01). None of the angiographic changes correlated with lipoprotein(a) concentrations. Per patient changes in % diameter stenosis and minimum lumen diameter in the two groups were as or more favourable than those observed in five published trials that assessed lipid-lowering drug therapy by quantitative coronary angiography. Although LDL apheresis combined with simvastatin was more effective than colestipol plus simvastatin in reducing LDL cholesterol and lipoprotein(a), it was less beneficial in influencing coronary atherosclerosis and should be reserved for patients unresponsive to drugs. Decreasing lipoprotein(a) seems to be unnecessary if LDL cholesterol is reduced to 3.4 mmol/L or less.",1995.0,0,0 2611,7900667,Reporting of coronary risk factors.,J Abrams,,1995.0,0,0 2612,7902394,Differences in radiation-induced micronuclei yields of human cells: influence of ras gene expression and protein localization.,A C Miller; J Gafner; E P Clark; D Samid,"Expression of ras has been correlated with increased intrinsic resistance to ionizing radiation. In this study we show that increased EJras expression in human cells is associated with a decrease in the frequency of radiation-induced micronuclei. The experimental system consisted of human osteosarcoma-derived cell lines which quantitatively vary in their EJras expression. There was a dose-dependent relationship between radiation dose and micronuclei formation in all cell lines tested. Human osteosarcoma cells, in which the ras level was undetectable, had the highest frequency of micronuclei production at all radiation doses tested. At 4 Gy the most radioresistant cells exhibited a 41.5 +/- 5% decrease in the production of micronuclei concomitant with high ras expression in comparison with the relatively radiosensitive parental cell line. Cells expressing a low amount of EJras demonstrated a 23 +/- 3% decrease in micronuclei induction compared with parental cells. Treatment of cells with lovastatin, an inhibitor of ras-encoded p21ras post-translational processing via the mevalonate pathway, markedly decreased the yield of micronuclei formation in cells transfected with ras; the drug had no effect on radiation-induced micronuclei formation in parental cells. The use of the in vitro micronuclei assay has provided a convenient way to visualize differences in the genotoxic damage induced by ionizing radiation in cells which express different amount of EJras. The results indicate that elevation of ras expression in human cells can lead to a decrease in the number of radiation-induced micronuclei formed and that this relationship is dependent on membrane association of ras-encoded p21.",1993.0,0,0 2613,7911877,"Defined daily doses in relation to hypolipidaemic efficacy of lovastatin, pravastatin, and simvastatin.",D R Illingworth; D W Erkelens; U Keller; G R Thompson; M J Tikkanen,,1994.0,0,0 2614,7915369,Efficacy of low-density-lipoprotein lowering with statins.,S Marshall; P A Meredith; H L Elliott,,1994.0,0,0 2615,7917813,A one-year multicentre study of simvastatin in the treatment of hypercholesterolaemia. UK and Eire Simvastatin Study Group.,,"A 1-year prospective study was conducted in 475 hypercholesterolaemic men and women who received simvastatin monotherapy 10-40 mg daily for 3 months followed by additional lipid-lowering medication after this period, if necessary, to reach a target of plasma cholesterol < 5.3 mmol/l. Of these, 403 subjects completed 1 year of follow-up. By the end of the 3-month monotherapy period, the following percentage mean changes were seen (with 95% confidence intervals): total cholesterol (TC) -31% (-30 to -32%), low-density lipoprotein cholesterol -39% (-38 to -40%), triglycerides -14% (-11 to -17%) and high-density lipoprotein cholesterol +12% (+11 to +14%). These levels were maintained for the remainder of the study. When subjects with a baseline TC of 6.5-7.8 mmol/l were considered (n = 89), 42.7% achieved the target TC levels on simvastatin monotherapy alone. Additional hypolipidaemic medication had no significant impact on plasma lipid and lipoprotein levels. Simvastatin was well tolerated both as monotherapy and in combination.",1994.0,0,0 2616,7923304,A review of clinical trials comparing HMG-CoA reductase inhibitors.,D R Illingworth; J A Tobert,"Four drugs that act as specific inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase--lovastatin, pravastatin, simvastatin, and, most recently, fluvastatin--have been approved by regulatory authorities throughout the world. In the present review, we have critically assessed the comparative hypocholesterolemic effects of these four drugs based on direct comparative studies, which were randomized, double-blind, and included more than 25 patients per treatment group. All studies were conducted in patients with primary hypercholesterolemia and the major end point of efficacy was reduction in the plasma concentrations of low-density lipoprotein (LDL)-cholesterol. Eight comparative trials have evaluated the efficacy and safety of lovastatin, simvastatin, or pravastatin, and one recently completed trial has compared lovastatin and fluvastatin. These trials confirm the log-linear dose response curves for all four of these drugs but indicate that on a milligram-for-milligram basis, lovastatin and pravastatin are approximately equipotent, whereas simvastatin is at least twice as effective per milligram of drug administered as lovastatin and pravastatin. Lovastatin at doses of 20 and 40 mg/d was of similar efficacy to fluvastatin at doses of 40 and 80 mg/d and would suggest that on a milligram-for-milligram basis, fluvastatin is half as potent as lovastatin. The side-effect profiles of all four drugs appeared similar, and earlier reports that suggested a higher incidence of sleep disorders in patients treated with the more lipophilic drugs, lovastatin and simvastatin, as compared with pravastatin, are not supported by more recent, controlled clinical trials. We conclude that although the currently available HMG-CoA reductase inhibitors differ in their relative hypolipidemic effects, as a class they constitute the most effective agents available to maximally reduce elevated concentrations of LDL-cholesterol.",1994.0,0,0 2617,7925476,GTP-blot analysis of small GTP-binding proteins. The C-terminus is involved in renaturation of blotted proteins.,F J Klinz,"Recombinant c-Ha-ras, ralA and rap2, but not rap1A or rap1B proteins retained their ability to bind [alpha-32P]GTP after SDS/PAGE and transfer to nitrocellulose. Recombinant c-Has-ras missing the C-terminal 23 amino acid residues failed to bind [alpha-32P]GTP after the blot, and the ability of recombinant ralA missing the C-terminal 28 amino acid residues to bind [alpha-32P]GTP was decreased many-fold. The presence of nonionic detergents of the polyoxyethylene type such as Tween 20, Triton X-100, Nonidet P40 or Lubrol PX in the incubation buffer was necessary to induce renaturation of blotted recombinant c-Ha-ras protein, whereas other types of detergents were ineffective. We propose that detergents of the polyoxyethylene type induce the refolding of some types of blotted small GTP-binding proteins and that the C-terminus is involved in the refolding process. Membranes from NIH3T3 fibroblasts overexpressing c-Ha-ras protein showed much weaker binding of [alpha-32P]GTP as expected from the level of ras immunoreactivity. Treatment of fibroblasts with lovastatin, an inhibitor of hydroxymethylglutaryl-coenzyme A reductase, caused the accumulation of the unfarnesylated form of c-Ha-ras in the cytosol. Examination of [alpha-32P]GTP-binding and immunoreactivity for cytosolic and membrane-bound c-Ha-ras revealed that binding of [alpha-32P]GTP to unprocessed c-Ha-ras was increased about threefold compared to the same amount of processed c-Ha-ras. Our results demonstrate that detection and quantification of small GTP-binding proteins in eukaryotic cells by GTP-blot analysis is hampered by the fact that these proteins differ strongly in their ability to renature after blotting to nitrocellulose.",1994.0,0,0 2618,7926550,Benign ulcers of the major papilla with gastrointestinal bleeding.,C E Nugent; M J Wiersema; H R Allen; E E Cravens; G A Lehman,,2001.0,0,0 2619,7930373,Effects of long-term simvastatin treatment on testicular and adrenal steroidogenesis in hypercholesterolemic patients.,G P Bernini; G F Argenio; M Gasperi; M S Vivaldi; F Franchi; A Salvetti,"Simvastatin is an inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, the key enzyme in the synthesis of cholesterol, recently introduced in the therapy of hypercholesterolemic patients. Cholesterol is the precursor of the biosynthesis of steroid hormones; thus, a reduction of the availability of cholesterol in the adrenal and testicular cells may reduce the synthesis of corticosteroids and androgens. To establish whether chronic therapy with simvastatin interferes with the integrity of the hypothalamic-pituitary-adrenal axis and with the adrenal and testicular reserve, we administered simvastatin orally in a single-day 10 mg dose for 6 months in 8 mildly hypercholesterolemic male patients. At weeks 0, 6 and 24 of treatment we evaluated the lipids, the activity of the hypothalamic-pituitary-adrenal axis by means of the Corticotropin-Releasing Hormone (CRH) test, the adrenal reserve by means of the Corticotropin rapid test and, finally, the testicular reserve by means of the Human Chorionic Gonadotropin (HCG) test. Total cholesterol and LDL-cholesterol were significantly reduced by Simvastatin, while the HDL-cholesterol and triglycerides did not change significantly. The hormonal responses to CRH, ACTH and HCG tests at weeks 6 and 24 of treatment were comparable to those obtained in basal conditions. We conclude that Simvastatin, while effective in reducing total and LDL-cholesterol in hypercholesterolemic male patients, did not interfere with hypothalamic-pituitary-adrenal axis activity or with basal and stimulated adrenal and testicular steroidogenesis.",1994.0,0,0 2620,7932517,,,,,0,0 2621,7935702,Lack of effect of lovastatin on restenosis after coronary angioplasty. Lovastatin Restenosis Trial Study Group.,W S Weintraub; S J Boccuzzi; J L Klein; A S Kosinski; S B King; R Ivanhoe; J C Cedarholm; M E Stillabower; J D Talley; S J DeMaio,"Experimental and clinical observations suggest that lowering serum lipid levels may reduce the risk of restenosis after coronary angioplasty. We report the results of a prospective, randomized, double-blind trial evaluating whether lowering lipid levels with lovastatin can prevent or delay restenosis after angioplasty. Seven to 10 days before angioplasty, we randomly assigned eligible patients to receive lovastatin (40 mg orally twice daily) or placebo. Patients who underwent successful, complication-free, first-time angioplasty of a native vessel (the index lesion) continued to receive therapy for six months, when a second coronary angiogram was obtained. The primary end point was the extent of restenosis of the index lesion, as assessed by quantitative coronary arteriography. Of 404 patients randomly assigned to study groups, 384 underwent angioplasty; 354 of the procedures were successful, and 321 patients underwent angiographic restudy at six months. At base line, the patients in the lovastatin group (n = 203) and the placebo group (n = 201) were similar with respect to demographic clinical, angiographic, and laboratory characteristics. At base line the mean (+/- SD) degree of stenosis, expressed as a percentage of the diameter of the vessel, was 64 +/- 11 percent in the lovastatin group, as compared with 63 +/- 11 percent in the placebo group (P = 0.22). Despite a 42 percent reduction in the serum level of low-density lipoprotein cholesterol in the lovastatin group, after six months of treatment the amount of stenosis seen in the second angiogram was 46 +/- 20 percent in the placebo group, as compared with 44 +/- 21 percent in the lovastatin group (P = 0.50). Similarly, there were no significant differences in minimal luminal diameter or other measures of restenosis. A trend was noted toward more myocardial infarctions in the lovastatin group, as a result of acute vessel closure or restenosis at the site of angioplasty, but there were no other important differences between the two groups in the frequency of fatal or nonfatal events at six months. Treatment with high-dose lovastatin initiated before coronary angioplasty does not prevent or delay the process of restenosis in the first six months after the procedure.",2001.0,1,1 2622,7937416,How to help diabetic patients avoid amputation. Prevention and management of foot ulcers.,S M Shenaq; M J Klebuc; D Vargo,"Foot ulcers are a weighty complication of diabetes whose significance is often underestimated. They are associated with a high degree of morbidity and mortality, and treatment is laborious and costly. The problem of susceptibility to foot ulceration is best addressed through a prevention program emphasizing patient education, pedal hygiene, regular follow-up visits, and lifestyle modification. Such programs are most efficiently administered by a healthcare team. When ulcers do occur, it is important to take a systematic approach to management, stressing infection control, metabolic stabilization, thorough debridement, and meticulous wound care.",1994.0,0,0 2623,7940820,Effect of pravastatin on renal transplant recipients treated with cyclosporine--4-year follow-up.,N Yoshimura; Y Ohmori; T Tsuji; T Oka,,1994.0,0,0 2624,7940824,Lovastatin treatment of hyperlipidemia in kidney transplant recipients on cyclosporine immunosuppression.,A Kandus; D Kovac; M Koselj; R Kveder; A F Bren,,1994.0,0,0 2625,7940825,Clinical efficacy and pharmacokinetics of HMG-CoA reductase inhibitors in heart transplant patients treated with cyclosporin A.,M B Regazzi; I Iacona; C Campana; A Gavazzi; M Viganò; G Perani,,1994.0,0,0 2626,7942524,Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up.,R H Bradford; C L Shear; A N Chremos; C A Dujovne; F A Franklin; R B Grillo; J Higgins; A Langendorfer; D T Nash; J L Pool,"The Expanded Clinical Evaluation of Lovastatin study, a randomized, double-blind, placebo- and diet-controlled multicenter trial, evaluated the efficacy and tolerability of lovastatin over 48 weeks in 8,245 patients with moderately severe hypercholesterolemia. During year 1 of follow-up of the full cohort, lovastatin at 20 or 40 mg/day, or 20 or 40 mg twice daily, produced dose-dependent decreases in low-density lipoprotein (LDL) cholesterol (24% to 40%) and triglyceride levels (10% to 19%), and increases in high-density lipoprotein (HDL) cholesterol (6.6% to 9.5%). In all, 977 patients continued their original blinded treatment for an additional year. In year 2, the LDL cholesterol response to lovastatin was maintained, the triglyceride reductions were somewhat less, and the increases in HDL cholesterol were moderately greater than in year 1. Successive transaminase elevations > 3 times the upper limit of normal were observed in only 1 patient in year 2, yielding a cumulative 2-year incidence of from 0.1% (placebo or lovastatin 20 mg/day) to 1.9% (lovastatin 80 mg/day). Myopathy occurred in only 1 patient during year 2, and over the 2-year study was observed rarely and only at lovastatin dosages of 40 and 80 mg/day. This study indicates that lovastatin maintains its efficacy over long-term follow-up, particularly in effectively lowering LDL cholesterol, is generally well tolerated, and has a favorable safety profile.",1994.0,1,1 2627,7942538,Effects of lovastatin therapy on plasminogen activator inhibitor-1 antigen levels.,J L Isaacsohn; J F Setaro; C Nicholas; J A Davey; L J Diotalevi; D S Christianson; E Liskov; E A Stein; H R Black,,1994.0,0,0 2628,7942548,Comparison of the effectiveness of lovastatin therapy for hypercholesterolemia after heart transplantation between patients with and without pretransplant atherosclerotic coronary artery disease.,M Anguita; L Alonso-Pulpón; J M Arizón; M A Cavero; F Vallés; J Segovia; F Pérez-Jiménez; M Crespo; M Concha,"With the aim of assessing the effectiveness and safety of lovastatin in patients with hypercholesterolemia after heart transplantation, as well as the potential differences in the lipid-lowering effect of lovastatin between patients with or without pretransplant coronary artery disease (CAD), we studied 63 heart transplant patients who had serum total cholesterol > 250 mg/dl in spite of dietary therapy. Mean age of subjects was 47 +/- 2 years. Triple-drug immunosuppressive therapy consisted of cyclosporine, azathioprine, and steroids. Thirty-nine patients (62%) had pretransplant CAD and 24 (38%) did not. Pretreatment serum lipid levels were: total cholesterol, 302 +/- 32 mg/dl; low-density lipoprotein (LDL) cholesterol, 201 +/- 35 mg/dl; high-density lipoprotein (HDL) cholesterol, 60 +/- 19 mg/dl; triglycerides, 205 +/- 86 mg/dl; and total/HDL cholesterol ratio, 5.4 +/- 1.6. Patients received 10 to 40 mg/day of lovastatin (mean dose 17 +/- 6) for 13 +/- 4 months. There were no serious adverse events. At 3 months, lovastatin decreased total cholesterol by 15% (p < 0.001), LDL cholesterol by 21% (p < 0.001), triglycerides by 17% (p < 0.05), and total/HDL cholesterol ratio by 17% (p < 0.001), and increased HDL cholesterol by 3% (NS). Although lovastatin was effective in both patients with pretransplant CAD and non-CAD, analysis of its effect in each subgroup (CAD and non-CAD) revealed that its lipid-lowering effect was higher for non-CAD patients (-20% vs -12% for total cholesterol, and -27% vs -17% for LDL cholesterol, both p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2629,7951551,Adrenal autotransplantation after total adrenalectomy: delayed determined function.,G Erdogan; S Kologlu; N Kamel; N Baskal; V Cesur; S Eraslan,"Adrenal autotransplantation after bilateral total adrenalectomy has been utilized to eliminate the need for replacement therapy and to prevent the late occurrence of Nelson's syndrome in some patients with Cushing's disease. It is possible to follow these cases up closely today, owing to the highly developed hormonal evaluation and imaging techniques. In this study, two patients who underwent bilateral total adrenalectomy and cortex autotransplantation are presented. The autografts were found functional and the patients had not required any steroid replacement therapy.",1994.0,0,0 2630,7952912,Postprandial lipid metabolism.,J S Cohn,"Several studies have shown that patients with coronary artery disease have an elevated plasma triglyceride response to a fat-rich meal. Recent evidence suggests that postprandial triglyceridemia is in fact an independent predictor of coronary and carotid atherosclerosis. In order to further characterize postprandial lipid metabolism, recently published studies have investigated the role of liver-derived lipoproteins in determining the magnitude of postprandial triglyceridemia, and have further defined the effect of glucose intolerance and lipid-lowering drugs on postprandial plasma lipoprotein parameters.",1994.0,0,0 2631,7954413,Screening of potential chemopreventive agents using biochemical markers of carcinogenesis.,S Sharma; J D Stutzman; G J Kelloff; V E Steele,"Ninety potential chemopreventive agents were screened using 6 chemoprevention-associated biochemical end points. These compounds were tested using rodent (tracheal epithelial or liver) cells and human cells [neonatal foreskin fibroblasts, bronchial epithelial cells, or human leukemic cells (HL-60)]. The effects measured were: (a) inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tyrosine kinase activity in HL-60 cells; (b) inhibition of TPA-induced ornithine decarboxylase (ODC) activity in rat tracheal epithelial cells; (c) inhibition of poly(ADP-ribose)polymerase in propane sultone-treated primary human fibroblasts; (d) inhibition of benzo[a]pyrene(B[a]P)-DNA binding in human bronchial epithelial cells; (e) induction of reduced glutathione in Buffalo rat liver cells; and (f) inhibition of TPA-induced free radical formation in primary human fibroblasts or HL-60 cells. Fifty compounds were highly effective in inhibiting TPA-induced tyrosine kinase activity. This assay identified compounds from a wide variety of chemical classes as effective inhibitors, including all the vitamins, retinoic acid analogues, protein kinase C inhibitors, and chemicals belonging to the amino acid category. Fifty-two chemicals were classified as highly positive compounds when examined for their ability to inhibit TPA-induced ODC activity. These agents showed a dose-dependent inhibition or inhibition at all doses. Retinoids, in general, exhibited strong inhibition of ODC activity. A category of compounds showing dose-dependent inhibition were the sulfur compounds, especially the thiols and thiones. Among the natural products, terpenes were strong inhibitors of ODC. Forty-seven compounds were classified as strong inhibitors of poly(ADP-ribose)polymerase. In the carcinogen-DNA binding inhibition assay, 21 compounds were identified as strong inhibitors, which include phenolic compounds as well as sulfur compounds. Vitamins and their analogues were also good inhibitors. Testing for induced glutathione yielded 19 compounds that were good inducers. Sulfur-containing compounds and most of the phenolic compounds were also inducers of glutathione. Twenty compounds were highly positive for inhibition of TPA-induced free radical formation. A significant number of phenolic and sulfur compounds were again strong oxygen radical scavengers. Some antiinflammatory agents were also identified as free radical inhibitors. In general, retinoids were quite active in all the assays. Eight compounds were positive in all of the six assays; these were vitamin C (ascorbic acid), bismuththiol, esculetin, etoperidone, folic acid, hydrocortisone, indole-3-carbinol, and tocopherol succinate. Agents that were positive in these assays may inhibit the carcinogenesis process by similar mechanisms in humans and are identified as candidates for development as chemopreventive agents.(ABSTRACT TRUNCATED AT 400 WORDS)",1994.0,0,0 2632,7955780,Clinical pharmacokinetics of pravastatin.,J A Quion; P H Jones,"The hypolipidaemic agent pravastatin differs from other US Food and Drug Administration (FDA)-approved HMG-CoA reductase inhibitors (e.g. lovastatin and simvastatin) because it has greater hydrophilicity, as a result of the hydroxyl group attached to its decalin ring. The hydrophilic nature of pravastatin accounts for its minimal penetration into the intracellular space of nonhepatic tissues, including an apparent inability to cross the blood-brain barrier. The drug is also well tolerated because it is rapidly absorbed and excreted, and does not accumulate in plasma even with repeated administration. Pravastatin is taken up into the liver by an active transport carrier system, and the hepatic extraction ratio is high (0.66). The drug and its metabolites are cleared through both hepatic and renal routes (53 and 47%, respectively). The dual route of elimination reduces the need for dosage adjustment if the function of either of these organs is impaired. Dosage adjustments are also not required on the basis of age or gender. Furthermore, the drug can be given without regard to food intake, an important consideration for compliance since lipid-lowering therapy is generally required long term. The drug is approximately 50% protein bound, and, therefore, compared with other members of its class the tendency for displacement of highly protein bound drugs such as warfarin is decreased. This minimal potential for drug-drug interactions is important for patients who are taking multiple drugs because of concomitant medical problems. However, as with any HMG-CoA reductase inhibitor, caution should be exercised when pravastatin is given with nicotinic acid (niacin), gemfibrozil or cyclosporin, because of increased risk for myopathy in patients receiving combination therapy.",1994.0,0,0 2633,7957515,,,,,0,0 2634,7957541,Fluvastatin efficacy and tolerability in comparison and in combination with cholestyramine.,E Hagen; H Istad; L Ose; E Bodd; H M Eriksen; V Selvig; J M Bard; J C Fruchart; M Borge; M C Wolf,"The aim of this study was to investigate the new synthetic HMG-CoA reductase inhibitor, fluvastatin, for efficacy, safety and tolerability in comparison to cholestyramine. One hundred fifty one primary hypercholesterolaemic patients participated in this double-blind, parallel-group, randomized study. During the first 12 weeks of the study, fluvastatin (20 mg and 40 mg daily) was compared with cholestyramine (16 g per day). In the subsequent, 6-week part of the study, the comparative efficacy, safety and tolerability of 20 mg fluvastatin, combined with cholestyramine (4 g, 8 g, or 16 g) were assessed. Fluvastatin (40 mg) reduced LDL cholesterol by 28.0%, triglycerides by 10.5% and increased HDL cholesterol by 3.7%. Cholestyramine (16 g) reduced LDL cholesterol by 35.0%, but raised triglycerides and HDL cholesterol by 12.3% (p < 0.01) and 3.7% respectively. The combination of fluvastatin 20 mg and cholestyramine (4 g, 8 g and 16 g) induced the following reductions in LDL cholesterol: 30.4%, 35.6% and 46.6% respectively. There was no significant change in triglycerides in either group although HDL cholesterol was raised by 4.9%, 8.3% and 7.2% respectively. One patient treated with fluvastatin and two treated with cholestyramine were withdrawn from the study due to elevation of liver transaminases. The most frequent subjective adverse effects in both treatment groups were mild, transient gastrointestinal complaints. Thus, fluvastatin was effective as a lipid-lowering agent; the effect was further enhanced when fluvastatin was combined with cholestyramine.",1994.0,0,0 2635,7964434,Risk factors for carotid and femoral atherosclerosis in hypercholesterolaemic men.,J T Salonen; R Salonen,,1994.0,0,0 2636,7964545,Fibrinogen: a new major risk factor for cardiovascular disease. A review of the literature.,G de la Serna,"During the last decade, several epidemiological studies have reliably demonstrated that plasma fibrinogen is a strong and independent risk factor for cardiovascular disease that is at least as important as more traditional risk factors for the disease. The deleterious effects of this protein seem to be mediated through its role in hemorrheology, hemostasis, and the atherogenic process itself. According to prospective epidemiological studies, the risk of developing a cardiovascular event such as ischemic heart disease or stroke is 1.8 to 4.1 times higher in subjects with fibrinogen levels in the top third than in those with levels in the lower third. Epidemiological studies, clinical trials, pathophysiology, and therapeutical possibilities are reviewed in this paper.",1994.0,0,0 2637,7964884,"Treatment of cerebrotendinous xanthomatosis: effects of chenodeoxycholic acid, pravastatin, and combined use.",M Kuriyama; Y Tokimura; J Fujiyama; Y Utatsu; M Osame,"Treatments by oral administration of chenodeoxycholic acid (CDCA) alone, 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitor (pravastatin) alone, and combination of the two drugs were attempted for 7 patients with cerebrotendinous xanthomatosis (CTX). CDCA treatment at a dose of 300 mg/day reduced serum cholestanol (67.3% reduction), lathosterol (50.8%), campesterol (61.7%) and sitosterol (12.7%). However, the sera of the patients changed to be ""atherogenic""; total cholesterol, triglyceride and low-density lipoprotein (LDL)-cholesterol were increased, while high-density lipoprotein (HDL)-cholesterol was decreased. Contrarily, pravastatin at a dose of 10 mg/day improved the sera of the patients to be markedly ""anti-atherogenic"", but the reductions of cholestanol (30.4%), lathosterol (44.0%), campesterol (22.9%) and sitosterol (9.6%) were inadequate. Combined treatment with CDCA and pravastatin showed good overlapping of the effects of each drug alone. The sera of the patients were apparently more ""anti-atherogenic"" than those after CDCA treatment. Serum cholestanol concentration was still 2.7 times higher than in controls, but the serum lathosterol level was within the normal range, indicating that the enhancement of overall cholesterol synthesis in the patients was sufficiently suppressed. Plant sterol levels were also within the normal range. The combination of CDCA and pravastatin was a good treatment for CTX, based on the improvement of serum lipoprotein metabolism, the suppression of cholesterol synthesis, and reductions of cholestanol and plant sterol levels. In all of 7 patients, the progression of disease was arrested, but dramatic effects on clinical manifestations, xanthoma, and electrophysiological findings could not be found after the treatment of these drugs.",1994.0,0,0 2638,7966875,Proof arrives: antilipids save lives.,M F Goldsmith,,1994.0,0,0 2639,7968073,Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S),,"Drug therapy for hypercholesterolaemia has remained controversial mainly because of insufficient clinical trial evidence for improved survival. The present trial was designed to evaluate the effect of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease (CHD). 4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol 5.5-8.0 mmol/L on a lipid-lowering diet were randomised to double-blind treatment with simvastatin or placebo. Over the 5.4 years median follow-up period, simvastatin produced mean changes in total cholesterol, low-density-lipoprotein cholesterol, and high-density-lipoprotein cholesterol of -25%, -35%, and +8%, respectively, with few adverse effects. 256 patients (12%) in the placebo group died, compared with 182 (8%) in the simvastatin group. The relative risk of death in the simvastatin group was 0.70 (95% CI 0.58-0.85, p = 0.0003). The 6-year probabilities of survival in the placebo and simvastatin groups were 87.6% and 91.3%, respectively. There were 189 coronary deaths in the placebo group and 111 in the simvastatin group (relative risk 0.58, 95% CI 0.46-0.73), while noncardiovascular causes accounted for 49 and 46 deaths, respectively. 622 patients (28%) in the placebo group and 431 (19%) in the simvastatin group had one or more major coronary events. The relative risk was 0.66 (95% CI 0.59-0.75, p < 0.00001), and the respective probabilities of escaping such events were 70.5% and 79.6%. This risk was also significantly reduced in subgroups consisting of women and patients of both sexes aged 60 or more. Other benefits of treatment included a 37% reduction (p < 0.00001) in the risk of undergoing myocardial revascularisation procedures. This study shows that long-term treatment with simvastatin is safe and improves survival in CHD patients.",1994.0,1,1 2640,7977011,Lipid-lowering trials: results and limitations.,C D Furberg,"Because the accumulation of lipids is central to the development and progression of coronary atherosclerosis, interventions (drugs, diet, or surgery) designed to reduce serum cholesterol levels have been tested in a large number of clinical trials, which began in the early 1960s. Data from such trials are now available on more than 45,000 participants, most of whom were men. Nevertheless, debate continues regarding the benefits of lipid-lowering therapy, to a large extent because of methodologic limitations that characterized most trials. Despite their limitations, however, the combined data from these trials demonstrate a reduction in incidence of coronary heart disease after a lag time of 2 or more years. This article reviews combined results of lipid-lowering trials based on published and nonpublished meta-analyses.",1994.0,0,0 2641,7979841,"Efficacy and safety of once-daily vs twice-daily dosing with fluvastatin, a synthetic reductase inhibitor, in primary hypercholesterolemia.",W Insull; D Black; C Dujovne; J D Hosking; D Hunninghake; L Keilson; R Knopp; J McKenney; E Stein; A J Troendle,"Fluvastatin sodium is a new, entirely synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor that may be an effective lipid-lowering agent in patients whose hyperlipidemia does not respond to dietary therapy. We conducted a study to evaluate the effects of fluvastatin on lipoprotein levels in subjects with primary hypercholesterolemia and to compare the efficacy and safety of two fluvastatin sodium dosing regimens: 20 mg once daily vs 10 mg twice daily. We conducted a double-blind, placebo-controlled, multicenter trial involving 207 patients with low-density lipoprotein cholesterol levels of 4.15 mmol/L (160 mg/dL) or higher despite dietary intervention and with triglyceride levels of 3.38 mmol/L or lower. Three parallel treatment groups received 6 weeks of treatment with 20 mg of fluvastatin sodium once daily, 10 mg of fluvastatin sodium twice daily, or a placebo. Total cholesterol and low-density lipoprotein cholesterol levels were reduced from baseline by 16% and 22%, respectively, with 20 mg of fluvastatin sodium once daily (P < .001) and by 17% and 23%, respectively, with 10 mg of fluvastatin sodium twice daily (P < .001). Fluvastatin was well tolerated, and there were no serious clinical or biochemical adverse events ascribable to the drug. Fluvastatin therapy demonstrated excellent short-term safety and efficacy in reducing total and low-density lipoprotein cholesterol levels in patients with primary hypercholesterolemia. Fluvastatin sodium, the first totally synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor to be used in clinical trials, appears to be both effective and well tolerated at 20 mg/d, given in either a single or divided dose.",2001.0,0,0 2642,7986302,Efficacy and safety of fluvastatin in hyperlipidaemic patients with non-insulin-dependent diabetes mellitus.,L A Jokubaitis; R H Knopp; J Frohlich,"In this preliminary report of a 20-week trial, 66 patients with non-insulin-dependent diabetes mellitus (NIDDM) and hyperlipidaemia who remained eligible after an 8-week dietary stabilization phase were randomly allocated to receive 20 mg of fluvastatin or placebo once daily for 6 weeks. Fluvastatin was subsequently increased to 20 mg twice daily and administered according to the same schedule, versus placebo, for a further 6 weeks. Both dosages of fluvastatin substantially improved serum lipid profiles compared with baseline and placebo. Both dosages of fluvastatin significantly reduced low-density- and very-low-density-lipoprotein (LDL, VLDL), cholesterol and triglyceride (TG) compared with placebo, and both dosages significantly elevated high-density-lipoprotein (HDL) cholesterol. The ratio of LDL to HDL was also significantly decreased. Amongst the 58 patients who completed the study, there was no evidence either of myopathy or of hepatotoxicity; mean creatine kinase values remained stable in the fluvastatin arm. Fasting glucose, glycosylated haemoglobin, and fructosamine levels were not markedly affected by active treatment. No serious adverse events attributable to the drug were reported. In conclusion, both dosages of fluvastatin appear to be effective and safe in the management of hyperlipidaemia in this outpatient, maturity-onset, diabetic population.",1994.0,0,0 2643,7986315,"Effect of fluvastatin on plasma apolipoprotein-B-containing particles, including lipoprotein(a). European Fluvastatin Study Group.",J Dallongeville; J C Fruchart; P Pfister; J M Bard,"Epidemiological studies have demonstrated an association between apolipoprotein-(apo)-B containing particles [lipoprotein (Lp) (a), LpE:B; LpC-III:B] and coronary heart disease (CHD). The effect of fluvastatin, a novel competitive inhibitor of HMG-CoA reductase, on these plasma lipoprotein levels was studied in patients with hypercholesterolaemia after 14 weeks of standard dietary therapy. The results of a placebo-controlled, dose-response study and of the combined data of the European double-blind, controlled studies on the effect of fluvastatin are presented. The patients were selected according to the following criteria of inclusion: plasma low-density-lipoprotein (LDL) cholesterol levels > 160 mg dL-1 and premature CHD and/or two associated risk factors, or LDL cholesterol > 190 mg dL-1 and no CHD, plus triglycerides < 300 mg dL-1. All measurements were performed at the Pasteur Institute Central Laboratory. Lp(a), LpE:B and LpC-III:B particles were measured by double-site ELISA. In the placebo-controlled, dose-response study, 429 subjects were randomly assigned to one of the following treatment groups: placebo, fluvastatin 2.5 mg q.p.m., 5 mg q.p.m., 10 mg q.p.m. and 20 mg q.p.m. Treatment with fluvastatin for 6 weeks was associated with a dose-dependent reduction of LDL cholesterol, apoB, LpE:B and LpCIII:B levels. In addition, treatment with fluvastatin 5 mg and 20 mg q.p.m. was associated with a significant reduction in median Lp(a) concentrations (3.2%, P < 0.05 and 6.4%, P < 0.05 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2644,7987882,Comparative efficacy and tolerability of 5 and 10 mg simvastatin and 10 mg pravastatin in moderate primary hypercholesterolemia. Simvastatin Pravastatin European Study Group.,E Steinhagen-Thiessen,"Simvastatin and pravastatin, two 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, were compared in a multinational, randomized, double-blind trial. Patients demonstrating moderate hypercholesterolemia after 10 weeks on a lipid-lowering diet received 6 weeks of treatment with 5 mg/day simvastatin (n = 143) or 10 mg/day pravastatin (n = 138); the simvastatin dose was increased to 10 mg for an additional 6 weeks while the pravastatin dose remained at 10 mg. When administered at lower or equivalent daily doses, simvastatin was significantly more effective than pravastatin in reducing total and low-density lipoprotein (LDL) cholesterol. Reductions in plasma total and LDL cholesterol were significantly greater with 5 mg simvastatin (16 and 23%) compared to 10 mg pravastatin (12 and 18%; p < or = 0.01). The efficacy of 10 mg simvastatin in lowering these lipid parameters was also superior (19 vs. 11% and 27 vs. 17%, respectively; p < or = 0.01). At 6 and 12 weeks, a significantly higher percentage of simvastatin patients (45 and 59%, respectively) achieved a desirable LDL cholesterol level of < 130 mg/dl (< 3.4 mmol/l) compared to pravastatin patients (32-33%; p < or = 0.05). Both drugs were well tolerated and had comparable safety profiles.",1994.0,1,1 2645,7989870,"Effects of lovastatin and chenodiol on bile acid synthesis, bile lipid composition, and biliary lipid secretion in healthy human subjects.",D S Hanson; W C Duane,"To assess the relationship between cholesterol synthesis and feedback inhibition of bile acid synthesis, we studied seven normal human subjects taking three different doses of chenodiol, 0, 5, and 15 mg/kg per day: once while taking no lovastatin and again while taking lovastatin 80 mg/day. Lovastatin and both doses of chenodiol significantly lowered bile acid synthesis measured by the 14CO2 method, but there was no significant interaction between the perturbations. Both also lowered cholesterol saturation index of gallbladder bile without appreciable interaction, and the combination was distinctly more effective than either medication alone. Lovastatin and low-dose chenodiol both lowered biliary cholesterol secretion without affecting bile acid secretion. Increasing the dose of chenodiol did not further lower cholesterol secretion, but did further reduce saturation index because of an increase in secretion of bile acid and phospholipid. These studies indicate that there is no interaction between cholesterol synthesis and feedback return of bile acid in the enterohepatic circulation with respect to either bile acid synthesis or biliary lipid secretion; that the combination of chenodiol and lovastatin is better than either alone for improving biliary cholesterol saturation; and that the mechanism by which chenodiol lowers cholesterol saturation is dose-dependent.",1994.0,0,0 2646,7991041,"Low-dose simvastatin is a well-tolerated and efficacious cholesterol-lowering agent in ciclosporin-treated kidney transplant recipients: double-blind, randomized, placebo-controlled study in 40 patients.",M Arnadottir; L O Eriksson; J I Germershausen; H Thysell,"The high prevalence of hypercholesterolemia in kidney transplant recipients probably contributes to the high cardiovascular mortality in these patients. Except for diet, there is no generally recommended cholesterol-lowering treatment. We conducted a double-blind, randomized, placebo-controlled study with low-dose simvastatin in 40 ciclosporin (CS)-treated kidney transplant recipients during 16 weeks, focusing on side effects and dose finding. In the simvastatin group, the mean serum total and LDL cholesterol concentrations decreased by 23 and 33%, respectively, and the mean serum HDL cholesterol concentration increased by 12%, after 4 weeks of treatment with simvastatin 10 mg daily. Increasing the dose to 20 mg daily in a few patients only resulted in marginal further reductions of the serum cholesterol concentrations at the expense of doubling the plasma simvastatin 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitory activity concentrations. The differences between the changes in the serum cholesterol concentrations in the simvastatin group and the negligible changes in the placebo group were statistically significant. There was no case of proximal myopathy and the serum creatine kinase concentrations did not differ between treatment groups. In conclusion, low-dose simvastatin appears to be a well tolerated and efficacious cholesterol-lowering treatment in CS-treated kidney transplant recipients. Simvastatin 10 mg daily seems to be the most suitable dose for the majority of these patients.",1994.0,0,1 2647,7992293,"[A comparison between lovastatin and pravastatin--effects on lipids, sleep and quality of life in primary hyperlipidemia].",S Tonstad; C Gørbitz; L Ose; U F Malt,"The efficacy and safety of treatment with recommended doses of lovastatin (20, 40 and 80 mg/day) and pravastatin (10, 20 and 40 mg/day) were compared in 48 men and women with primary hyperlipidemia and LDL-cholesterol > or = 4.1 mmol/l following dietary intervention. Each dose was taken for six weeks in this double-blind, parallel, randomized study. Lovastatin was found to reduce LDL-cholesterol by 22-37% and pravastatin by 18-26%. HDL-cholesterol levels increased and triglyceride levels decreased to the same extent in both groups. The number of patients who reported adverse events in the course of the study was small. No clinically significant changes occurred in laboratory tests, nor in sleep scores obtained from a standardized questionnaire. Neither drug had any effect on the responses to a quality of life screening questionnaire, nor were any significant changes in depressive symptoms seen during the 18 weeks of treatment.",1994.0,0,0 2648,7997016,Scandinavian simvastatin study (4S),E Manzato,,1994.0,0,0 2649,8001298,Dyslipidemia and coronary artery disease.,P T Kuo,"Genetically determined and metabolically induced disturbances in lipid metabolism, as manifested in several types of dyslipidemia, have been shown to be causally related to the development of coronary artery disease (CAD). A diversity of clinical and angiographic studies has been made to evaluate the linkage between plasma lipid-control therapy in the development of initial and recurrent cardiovascular events. The plan of treatment invariably begins with a low-fat, low-cholesterol diet before initiation of drug therapy. However, many patients have difficulty in adhering to the low-fat diet. Fortunately, metabolic studies show that foods which contain fats rich in stearic (saturated) and oleic (monounsaturated) fatty acids may be given in limited amounts to boost patients' compliance to a low-fat diet and to prevent their blood lipids from rising to abnormal levels. A bile acid sequestrant (cholestyramine or colestipol) is the first-line drug for control of hypercholesterolemia. Either gemfibrozil or gemfibrozil plus niacin is prescribed to raise high-density lipoprotein (HDL) levels of CAD patients. Approval of two HMG CoA reductase inhibitors, pravastatin and simvastatin, by the FDA gives physicians the additional flexibility of employing a single or a combination drug therapy for optimal control of dyslipidemia. The association of low serum cholesterol level (< 160 mg/dl) with increase in noncardiac mortality has prompted health professionals to consider modifying the universal screening and treatment of serum cholesterol in children and young women and to use hypolipidemic drugs in patients judiciously.",1994.0,0,0 2650,8001304,A multinational study of the effects of low-dose pravastatin in patients with non-insulin-dependent diabetes mellitus and hypercholesterolemia. Pravastatin Multinational Study Group for Diabetes.,B D Behounek; M E McGovern; K B Kassler-Taub; J S Markowitz; M Bergman,"This multinational, 16-week, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of low-dose pravastatin in 325 patients with non-insulin-dependent diabetes mellitus (NIDDM) and hypercholesterolemia [serum total cholesterol concentrations of 5.2-7.8 mmol/l (200 to 300 mg/dl)]. Patients were randomized to receive pravastatin 10 mg or matching placebo with doubling of the dose after 8 weeks if predefined target levels for total cholesterol [(i.e., < 5.2 mmol/l (200 mg/dl) or > 15% decrease from baseline] had not been achieved. At Week 16, pravastatin-treated patients showed a 21.4% decrease in serum low-density lipoprotein cholesterol (LDL-C) and a 13.5% reduction in serum total cholesterol (TC) concentrations (p < 0.001 compared with placebo). Levels of triglycerides (TG) were reduced 9.6% during pravastatin treatment (p < 0.05 compared with placebo) while high-density lipoprotein cholesterol (HDL-C) levels were increased 4.4% (p = NS). Adverse events and laboratory test abnormalities were similar among patients treated with pravastatin or placebo. Glycosylated hemoglobin (HbA1C) levels remained unchanged. The results of this study demonstrate that low-dose pravastatin is effective and well tolerated for lowering elevated cholesterol concentrations during short-term treatment of patients with NIDDM and hypercholesterolemia.",1994.0,0,0 2651,8002861,Dyslipidaemia in non-insulin dependent diabetes: the need for a clinical intervention trial.,T A Welborn,,1994.0,0,0 2652,8005129,,,,,0,0 2653,8007738,ACAT inhibitors as antiatherosclerotic agents: compounds and mechanisms.,K Matsuda,"Atherosclerosis is a major death cause in western industrialized countries. A diagnosing system, medical prevention, and treatment of atherosclerosis is not sufficient so far. A direct acting antiatherosclerotic agent is eagerly waited. ACAT inhibitor approach could provide such an agent. In the formation of atherosclerosis, cholesteryl esters, which are the lipids which accumulate in atheromatous plaques by an aid of macrophages and smooth muscle cells, forming foam cells, may play an important role. ACAT enzyme is responsible for the acylation of cholesterol to cholesteryl esters, a transformation which can be essential in not only cholesteryl esters accumulation at arterial walls but also the absorption of cholesterol in the intestine and the excretion of cholesterol in the liver. From these points, ACAT inhibitors might work against atherosclerosis in three different ways: first, cholesteryl ester accumulation inhibition at arterial walls could be a direct antiatherosclerotic effect; second, cholesterol absorption inhibition at the intestine; and third, cholesterol excretion acceleration at the liver, while the later two effects would result in a reduction of blood cholesterol level--a major risk factor of atherosclerosis. Taking account of this discussion, the ACAT inhibitors would be potent antiatherosclerotic agents. Medicinal research has been contributing full strength to produce an ultimate compound. These efforts should provide a drug which will be useful to patients.",1994.0,0,0 2654,8014585,Effects of lovastatin and dietary cholesterol on bile acid kinetics and bile lipid composition in healthy male subjects.,W C Duane,"We measured bile acid kinetics and bile lipids in 12 human subjects on a metabolic ward in four randomly allocated, 6-7 week periods: 1) lovastatin (40 mg b.i.d) + low cholesterol diet (mean 246 mg/day); 2) lovastatin+high cholesterol diet (mean 1071 mg/day); 3) low cholesterol diet alone; and 4) high cholesterol diet alone. Lovastatin did not significantly alter fractional turnover, synthesis, absorption, enterohepatic cycling, or pool sizes of bile acid measured by the Lindstedt method. The high cholesterol diet increased fractional turnover and synthesis rate of cholic acid, but not chenodeoxycholic acid, without altering pool size of either bile acid. The high cholesterol diet decreased bile acid absorption, but only during lovastatin treatment, suggesting the possibility of a ""cholestyramine-like"" effect of dietary cholesterol, appreciable at least when biliary cholesterol secretion is reduced by lovastatin. As in previous studies, lovastatin markedly lowered saturation index of gallbladder bile. Increased cholesterol consumption did not significantly alter cholesterol saturation index, suggesting that dietary cholesterol may not be a major factor in cholesterol gallstone pathogenesis.",1994.0,0,0 2655,8017448,Efficacy and safety of pravastatin in the long-term treatment of elderly patients with hypercholesterolemia.,J T Santinga; H S Rosman; M Rubenfire; J J Maciejko; L Kobylak; M E McGovern; B D Behounek,"Elevated cholesterol levels are a major risk factor for coronary heart disease, which remains a significant problem in patients beyond age 65 years. Because drug therapy for the control of hypercholesterolemia in elderly patients is frequently considered to be indicated, we investigated the efficacy and safety of pravastatin in the treatment of elderly subjects with primary hypercholesterolemia. In this 96-week, multicenter, double-blind, placebo-controlled study, 142 subjects (95 women, 47 men) 64 to 90 years of age with elevated cholesterol levels despite dietary intervention were randomized to receive pravastatin 20 mg at bedtime or matching placebo (2:1). Dosage could be doubled after 8 weeks, a bile acid-binding resin could be added after 16 weeks, and nicotinic acid or probucol could be added after 32 weeks, as needed, to adequately lower the low-density lipoprotein cholesterol (LDL-C) levels. Significant reductions in the levels of LDL-C (-30.9%), total cholesterol (Total-C; -21.9%), and triglycerides (TG; -16.7%) and significant increases in the levels of high-density lipoprotein cholesterol (HDL-C; 11.3%) were noted in the group receiving pravastatin treatment at 16 weeks (P < or = 0.001 compared with baseline, P < or = 0.01 compared with placebo). The cholesterol-lowering effects of pravastatin were sustained throughout the 96 weeks of the trial. Pravastatin was well tolerated, with an overall incidence of adverse events nearly identical to that of placebo. In this study, pravastatin was well tolerated and effective in lowering LDL-C, Total-C, and TG and in raising HDL-C during long-term treatment of elderly patients with primary hypercholesterolemia.",1994.0,0,0 2656,8023779,Fluvastatin with and without niacin for hypercholesterolemia.,T A Jacobson; M M Chin; G J Fromell; L A Jokubaitis; L F Amorosa,"Seventy-four patients with plasma low-density lipoprotein cholesterol levels > or = 160 mg/dl after an American Heart Association phase 1 diet were randomized to double-blind treatment with fluvastatin, 20 mg/day, or placebo for 6 weeks. Immediate-release niacin was then added to both treatment regimens and titrated to a maximum of 3 g/day for a further 9 weeks. After 6 weeks of fluvastatin monotherapy, low-density lipoprotein cholesterol levels decreased by 21% (p < 0.001 vs placebo), and after the addition of niacin, response was potentiated to 40% compared with 25% for the niacin control group at study end point (p < 0.001). Fluvastatin, alone and in combination with niacin, also significantly improved high-density lipoprotein cholesterol (increases of about 30%) and triglyceride profiles (decreases of approximately 28%) from baseline. Lipoprotein(a) decreased by 37% in those receiving fluvastatin-niacin but was unaltered in those receiving fluvastatin alone. No serious adverse events were ascribed to fluvastatin, and no cases of myositis were observed. Small, transient, asymptomatic increases in aspartate aminotransferase were noted with fluvastatin-niacin treatment but were not considered clinically relevant. Although the fluvastatin-niacin combination in this study was without evidence of significant transaminitis, myopathy, or rhabdomyolysis, it would seem prudent to continue to monitor its safety with longer term use. In conclusion, fluvastatin, both as monotherapy and in combination with niacin, proved to be an effective, safe, and well-tolerated therapeutic alternative for hypercholesterolemia.",1994.0,0,0 2657,8026027,Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin.,H N Hodis; W J Mack; S P Azen; P Alaupovic; J M Pogoda; L LaBree; L C Hemphill; D M Kramsch; D H Blankenhorn,"The Monitored Atherosclerosis Regression Study, a randomized, double-blind, placebo-controlled, 2-year trial of lovastatin monotherapy, found that coronary lesions < 50% diameter stenosis (%S) and coronary lesions > or = 50% S at baseline had different responses to therapy. We now report on clinical, lipid, and nonlipid risk factors of treatment response in these lesion subsets. Two hundred seventy subjects, 37 to 67 years old, with plasma total cholesterol (TC) 190 to 295 mg/dL (4.91 to 7.63 mmol/L) and total triglyceride < 500 mg/dL (5.65 mmol/L) were randomized to low-fat, low-cholesterol diet and either lovastatin 80 mg/d or placebo. Logistic regression was used to model the association between risk factors and coronary lesion progression in mild/moderate (< 50% S) and severe (> or = 50% S) lesions in 220 angiogram pairs analyzed by computer quantitative coronary angiography. In the placebo group, risk factors (P < .05) for the progression of mild/moderate lesions were triglycerides and TC/high-density lipoprotein cholesterol (HDL-C). Risk factors for the progression of severe lesions were HDL-C (negative), low-density lipoprotein cholesterol (LDL-C)/HDL-C, and TC/HDL-C. TC/HDL-C was the predominant risk factor for both mild/moderate and severe lesions in the multivariate analysis. In the lovastatin group, with aggressive lowering of LDL-C and TC below 85 mg/dL and 156 mg/dL, respectively, risk factors for mild/moderate lesions included triglycerides and very-low-density lipoprotein-LDL-associated apolipoprotein C-III (apo C-III-heparin precipitate), a marker of triglyceride-rich lipoprotein particles. Apo C-III-heparin precipitate was the predominant risk factor in the multivariate analysis. Risk factors for severe lesions were LDL-C, LDL-C/HDL-C, TC/HDL-C, and apo B; LDL-C/HDL-C was the predominant risk factor. These results indicate that triglyceride-rich lipoproteins and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression, respectively. These results add to the growing evidence of the importance of triglyceride-rich lipoproteins as a risk factor for coronary artery disease and the need for treatment in the progression of atherosclerosis.",1994.0,0,0 2658,8031204,Nicotinic acid as a lipoprotein-altering agent. Therapy directed by the primary physician.,J L Probstfield; D B Hunninghake,,1994.0,0,0 2659,8031206,Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial.,D R Illingworth; E A Stein; Y B Mitchel; C A Dujovne; P H Frost; R H Knopp; P Tun; R V Zupkis; R A Greguski,"Niacin and lovastatin are both effective drugs for the treatment of hypercholesterolemia and are among the drugs of first choice recommended by the adult treatment panel. To date, however, no studies have directly compared the lipoprotein-modifying effects and safety of lovastatin and niacin across their usual dosage range in patients with primary hypercholesterolemia. The efficacy and safety of lovastatin and niacin were compared in a controlled, randomized, open-label study of 26 weeks' duration that was conducted at five lipid clinics. One hundred thirty-six patients with primary hypercholesterolemia participated in the study. Entry criteria were a low-density lipoprotein (LDL) cholesterol level greater than 4.37 mmol/L (160 mg/dL) with coronary heart disease and/or more than two coronary heart disease risk factors or an LDL cholesterol level greater than 5.19 mmol/L (190 mg/dL) in patients without coronary heart disease or less than two coronary heart disease risk factors. The study consisted of a 4-week diet run-in period after which eligible patients were randomly assigned to receive treatment with either lovastatin (20 mg/d) or niacin (1.5 g/d) for 10 weeks. On the basis of the LDL cholesterol response and patient tolerance, the doses were sequentially increased to 40 and 80 mg/d of lovastatin or 3 and 4.5 g/d of niacin after 10 and 18 weeks of treatment, respectively. In the two patient groups, 66% of patients treated with lovastatin and 54% of patients treated with niacin underwent full dosage titration. At all time points, lovastatin was significantly (P < .01) more effective than niacin in reducing LDL cholesterol levels (26% vs 5% at week 10, 28% vs 16% at week 18, and 32% vs 23% at week 26), whereas niacin was more effective (P < .01) in increasing high-density lipoprotein cholesterol levels (6% vs 20% at week 10, 8% vs 29% at week 18, and 7% vs 33% at week 26). Niacin reduced Lp(a) lipoprotein levels by 35% at week 26, whereas lovastatin had no effect. Cutaneous flushing was the most common side effect during treatment with niacin. Lovastatin and niacin both exerted favorable dose-dependent changes on the concentrations of plasma lipids and lipoproteins. Lovastatin was more effective in reducing LDL cholesterol concentrations, whereas niacin was more effective in increasing high-density lipoprotein cholesterol concentrations and reducing the Lp(a) lipoprotein level. Lovastatin was better tolerated than niacin, in large part because of the common cutaneous side effects of niacin.",1994.0,0,0 2660,8033951,Enhanced cellular metabolism of very low density lipoprotein by simvastatin. A novel mechanism of action of HMG-CoA reductase inhibitors.,E Sehayek; E Butbul; R Avner; H Levkovitz; S Eisenberg,"To test the possibility that HMG-CoA reductase inhibitors reduce LDL mass by an increased VLDL catabolism, we determined the effect of simvastatin therapy on cellular metabolism of VLDL in 18 patients with primary hypercholesterolaemia. Six months of simvastatin therapy was followed by 26%, 31% and 21% reduction of plasma total cholesterol, LDL-cholesterol and plasma triglyceride levels, respectively. Before therapy, patients' VLDL metabolism in cultured human normal skin fibroblasts was similar to control VLDL. Six months after therapy was initiated, a remarkable 2-5-fold increase in VLDL cell metabolism was found. These effects were even more marked when the VLDL was enriched with exogenous recombinant apo E-3. A comparison of the metabolism of the patients' VLDL to control VLDL and LDL, revealed that simvastatin increased metabolic ratios of 60-70% and 45-95%, respectively. Simvastatin therapy was associated with a decrease of VLDL cholesteryl ester content of 19% and increase of the phospholipid content of 13%. The data strongly indicate that simvastatin therapy stimulates VLDL: cell interactions and catabolism, possibly reflecting alterations of the physico-chemical properties of the particle. It is proposed that in addition to other previously described pathways, HMG-CoA reductase inhibitors decrease LDL mass through a novel mechanism of enhanced VLDL catabolism prior to the conversion to LDL.",1994.0,0,0 2661,8036706,Safety and efficacy of low dose simvastatin in cardiac transplant recipients treated with cyclosporine.,J Vanhaecke; J Van Cleemput; J Van Lierde; W Daenen; H De Geest,"Hyperlipidemia is common in heart transplant patients. Lipid-lowering therapy poses special problems, yet may be important because accelerated graft atherosclerosis is the major factor limiting long-term survival. Simvastatin 5 mg/day was started > 6 months after surgery in 26 consecutive cardiac transplant recipients with a total serum cholesterol level of > 250 mg/dl. The dose of simvastatin was increased in 5-mg increments until total serum cholesterol fell below 220 mg/dl or until side effects developed or up to a maximal dose of 20 mg/day. The final average daily dose was 10 mg. Changes in serum lipid levels after 6 months of therapy were compared with data from a matched and concurrent control group of heart transplant patients not taking simvastatin. Immunosuppression for both groups consisted of CsA, AZA, and corticosteroids. In the simvastatin-treated group, the serum level of total cholesterol decreased by 27% from 315 +/- 53 to 230 +/- 38 mg/dl (P < 0.0001), low density lipoprotein cholesterol decreased by 40% from 205 +/- 30 to 123 +/- 32 mg/dl (P < 0.0001), and triglycerides decreased by 21% from 177 +/- 89 to 140 +/- 49 mg/dl (P < 0.01). There was no significant change in high density lipoprotein cholesterol level. Body weight and CsA blood levels remained stable. Steroid intake decreased during the study period to a similar extent in both the treated and the control groups. In the control group, no significant changes in serum lipid levels were observed. Two patients experienced a mild form of myotoxicity. In one other patient simvastatin treatment was stopped after an acute pancreatitis of uncertain etiology developed. Low dose simvastatin effectively lowers total serum cholesterol, low density lipoprotein cholesterol, and triglycerides in heart transplant patients. With due precautions, the safety profile of the drug in this patient population seems reasonable.",1994.0,0,0 2662,8038303,Associations of cholesterol lowering by statins with anger and hostility in hypercholesterolemic men.,T E Strandberg; K Räikkönen; M Partinen; S Pihl; H Vanhanen; T A Miettinen,,1994.0,0,0 2663,8039527,Prediction of the therapeutic response to simvastatin by pretreatment lipid concentrations in 2082 subjects.,A R Miserez; F A Rossi; U Keller,"2082 hypercholesterolemic subjects were treated with simvastatin for 12 weeks. In 530 patients the dose was increased after 6 weeks from 10 to 20 mg because of persistently high cholesterol concentrations. Total cholesterol (TC) in the 1552 patients taking 10 mg fell by 1.61 mmol.l-1 (18.4%), LDL cholesterol (LDLC) by 1.53 mmol.l-1 (25.2%), and triglycerides (TG) by 0.13 mmol.l-1 (5.5%); HDL cholesterol (HDLC) significantly increased by 0.05 mmol.l-1 (3.6%). In the 530 patients taking 20 mg TC fell by 1.89 mmol.l-1 (19.9%), LDLC by 1.78 mmol.l-1 (26.0%), and TG by 0.13 mmol.l-1 (5.5%); HDLC increased by 0.05 mmol.l-1 (3.7%). The reductions in TC, LDLC, and TG were positively correlated and the increase in HDLC negatively correlated with their respective baseline values. There were independent significant correlations of the fall in LDLC with sex (MANOVA), baseline TG, and adherence to a lipid-lowering diet. The falls in TG significantly correlated with baseline fructosamine concentrations and dietary adherence. There were 571 adverse events in 16.6% of the patients but no case of myopathy. These results show that simvastatin is usually well tolerated and that its effects on TC and LDLC depend on their baseline concentrations.",1994.0,0,0 2664,8041244,Hyperlipidemia in renal transplant recipients: natural history and response to treatment.,C S Ong; C A Pollock; R J Caterson; J F Mahony; D A Waugh; L S Ibels,"The lipid profiles of 192 patients with functioning renal transplants and their etiologic associations and response to therapy, in particular simvastatin, were assessed. Hypercholesterolemia was present in 71.3% of patients within 3 years following transplantation. There were independent associations of serum cholesterol with prednisone dosage (p < 0.05), renal function (p < 0.05), and smoking (p < 0.05) in the early posttransplant period (up to 3 months posttransplant). Those patients whose immunosuppression included cyclosporin had lower serum cholesterol levels than those receiving azathioprine and prednisone (p < 0.02). Plasma triglyceride levels reflected a marked interindividual variation, and no independent correlations were observed. The presence of diabetes mellitus, hypertension (or the use of antihypertensive agents), or the form or duration of prior dialysis did not independently influence the lipid profiles. During the study period 22 patients died, 54.5% due to vascular causes. Those who died of vascular causes had higher serum cholesterol levels than those who died of other causes, which reached statistical significance at 3 years posttransplant (7.74 +/- 0.4 versus 5.5 +/- 0.52 mmol/L; p < 0.02). Cholestyramine was introduced in 30 patients, only 2 of whom continued with therapy beyond 3 months. Simvastatin was used in 43 patients, 20 of whom were receiving cyclosporin, resulting in a mean reduction in serum cholesterol of 16.5% (p < 0.001) and in serum triglycerides of 21% (p < 0.05). No clinical or biochemical evidence of muscle, liver, or renal toxicity occurred in 15.4 +/- 0.9 months of follow-up.",1994.0,0,0 2665,8044919,Coronary artery disease regression. Convincing evidence for the benefit of aggressive lipoprotein management.,H R Superko; R M Krauss,"Numerous reports suggest that coronary artery disease can regress with lipoprotein manipulation. Many of these reports lack control groups and contain relatively small numbers. Ten randomized controlled clinical trials using coronary arteriography to assess the effect of lipoprotein manipulation on the rate of progression and regression of atherosclerosis have been either published or reported as an abstract at a national meeting. These studies were critically reviewed for individual differences and combined clinically applicable lessons. These trials involved a total of 2095 subjects and have consistently reported reduction in the percentage of patients arteriographically defined as progressing (mean, 23.6%) and an increase in the percentage regressing (mean, 20.0%) compared with control groups. Compared with large clinical trials using clinical end points, lipoprotein change was greater, achieving on average a 28% reduction in low-density lipoprotein cholesterol, 11% reduction in triglycerides, and 11% increase in high-density lipoprotein cholesterol compared with control groups. Four investigations used a nonpharmacological approach, and seven used single and multiple drug therapy combined with diet. Despite the relatively brief treatment time of often 2 to 4 years, clinical events were fewer in the treatment groups; within some studies, this reached statistical significance. Side effects from the different therapies were tolerated by most patients, and severe adverse clinical events were few. These trials present convincing evidence that aggressive lipoprotein manipulation can result in improved arteriographic measurements and fewer cardiovascular events in a relatively short period of time of 2 to 4 years. Extrapolation of this information to the larger population with known coronary artery disease suggests that directed lipoprotein manipulation can reduce clinical events in a cost-effective manner.",1994.0,0,0 2666,8050207,Long-term effect of lovastatin on lipoprotein profile in patients with primary nephrotic syndrome.,M M Prata; A C Nogueira; J R Pinto; A M Correia; O Vicente; M C Rodrigues; M J Miguel,"Eight patients with biopsy-proven primary nephrotic syndrome were included in an open, prospective, two-year study of lovastatin. One patients was withdrawn after 6 months due to an asymptomatic rise in creatinine phosphokinase, which was rapidly reversed after interruption of lovastatin. In the remaining patients, treatment was well-tolerated and produced no side effects. After 2 years of treatment, these 7 patients had decreases in total cholesterol from 446 +/- 165 to 250 +/- 57 mg/dl (p < 0.001), LDL cholesterol from 343 +/- 121 to 174 +/- 49 mg/dl (p < 0.001), Apo B lipoprotein from 162 +/- 60 to 108 +/- 42 mg/dl (p < 0.05), triglycerides from 336 +/- 273 to 182 +/- 71 mg/dl (p < 0.04). There was no change in HDL cholesterol. The LDL/HDL cholesterol and the total/HDL cholesterol ratios fell from 15.0 +/- 12.1 and 19.1 +/- 17.2 mg/dl before the study to 4.4 +/- 1.2 and 6.3 +/- 1.6 mg/dl, respectively, at 2 years. A decrease in proteinuria from 8.6 +/- 4.6 to 5.0 +/- 3.7 g/24 h (p < 0.02) was noted in 4 patients on concomitant ACE inhibitor therapy. Renal function remained stable in all patients throughout the study, except for one whose moderate impairment progressed to end-stage renal failure requiring dialysis 3 months poststudy. We conclude that long-term lovastatin in patients with primary nephrotic syndrome is an effective and generally safe treatment for accompanying dyslipidemia.",1994.0,0,0 2667,8050214,Hypercholesterolemia treatment in a renal transplant patient.,O Devuyst; E Goffin; Y Pirson; C van Ypersele de Strihou,,1994.0,0,0 2668,8054965,A small step for gene therapy.,,,1994.0,0,0 2669,8054972,Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia.,M Grossman; S E Raper; K Kozarsky; E A Stein; J F Engelhardt; D Muller; P J Lupien; J M Wilson,"An ex vivo approach to gene therapy for familial hypercholesterolaemia (FH) has been developed in which the recipient is transplanted with autologous hepatocytes that are genetically corrected with recombinant retroviruses carrying the LDL receptor. We describe the treatment of a 29 year old woman with homozygous FH by ex vivo gene therapy directed to liver. She tolerated the procedures well and in situ hybridization of liver tissue four months after therapy revealed evidence for engraftment of transgene expressing cells. The patient's LDL/HDL ratio declined from 10-13 before gene therapy to 5-8 following gene therapy, improvements which have remained stable for the duration of the treatment (18 months). This represents the first report of human gene therapy in which stable correction of a therapeutic endpoint has been achieved.",1994.0,0,0 2670,8060425,Magnetic resonance spectroscopy in Niemann-Pick disease type C: correlation with diagnosis and clinical response to cholestyramine and lovastatin.,M Sylvain; D L Arnold; C R Scriver; R Schreiber; M I Shevell,"Niemann-Pick type C is an autosomal-recessive, neurovisceral storage disorder that results from defective cholesterol esterification. Cholesterol-lowering agents have been demonstrated to decrease hepatic lipids in Niemann-Pick type C patients. The objective was to determine the effects of cholesterol-lowering agents on neurologic features and to develop a noninvasive method of monitoring clinical response. A 9-month-old boy with progressive hepatosplenomegaly and neurodevelopmental delay was studied. Water-suppressed proton magnetic resonance spectra from a supraventricular volume of central white and gray matter revealed an abnormal lipid signal. The patient was treated with cholesterol-lowering agents (i.e., cholestyramine, lovastatin). Repeat standardized neurodevelopmental assessments (Peabody and Griffith scales) at 13 and 19 months were normal and magnetic resonance spectra no longer detected the previously observed lipid resonance. Early treatment of Niemann-Pick type C patients with cholesterol-lowering agents appeared to have short-term beneficial effects. Magnetic resonance spectra provided a noninvasive means of monitoring CNS response.",1994.0,0,0 2671,8062305,Recent advances and future directions in myocardial infarction.,A Avezum; M Flather; S Yusuf,"Cardiovascular disease is the leading cause of death in most industrialised countries and is a major source of health care expenditure worldwide. Identification and management of risk factors for the development of coronary heart disease (CHD) have enormous potential for improving health and reducing health care costs. There is evidence that the reduction in deaths from CHD has occurred earlier and to a greater extent in countries with aggressive policies of cardiovascular risk factor intervention. Likewise, the treatment of patients presenting with acute myocardial infarction (MI) should be aimed at both extending event-free survival and improving the quality of life. This review focuses on recent advances and future directions in the understanding of risk factor modification before an MI (prevention), treatment of MI including thrombolysis and primary percutaneous transluminal coronary angioplasty, and the subsequent management of patients after MI.",2001.0,0,0 2672,8067175,Efficacy of simvastatin for lowering cholesterol in non-insulin dependent diabetic patients with hypercholesterolemia.,J C Daubresse; R Machowski; E Pulinx,"Patients with non-insulin-dependent diabetes mellitus (NIDDM) are at high risk of cardiovascular disease for many reasons and especially due to the fact that dyslipidemias are more frequent in this group of patients. Fibrate derivatives are the drugs of choice when hypertriglyceridemia is the main lipid anomaly. When hypercholesterolemia is predominant, the use of resins and nicotinic acid has been advocated but these drugs are poorly tolerated on a long-term basis. We assessed the effect of simvastatin, a recent HMG-CoA reductase inhibitor in 12 NIDDM patients with hypercholesterolemia. After 4 weeks of placebo, which did not significantly modify the lipid values, patients were given simvastatin at increasing dosages (from 10 to a maximum of 40 mg daily) during 24 weeks. Compliance and clinical tolerance were excellent. There was no major biological side effect, but a significant deterioration of glucose control was noted at the end of the study. Simvastatin reduced total cholesterol by 28%, LDL-cholesterol by 36% and apo B by 31%. Concomitantly, there was an increase of HDL-cholesterol by 15%. This improvement of lipid profile persisted during the 24 weeks of treatment. Comparing the patients with pure hypercholesterolemia to those presenting combined hyperlipidemia, it was evident that the hypolipidemic effect was more marked in the diabetic subjects with combined hyperlipidemia.",1994.0,0,0 2673,8067656,Cost-effectiveness of combined statin-resin therapy.,D L Katz,,1994.0,0,0 2674,8070502,Pravastatin treatment in combined hyperlipidaemia. Effect on plasma lipoprotein levels and size.,S Zambon; A Cortella; G Sartore; G Baldo-Enzi; E Manzato; G Crepaldi,"Combined hyperlipidaemia and the presence of small and dense LDL particles in the circulation are associated with an increased risk of myocardial infarction. The effect of pravastatin on plasma lipoproteins and on LDL size has been evaluated in a single-blind, randomised, placebo-controlled study in 24 patients with combined hyperlipidaemia; 12 patients on pravastatin and 12 on placebo. After 16 weeks on pravastatin, plasma total (-15%) and LDL (-23%) cholesterol and apo B (-13%) levels were significantly reduced and apo AI (+6%) had increased. LDL size (measured by gradient gel electrophoresis) had not changed. No adverse effect was observed. The study suggests that, in combined hyperlipidaemia, LDL size is not affected by variation in LDL receptor activity.",1994.0,0,0 2675,8076581,Dyslipidemia in non-insulin-dependent diabetes mellitus.,B V Howard; W J Howard,,1994.0,0,0 2676,8078332,,,,,0,0 2677,8086488,The transporter for the HMG-CoA reductase inhibitor pravastatin is not present in Hep G2 cells. Evidence for the nonidentity of the carrier for pravastatin and certain transport systems for BSP.,K Ziegler; M Blumrich; S Hummelsiep,"The hydrophilic HMG-CoA reductase inhibitor pravastatin is not taken up via a carrier-mediated system into Hep G2 cells. Therefore, Hep G2 cells are not a good model for human hepatocytes with respect to elucidation of the effect of hydrophilic HMG-CoA reductase inhibitors. Sulfobromophthalein (BSP), on the other hand, is taken up into Hep G2 cells by carrier systems with Km and Vmax values almost identical to freshly isolated hepatocytes. These results indicate that the hepatocellular BSP transporting proteins expressed in Hep G2 cells (bilitranslocase and BSP/bilirubin binding protein) are not involved in the hepatocellular uptake of pravastatin. In contrast to the hepatocellular sodium-taurocholate cotransporter, which is not functioning in Hep G2 cells, we found a saturable transport of cholate with Km and Vmax values identical to those in cultured rat hepatocytes in the presence of sodium.",1994.0,0,0 2678,8087964,Reversal of coronary atherosclerosis. Clinical promise as the basis for noninvasive management of coronary artery disease.,K L Gould,,1994.0,0,0 2679,8089776,Post-cholecystectomy biliary pain and dyspepsia (response to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors).,H A Saadah,"The so called post-cholecystectomy syndrome is common, intractable, often progressive, causes prolonged suffering, and has no approved treatment. It usually presents with episodic biliary pains (colics), and postprandial dyspepsia (bloating and indigestion). Because treating a very recalcitrant case with lovastatin provided prolonged remission, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were given to 12 subsequent patients with similar symptoms. To determine whether HMG-CoA reductase inhibitors are useful in the therapy of post-cholecystectomy biliary pain and dyspepsia. Open clinical trial in an internal medicine, private practice setting; data were collected from the patients' charts and from telephone interviews, five years after the index case had been treated. Eight of 12 patients experienced total resolution of their symptoms after many years of suffering; response occurred slowly within the first three months of treatment. Two other patients responded, stopped their medications, relapsed, and continue to be symptomatic. One patient did not take her medication and remains symptomatic; one other patient did not respond, was diagnosed with carcinoma of the pancreas, and died from it. These preliminary results suggest that HMG-CoA reductase inhibitors may be useful in relieving the symptoms of this common and intractable disorder. Controlled studies are needed.",1994.0,0,0 2680,8093139,Low-dose combined therapy with fluvastatin and cholestyramine in hyperlipidemic patients.,D L Sprecher; J Abrams; J W Allen; W F Keane; S G Chrysant; H Ginsberg; J J Fischer; B F Johnson; P Theroux; L Jokubaitis,"To compare the low-density lipoprotein (LDL) cholesterol-lowering efficacy of low-dose combinations of cholestyramine and fluvastatin. Randomized, double-blind, parallel group, placebo-controlled trial with a 24-week double-blind treatment period divided into three phases. Office-based clinics. Hypercholesterolemic, with LDL cholesterol of 4.14 mmol/L or greater (> or = 160 mg/dL) and plasma triglycerides of 3.39 mmol/L or less (< or = 300 mg/dL). Four hundred sixty patients were screened; 224 patients were randomized into a double-blind treatment period; 203 completed the study; 6 dropped out because of adverse events. Patients were treated with 10 mg or 20 mg of fluvastatin alone, 8 g or 16 g of cholestyramine alone, or combinations of these fluvastatin and cholestyramine dosages (six treatment groups). Changes in lipid variables, particularly LDL cholesterol. The 10-mg and 20-mg fluvastatin monotherapy groups showed considerable reductions in LDL cholesterol initially (-20.1% [SD, 8.8%] and -20.2% [SD, 10.1%], respectively); these reductions were maintained. Reductions in LDL cholesterol that resulted from the addition of cholestyramine, 8 g/d, to 10 mg of fluvastatin and 20 mg of fluvastatin were greater than those observed with monotherapy (10-mg fluvastatin--[10-mg fluvastatin plus cholestyramine], 9.1%; 95% CI, 3.8% to 14.4%) and 20-mg fluvastatin--[20-mg fluvastatin plus cholestyramine], 11.6%; CI, 6.5% to 16.8%). The increase in cholestyramine dose to 16 g/d in the three combination groups provided only a modest additional response. Low-density lipoprotein cholesterol reductions of about 25% to 30% can be achieved with low-dose combination therapy with fluvastatin and cholestyramine. The addition of low-dose resin appears to produce greater overall cholesterol reduction than does a simple doubling of the fluvastatin dosage. The low-dose combination treatment was highly successful in achieving the goals of the National Cholesterol Education Program guidelines.",1994.0,0,0 2681,8106688,Investigation of decreased availability of nitric oxide precursor as the mechanism responsible for impaired endothelium-dependent vasodilation in hypercholesterolemic patients.,P R Casino; C M Kilcoyne; A A Quyyumi; J M Hoeg; J A Panza,"The purpose of this study was to determine whether the impaired endothelium-dependent vasodilation of hypercholesterolemic patients is due to decreased availability of L-arginine, the substrate for nitric oxide. Patients with hypercholesterolemia have impaired endothelium-dependent vasodilation that is related to a defect in the endothelium-derived nitric oxide system. However, the precise location of this abnormality has not been determined. The study included 12 hypercholesterolemic patients (6 men, 6 women; 52 +/- 9 years old; serum cholesterol > 240 mg/dl) and 15 normal volunteers (8 men, 7 women; 50 +/- 6 years old; serum cholesterol < 210 mg/dl). The forearm vascular responses to intraarterial infusion of acetylcholine, an endothelium-dependent vasodilator (7.5, 15, 30 micrograms/min), and sodium nitroprusside, a direct smooth muscle dilator (0.8, 1.6, 3.2 micrograms/min) were studied before and during infusion of L- or D-arginine (a stereoisomer of arginine that is not a nitric oxide precursor). The response to acetylcholine was lower in hypercholesterolemic patients than in control subjects. However, no significant difference was observed with sodium nitroprusside infusion. L-Arginine augmented the response to acetylcholine in normal subjects (maximal blood flow increased from 14.4 +/- 7 to 18.9 +/- 10 ml/min per 100 ml, p < 0.002). In contrast, in the hypercholesterolemic patients, only a mild but not significant improvement in the response to acetylcholine was observed with the infusion of L-arginine (maximal blood flow increased from 6.8 +/- 4 to 8.4 +/- 5 ml/min per 100 ml; p = 0.16); however, a similar mild but not significant change was also observed with D-arginine (maximal blood flow increased from 6.8 +/- 4 to 8.3 +/- 4 ml/min per 100 ml, p = 0.07). L-Arginine did not modify the response to sodium nitroprusside in either group. The augmentation of endothelium-dependent vasodilation by L-arginine, the nitric oxide precursor, is defective in hypercholesterolemic patients. This supports the concept of an abnormal endothelium-derived nitric oxide system in hypercholesterolemia and indicates that decreased availability of nitric oxide substrate is not responsible for the impaired endothelial function in this condition.",1994.0,0,0 2682,8106695,Benefits of lipid-lowering therapy in men with elevated apolipoprotein B are not confined to those with very high low density lipoprotein cholesterol.,B F Stewart; B G Brown; X Q Zhao; L A Hillger; A D Sniderman; A Dowdy; L D Fisher; J J Albers,"Do the benefits of intensive lipid-lowering therapy extend to patients with only borderline or moderately elevated levels of low density lipoprotein (LDL) cholesterol? The merits of the present LDL cholesterol treatment goal of < or = 100 mg/dl need to be clarified for patients without high levels of LDL cholesterol, particularly for those patients previously classified as having only borderline high (130 to 159 mg/dl) or desirable (101 to 130 mg/dl) levels. Disease change and clinical events were examined in LDL cholesterol subgroups in the Familial Atherosclerosis Treatment Study (FATS) trial, a randomized, blinded, quantitative arteriographic comparison of one conventional and two intensive lipid-lowering strategies in men with coronary artery disease, a positive family history and apolipoprotein B > or = 125 mg/dl. The primary end point, disease change per patient, was measured as the mean change in severity of stenosis (delta %SProx) among nine standard proximal segments. Of the 120 patients completing the 30-month protocol, 60 had a baseline LDL cholesterol < 90th percentile (mean LDL cholesterol 152 mg/dl) and 60 > 90th percentile (mean LDL cholesterol 221 mg/dl). Thirty-one patients had levels < 160 mg/dl (mean LDL cholesterol 134 mg/dl) and 89 > 160 mg/dl (mean LDL cholesterol 205 mg/dl). Patients with LDL cholesterol < 90th percentile benefited angiographically from therapy (delta %SProx = -1.5% diameter stenosis [regression] during intensive therapy vs. +2.3% diameter stenosis [progression] during conventional therapy, p < 0.01), as did patients with LDL cholesterol < 160 mg/dl (delta %SProx = -4.2% vs. +3.3% diameter stenosis, p = 0.0001). By comparison, angiographic benefit was less pronounced among those entering with very high LDL cholesterol (delta %SProx = -0.2% vs. +1.9% diameter stenosis, p = 0.07) or with LDL cholesterol > or = 160 mg/dl (delta %SProx = +0.2% vs. +1.6% diameter stenosis, p = 0.13). Intensive therapy resulted in a statistically significant reduction in clinical events only in the subgroup with baseline LDL cholesterol < 90th percentile (2 of 42 vs. 8 of 29 patients initially enrolled, p = 0.01) and a trend toward fewer events in patients with LDL cholesterol < 160 mg/dl (2 of 20 vs. 6 of 15 patients, p = 0.05). No such difference was seen in the higher LDL cholesterol subgroups. Treatment benefit in the FATS trial was not confined to patients with very high levels of LDL cholesterol and was in fact particularly evident in those patients with levels < 160 mg/dl. Such patients should be considered more likely, not less, to benefit from intensive lipid-lowering therapy.",1994.0,0,0 2683,8107933,The effect of simvastatin treatment on the low-density lipoprotein subfraction profile and composition in familial hypercholesterolaemia.,J de Graaf; P N Demacker; A F Stalenhoef,"The effect of simvastatin treatment on the low-density lipoprotein (LDL) subfraction profile was studied in 26 patients with familial hypercholesterolaemia. Before treatment LDL consisted of three LDL subfractions, using density-gradient ultracentrifugation (LDL1, LDL2 and LDL3) present in a relatively narrow density range (d = 1.030-1.045 g/ml). Simvastatin did not influence this profile with respect to the number and density range of the LDL subfractions. However, the composition of the isolated LDL subfractions changed after treatment, as evidenced by the reversal towards normal of the increased cholesterol/protein ratio (mean 1.51 before vs. 1.38 after therapy, p < 0.01; mean 1.36 in normolipidaemic subjects). When the subjects were stratified by their plasma triglyceride levels or the change in plasma triglycerides during simvastatin therapy, a strong dependence of the LDL subfraction profile and its composition on plasma triglyceride levels was observed; increasing plasma triglyceride levels were associated with a more dense LDL subfraction profile, characterized by a high relative contribution of dense LDL3 to total LDL and changes in LDL composition, reflected by a relatively low cholesterol/protein ratio. Our results indicate that in patients with familial hypercholesterolaemia: (1) plasma triglyceride levels have an important role in determining the properties of LDL and (2) simvastatin treatment results in changes in composition of LDL, which may affect the intrinsic metabolic characteristics and thus the atherogenic potential of LDL.",1993.0,0,0 2684,8108314,"Effects of simvastatin and pravastatin on 6 beta-hydroxycortisol excretion, a potential marker of cytochrome P-450 3A.",Y Horsmans; J P Desager; V van den Berge; M Abrassart; C Harvengt,"The influence of two inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, simvastatin and pravastatin, on the level of urinary 6 beta-hydroxycortisol/17-hydroxycorticosteroids (6 beta-OHC/17-OHCS) ratio was determined in two groups of normolipidemic Caucasian subjects (n = 18 and n = 14, respectively). The 6 beta-OHC/17-OHCS ratio increased significantly after simvastatin administration (20 mg day-1 for 17 days) (P = 0.0125) whereas no modification was observed after pravastatin administration (20 mg day-1 during 17 days). As the level of 6 beta-OHC/17-OHCS ratio is a function of cytochrome P-450 3A activity, these results suggest that in Caucasian subjects, simvastatin but not pravastatin could be a weak inducer of cytochrome P-450 3A. This contrasting effect could be related to the major pharmacological differences existing between these two drugs.",1993.0,0,0 2685,8109547,"Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemia.",J Davignon; G Roederer; M Montigny; M R Hayden; M H Tan; P W Connelly; R Hegele; R McPherson; P J Lupien; C Gagné,"In a comparative study, 158 patients with type IIa or IIb primary hypercholesterolemia received either placebo, nicotinic acid extended-release capsules (0.5 to 1.0 g twice daily), pravastatin (40 mg at bedtime), or the combination for a short-term, 8-week period. A long-term, 88-week phase followed in which the addition of other lipid-lowering agents was permitted. During the short-term phase, low-density lipoprotein cholesterol levels were lower, in relation to baseline, with nicotinic acid treatment (-21%) than with placebo (P < or = 0.05), with pravastatin (-33%) than with either placebo (p < or = 0.001) or nicotinic acid (p < or = 0.05) and with combination therapy (-49%) than with the other 3 treatments (p < or = 0.05) at all weeks measured. At week 8, high-density lipoprotein cholesterol levels were increased, in relation to placebo, by nicotinic acid treatment (12%; p < or = 0.05), pravastatin therapy (13%; p < or = 0.01) and combination therapy (16%; p < or = 0.01). Adverse events were less frequent in the pravastatin and placebo groups (p < or = 0.05). In comparison with placebo, treatment with nicotinic acid resulted in significant increases in aspartate and alanine aminotransferase. The placebo and pravastatin groups did not differ significantly regarding adverse events or laboratory parameters. Similar results were observed in the long-term phase. Therefore, pravastatin is very effective and well tolerated in the treatment of type IIa or IIb primary hypercholesterolemia, and is superior to nicotinic acid in both efficacy and adverse event profile.(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2686,8112375,"The actions of lovastatin on platelet function and platelet eicosanoid receptors in type II hypercholesterolaemia. A double-blind, placebo-controlled, prospective study.",D Kaczmarek; T Hohlfeld; G Wambach; K Schrör,"We have studied the effects of 12 weeks of lovastatin (20 mg per day) on platelet function and thromboxane formation in 18 patients with type II hypercholesterolaemia in a double-blind, placebo-controlled, prospective study. Lovastatin significantly reduced total serum and LDL-cholesterol by 20% and 25% respectively. Washed platelets of lovastatin-treated patients had significantly reduced collagen-induced aggregation and thromboxane formation ex vivo. There was no change in ADP-induced platelet aggregation, but a significant increase in prostacyclin (iloprost)-stimulated platelet cyclic AMP concentrations in lovastatin-treated patients. This was associated with a significant increase in the number of prostacyclin receptors in platelet membranes prepared from lovastatin-treated patients. There was also an increase in platelet thromboxane receptors. There were no such changes in the placebo group. These data confirm our original observation of normalization of platelet function in hypercholesterolaemia by HMGCoA reductase inhibitors and suggest changes in platelet membrane composition at the megakaryocyte level as a possible site of action.",1993.0,0,0 2687,8115891,Impact of intensive lipid modulation on angiographically defined coronary disease: clinical implications.,R W Paterson; J J Paat; G H Steele; S C Hathaway; J G Wong,"We reviewed all randomized, controlled angiographic trials to assess the impact of intensive lipid modulation on the progression or regression of angiographically defined coronary disease. Five of seven trials satisfied selection criteria: Cholesterol-Lowering Atherosclerosis Study, Program on the Surgical Control of the Hyperlipidemias, Familial Atherosclerosis Treatment Study, Regression of Coronary Atherosclerosis During Treatment of Familial Hypercholesterolemia, and St. Thomas' Atherosclerosis Regression Study. We compared patient selection, baseline and on-trial lipid values, changes in angiographic disease scores, and clinical outcomes. In all five trials, treatment reduced levels of low-density lipoprotein (LDL) cholesterol substantially (range -32% to -46%). Treatment reduced risk of angiographic progression by almost 50% compared to controls. Furthermore, nearly one third of drug-treated patients showed angiographic regression of disease. Regression correlated well with reduction in LDL cholesterol. Although overall improvement in stenosis was modest, reduction in clinical events was impressive. Intensive lipid modulation may ""stabilize"" existing lesions, making them less ""active"" (ie, less prone to rupture or thrombosis), thereby reducing risk of acute coronary syndromes. These studies clearly support intensive lipid modulation in patients with established coronary disease.",1994.0,0,0 2688,8117177,Comparative efficacy and safety of micronized fenofibrate and simvastatin in patients with primary type IIa or IIb hyperlipidemia.,M Farnier; F Bonnefous; N Debbas; A Irvine,"Few studies have been performed to compare fenofibrate, a second-generation fibrate, and simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. This study was aimed to compare the efficacy of both drugs in reducing atherogenic risk factors in type IIa or IIb hyperlipidemia. Sixty-three patients entered this single-center, double-blind, crossover trial. Sixty patients (32 with type IIa and 28 with type IIb hyperlipidemia) were randomized to treatment for 3 months with a single daily 200-mg dose of micronized fenofibrate or 20 mg of simvastatin and then changed to the alternative treatment for a further 3-month period. After the first treatment period, in both types IIa and IIb, fenofibrate and simvastatin produced similar significant reductions in levels of total cholesterol and low-density lipoprotein cholesterol; high-density lipoprotein cholesterol levels were increased with both drugs in type IIb. Only fenofibrate decreased total triglyceride levels in type IIb, Lp(a) lipoprotein levels in patients with high baseline values, and fibrinogen. After the second period of treatment, in both types IIa and IIb, switching from fenofibrate to simvastatin resulted in a further reduction in total cholesterol and low-density lipoprotein cholesterol levels. The difference in the response of the two treatments on levels of total triglycerides, Lp(a) lipoprotein, and fibrinogen was confirmed after changing over to the alternative treatment. This short-term study showed few adverse effects for both drugs. Fenofibrate and simvastatin provide similar variations on total cholesterol and low-density lipoprotein cholesterol levels after a 3-month treatment period, with simvastatin having the capacity to decrease these measures further when administered after fenofibrate. However, fenofibrate exhibits a significant effect on other established risk factors, such as total triglyceride, fibrinogen, and Lp(a) lipoprotein levels, and accordingly has a broader spectrum of activity than simvastatin.",1994.0,0,0 2689,8120870,Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols.,B C Pearce; R A Parker; M E Deason; D D Dischino; E Gillespie; A A Qureshi; K Volk; J J Wright,"Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibitors. The in vitro cholesterol-biosynthesis-inhibitory and HMGR-suppressive activities in HepG2 cells of an expanded series of benzopyran and tetrahydronaphthalene isosteres and the hypocholesterolemic activity of selected compounds assessed in orally dosed chickens are presented. Preliminary antioxidant data of these compounds have been obtained using cyclic voltammetry and Cu-induced LDL oxidation assays. The farnesyl side chain and the methyl/hydroxy substitution pattern of gamma-tocotrienol deliver a high level of HMGR suppression, unsurpassed by synthetic analogues of the present study. In orally dosed chickens, 8-bromotocotrienol (4o), 2-desmethyltocotrienol (4t), and the tetrahydronaphthalene derivative 35 exhibit a greater degree of LDL cholesterol lowering than the natural tocotrienols.",1994.0,0,0 2690,8122478,Efficacy and tolerability of simvastatin 20 mg vs pravastatin 20 mg in patients with primary hypercholesterolemia. European Study Group.,L J Lambrecht; P L Malini,"The safety, tolerability, and efficacy of 20 mg daily doses of simvastatin and pravastatin were compared in this double-blind, randomized trial of 210 patients with primary hypercholesterolemia. Simvastatin was found to produce significantly greater mean percent reductions from baseline in total cholesterol (28% versus 21%), LDL cholesterol (38% versus 29%), and apolipoprotein B concentrations (25% versus 17%) than did pravastatin, and a greater percentage of patients receiving simvastatin (94% versus 80%) had at least a 20% reduction in LDL cholesterol. Both simvastatin and pravastatin produced similar significant mean percent reductions from baseline in triglyceride concentrations (14% and 11%) and significant mean percent increases in the concentrations of HDL cholesterol (7% for both) and apolipoprotein A-I (4% for both). Resulting reductions in the ratios of total cholesterol: HDL cholesterol, LDL cholesterol: HDL cholesterol, and apolipoprotein B: apolipoprotein A-I were significantly greater in the simvastatin group. Both simvastatin and pravastatin were well tolerated. The incidence and severity of clinical and laboratory adverse experiences were similar in both groups, and none were classified as serious. The results of this study confirm the results of prior studies that have found simvastatin to produce lipid-lowering effects superior to those of pravastatin when administered at equivalent mg doses, while demonstrating similar safety profiles.",1993.0,1,1 2691,8122946,Cholesterol lowering in the elderly. Results of the Cholesterol Reduction in Seniors Program (CRISP) pilot study.,J C LaRosa; W Applegate; J R Crouse; D B Hunninghake; R Grimm; R Knopp; J H Eckfeldt; C E Davis; D J Gordon,"Total and lipoprotein cholesterol levels continue to be predictors of coronary heart disease risk in men and women over 65 years old. Cholesterol-lowering trials, however, while sometimes including such subjects, have not concentrated on this age group. The Cholesterol Reduction in Seniors Program was a five-center pilot study to assess feasibility of recruitment and efficacy of cholesterol lowering in this age group. The study was a randomized, double-masked clinical trial with placebo, 20-mg lovastatin, and 40-mg lovastatin arms. Major efforts were made to recruit women and minorities. Participants were followed up for 1 year on a cholesterol-lowering diet plus placebo or study drug. End points were changes in blood lipid levels. Data on other blood chemistry values, as well as quality-of-life measures and coronary heart disease morbidity and mortality, were also collected. Four hundred thirty-one subjects with low-density lipoprotein cholesterol levels greater than 4.1 and less than 5.7 mmol/L (159 and 221 mg/dL) were randomized, of whom 71% were women and 21% were African Americans; the mean age was 71 years. In the 20- and 40-mg lovastatin groups, total cholesterol levels fell 17% and 20%; low-density lipoprotein cholesterol levels fell 24% and 28%; triglyceride levels fell 4.4% and 9.9%, respectively. High-density lipoprotein cholesterol levels rose 7.0% and 9.0%, respectively. No changes were observed in the placebo group. Gender, race, and age did not significantly affect responses. Coronary heart disease morbidity and mortality data were collected but not analyzed for this study. Older subjects of both genders and a variety of racial and ethnic groups can be successfully recruited into a cholesterol-lowering trial. Lovastatin has effects similar to those reported in younger subjects in previous controlled trials. There is little advantage to the higher lovastatin daily dose. Side effects were remarkably low in all groups.",2001.0,0,0 2692,8124836,Effects of monotherapy with an HMG-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography. The Canadian Coronary Atherosclerosis Intervention Trial.,D Waters; L Higginson; P Gladstone; B Kimball; M Le May; S J Boccuzzi; J Lespérance,"3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are widely prescribed for hyperlipidemia, yet their effect on the evolution of coronary atherosclerosis has not been defined. To address this issue, 331 patients with diffuse but not necessarily severe coronary atherosclerosis documented on a recent arteriogram and with fasting serum cholesterol between 220 and 300 mg/dL were enrolled in a randomized, double-blind, placebo-controlled trial. All patients received intensive dietary counseling. Lovastatin or placebo was begun at 20 mg/d and was titrated to 40 and 80 mg during the first 16 weeks to attain a fasting low-density lipoprotein (LDL) cholesterol < or = 130 mg/dL. The mean lovastatin dose was 36 mg/d. Coronary arteriography was repeated after 2 years. In 299 patients (90%), 3858 coronary segments containing 2309 stenoses were measured blindly on pairs of films with an automated computerized quantitative system. Total and LDL cholesterol decreased by 21 +/- 11% and 29 +/- 11%, respectively, in the lovastatin-treated group but changed by < 2% in placebo patients. The primary end point, coronary change score, defined as the per-patient mean of the minimum lumen diameter changes (follow-up minus baseline angiogram) for all lesions measured, excluding those < 25% on both films, worsened by 0.09 +/- 0.16 mm in the placebo group and by 0.05 +/- 0.13 mm in the lovastatin group (P = .01). Progression (a worsening in minimum diameter of one or more stenoses by > or = 0.4 mm) with no regression at other sites occurred in 48 of 146 lovastatin and 76 of 153 placebo patients (33% versus 50%, P = .003). New coronary lesions developed in 23 lovastatin and 49 placebo patients (P = .001). The beneficial effect of treatment was most pronounced in the more numerous, milder lesions and in patients whose baseline total or LDL cholesterol levels were above the group median. Lovastatin slows the progression of coronary atherosclerosis and inhibits the development of new coronary lesions.",1994.0,1,1 2693,8148715,Measuring prescribing: the shortcomings of the item.,S M Bogle; C M Harris,"To assess the validity of the item as a measure of the volume of a drug prescribed; and to investigate the possibility that higher quantities per item are prescribed for patients who are not exempt from the prescription charge. Five substudies. For the first, a frequency distribution was derived of the different quantities per item of 10 commonly used drugs prescribed by 20 randomly selected practices in each of five family health service authority areas. For the second, the variation in average quantity per item for the same drugs in the same practices was calculated. For the third and fourth, variation in average quantity per item for 90 commonly used drugs was calculated for all 90 family health service authorities and for all 14 regional health authorities in England. For the fifth, the average quantity per item for each of the 90 drugs was regressed on the percentage of items exempt from the prescription charge, at family health service authority level, and the percentage of variation explained by the regression found. Distribution of quantity per item; variation in average quantity per item between the practices, between family health service authorities, and between regions; and percentage of variation between family health service authorities accounted for by exemption from the prescription charge. Wide variation was found in the quantities per item prescribed by the practices, and in the average quantity per item between practices and between family health service authorities. No family health service authority was consistently high or low in quantity per item across the 90 drugs. Variation in average quantity per item was less at regional than at family health service authority level, though still high for many of the drugs. The proportion of variation accounted for by exemption from prescription charges ranged from 0% to 49% across the 90 drugs. The item is unsuitable as a measure of prescribing volume, even at regional level: a new measure, based on standard daily dosages, is needed. The percentage of the variation in quantity per item accounted for by exemption is inconsistent, and in over half the 90 drugs it was below 20%--therefore it is not a useful predictor.",1994.0,0,0 2694,8149518,,,,,0,0 2695,8149677,I-123 metaiodobenzylguanidine--thallium-201 mismatch following myocardial infarction.,J Lekakis; A Antoniou; N Vassilopoulos; D Tsinikas; C Palaistides; P Kostamis; S Moulopoulos,"Experimental data show that myocardial infarction (MI) results in regional depletion of myocardial catecholamines more extensively than necrosis. To investigate the extent of adrenergic denervation post MI in humans, we examined 16 patients, 59 +/- 12 years old, with recent (7-12 days) MI. Resting thallium-201 (201Tl) single photon emission computerized tomography (SPECT) imaging was performed to assess necrosis; metaiodobenzylguanidine I123 (MIBG) SPECT was used to evaluate adrenergic denervation. 201Tl and I123 MIBG defects were evaluated quantitatively using polar maps, and differences in defects were expressed as percent of total polar map. In all patients, I123 MIBG defect was larger than 201Tl defect, and difference ranged from 19 to 61% (39.5 +/- 13.2%). Thrombolysis and age > 60 did not influence the difference. Anterior MI showed larger differences (44 +/- 13 vs. 32 +/- 11%, p < 0.05); patients with ischemic electrocardiographic (ECG) changes in leads without abnormal Q waves had larger differences (45 +/- 9 vs. 33 +/- 14%, p < 0.05). It was concluded that (a) patients with recent MI present denervation larger than 201Tl perfusion defect, and (b) patients with anterior MI and ischemic ECG changes present a larger area of denervation.",1994.0,0,0 2696,8154645,The association between cholesterol and death from injury.,P Cummings; B M Psaty,"To review the association between low serum cholesterol and death from injury. Relevant English-language papers identified through MEDLINE and Current Contents searches and bibliographies of identified articles. More than 150 articles were reviewed to identify data, meta-analyses, or important reviews of the association between low cholesterol and injuries. Estimates of the association between cholesterol and death from injury were extracted from published reports. Animal studies and descriptive studies have provided little information about serum cholesterol and injuries. The Conference on Low Blood Cholesterol pooled results from 14 cohort studies in men and found a relative risk of 1.4 for death from injury in men whose cholesterol levels were lower than 4.14 mmol/L (160 mg/dL) compared with men whose cholesterol levels were 4.14 to 5.15 mmol/L (P = 0.003). Most cohort studies support this finding. The strongest evidence that cholesterol and death from injury are related comes from a meta-analysis of six randomized cardiac primary prevention trials of cholesterol reduction; the relative risk for death from injury for treated men compared with controls was 1.42 (95% Cl, 0.94 to 2.15). In cohort studies, the strength of the association between low serum cholesterol levels and subsequent death from injury is weak and may be caused by confounding factors such as socioeconomic status. The modestly elevated risk ratio found in a meta-analysis of trials of cholesterol reduction in men is of borderline statistical significance. This association may be related to efforts to lower cholesterol rather than to low absolute levels of serum cholesterol. Until more data are available, the hypothesized relation between low cholesterol and injuries remains unsettled.",1994.0,0,0 2697,8157036,Efficacy and safety of high dose fluvastatin in patients with familial hypercholesterolaemia.,E Leitersdorf; S Eisenberg; O Eliav; N Berkman; E J Dann; D Landsberger; E Sehayek; V Meiner; T K Peters; E N Muratti,"The efficacy and safety of the HMG CoA reductase inhibitor fluvastatin have been evaluated in a double blind study in 52 patients with familial hypercholesterolaemia. A standard AHA Phase II lipid lowering diet was prescribed throughout the study. After 6 weeks of a single blind dosage stabilisation period, in which patients received fluvastatin 40 mg qPM, patients were randomly allocated to one of two double blind treatment groups: group A (n = 24) received fluvastatin 20 mg b.d. for 12 weeks and fluvastatin 20 mg AM + 40 mg PM for an additional 12 weeks; Group B (n = 28) received fluvastatin 40 mg qPM during the entire study. Safety and tolerability were evaluated by the analysis of biochemical and haematological parameters, and ophthalmological and physical examinations. Efficacy was analysed by the determination of plasma lipids, lipoproteins and apoproteins. Fluvastatin 40 mg/d was associated with up to a 27.4% decrease in LDL-C and a 9.6% increase in HDL-C concentrations. Increasing the dose of fluvastatin from 20 mg b.d. to 60 mg per day in Group A was associated with a 7.1% decrease in LDL-C, a 12.1% increase of HDL-C and a 12.8% decrease in the LDL-C/HDL-C ratio. In comparison with Group B (40 mg qPM) LDL-C, HDL-C and the LDL-C/HDL-C ratio in Group A (60 mg) differed by -8.9%, 6.6% and -12%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)",1993.0,0,0 2698,8162627,A randomized pilot trial of low-dose combination lipid-lowering therapy following coronary artery bypass grafting.,M Barbir; B J Hunt; D Galloway; A Taylor; C Ilsley; A Mitchell; M Yacoub,"Vein graft atherosclerosis is a common and serious complication of coronary artery bypass grafting (CABG). There is mounting evidence that lipoprotein abnormalities play an equally important role in the development of lesions in saphenous vein grafts after CABG as in native coronary vessel disease. The potential benefit of low-dose lipid lowering combination therapy in these patients has not been investigated. In a randomized, double-blind, placebo-controlled study, we compared the efficacy and safety of a low-dose combination of colestipol 10 g and simvastatin 10 mg/day (CS) to colestipol 10 mg and bezafibrate 400 mg/day (CB) for 2 months in 33 patients with serum total cholesterol > 6.5 mmol/l and triglyceride < 4.5 mmol/l who had undergone CABG for severe coronary artery disease. In the CS group, total cholesterol decreased by 29% and low-density lipoprotein (LDL) cholesterol by 42%; similarly, CB reduced total cholesterol by 17%, LDL cholesterol by 23%, triglyceride by 19%, and increased high-density lipoprotein (HDL) cholesterol by 14%. Lipoprotein (a) and hemostatic factors were unaffected by either therapy in this study. Both combination therapies were well tolerated with no significant clinical or biochemical side effects. We conclude that low-dose combinations of colestipol and simvastatin or colestipol and bezafibrate are effective and well tolerated in the management of moderate hyperlipidemia in patients who had undergone CABG.",1994.0,0,0 2699,8166080,"Comparison of the efficacy, safety and tolerability of simvastatin and pravastatin.",J Emmerich,,1994.0,0,0 2700,8166438,Effects of isoprenoids on growth of normal human mammary epithelial cells and breast cancer cells in vitro.,O Larsson,"The possible growth regulatory role of isoprenoids (mevalonate-derived products) in secondary cultures of normal human mammary epithelial cells (HMEC), as compared to the two human breast cancer cell lines Hs578T and MDA231, was investigated. All three cell types responded promptly to inhibitors of HMG CoA reductase and thereby became arrested. Whereas the growth of MDA231 cells was totally independent of exogenous growth factors, the proliferation of HMEC and Hs578T was blocked or partially blocked, respectively, following growth factor-depletion. Closer analysis showed that the depressive effects on cell growth, induced by HMG CoA reductase inhibition and growth factor depletion, were from a kinetic point of view identical. These data suggest that the biosynthesis of isoprenoids may comprise one event involved in the intracellular mechanisms lying behind the growth factor-mediated growth of mammary epithelial cells. The effects of addition of different known isoprenoids on growth of cells subjected to HMG CoA reductase inhibition or growth factor depletion were also investigated. It was found that coenzyme Q and dolichol significantly delayed growth arrest in all three cell types. In contrast, cholesterol and isopentenyladenine were ineffective.",1994.0,0,0 2701,8172091,Method of administration influences the serum cholesterol-lowering effect of psyllium.,T M Wolever; D J Jenkins; S Mueller; D L Boctor; T P Ransom; R Patten; E S Chao; K McMillan; V Fulgoni,"To determine whether psyllium must be mixed with food to lower serum cholesterol, 18 modestly hypercholesterolemic subjects were studied for three 2-wk periods, in random order, separated by a 2-wk return to a National Cholesterol Education Program Step 2 diet. Compared with values for subjects consuming control wheat-bran cereal (63 g/d), after 2 wk of 54 g psyllium-enriched cereal/d containing 7.3 g psyllium, serum total, LDL, and HDL cholesterol, respectively, were reduced by 8% (6.15 +/- 0.15 vs 6.71 +/- 0.19 mmol/L, P < 0.01), 11% (4.24 +/- 0.15 vs 4.78 +/- 0.19 mmol/L, P < 0.02), and 7% (0.99 +/- 0.05 vs 1.07 +/- 0.05 mmol/L, P < 0.01). When 7.6 g of the same type of psyllium as in the test cereal was taken between meals, serum total (6.50 +/- 0.19 mmol/L), LDL (4.50 +/- 0.21 mmol/L), and HDL (1.06 +/- 0.06 mmol/L) cholesterol were no different from control values, and total cholesterol was greater than after psyllium cereal (P < 0.05). We conclude that psyllium must be mixed with foods to have the maximum effect on serum cholesterol.",2001.0,0,0 2702,8179675,Lovastatin in pravastatin comparative trial: cost-effectiveness.,S Farbstein,,1994.0,0,0 2703,8180510,"Recent advances in lipoprotein and atherosclerosis research at Baylor College of Medicine. Apolipoprotein B, lipoprotein[a], and transplantation arteriopathy.",C M Ballantyne; L Chan; J Guevara; J D Morrisett; M P Mims; A M Gotto,"A multidisciplinary team approach with focused objectives characterizes research at Baylor College of Medicine into the causes, prevention, and treatment of atherosclerotic disease. Current clinical activities range from programs to modify lifestyle for the primary prevention of coronary artery disease to a large, angiographically monitored lipid-lowering trial. In basic research, much attention has been focused on the plasma lipoproteins and their roles in atherogenesis. The current review highlights recent advances in ongoing basic research involving 1) apolipoprotein (apo) B, whose form apo B-100 serves as a ligand for the low-density lipoprotein receptor; 2) lipoprotein[a], elevated plasma levels of which are predictive of atherosclerotic disease; and 3) transplantation arteriopathy, which impedes long-term survival of cardiac transplant recipients.",2001.0,0,0 2704,8182841,Endocrinology.,N B Watts; L S Blevins,We now have conclusive proof that intensive treatment reduces the microvascular complications of IDDM. ACE inhibitors appear to slow the progression of established nephropathy. Drug-induced malabsorption has the potential to increase levothyroxine dose requirement.,2001.0,0,0 2705,8184812,Comparison of effects on sleep of lovastatin and pravastatin in hypercholesterolemia.,M Partinen; S Pihl; T Strandberg; H Vanhanen; E Murtomäki; G Block; R Neafus; J Haigh; T Miettinen; S Reines,"The effects on sleep of lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor administered as a lipophilic lactone prodrug, and pravastatin, an inhibitor administered in its active, hydrophilic, open-acid form, were compared by polysomnographic sleep monitoring. Twenty-four men with primary hypercholesterolemia (low-density lipoprotein 4 to 7 mmol/liter) each received 2 of the following 3 treatments in a randomized, incomplete block, crossover design study: lovastatin (40 mg/day), pravastatin (40 mg/day), and placebo. Test drug was administered once daily for 4 weeks during each half of the crossover study. Subjective sleep assessments were obtained throughout each treatment period, and polysomnographic recordings were obtained at the end of the 4-week treatment periods. Treatment periods were separated by a 1-week washout. Lovastatin did not differ from placebo regarding any polysomnographic parameter except ""number of entries to wake,"" for which it produced fewer entries (i.e., change was in the direction of improvement). Pravastatin did not differ from placebo regarding any polysomnographic measures, but was associated with worsening in relation to lovastatin in the following parameters: sleep efficiency, entries to wake, percent rapid eye movement sleep, wake time during sleep, and total wake time. For each of these 4 parameters, although neither drug showed marked differences from placebo, the mean change in the lovastatin group was in the direction of improved sleep, whereas the change in the pravastatin group was in the direction of disturbed sleep. Neither lovastatin nor pravastatin had any effect on subjective, qualitative sleep ratings.(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2706,8185133,Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease.,D J Rader; J M Hoeg; H B Brewer,"To review current knowledge of apolipoprotein quantitation used in the clinical management of persons with or at risk for the development of premature coronary artery disease. The English-language literature was analyzed using MEDLINE (1975 to 1993) with key words ""apolipoproteins,"" ""quantitation,"" and ""coronary artery disease."" Article bibliographies were also reviewed to obtain additional references. Published, peer-reviewed retrospective and prospective studies relevant to the association of plasma apolipoprotein levels with coronary artery disease in humans. Most studies concerned apolipoprotein A-I (apo A-I), apolipoprotein B (apo B), and lipoprotein(a) [Lp(a)]. In retrospective cross-sectional studies, apo A-l levels were not substantially more predictive of coronary artery disease than were high-density lipoprotein (HDL) cholesterol levels. In contrast, levels of apo B and Lp(a) were often more strongly associated with coronary artery disease than were traditional lipid measurements. In studies of the relation between apolipoprotein levels in children and premature coronary artery disease in their parents, Lp(a) levels, but not apo A-l and apo B levels, were consistently predictive of familial coronary artery disease. Prospective studies have yielded variable results for all three apolipoproteins. Low apo A-l levels were consistently associated with coronary artery disease in six prospective studies but were not more predictive than HDL levels. Apolipoprotein B levels were strongly associated with coronary artery disease in four of five prospective studies but were more predictive of coronary artery disease than were total cholesterol levels in only two of the four studies. Lipoprotein(a) levels were strongly associated with coronary artery disease in five of seven prospective studies but were not associated in two of the four largest studies. Too few large prospective studies of apolipoprotein quantitation using validated assay methods, both in general unselected populations and in subgroups of persons with premature coronary artery disease or family histories of premature coronary artery disease, are available to make definitive recommendations concerning clinical utility. The data do not support use of apolipoprotein quantitation as a screening tool to predict coronary artery disease risk in the general population. However, the data suggest that quantitation of apo B and Lp(a) may be indicated in subgroups of persons with premature coronary artery disease or with family histories of premature coronary artery disease. In these persons, an increased apo B or Lp(a) level or both could be a clinical indication for more aggressive treatment of low-density lipoprotein cholesterol.",2001.0,0,0 2707,8187355,Effects of simvastatin on lipoprotein (a) and lipoprotein composition in patients with nephrotic syndrome.,C Wanner; J Böhler; H G Eckardt; H Wieland; P Schollmeyer,"The influence of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase, on quantitative and qualitative changes in lipoprotein metabolism was investigated in 18 patients (group I, 10 with primary kidney disease and group II, 8 with diabetic nephropathy) with nephrotic syndrome. Nephrotic patients exhibited severe hyperlipidemia (serum cholesterol 390 +/- 17 mg/dl and triglyceride 335 +/- 42 mg/dl; mean +/- SEM) and had significantly higher lipoprotein (a) [Lp(a)] levels (54 +/- 12 mg/dl; median 31 mg/dl, p < 0.01) compared with 20 healthy subjects (mean 12 +/- 1.8 mg/dl; median 7 mg/dl). Fifty-six percent of the patients and 15% of the controls had values greater than 30 mg/dl. Treatment with simvastatin in increasing doses over a period of three months (13 patients received 40 mg/day and 5 patients 20 mg/day at the end of the third month) reduced LDL-cholesterol in both groups of patients (35% and 54%) as well as apolipoprotein B (apoB) (31% and 46%) significantly, but Lp(a) levels were not influenced (57 +/- 21 vs 59 +/- 20 and 50 +/- 14 vs 53 +/- 16 mg/dl, respectively). On the other hand a complex change in lipoprotein composition occurred. The ratio of LDL apoB/LDL cholesterol-ester increased significantly (0.75 +/- 0.03 to 0.84 +/- 0.03 and 0.80 +/- 0.03 to 1.02 +/- 0.1, respectively) and cholesterol concentration in VLDL (64 +/- 16 to 39 +/- 7 and 74 +/- 18 to 55 +/- 74 mg/dl, respectively) was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0 2708,8192170,Efficacy and safety of a combination fluvastatin-bezafibrate treatment for familial hypercholesterolemia: comparative analysis with a fluvastatin-cholestyramine combination.,E Leitersdorf; E N Muratti; O Eliav; V Meiner; S Eisenberg; E J Dann; E Sehayek; T K Peters; Y Stein,"Familial hypercholesterolemia (FH) carries a markedly increased risk for coronary artery disease (CAD). Reduction of plasma low-density lipoprotein cholesterol (LDL-C) levels to the normal range may prevent premature atherosclerosis and usually requires a combination of cholesterol-lowering drugs. The major objective of this study is to compare two different drug combinations for the treatment of heterozygous FH. The current investigation is a short-term, double-blind study comparing the efficacy and safety of fluvastatin when combined with cholestyramine (group 1) or with bezafibrate (group 2) in 38 patients with heterozygous FH. After 6 weeks of combination treatment, in comparison to a drug-free baseline (patients receiving single-blind placebo during the lead-in period of an earlier study, ie, before ever receiving fluvastatin), the combination of 40 mg/d of fluvastatin with 400 mg/d of bezafibrate in group 2 reduced plasma LDL-C levels by 35% as compared with 32% in group 1, and reduced the LDL-C/high-density cholesterol (HDL-C) ratio by 46%, compared to 37% in group 1 (a non-significant difference for both comparisons). When compared to an intermittent 6-week open-label administration of 40 mg fluvastatin monotherapy, the addition of cholestyramine or bezafibrate each reduced LDL-C by an additional 13% (P < 0.01 for both regimens). Fluvastatin-bezafibrate is superior to a fluvastatin-cholestyramine combination for lowering serum triglycerides and elevating HDL-C serum levels in patients in conjunction with a significant lowering of LDL-C/HDL-C ratios, and may be an effective synergistic therapy for heterozygous FH. No episodes of myositis were seen in this short-term study, a finding that is in agreement with most of the reported studies on statin-fibrate combinations reviewed here.",1994.0,0,0 2709,8193425,"Lipoprotein(A): physiologic function, association with atherosclerosis, and effects of lipid-lowering drug therapy.",S A Spinler; M J Cziraky,"To review the structure and physiologic function of lipoprotein(a) [Lp(a)], review the association of Lp(a) with the development of atherosclerosis, and to critically evaluate the current literature regarding the effects of lipid-lowering drug therapy on Lp(a) serum concentrations. English language clinical and animal studies, abstracts, and review articles pertaining to Lp(a). Relevant human and animal studies examining Lp(a)'s role in atherosclerosis and the effect of drug therapy on Lp(a) serum concentrations. Possible physiologic functions and potential atherogenic mechanisms of Lp(a) are discussed. Evidence supporting the association of Lp(a) with atherosclerosis is presented. Studies evaluating the effects of lipid-lowering drug therapy on Lp(a) concentrations are reviewed and critiqued. Lp(a) concentrations are correlated with the risk of atherosclerotic vascular disease (AVD) in both animals models and human studies. Drug therapies that have produced a consistent reduction in Lp(a) concentration include niacin alone or in combination with a bile acid sequestrant or neomycin. However, additional, larger studies are needed to evaluate the ability of drug therapies to specifically reduce elevated Lp(a) concentrations. Preliminary information suggests that reduction in Lp(a) concentrations may be associated with atherosclerotic plaque regression. Although drugs are available to lower Lp(a), one cannot conclude that lowering of Lp(a) is warranted until clinical trials demonstrating beneficial effects have been published.",1994.0,0,0 2710,8196151,The effect of pravastatin on prevention of restenosis after successful percutaneous transluminal coronary angioplasty.,H Onaka; Y Hirota; Y Kita; R Tsuji; K Ishii; T Ishimura; K Kawamura,"Numerous attempts have been made to prevent late restenosis after successful percutaneous transluminal coronary angioplasty (PTCA), but there is still no effective treatment. This report describes the effect of an oral lipid-lowering agent, pravastatin, on restenosis after successful PTCA. Sixty-six patients who underwent successful elective PTCA were assigned to a pravastatin-treated group (Group 1, n = 29) or an untreated group (Group 2, n = 37) in a prospective and randomized fashion. Pravastatin (5 mg or 10 mg twice a day) was given to Group 1 patients from day 3 after the procedure. Selective coronary angiography was repeated 3 to 5 months later, or sooner if the patient developed angina pectoris. The serum cholesterol level was decreased significantly in Group 1 (from 215.7 +/- 44.3 mg/dl to 181.2 +/- 30.3 mg/dl, p < 0.001), but not in Group 2 (from 191.9 +/- 30.8 mg/dl to 191.8 +/- 33.3 mg/dl, p = ns), at the time of repeat coronary angiography. However, there were no differences between the groups with regard to the recurrence of angina, the need for repeat PTCA, or restenosis, as assessed by quantitative analysis of coronary cineangiograms. These results suggest that oral pravastatin therapy does not effectively prevent late restenosis after successful PTCA by this mode of administration.",1994.0,0,0 2711,8198043,"Pravastatin, lipids, and major coronary events.",C D Furberg; R P Byington; J R Crouse; M A Espeland,,1994.0,0,1 2712,8198930,"Do cholesterol-lowering agents affect brain activity? A comparison of simvastatin, pravastatin, and placebo in healthy volunteers.",R W Harrison; C H Ashton,"1. The effects of simvastatin and pravastatin on measures of central nervous system activity were investigated in a double-blind, placebo-controlled, randomised crossover study. 2. Twenty-five healthy volunteers sequentially took 40 mg day-1 simvastatin, 40 mg day-1 pravastatin or placebo for 4 weeks, separated by a 4-6 week washout phase. 3. CNS measures included EEG evoked potentials, power spectral analysis, Leeds Sleep Questionnaire, Hospital Anxiety Depression (HAD) Scale, and Digit Symbol Substitution Test (DSST); biochemical measures included plasma cholesterol, liver enzymes (gamma-GT, AST, ALT) and creatine kinase. 4. Mean cholesterol concentrations with both drugs were significantly lower than with placebo, and the cholesterol-lowering effect was greater with simvastatin. There were no significant differences between treatment in EEG evoked potentials, HAD Scale, or DSST scores. On the sleep measure, subjects reported significantly greater difficulty in getting to sleep while on simvastatin than on pravastatin, but neither score differed from placebo. No significant correlations were observed between sleep ratings and either plasma cholesterol concentrations or EEG evoked potentials. 5. The study showed that, while both drugs reduced plasma cholesterol concentrations, neither exerted significant effects, compared with placebo, on EEG evoked potentials, mood, sleep, or cognitive performance after 4 weeks of chronic administration in healthy volunteers.",1994.0,0,0 2713,8199696,Effects of pravastatin and ursodeoxycholic acid on cholesterol and bile acid metabolism in patients with cholesterol gallstones.,S Okamoto; K Nakano; K Kosahara; M Kishinaka; H Oda; H Ichimiya; K Chijiiwa; S Kuroki,"To investigate the effects of pravastatin and ursodeoxycholic acid (UDCA) on cholesterol and bile acid metabolism in humans, 41 patients with cholesterol gallstone disease were allocated to four groups and treated with pravastatin (20 mg/day), UDCA (600 mg/day), both pravastatin and UDCA, or neither drug (control) for 1-2 weeks prior to elective cholecystectomy. Cholesterol 7 alpha-hydroxylase activity and serum levels of total 7 alpha-hydroxycholesterol were significantly increased by pravastatin and unaffected by UDCA. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity was markedly increased by pravastatin and decreased by UDCA. UDCA significantly decreased biliary cholesterol concentration and the cholesterol saturation index and prolonged the nucleation time; however, pravastatin alone had little effect on biliary lithogenicity. Serum total and low-density lipoprotein (LDL)-cholesterol levels were reduced most by the combined administration of pravastatin and UDCA. In conclusion, at a dose of 20 mg/day, pravastatin increased bile acid synthesis but did not decrease biliary lithogenicity. UDCA had no significant effect on bile acid synthesis, but markedly decreased biliary lithogenicity.",1994.0,0,0 2714,8200011,"[Efficacy and tolerability of simvastatin and omega-3 fatty acid combination in patients with coronary disease, hypercholesterolemia and hypertriglyceridemia].",R Tomei; L Rossi; E Carbonieri; L Franceschini; C Cemin; K Ghebremariam-Tesfau; P Zardini,"Patients with ischemic heart disease are often affected by a mixed hyperlipoproteinemia, where a hypercholesterolemia of various severity is accompanied by slight or moderate hypertriglyceridemia (type IIb dyslipidemia). Current epidemiologic evidence suggests that hypertriglyceridemia has not to be disregarded, particularly in certain subgroups of patients. We evaluated the effect of the association of simvastatin 10 mg/day [an hydroxymethyl-glutaryl-CoA (HMG-CoA) reductase inhibitor] and omega-3 polyunsaturated fatty acids (n3-PUFA) in comparison with simvastatin 10 mg/day alone. The subjects undergoing the study were affected by coronary artery disease and showed hypercholesterolemia (LDL-cholesterol > 160 mg/dl) and moderate hypertriglyceridemia (serum triglycerides 200-400 mg/dl) after 2 months of moderate dietary therapy for hyperlipidemia (Step 1 of the National Cholesterol Education Program [NCEP]). Thirty-nine patients were randomized to have 1 of 2 scheduled treatments. At the same time the patients underwent severe dietary therapy for hyperlipidemia (Step 2 of the NCEP). After 3 months of treatment, total-cholesterol, LDL-cholesterol, and triglycerides were significantly lower than basal values in both groups (p < 0.05). Total-cholesterol, LDL-cholesterol, and triglycerides were lower in the group treated with n3-PUFA and simvastatin compared to simvastatin alone. However, only for triglycerides was the difference significant (-39.99% in patients treated with n3-PUFA and simvastatin versus -25.65% in patients treated with simvastatin alone, particularly in the first group of 35.85%; p < 0.05). With regard to HDL-cholesterol, the differences between the basal values and the 2 groups of treatments were non significant. Remarkable side effects were not observed in the 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS)",1993.0,0,0 2715,8205598,Therapeutic use of lovastatin in the treatment of hypercholesterolemia.,D R Illingworth,"The present review discusses the mechanism of action, efficacy, safety profile, and potential uses of lovastatin in patients with hypercholesterolemia. Data on the efficacy of lovastatin are evaluated in different patient populations; also, the efficacy of this agent in the long-term treatment of patients followed by the author is presented. No new safety concerns have emerged during long-term treatment of selected patients with lovastatin, and, in compliant patients, hypolipidemic effects are maintained during continuous treatment with therapy that exceeds 5 years. On the basis of available data, lovastatin should be regarded as one of the drugs of first choice in the treatment of adult patients with hypercholesterolemia and increased plasma concentrations of low-density lipoproteins.",1994.0,0,0 2716,8205659,Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia.,K Egashira; Y Hirooka; H Kai; M Sugimachi; S Suzuki; T Inou; A Takeshita,"This study aimed to determine if cholesterol-lowering therapy improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Nine patients with hypercholesterolemia were studied before and after cholesterol-lowering therapy with pravastatin (an inhibitor of HMG-CoA reductase) for 6 +/- 3 months, which lowered serum cholesterol from 272 +/- 8 to 187 +/- 16 mg/dL (P < .01). Control patients with serum cholesterol of 218 +/- 23 mg/dL also were studied twice in a similar interval (8 +/- 2 months) with no cholesterol-lowering drugs. Acetylcholine (the endothelium-dependent vasodilator) and papaverine and nitrate (endothelium-independent vasodilators) were infused into the study coronary artery. Changes in the diameter of the epicardial coronary artery and coronary blood flow were assessed by quantitative coronary arteriography and an intracoronary Doppler catheter. In patients with hypercholesterolemia, acetylcholine-induced vasoconstriction of the epicardial artery was less (P < .05) and the acetylcholine-induced increases in coronary blood flow were greater (P < .001) after than before pravastatin. In control patients, responses of the epicardial coronary artery and coronary blood flow to acetylcholine did not change over the follow-up period. The vasomotor responses to papaverine or nitrate were similar between the two groups, and no interval changes in their responses were noted in either group. These results suggest that cholesterol-lowering therapy with pravastatin may improve endothelium-dependent coronary vasomotion, which may possibly contribute to the improvement of myocardial perfusion as well as the regression of coronary atherosclerosis.",1994.0,0,0 2717,8208513,Inhibition of the membrane localization of p21 ras proteins by lovastatin in tumor cells possessing a mutated N-ras gene.,R Girgert; P Marini; A Janessa; G Bruchelt; J Treuner; P Schweizer,Mutated ras genes are found in a variety of human tumors. For biological activity the gene product p21 ras needs to be bound to the cell membrane by a farnesyl residue. Treatment of tumor cells with lovastatin reduces the availability of farnesyl pyrophosphate for the modification of the ras proteins. The membrane localization of p21 ras has been reduced by 30-36% after the tumor cells have grown in the presence of 10 microM lovastatin for 7 days. The extent of the inhibition depends on the growth kinetics of the cell lines.,1994.0,0,0 2718,8209875,Prevalence of subclinical atherosclerosis and cardiovascular disease and association with risk factors in the Cardiovascular Health Study.,L Kuller; N Borhani; C Furberg; J Gardin; T Manolio; D O'Leary; B Psaty; J Robbins,"The prevalence of subclinical atherosclerosis and cardiovascular disease was evaluated among the 5,201 adults aged > or = 65 years in four communities participating in the Cardiovascular Health Study from June 1989 through May 1990. A combined index based on electrocardiogram and echocardiogram abnormalities, carotid artery wall thickness and stenosis based on carotid ultrasound, decreased ankle-brachial blood pressure, and positive response to a Rose Questionnaire for angina or intermittent claudication defined subclinical disease. The prevalence of subclinical disease was 36% in women and 38.7% in men and increased with age. Among women, low-density lipoprotein cholesterol, systolic blood pressure, blood glucose, and cigarette smoking were positively associated, and high-density lipoprotein cholesterol negatively associated, with subclinical disease. In men, systolic blood pressure, blood glucose, and cigarette smoking were independent risk factors in multiple logistic regression analyses. The risk factors for subclinical disease are, therefore, similar to those for clinical disease at younger ages, especially among women. It is possible that older individuals with subclinical disease are at very high risk of developing clinical disease and that more aggressive interventions to prevent clinical disease should be oriented to individuals with subclinical disease.",1994.0,0,0 2719,8246234,"Inhibitors of cholesterol biosynthesis. 2. 3,5-Dihydroxy-7-(N-pyrrolyl)-6-heptenoates, a novel series of HMG-CoA reductase inhibitors.",P A Procopiou; C D Draper; J L Hutson; G G Inglis; B C Ross; N S Watson,"A series of 7-[2,3-diaryl-5-(1-methylethyl)-1H-pyrrol-1-yl]-3,5- dihydroxy-6-heptenoates was prepared and evaluated for its ability to inhibit the enzyme HMG-CoA reductase in vitro. Maintaining a 5-(1-methylethyl) substituent found to be optimal in related studies, structure-activity relationships were established for compounds modified at positions 2, 3, and 4 of the pyrrole ring. The 4-fluorophenyl group was preferred at the pyrrole 2-position, while incorporation of a range of substituted phenyl groups and pyridyl substituents at the 3-position provided compounds with equivalent enzyme inhibitory activities and widely different lipophilicities. Pentasubstituted pyrrole 3h was found to have a 10-fold greater potency than lovastatin.",1993.0,0,0 2720,8252687,Effects of intensive lipid-lowering therapy on the coronary arteries of asymptomatic subjects with elevated apolipoprotein B.,X Q Zhao; B G Brown; L Hillger; D Sacco; B Bisson; L Fisher; J J Albers,"Do the benefits of intensive lipid-lowering therapy seen in symptomatic patients extend to high-risk subjects who have never had symptoms? Of 120 men completing the FATS trial, 91 were symptomatic and 29 asymptomatic. All had apolipoprotein B > or = 125 mg/dL, a positive family history, and coronary atherosclerosis. All were counseled in diet and randomized to intensive therapy: colestipol 10 g TID plus either niacin 1 g QID or lovastatin 20 mg BID or to conventional therapy: placebos, or colestipol if low-density lipoprotein cholesterol was elevated. End points included quantitative arteriographic disease change and clinical events over a 2.5-year interval. At baseline, symptomatic and asymptomatic patients had comparable risk profiles, but proximal stenosis severity averaged 36% for symptomatic and 23% for asymptomatic patients (P < .001). Among the 91 symptomatic patients, those in the intensive group experienced definite (> or = 10%S) proximal lesion progression less frequently than conventional (24% of intensive versus 48% of conventional) and definite regression more frequently (36% of intensive versus 15% of conventional) (P = .009). Similarly, among the 29 asymptomatic patients, 19% of intensive versus 38% of conventional had progression and 31% of intensive versus 0% of conventional, regression (P = .04). Ischemia on baseline exercise tolerance testing was associated with significantly greater proximal disease progression among the asymptomatic patients. Clinical cardiovascular events (death, infarction, or revascularization) occurred in 10 of 38 symptomatic patients originally assigned to conventional therapy, compared with 5 of 76 symptomatic patients assigned to intensive (P < .01); no asymptomatic patient had an event. Asymptomatic subjects with this high-risk profile have less coronary disease at baseline than comparable symptomatic patients, and they have an excellent short-term clinical prognosis. However, asymptomatic subjects are indistinguishable from symptomatic patients in terms of their arterial disease progression with conventional therapy and their regression with intensive. These findings may justify an active treatment strategy in such subjects, particularly those with provokable ischemia.",1993.0,0,0 2721,8257447,Effects of pravastatin on apolipoprotein-specific high density lipoprotein subpopulations and low density lipoprotein subclass phenotypes in patients with primary hypercholesterolemia.,M C Cheung; M A Austin; P Moulin; A C Wolf; D Cryer; R H Knopp,"The HMG-CoA reductase inhibitor class of cholesterol-lowering agents reduces very low density lipoproteins (VLDL) and low density lipoproteins (LDL) and slightly increases high density lipoproteins (HDL). However, the effects of these agents on subclasses within the LDL and HDL fractions are not well understood. We have employed an HMG-CoA reductase inhibitor, pravastatin, to determine if LDL subclass phenotypes, as determined by gradient gel electrophoresis, and HDL particles containing both apolipoprotein (apo) A-I and A-II, Lp(AI w AII), and those containing apo A-I but not A-II, Lp(AI w/o AII) are affected by pravastatin (10 mg daily). Twenty-four subjects with LDL-cholesterol (LDL-C) > 160 mg/dl, triglyceride (TG) < 350 mg/dl and no recent myocardial infarction or secondary causes of hypercholesterolemia were enrolled. Compared with an age- and sex-matched normolipidemic reference group (controls), the hypercholesterolemic subjects had reduced levels of Lp(AI w/o AII) and increased levels of Lp(AI w AII) at baseline. In addition, both of their HDL subpopulations had significantly more small (7.0-8.2 nm) particles (P < 0.02 and 0.0001) but significantly fewer large (9.2-11.2 nm) particles (P < 0.002 and 0.0001). Pravastatin induced statistically significant (P < 0.001) reductions in plasma total C (15%), LDL-C (18%), and apo B (16%). While apo A-I and A-II levels increased 5% (P < 0.001) and 6% (P < 0.05), respectively, concentration, composition, and size abnormalities in Lp(AI w AII) and Lp(AI w/o AII) persisted. Lp(a), apo E and cholesteryl ester transfer protein (CETP) levels also did not change. Although changes in LDL subclass phenotypes were observed, all changes involved the intermediate phenotype, and no significant changes in LDL peak particle diameter were seen in either group. Interrelationships between CETP, LDL subclass phenotypes and HDL subpopulations were also seen. Although pravastatin decreased plasma apo B and LDL lipid concentrations, no major changes were seen in LDL subclass phenotypes or HDL subpopulations even in the presence of abnormalities associated with arteriosclerosis. Similarly, CETP, which is believed to play a role in HDL and LDL particle size distribution, did not change with pravastatin treatment. Further research is needed to determine the pathophysiological basis of abnormal HDL and LDL subclasses in hypercholesterolemia and explore methods of rectifying the abnormalities.",1993.0,0,0 2722,8262165,Effect of hydroxymethylglutaryl-CoA reductase inhibitors on the functional properties of erythrocyte membranes.,R A Rabini; M Polenta; R Staffolani; M Tocchini; R Signore; I Testa; L Mazzanti,"We studied 56 patients affected by primary hypercholesterolemia treated with placebo for 1 month and with simvastatin (20 mg/day) or pravastatin (20 mg/day) for 6 months during a double-blind clinical trial. At 1-month intervals we determined the following parameters in the serum: total and HDL cholesterol, triglycerides, and apolipoprotein A-1 and B. At the same time intervals we also determined the cholesterol and phospholipid concentration, the Na+/K+ ATPase activity, and the fluidity of erythrocyte membranes. Our results demonstrated the following modifications in the erythrocyte membranes during simvastatin and pravastatin treatments: (1) an initial increase in cholesterol concentration and in cholesterol/phospholipid molar ratio, with a significant decrease only after 4 months; (2) a similar behavior of membrane fluidity, with an initial decrease and an elevation after 4 months; (3) an increase in the Na+/K+ ATPase activity only after 4 months. We hypothesize that simvastatin and pravastatin not only inhibit the hepatic synthesis of cholesterol, but also modify the cholesterol exchange between plasma and the erythrocyte membrane.",1993.0,0,0 2723,8264145,Simvastatin therapy for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria.,M E Thomas; K P Harris; C Ramaswamy; J M Hattersley; D C Wheeler; Z Varghese; J D Williams; J Walls; J F Moorhead,"Experimental evidence suggests that lipid lowering therapy could slow the progression of renal disease in humans. We have conducted a double-blind, placebo controlled trial of the HMG CoA reductase inhibitor simvastatin in patients with the nephrotic syndrome or significant proteinuria (> 1 g/day) and hypercholesterolemia (> or = 6.5 mmol/liter). Patients were placed on a lipid lowering diet for at least 10 weeks before randomization. After a four-week placebo run-in, 30 adults were randomized to simvastatin or placebo therapy (10 mg/day, increasing to 20 to 40 mg/day as required) for 24 weeks. There were seven dropouts, none of whom were ""definitely"" related to drug therapy. Total and LDL cholesterol levels fell by a mean of 33 and 31%, respectively, in simvastatin treated patients, compared with only 5 and 1% in patients on placebo (P < 0.001, P = 0.002, respectively). Apolipoprotein B100 levels fell by a mean of 31% in the simvastatin group but rose 0.3% in the placebo group (P = 0.014). There were no significant changes in HDL levels. There were no significant differences between the groups in their urine protein levels, their rise in plasma creatinine, or decline in plasma inulin clearance. Simvastatin is a safe, effective therapy for hypercholesterolemia in proteinuric states. A much larger trial is needed to show if potent lipid-lowering therapy slows progression of hypercholesterolemic proteinuric diseases.",1993.0,0,0 2724,8267492,"Lipoprotein responses to treatment with lovastatin, gemfibrozil, and nicotinic acid in normolipidemic patients with hypoalphalipoproteinemia.",G L Vega; S M Grundy,"The lipoprotein responses to conventional lipid-modifying drugs have not been adequately evaluated in normolipidemic patients with hypoalphalipoproteinemia (low levels of high-density lipoproteins). The purpose of this study was to compare responses to lovastatin, gemfibrozil, and nicotinic acid in such patients. The first phase of the study compared lipoprotein responses to lovastatin and gemfibrozil in 61 middle-aged men with low levels of high-density lipoproteins. In the second phase, 37 patients agreed to take nicotinic acid; 27 patients finished this phase at a dose of 4.5 g/d. Nicotinic acid results were compared with those with lovastatin and gemfibrozil in the same patients. In the first phase, both drugs effectively lowered triglyceride levels. Gemfibrozil therapy increased high-density lipoprotein cholesterol levels by 10% and lovastatin by 6%, but lovastatin was much more effective for reducing low-density lipoprotein levels. Nicotinic acid did not significantly lower low-density lipoprotein levels in the second phase, but it raised high-density lipoprotein levels by 30%. Gemfibrozil therapy produced the least favorable response of the three drugs. Lovastatin markedly lowered low-density lipoprotein levels but only modestly raised levels of high-density lipoprotein, whereas nicotinic acid had the opposite effect. Consequently, the latter two drugs similarly reduced low-density lipoprotein-high-density lipoprotein ratios, although these effects were obtained in different ways. Between these two drugs, lovastatin therapy was more likely to reduce low-density lipoprotein cholesterol levels to below 2.6 mmol/L (100 mg/dL), and in view of recent recommendations, it may be preferable to nicotinic acid for many normolipidemic patients with established coronary heart disease.",1994.0,0,0 2725,8269217,Pharmacologic prevention of restenosis after coronary angioplasty: review of the randomized clinical trials.,S M Franklin; D P Faxon,,1993.0,0,0 2726,8269456,Experimental use of pravastatin in patients with primary biliary cirrhosis associated with hypercholesterolemia.,T Kurihara; M Akimoto; K Abe; H Ishiguro; A Niimi; A Maeda; M Shigemoto; K Yamashita; I Yokoyama; Y Suzuki,"Primary biliary cirrhosis (PBC) is a refractory liver disease for which no medical treatment has been established. The investigators administered 20 mg/day of pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, to 2 PBC patients with hypercholesterolemia (1010 and 306 mg/dl) for 3 years and 10 months in order to decrease the blood concentration of bile acids and prevent adverse effects on the hepatocellular membrane. The drug markedly decreased not only cholesterol levels but also total bile acid levels, producing particularly pronounced decreases in cholic acid and chenodeoxycholic acid. Histologically, progression was inhibited in one patient, whereas improvement was seen in the other. Bile duct enzymes and other biochemical parameters showed improvement in both cases. General pruritus and blepharal and palmar xanthoma also improved. These findings suggest that pravastatin may be useful in the treatment of PBC associated with hypercholesterolemia.",1993.0,0,0 2727,8276043,Actual versus prescribed timing of lovastatin doses assessed by electronic compliance monitoring.,W Kruse; T Nikolaus; J Rampmaier; E Weber; G Schlierf,"The objective of the study was to compare compliance with and the hypocholesterolaemic effect of lovastatin given once daily as a morning or an evening dose. Twenty-four out-patients with familial hypercholesterolaemia were randomly assigned to receive placebo first, then lovastatin 20 mg, to be taken once daily for 4 weeks, either with the breakfast or evening meal, in a single-blind fashion. Drug compliance was assessed by pill counts and continuous electronic monitoring. Two compliance parameters were evaluated, consumption, defined as percentage of prescribed doses taken, and time compliance, the percentage of total dosing events recorded within defined intervals (6.00-10.00 h, and 17.00-21.00 h), for the morning and evening regimes. Both regimes satisfactorily reduced the total and LDL-cholesterol concentrations, and there was no significant difference in the extent of the reductions. Pill counts overestimated compliance, as revealed by the monitoring method. The times of actual consumption of doses by the patients often differed from that prescribed, predominantly in patients who were told to take the evening dose. Partial time compliance may have confounded the efficacy of the drugs. Electronic compliance monitoring appears to be particularly useful in chronopharmacological studies.",1993.0,0,0 2728,8279377,Characteristics and radiofrequency ablation therapy of intermediate septal accessory pathway.,S J Yeh; C C Wang; M S Wen; F C Lin; C C Koo; Y S Lo; D Wu,"Fourteen patients (5%) with an intermediate septal accessory pathway were identified among 283 consecutive patients with the Wolff-Parkinson-White syndrome who had electrophysiologic study and radiofrequency ablation therapy. Nine were women and 5 were men (mean age 33 +/- 13 years). The resting electrocardiogram showed ventricular preexcitation in 8 patients and normal PR interval in 6. Anterograde and retrograde mapping studies revealed that the accessory pathway was para-Hisian in 11 patients and paranodal in 3. The accessory pathway was successfully ablated in 10 patients (9 para-Hisian and 1 paranodal) and damaged in 1 (para-Hisian). Treatment of 3 patients was complicated by transient atrioventricular (AV) block, of 1 by intermittent second-degree AV block, and of another by permanent complete AV block requiring implantation of a permanent pacemaker. Six patients underwent a follow-up electrophysiologic study 84 +/- 55 days after ablation; none had induction of tachycardia even after isoproterenol infusion. It is concluded that radiofrequency ablation therapy for intermediate septal accessory pathway is feasible. However, the success rate is only modest (71%), whereas complications with heart block (36%) or complete right bundle branch block (29%) are high. Thus, the procedure should be reserved for patients with life-threatening or troublesome symptomatic tachyarrhythmias.",1994.0,0,0 2729,8279987,[Reductions in lipid fraction plasma levels induced by simvastatin and bezafibrate. Brazilian multicenter study].,N Forti,"To compare the effects of simvastatin and bezafibrate on the lipid profile to attain the objectives proposed by National Cholesterol Education Program (NCEP). One hundred twenty six hypercholesterolemic patients (69 females and 57 men, 56.0 +/- 10.0 years old), after selection and placebo period (4 weeks) were maintained on lipid-lowering diet and were randomly assigned in a double-blind fashion to receive for 12 weeks, bezafibrate (B, 200mg t.i.d. - BG(n = 66)) or simvastatin (S, 10-40mg q.p.m. - SG(n = 60)). During the study, 28 patients (SG0) received S 10mg; in 14 patients (SG1) dosage was titrated to 20mg and in 18 cases (SG2) to 40mg. Clinical examination, lipid profile and safety determinations, and adverse effects were assessed in different periods of the study. Mean profile analysis showed different behaviour of BG, SG0, SG1 and SG2 through time for TC, TG, LDL-C and VLDL-C. Mean reductions of TC and LDL-C were more marked in SG (30.3 and 40.9%) than in BG (18.8 and 24.8%). BG showed greater increase of TG (33.7%) and HDL-C (25.9%) than did SG (16.3 and 7.7% respectively). Reduction greater than 30% (optimal responses) and between 20 and 29% (good responses) were more frequent in SG and LDL-C. BG showed greater frequency of good and optimal responses for TG reduction and HDL-C increase. NCEP goals were achieved in 75.4% of SG and 46.9% of BG (p = 0.001). No clinical or laboratorial adverse experiences were reported in any treatment groups. Simvastatin was more effective in the reduction of plasma levels of atherogenic lipid fractions (TC and LDL-C) and this treatment allowed earlier achievement of the goals proposed by NCEP in a greater number of patients.",1993.0,0,0 2730,8283930,The effects of lowering serum cholesterol on coronary heart disease risk.,J E Rossouw,"The clinical trials and angiographic studies of cholesterol lowering have been of decisive importance in persuading scientific and public opinion that elevated serum cholesterol is a causal element in the chain of events leading to CHD and that treatment by diet and drugs is effective in lowering the risk of CHD. The appropriateness of these opinions is well illustrated by the analyses of the combined trials, which show that the clinical event rate can be lowered by about 20% if cholesterol levels are lowered by 10%. The reduced risk for CHD applies to both primary and secondary prevention. Further, the angiographic studies have now demonstrated that vigorous lipid-lowering therapy leads to improvements in the angiographic appearance of coronary vessels, which are accompanied by large reductions in CHD risk. Diet and a variety of drugs appear to modify the risk of CHD. The results of studies using combinations of drugs, for example, bile acid-binding resins with either niacin or hydroxymethylglutaryl coenzyme A reductase inhibitors, are particularly impressive. The primary purpose of treatment remains the reduction of total and LDL cholesterol; however, the possibility of an additional benefit from improving other aspects of the lipid profile (such as raising HDL cholesterol levels) at the same time should not be ignored. In many instances, combinations of drugs are needed to achieve optimal lowering of serum cholesterol or to treat all elements of the disorder. Although the treatment of high-risk but apparently healthy individuals should not be neglected, it would be particularly appropriate to institute intensive diet and combination drug therapy in patients with existing CHD, in view of their high risk of reinfarction if left untreated. The secondary prevention trials provide evidence that clinical events can be reduced in such patients. The angiographic studies strongly suggest that large reductions in cholesterol to much lower levels (in-treatment LDL cholesterol levels below 100 mg/dL were frequently observed) than those achieved in the secondary prevention trials markedly reduce the rate of coronary events in patients with existing disease.",1994.0,0,0 2731,8285861,[Lovastatin in the treatment of hypercholesterolemia in non-insulin-dependent diabetes mellitus patients].,M T Zanella; F Plavinik; M Zampieri; R B Peres; A B Ribeiro,"To evaluate the effects of lovastatin as an hypocholesterolemic agent in non-insulin dependent diabetic (NIDDM) patients with high cholesterol plasma levels. Twenty NIDDM patients were included in this study. Hypercholesterolemia was defined as LDL-cholesterol plasma levels above 160mg/dl in female patients and above 130mg/dl in male patients or in women presenting any other risk factor for cardiovascular disease. From the 20 patients included, 18 had also high levels of arterial blood pressure. They were evaluated for admission in the study after they have substituted the antihypertensive medication for at least 6 weeks, from beta-blockers or diuretics to angiotensin converting enzyme inhibitors or calcium channel blockers. Lovastatin was administered in a initial daily dose of 20mg to all patients for 6 weeks. After this period this dose was increased to 40mg in 11 patients with LDL-cholesterol levels above 130mg/dl. All patients were treated for a total period of 24 weeks. Lovastatin therapy for 24 weeks reduced LDL-cholesterol and total cholesterol plasma levels in 30% and 21%, respectively, while no changes in HDL-cholesterol or triglycerides plasma levels were observed. The medication was well tolerated and no changes in bilirrubins or transaminases plasma levels were detected. In 9 patients the serum levels of alkaline phosphatase showed an elevation and the mean level of all group increased from 109 +/- 59 to 188 +/- 60m mu/ml (p < 0.05). This was an isolated abnormality without any other clinical manifestation. Lovastatin in NIDDM showed to be an efficient agent to reduce high levels of LDL-cholesterol and total cholesterol. However, the importance of the abnormality observed in serum alkaline phosphatase levels deserves further investigation. In this condition we recommend discontinuation of lovastatin therapy.",1993.0,0,0 2732,8287162,C-peptide and the classification of diabetes mellitus patients in the Early Treatment Diabetic Retinopathy Study. Report number 6. The ETDRS Research Group.,M J Prior; T Prout; D Miller; R Ewart; D Kumar,"The Early Treatment Diabetic Retinopathy Study (ETDRS), conducted at 22 clinical centers during the period 1980 to 1989, collected baseline data on C-peptide levels after ingestion of Sustacal in 582 patients with diabetes mellitus, prior to enrollment in the trial. Data on several clinical factors associated with diabetes were also collected from all 3711 enrolled patients. C-peptide data were used to develop sets of clinical criteria for the classification of ETDRS patients and to compare and contrast definitions of type of diabetes used in previous studies. The distribution of C-peptide levels was strikingly bimodal, suggesting a division of study participants into two groups--those with levels at 80 pmol/L or less and those with more than 80 pmol/L of C-peptide after Sustacal ingestion. Constellations of clinical characteristics that could serve as proxies for C-peptide level were ascertained. The result was two sets of clinically developed definitions for type of diabetes in the ETDRS. According to the more restrictive set of definitions, three groups were identified, compared to two groups using the ""broad"" set of definitions. Discriminant analysis was also used to classify ETDRS patients, yielding similar results. A comparison of definitions of type of diabetes used in the ETDRS and in previous studies revealed that even in the absence of C-peptide data, clinically derived definitions provided good discrimination between type I and type II diabetes.",1993.0,0,0 2733,8287511,Which patients need aggressive lipid-altering therapy?,D B Hunninghake,,1993.0,0,0 2734,8288727,Effects of lovastatin on natural killer cell function and other immunological parameters in man.,R McPherson; C Tsoukas; M G Baines; A Vost; M R Melino; R V Zupkis; H F Pross,"Suppression of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, such as lovastatin, has been shown to inhibit mitogen stimulated proliferation of natural killer (NK) cells and other lymphocytes in vitro. This effect is only partially overcome by provision of exogenous free or lipoprotein cholesterol but is reversed by mevalonate, suggesting that proliferating lymphocytes have a specific requirement for a nonsterol isoprenoid product of mevalonate. The effect of lovastatin (20 mg bid) on a range of immune function parameters was determined in a randomized, placebo-controlled, double-blind ex vivo study in 52 patients with primary hypercholesterolemia. No significant differences (P < 0.05) were found between lovastatin and placebo groups for basal NK or interleukin-2 (IL-2)-induced cell-mediated cytotoxicity, PHA-stimulated lymphocyte proliferation, or relative numbers of T lymphocytes (CD3+), B lymphocytes (CD19+), total NK cells (CD3-, CD16+, CD56+) and CD57+ NK cells or in immunoglobulin levels after 4 or 8 weeks of treatment. In contrast to previous in vitro data, no statistically or clinically significant changes were observed in any parameter of lymphocyte function in patients treated with lovastatin.",1993.0,0,0 2735,8290485,Evaluation of sustained/controlled-release dosage forms of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) reductase inhibitors in dogs and humans.,H Cheng; S C Sutton; J D Pipkin; G M Zentner; J D Rogers; J I Schwartz; Y B Mitchel; K Grasing; M S Schwartz; R D Amin,"Seven sustained/controlled-release dosage forms were designed for gastrointestinal delivery of lovastatin or simvastatin, two potent HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia. The in vivo performance of these formulations was evaluated in dogs and healthy volunteers in terms of the cholesterol lowering efficacy and/or systemic concentrations of HMG-CoA reductase inhibitors. Results from the present and previous studies suggest that, through the controlled release of HMG-CoA reductase inhibitors, sustained lower plasma concentrations of HMG-CoA reductase inhibitors may result in an equal or better therapeutic efficacy.",1993.0,0,0 2736,8295321,Hypercholesterolemia in postmenopausal women. Metabolic defects and response to low-dose lovastatin.,M Arca; G L Vega; S M Grundy,"To determine the metabolic mechanisms underlying hypercholesterolemia in postmenopausal women and to determine whether a low dose of lovastatin will correct this abnormality. In the first part of the study, turnover rates of autologous low-density lipoprotein (LDL) were measured in hypercholesterolemic and control women. In the second part, hypercholesterolemic women participated in a placed-controlled, randomized, double-blind study using lovastatin as the therapeutic agent. The General Clinical Research Center of the University of Texas Southwestern Medical Center, Dallas, utilizing inpatient and outpatient facilities, and the Veterans Affairs Medical Center, Dallas, Tex. For the LDL turnover study, 26 postmenopausal women with moderate hypercholesterolemia (mean +/- SD LDL cholesterol, 4.78 +/- 0.59 mmol/L [185 +/- 23 mg/dL]) and 13 postmenopausal women with normal levels of plasma lipids and lipoproteins (mean +/- SD LDL cholesterol, 3.31 +/- 0.39 mmol/L [128 +/- 15 mg/dL]) were studied. Sixteen postmenopausal women participated in the drug study. In the drug study, patients received blindly both lovastatin (10 mg/d) and placebo. In the first study, kinetic parameters of LDL metabolism; in the second study, response in lipids and lipoproteins to lovastatin therapy. In the LDL turnover study, mean (+/- SD) input (production) rates for LDL apolipoprotein B (apo B) were similar for hypercholesterolemic women and control women (12.4 [+/- 3.2] mg/kg per day and 11.1 [+/- 2.2] mg/kg per day, respectively). In contrast, mean (+/- SD) fractional catabolic rates for LDL apo B in hypercholesterolemic women (0.29 [+/- 0.04] pools per day) were significantly lower than those in normolipidemic women (0.35 [+/- 0.03] pools per day). In the drug trial, lovastatin therapy reduced mean (+/- SD) total cholesterol and LDL cholesterol from 7.03 (+/- 1.16) mmol/L (272 [+/- 45] mg/dL) and 4.42 (+/- 0.80) mmol/L (171 [+/- 31] mg/dL, respectively, to 5.70 (+/- 1.03) mmol/L (221 [+/- 40] mg/dL) and 3.46 (+/- 0.85) mmol/L (134 [+/- 33] mg/dL). The turnover data suggest that hypercholesterolemia in post-menopausal women is primarily attributable to a reduced activity of LDL receptors. In accord, the hypercholesterolemia in these women was effectively lowered by low doses of lovastatin. Thus, a low dose of lovastatin appears highly effective for treatment of moderate hypercholesterolemia in most postmenopausal women, presumably because it reverses the reduction in LDL receptor activity associated with menopause.",1994.0,0,0 2737,8296701,"Effect of pravastatin treatment on glucose, insulin, and lipoprotein metabolism in patients with hypercholesterolemia.",W H Sheu; S M Shieh; D D Shen; M M Fuh; C Y Jeng; Y D Chen; G M Reaven,"Treatment of patients with type IIA hyperlipoproteinemia (HLP) with pravastatin for 3 months led to significant decreases (p < 0.001) in total cholesterol (7.18 +/- 0.30 to 5.75 +/- 0.30 mmol/L), LDL cholesterol (5.56 +/- 0.33 to 4.02 +/- 0.32 mmol/L), and ratio of total cholesterol to HDL cholesterol (6.5 +/- 0.4 to 4.6 +/- 0.4). Decreases of a similar magnitude were also seen in patients with type IIB HLP. Plasma glucose and insulin concentrations after an oral glucose load and from 8 AM to 4PM in response to meals were higher in patients with Type IIB HLP, who also had higher steady-state plasma glucose concentrations after an infusion of somatostatin, insulin, and glucose (12.4 +/- 1 vs 5.5 +/- 0.8 mmol/L, p < 0.001). Because steady-state plasma insulin concentrations were similar in both groups, patients with type IIB HLP were relatively insulin resistant. Furthermore, day-long plasma glucose concentrations and insulin resistance were modestly, but significantly (p < 0.01), greater after treatment in both groups. In conclusion, LDL cholesterol metabolism improved in hypercholesterolemic subjects treated with pravastatin, but the hypertriglyceridemia, insulin resistance, relative glucose intolerance, and hyperinsulinemia present in patients with type IIB HLP either did not improve with treatment or was somewhat worse.",1994.0,0,0 2738,8297223,[Pravastatin: efficacy and safety in elderly patients with primary hypercholesterolemia. Open multicenter study].,S D Giannini; J Diament,"To analyze the response of hypercholesterolemic elderly patients to pravastatin. Two hundred and sixty six primary hypercholesterolemics, 65 to 80 years of age, after ingesting a standard diet for four weeks, received 10mg of pravastatin for 12 weeks. Average reductions of 24% or more were observed for TC and LDL-C, and more than 60% of those reductions were considered good or excellent (above 20%). Increases in HDL-C (6.6%) and the reduction of TG (21.2%) were significant. Patients 65 to 70 years old compared to patients 71 to 80 years old did not show significant response differences, however, the 71 to 80 year old patients had smaller reductions in TC and LDL-C but greater increases in HDL-C. The drug was very well tolerated, with an incidence of adverse events of only 10.5%, none of which resulted in the discontinuation of drug administration. There were significant increases in hepatic enzymes (SGOT and SGTP), however the variations did not have clinical significance. For CK changes were not significant. Primary hypercholesterolemic elderly seem to respond to pravastatin in a similar way as middle age patients. The effects on the lipid fractions are significant, adverse effects are rare and the drug is very well tolerated. Thus it should be considered a first line hypolipidemic drug.",1993.0,0,0 2739,8301234,"Cholesterol and sphingomyelin syntheses are regulated independently in cultured human intestinal cells, CaCo-2: role of membrane cholesterol and sphingomyelin content.",H Chen; E Born; S N Mathur; F J Field,"There is a presumed association between cellular cholesterol and sphingomyelin metabolism. To study this relationship in the intestine, the activity of the rate controlling enzyme of sphingolipid synthesis, serine palmitoyltransferase (SPT), and the biosynthesis of long-chain bases were characterized in cultured human intestinal cells, CaCo-2. Cells were then incubated with substances known to alter cholesterol biosynthesis, and the effect of these mediators on SPT activity and long-chain base synthesis was determined and compared with their effects on HMG-CoA reductase activity and cholesterol synthesis. The polar sterol, 25-hydroxycholesterol, the squalene epoxide inhibitor, U18666A, and the inhibitor of HMG-CoA reductase, lovastatin, all significantly inhibited the synthesis of cholesterol without altering either SPT activity or long-chain base synthesis. Mevalonate, which increased cholesterol production 3-fold, also had no affect on SPT activity or sphingoid base synthesis. Serine, which significantly increased the synthesis of long-chain bases, did not alter cholesterol biosynthesis. Moreover, the suicide inhibitors of SPT, beta-chloroalanine and cycloserine, did not alter cholesterol synthesis while markedly decreasing long chain base synthesis. Cells were incubated with palmitic, oleic, linoleic, and eicosapentaenoic acids. Only palmitic acid, the preferred substrate for SPT, increased the production of long-chain bases. Both palmitic and oleic acids, however, increased the synthesis of cholesterol. Cells enriched in sphingomyelin had higher rates of synthesis of both cholesterol and long-chain bases compared to their controls. In contrast, cholesterol and long-chain base syntheses were significantly decreased in cells enriched in cholesterol. Control cells incubated with phospholipid liposomes alone had higher rates of synthesis of both lipids.(ABSTRACT TRUNCATED AT 250 WORDS)",1993.0,0,0 2740,8311595,Cholesterol-lowering intervention and coronary artery disease after cardiac transplantation.,M Carrier; G B Pelletier; J Genest; R Cartier; Y Leclerc; L C Pelletier,"Allograft coronary artery disease is a major threat to long-term survival after cardiac transplantation. It has been suggested that hyperlipidemia plays a major role in allograft coronary disease. The objective of the present study was to evaluate the effect of a lipid-lowering intervention with diet and drug therapy after cardiac transplantation. Forty-six patients who underwent transplantation between 1988 and 1991 and who were treated with the American Heart Association phase 1 diet and an HMG coenzyme A reductase inhibitor (lovastatin or simvastatin) when low-density lipoprotein cholesterol levels were higher than 3.4 mmol/L were compared with 35 untreated patients having transplantation between 1983 and 1988. Annual coronary angiograms were obtained in both groups. Cholesterol, triglyceride, and low-density lipoprotein levels were significantly lower in the treated group. Actuarial survival and event-free survival (survival free from allograft coronary artery disease) were similar in both groups. Low-density lipoprotein levels lower than 3 mmol/L at the last follow-up had a positive effect on event-free survival. The cholesterol-lowering intervention was not effective in decreasing the prevalence of allograft coronary artery disease. This study suggests that more aggressive measures to lower low-density lipoprotein levels may be necessary to significantly affect allograft disease. Clinical trials should be developed to address this hypothesis.",2001.0,0,0 2741,8312683,Therapy of severe familial heterozygous hypercholesterolemia by low-density lipoprotein apheresis with immunoadsorption: effects of the addition of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors to therapy.,B G Jacob; W O Richter; P Schwandt,To establish whether additional therapy with 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors enhances the low-density lipoprotein (LDL) cholesterol lowering effect of LDL apheresis with immunoadsorption in the treatment of patients with familial heterozygous hypercholesterolemia and coronary artery disease we studied eight patients initially on immunoadsorption therapy alone for 3 years. The adding of HMG CoA reductase inhibitors decreased pretreatment LDL cholesterol from 6.76 +/- 0.98 to 4.97 +/- 0.98 mmol/l and posttreatment LDL cholesterol from 2.33 +/- 0.80 to 1.94 +/- 0.67 mmol/l and increased pre- and posttreatment high-density lipoprotein (HDL) cholesterol by 0.08 and 0.13 mmol/l respectively. The LDL/HDL ratio was reduced from 4.0 to 2.8 (prior to any therapy the ratio was 13.4). The increase in LDL cholesterol between weekly treatments was less steep under the combined therapy. At the same time the treated plasma volume during LDL apheresis could be decreased from 5070 +/- 960 to 4370 +/- 1200 ml. We conclude that in patients with severe familial heterozygous hypercholesterolemia LDL apheresis should be combined with HMG CoA reductase inhibitors.,1993.0,0,0 2742,8312689,Effect of pravastatin on metabolic parameters of apolipoprotein B in patients with mixed hyperlipoproteinemia.,K G Parhofer; P H Barrett; J Dunn; G Schonfeld,"3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors reduce plasma cholesterol in different forms of hyperlipoproteinemia. Although an increase in low-density lipoprotein (LDL) receptor activity is the proven mechanism of this therapy in familial hypercholesterolemia, the mechanism remains controversial in mixed hyperlipoproteinemia. A decreased production of apolipoprotein B (apoB) and/or an increased removal of lipoproteins could mediate the hypocholesterolemic effect of these drugs. The effect of pravastatin on the metabolism of apoB was evaluated in a randomized, double blind, placebo controlled, cross-over study in five men with mixed hyperlipoproteinemia. Metabolic parameters for apoB were determined using endogenous labeling with [1-13C]leucine and [15N]glycine and multicompartmental modeling. During pravastatin therapy cholesterol, LDL cholesterol, apoB, and LDL apoB levels were significantly reduced (P < 0.01) by 18%, 20%, 27%, and 29%, respectively, while triglyceride and high-density lipoprotein cholesterol levels remained unchanged. Pravastatin therapy increased the fractional catabolic rate of very low density lipoprotein apoB from 3.9 +/- 0.6 to 5.1 +/- 1.7 per day (P = 0.08) and that of LDL apoB from 0.37 +/- 0.09 to 0.46 +/- 0.10 per day (P < 0.01). The apoB production (placebo 35.2 +/- 11.9 mg/kg per day; pravastatin 25.8 +/- 8.7 mg/kg per day) and conversion of very low density lipoprotein apoB to LDL apoB (placebo 65%, pravastatin 57%) remained stable. Thus, also in mixed hyperlipoproteinemia 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase the catabolism of apoB-containing lipoproteins without significantly affecting the production of apoB.",1993.0,0,0 2743,8520093,Comparative evaluation of the safety and efficacy of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia.,I Hsu; S A Spinler; N E Johnson,"To evaluate the comparative efficacy and safety of the 4 currently available hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, fluvastatin, lovastatin, pravastatin, and simvastatin, in the treatment of primary hypercholesterolemia. English-language clinical studies, abstracts, and review articles identified from MEDLINE searches and bibliographies of identified articles. Unpublished data were obtained from the Food and Drug Administration in accordance with the Freedom of Information Act. Placebo-controlled and comparative studies of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Pertinent studies were selected and the data were synthesized into a review format. The chemistry, pharmacology, and pharmacokinetics of the 4 HMG-CoA reductase inhibitors are reviewed. Clinical trials evaluating the hypocholesterolemic efficacy of the HMG-CoA reductase inhibitors are examined, and results on the comparative efficacy and safety of these agents are summarized. On a milligram-per-milligram basis, simvastatin is twice as potent as lovastatin and pravastatin. The hypocholesterolemic effects of fluvastatin appear to be approximately 30% less than that of lovastatin. In posttransplant patients receiving cyclosporine, safety has been documented for low doses of lovastatin and simvastatin, but when a higher dosage of an HMG-CoA reductase inhibitor is warranted, pravastatin should be considered the drug of choice because of a lower incidence of myopathy. Relevant data on the incidence of adverse effects are presented. Pertinent outcomes data from clinical trials evaluating the effect of HMG-CoA reductase inhibitors on atherosclerosis regression and coronary mortality, as well as published economic analyses of cholesterol-lowering agents, are summarized. Recommendations on the selection of an HMG-CoA reductase inhibitor in various clinical situations are provided. The literature supports the comparable safety and tolerability of all 4 currently available HMG-CoA reductase inhibitors. Therefore, the choice of an HMG-CoA reductase inhibitor should depend on the extent of cholesterol lowering needed to meet the recommended treatment goal established by the National Cholesterol Education Program. Direct comparative studies are needed to confirm the relative, long-term cost-effectiveness of the various HMG-CoA reductase inhibitors in the treatment of primary hypercholesterolemia.",1995.0,0,0 2744,8520448,Modulation of coronary endothelial function by lovastatin.,A Misra,,1995.0,0,0 2745,8520845,Profiling a landmark clinical trial: Scandinavian Simvastatin Survival Study.,S Guptha,,1995.0,0,0 2746,8520846,Statin therapy in clinical practice: new developments.,J Shepherd,,1995.0,0,0 2747,8521762,Simvastatin. A reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolaemia.,G L Plosker; D McTavish,"Simvastatin is an HMG-CoA reductase inhibitor used in the treatment of patients with hypercholesterolaemia. Since the time simvastatin was previously reviewed in Drugs, a number of large clinical trials have confirmed its clinical efficacy. Thus, reductions from baseline were approximately 20 to 40% for serum levels of total cholesterol, 35 to 45% for low density lipoprotein (LDL)-cholesterol and 10 to 20% for triglycerides in patients with primary hypercholesterolaemia receiving simvastatin 10 to 40 mg/day. High density lipoprotein (HDL)-cholesterol levels were increased modestly by about 5 to 15%. Recent data from long term studies indicate that little or no attenuation of these changes in serum lipid and lipoprotein levels occurred with administration of simvastatin for 3 to 5.4 years. Comparative studies with other HMG-CoA reductase inhibitors (lovastatin, pravastatin and fluvastatin), which were lacking at the time of the previous review of simvastatin, demonstrated greater reductions in serum levels of total cholesterol and LDL-cholesterol with simvastatin than equal dosages of lovastatin or pravastatin. Reductions in serum levels of total cholesterol and LDL-cholesterol were similar between agents only when lovastatin or pravastatin were administered at a total daily dosage twice that of simvastatin and when fluvastatin was administered at a total daily dosage approximately 8 times that of simvastatin. In general, simvastatin 10 to 40 mg/day was also more effective than standard dosages of bile acid sequestrants, fibrates or probucol in lowering serum levels of total cholesterol and LDL-cholesterol; however, fibrates usually produced greater reductions in serum triglycerides and greater elevations in HDL-cholesterol levels. The Scandinavian Simvastatin Survival Study (4S), a large secondary prevention study in patients with coronary heart disease and concomitant hypercholesterolaemia, demonstrated that simvastatin 20 to 40 mg/day for a median of 5.4 years significantly reduced overall mortality (the primary end-point of the study) by 30% compared with placebo, which was attributed to a 42% relative reduction in coronary mortality. Coronary morbidity was also significantly reduced by simvastatin in the 4S trial. The tolerability profile of simvastatin appears to be comparable to that of other HMG-CoA reductase inhibitors. The most frequently reported adverse events are gastrointestinal disturbances, which are generally mild and tend to occur less frequently than with cholestyramine. In conclusion, simvastatin is among the most effective agents available for treating patients with hypercholesterolaemia.(ABSTRACT TRUNCATED AT 400 WORDS)",1995.0,0,0 2748,8529086,A controlled trial of a behavioral and educational intervention following coronary artery bypass surgery.,B Oldenburg; A Martin; J Greenwood; L Bernstein; R Allan,"Patients who have undergone coronary artery bypass graft surgery (CABG) are obvious candidates for rehabilitation programs because of the potential for progression of disease. Such programs have been shown to foster risk-factor modification, improve quality of life, and prolong survival among post-myocardial infarction (MI) patients. However, the efficacy of these programs has not been established among patients who have undergone CABG. A randomized controlled trial was employed to evaluate whether a behavioral and educational cardiac rehabilitation program was effective in modifying cardiovascular disease risk factors and improving quality of life in a cohort of 86 patients after CABG. Patients were recruited from the cardiac ward of a large teaching hospital and were block-randomized to either an intervention group or routine care. Subjects in the intervention group attended 6 weekly group sessions following hospital discharge, and booster sessions at 8 months and 1 year. They also received a personalized behavior modification program based on their baseline risk factors. Risk factor and quality of life measures were recorded at baseline (6 weeks after surgery), 4 months, 8 months, and 1 year. The results indicated few differences between the study groups. However, the intervention group's aerobic capacity (VO2max) improved over that of the routine care group. With regard to the quality of life variables, all patients tended to improve steadily over time. The relatively moderate success of this intervention program compared with various post-MI studies may be indicative of differences between the treatment needs of patients after acute myocardial infarction or CABG. Future post-CABG rehabilitation research should explore these patients' unique treatment needs, and investigate a variety of program strategies.",1995.0,0,0 2749,8529087,Five years of physical exercise and low fat diet: effects on progression of coronary artery disease.,J Niebauer; R Hambrecht; G Schlierf; C Marburger; B Kälberer; W Kübler; G Schuler,"This study was designed to assess the long-term effects of low-fat diet and intensive physical exercise. Long-term efficacy of exercise and diet was assessed in 18 nonselected, fully employed patients with symptomatic coronary artery disease. Results were compared to 18 patients on usual care. In the intervention group at 1 year, serum lipoproteins were brought to ideal levels, exercise-induced myocardial ischemia was significantly reduced, and progression in coronary atherosclerosis was retarded. After more than 5 years, patients in the intervention group showed a significant reduction in lipoprotein levels (total cholesterol, 248 [179-299] vs 214 [173-272] mg/dL, P < .01; low density lipoprotein, 146 [83-216], vs 152 [121-197] mg/dL, P < .005 vs control; triglycerides; 151 [80-303] mg/dl, vs 98 [46-182] mg/dL; P < .005) and body mass index (26 +/- 2.9 vs 25.4 +/- 3.3 kg/m2; P < .05). Exercise induced myocardial ischemia, measured by 201thallium scintigraphy, decreased by 29% (41 degrees +/- 36 degrees vs 29 degrees +/- 29 degrees, P = NS) and coronary atherosclerosis, assessed by angiography and digital image processing, progressed at a slower pace in light of a 21% increase in physical work capacity (169 +/- 40 vs 205 +/- 50, P < .01) and a 28% increase in maximal rate pressure product (25 +/- 6 vs 32 +/- 4, P < .004). In contrast, patients in the control group showed only poorly controlled coronary risk factors (total cholesterol, 243 [179-306] vs 26 [178-304] mg/dL, P = NS; low density lipoprotein, 151 [79-229] vs 196 [107-238] mg/dL, P < .0005 vs intervention; body mass index 25.7 +/- 2.5 vs 27.5 +/- 3.5 kg/m2, P < .01), whereas their physical work capacity tended to deteriorate (165 +/- 45 vs 142 +/- 62 Watts, P = not significant). These data demonstrate that current usual care is insufficient in controlling risk factors of coronary artery disease. However, intensive physical exercise and low-fat diet remain an effective form of treatment after more than 5 years.",1995.0,0,0 2750,8530597,Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: double blind placebo-controlled trial with clomiphene citrate.,A T Guay; S Bansal; G J Heatley,"Secondary hypogonadism is not an infrequent abnormality in older patients presenting with the primary complaint of erectile dysfunction. Because of the role of testosterone in mediating sexual desire and erectile function in men, these patients are usually treated with exogenous testosterone, which, while elevating the circulating androgens, suppresses gonadotropins from the hypothalamic-pituitary axis. The response of this form of therapy, although extolled in the lay literature, has usually not been effective in restoring or even improving sexual function. This failure of response could be the result of suppression of gonadotropins or the lack of a cause and effect relationship between sexual function and circulating androgens in this group of patients. Further, because exogenous testosterone can potentially increase the risk of prostate disease, it is important to be sure of the benefit sought, i.e. an increase in sexual function. In an attempt to answer this question, we measured the hormone levels and studied the sexual function in 17 patients with erectile dysfunction who were found to have secondary hypogonadism. This double blind, placebo-controlled, cross-over study consisted of treatment with clomiphene citrate and a placebo for 2 months each. Similar to our previous observations, LH, FSH, and total and free testosterone levels showed a significant elevation in response to clomiphene citrate over the response to placebo. However, sexual function, as monitored by questionnaires and nocturnal penile tumescence and rigidity testing, did not improve except for some limited parameters in younger and healthier men. The results confirmed that there can be a functional secondary hypogonadism in men on an out-patient basis, but correlation of the hormonal status does not universally reverse the associated erectile dysfunction to normal, thus requiring closer scrutiny of claims of cause and effect relationships between hypogonadism and erectile dysfunction.",1995.0,0,0 2751,8531288,Carcinogenicity of lipid-lowering drugs.,T B Newman; S B Hulley,"To review the findings and implications of studies of rodent carcinogenicity of lipid-lowering drugs. Summaries of carcinogenicity studies published in the 1992 and 1994 Physicians' Desk Reference (PDR), additional information obtained from the US Food and Drug Administration, and published articles identified by computer searching, bibliographies, and consultation with experts. We tabulated rodent carcinogenicity data from the 1994 PDR for all drugs listed as ""hypolipidemics."" For comparison, we selected a stratified random sample of antihypertensive drugs. We also reviewed methods and interpretation of carcinogenicity studies in rodents and results of clinical trials in humans. All members of the two most popular classes of lipid-lowering drugs (the fibrates and the statins) cause cancer in rodents, in some cases at levels of animal exposure close to those prescribed to humans. In contrast, few of the antihypertensive drugs have been found to be carcinogenic in rodents. Evidence of carcinogenicity of lipid-lowering drugs from clinical trials in humans is inconclusive because of inconsistent results and insufficient duration of follow-up. Extrapolation of this evidence of carcinogenesis from rodents to humans is an uncertain process. Longer-term clinical trials and careful postmarketing surveillance during the next several decades are needed to determine whether cholesterol-lowering drugs cause cancer in humans. In the meantime, the results of experiments in animals and humans suggest that lipid-lowering drug treatment, especially with the fibrates and statins, should be avoided except in patients at high short-term risk of coronary heart disease.",1996.0,0,0 2752,8531308,"Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia.",R G Bakker-Arkema; M H Davidson; R J Goldstein; J Davignon; J L Isaacsohn; S R Weiss; L M Keilson; W V Brown; V T Miller; L J Shurzinske; D M Black,"To assess the lipid-lowering effect of atorvastatin (a new 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitor) on levels of serum triglycerides and other lipoprotein fractions in patients with primary hypertriglyceridemia, determine if atorvastatin causes a redistribution of triglycerides in various lipoprotein fractions, and assess its safety by reporting adverse events and clinical laboratory measurements. Randomized double-blind, placebo-controlled, parallel-group, multicenter trial. Community- and university-based research centers. A total of 56 patients (aged 26 to 74 years) with a mean baseline triglyceride level of 6.80 mmol/L (603.3 mg/dL) and a mean baseline low-density lipoprotein cholesterol (LDL-C) level of 3.07 mmol/L (118.7 mg/dL). Cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step I Diet) and either 5 mg, 20 mg, or 80 mg of atorvastatin, or placebo. Percent change from baseline in total triglycerides for three dose levels of atorvastatin compared with placebo. Mean reductions in total triglycerides between 5 mg, 20 mg, and 80 mg of atorvastatin and placebo after 4 weeks of treatment were -26.5%, -32.4%, -45.8%, and -8.9%, respectively. Mean reductions in LDL-C were -16.7%, -33.2%, -41.4%, and -1.4%, respectively, and very low-density lipoprotein cholesterol (VLDL-C) were -34.3%, -45.9%, -57.7%, and -5.5%, respectively. Similar mean changes in total apolipoprotein B (apo B) (-16.9%, -32.8%, -41.7%, and +1.0%), apo B in LDL (-14.8%, -29.8%, -42.0%, and -3.1%), and apo B in VLDL (-23.8%, -35.8%, -34.4%, and +11.7%) were observed. In addition, comparable mean changes in LDL triglycerides (-22.5%, -30.7%, -39.9%, and +3.9%) and VLDL triglycerides (-28.1%, -34.0%, -47.3%, and -10.8%) were seen. In atorvastatin treatment groups, total serum triglyceride levels decreased in a dose-dependent manner, reductions in the 20-mg and 80-mg groups were statistically significant (P < .05) compared with placebo. Atorvastatin did not cause a redistribution of triglycerides but consistently lowered triglycerides in all lipoprotein fractions. Atorvastatin was well tolerated.",1996.0,0,0 2753,8534671,Absence of effect of simvastatin on the progression of lens opacities in a randomised placebo controlled study. Oxford Cholesterol Study Group.,M L Harris; A J Bron; N A Brown; A C Keech; K R Wallendszus; J M Armitage; S MacMahon; G Snibson; R Collins,"A detailed assessment of ophthalmic effects of an HMG CoA reductase inhibitor, simvastatin, was performed. Six hundred and twenty one individuals considered to be at increased risk of coronary heart disease were randomised, following an 8 week placebo 'run in' period, to receive 40 mg daily simvastatin, 20 mg daily simvastatin, or matching placebo. Patients with a baseline corrected visual acuity better than 6/24 and without a history of cataract were eligible for detailed ophthalmic assessment at 6 months (539 patients assessed) and at 18 months (474 patients assessed). No significant differences between the treatment groups were detected at the 6 month or 18 month visit in the refractive condition of the eye or in the mean intraocular pressure. Nor were there clear differences in the Oxford grading system scores for various measures of the major types of cataract (cortical spokes, posterior subcapsular cataract, nuclear brunescence, white scatter) or for other morphological features visible within the lens (fibre folds or focal dots). Scheimpflug slit image photographs and retroillumination analysis of the percentage of cataract within a defined region of the lens were also performed at each visit, with no clear differences observed between the treatment groups. This single centre double blind study found no good evidence of any adverse effects of 18 months of simvastatin treatment on lens opacity formation, using a variety of validated techniques to assess cataract development. Routine clinic follow up of visual symptoms and admission to hospital for ophthalmic procedures over 5 years of treatment was also reassuring, with no excess adverse outcomes observed with simvastatin.",1995.0,0,0 2754,8538301,Inhibition of the mevalonate pathway: benefits beyond cholesterol reduction?,Z A Massy; W F Keane; B L Kasiske,,1996.0,0,0 2755,8538331,Statin therapy and CHD.,J A Tobert,,1996.0,0,0 2756,8540464,The efficacy and safety of pravastatin in patients aged 60 to 85 years with low-density lipoprotein cholesterol > 160 mg/dl.,S P Glasser; R DiBianco; B A Effron; F Faas; F W Germino; L E Shane; A H Unger; J E Staggers,This study demonstrated that pravastatin 20 mg once daily significantly lowered total cholesterol (by 19%) and LDL cholesterol by 25%.,1996.0,0,0 2757,8540887,Mitochondrial myopathy developing on treatment with the HMG CoA reductase inhibitors--simvastatin and pravastatin.,J D England; J C Walsh; P Stewart; I Boyd; A Rohan; G M Halmagyi,,1995.0,0,0 2758,8543958,Computerised record linkage: compared with traditional patient follow-up methods in clinical trials and illustrated in a prospective epidemiological study. The West of Scotland Coronary Prevention Study Group.,,"Computerised record linkage systems have great potential for enhancing or even replacing traditional methods of adverse event reporting based on active patient follow-up, both in clinical trials and in epidemiological studies. However, these methods must be evaluated. The West of Scotland Coronary Prevention Study (WOSCOPS) is a randomised double-blind clinical trial of pravastatin versus placebo in the primary prevention of coronary heart disease, with coronary heart disease death plus nonfatal myocardial infarction as its primary end point. Adverse event reporting is based on active patient follow-up at routine trial visits. In parallel with this approach, we have obtained computer records of all deaths, incident cancers, and hospitalisations for our subjects by linking their names, dates of birth, and postcodes of their home addresses with a Scottish national database operated by the Scottish Record Linkage system. The results of this comparative study, based on follow-up of the 6595 men ages 45-64 randomised in WOSCOPS, demonstrate minor flaws in both systems, show that follow-up based on computerised linkage alone can be as effective as reporting based on direct contact with the patients, and show that a system based on both approaches provides a direct cross-validation of the two approaches to adverse event reporting while minimising the frequency of unreported events. Preliminary results are reported for a prospective epidemiological study of 80,184 men, ages 45-64 years, who were screened for coronary heart disease risk factors as part of WOSCOPS. This study is based solely on computerised linkage reporting of events on these subjects. This provides an indication of the number of events in various categories that will be available for analysis in future reports. The associations between death rates and standard risk factors such as age, blood pressure, total cholesterol level, and smoking status mirror those reported in other studies.",1995.0,0,0 2759,8546093,Costs of coronary restenosis (Lovastatin Restenosis Trial).,S P Gilbert; W S Weintraub; J D Talley; S J Boccuzzi,"Within the Lovastatin Restenosis Trial, restenosis has been clearly shown to increase resource utilization and costs. While it is not possible to generalize these results to other patient populations, it is clear that successful efforts to decrease restenosis will certainly improve efficacy while decreasing follow-up costs and increasing the cost-effectiveness of intervention in the coronaries.",1996.0,0,1 2760,8546123,Lipoprotein(a) in renal disease.,F Kronenberg; G Utermann; H Dieplinger,"Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic vascular disease. Several studies have described a correlation between high Lp(a) plasma levels and coronary heart disease, stroke, and peripheral atherosclerosis. In healthy individuals Lp(a) plasma concentrations are almost exclusively controlled by the apolipoprotein(a) [apo(a)] gene locus on chromosome 6q2.6-q2.7. More than 30 alleles at this highly polymorphic gene locus determine a size polymorphism of apo(a). There exists an inverse correlation between the size (molecular weight) of apo(a) isoforms and Lp(a) plasma concentrations. Average Lp(a) levels are high in individuals with low molecular weight isoforms and low in those with high molecular weight isoforms. Mean Lp(a) plasma levels are elevated over controls in patients with renal disease. Patients with nephrotic syndrome exhibit excessively high Lp(a) plasma concentrations, which can be reduced with antiproteinuric treatment. The mechanism underlying this elevation is unclear, but the general increase in protein synthesis caused by the liver due to high urinary protein loss is a likely explanation. Patients with end-stage renal disease (ESRD) also have elevated Lp(a) levels. These are even higher in patients treated by continuous ambulatory peritoneal dialysis than in those receiving hemodialysis. Lipoprotein(a) concentrations decrease to values observed in controls matched for apo(a) type following renal transplantation. This clearly demonstrates the nongenetic origin of Lp(a) elevation in ESRD. Both the increase in ESRD and the decrease following renal transplantation are apo(a) phenotype dependent. Only patients with high molecular weight phenotypes show the described changes in Lp(a) levels. In patients with low molecular weight types the Lp(a) concentrations remain unchanged during both phases of renal disease. As in the general population, Lp(a) is a risk factor for cardiovascular events in ESRD patients. In this patient group the apo(a) phenotype seems to be equally or better predictive of the degree of atherosclerosis than is Lp(a) concentration. Further prospective studies will be necessary to confirm these observations. Whether Lp(a) also plays a key role in the pathogenesis and progression of renal diseases needs further study. Controversial data on the role of the kidney in Lp(a) metabolism result from insufficient sample sizes of several studies. Due to the broad range and skewed distribution of Lp(a) plasma concentrations, large study groups must be investigated to obtain reliable results.",1996.0,0,0 2761,8547405,Anticancer drugs acting against signaling pathways.,G Powis,"This review deals with anticancer drugs with activity against signaling targets that have been studied in cancer patients. The major categories of drugs studied so far are modulators of the activity of protein kinase C, inhibitors of protein kinase A, protein tyrosine kinase, and receptor-operated Ca2+ channels. Drugs that may modulate ras function have also been studied. None of the agents have yet received extensive clinical trials. Toxicities and anecdotal cases of antitumor activity have been reported. There are a number of other anticancer drugs with activity against signaling targets awaiting clinical trial.",1995.0,0,0 2762,8549941,Effects of simvastatin and cholestyramine on bile lipid composition and gall bladder motility in patients with hypercholesterolaemia.,J W Smit; K J Van Erpecum; P Portincasa; W Renooij; D W Erkelens; G P Van Berge-Henegouwen,"Although the effects of 3-hydroxy, 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and bile acid sequestrants on bile lipid composition have been studied separately, no data are available on combination therapy of these drugs. Moreover, the effects of prolonged (four weeks) administration of these drugs on gall bladder motility, an important determinant of cholesterol gall stone formation, have not been studied so far. A prospective study was therefore performed with eight patients who had hypercholesterolaemia (age 53 (5) (SEM), body mass index 27.4 (1.1) kg m-2, low density lipoprotein cholesterol 5.9 (0.3) mmol/l). They received treatment during three periods of four weeks with simvastatin 20 mg/day, cholestyramine 4 g twice daily, and a combination of both in random order, each treatment period separated by a two week wash out period. Before treatment and after each treatment period, postprandial gall bladder motility was studied with ultrasound, followed by duodenal bile sampling. Serum cholesterol decreased in all subjects in any treatment period illustrating good compliance. Molar percentages in duodenal bile of cholesterol, phospholipids, and bile salts were unchanged during simvastatin and cholestyramine treatment. During combined therapy percentage bile salts was lower (72.5 (2.9)% v 77.8 (1.7)% at baseline, p < 0.05) whereas phospholipids were higher (21.2 (2.4)% v 16.4 (1.3)% at baseline, p < 0.05). As a result cholesterol saturation index (CSI) did not change in any treatment period. No cholesterol crystals were detected in any bile sample, taken at baseline and after each treatment period. Bile salt hydrophobicity index during cholestyramine (0.19 (0.02)) and combined treatment (0.22 (0.01)) decreased strongly compared with baseline (0.34 (0.01), p < 0.001, p < 0.01, respectively), resulting from increased proportions of glycocholate (59.4 (3.9)% (cholestyramine), 55.6 (2.4)% (combination), and 28.2 (2.2) (baseline), p < 0.001)) and decreased proportions of deoxycholic acid and chenodeoxycholic acid. Fasting gall bladder volume was increased during simvastatin (28.7 (2.8) ml) v baseline (23.2 (2.3) ml, p < 0.01) whereas, residual volume did not differ (5.7 (0.9) ml (simvastatin) v 5.9 (0.7) (baseline). During cholestyramine and combined treatment, no significant differences in gall bladder motility were seen. In conclusion, this study suggests that HMG-CoA reductase inhibitors alone and combined with cholestyramine do not affect major determinants of cholesterol gall stone formation, for example, CSI and gall bladder emptying. In addition cholestyramine alone and combined with simvastatin leads to a strong decrease of bile salt hydrophobicity, which may be beneficial in the prevention of nucleation of cholesterol crystals.",1995.0,0,0 2763,8554498,[Comparative study of gemfibrozil versus pravastatin in the treatment of patients with coronary artery disease and low HDL cholesterol levels].,R D Santos; A P Mansur; J Safi Júnior; R R Giraldez; R C Maranhão; F Pileggi; J A Ramires,"To evaluate the effects of gemfibrozil and pravastatin in coronary artery disease patients with HDL-cholesterol (HDL-C) < 35 mg/dl). Twenty-nine patients (20 males, 60 +/- 9) were divided in a gemfibrozil group (G) (1200 mg/day n = 15) and a pravastatin group (P) (10 or 20 mg n = 10 and 4, respectively). The plasma lipid profile (LP) e.g. total cholesterol (TC), fractions and triglycerides (TG) was determined at 4 and 12 weeks of treatment. HDL-C was not affected in P, TC and LDL-cholesterol (LDL-C) reductions were superior to those in G (31.3% vs 13.4% and 38.7 and 11.5%, p < 0.05 and < 0.01 respectively). In G HDL-C raised by 50% (12th week p < 0.01). Gemfibrozil reduced TG levels in 44.7% while in P it varied -32.2% (12th week p < 0.01 and < 0.05 respectively). Gemfibrozil is more effective in reducing TG and raising HDL-C than pravastatin. On the other hand, pravastatin was more potent in reducing LDL-C levels.",1995.0,0,0 2764,8554733,The effectiveness and safety of low dose pravastatin in elderly hypertensive hypercholesterolemic subjects on antihypertensive therapy.,P Chan; C B Lee; T S Lin; J T Ko; W H Pan; Y S Lee,"To evaluate the efficacy and safety of low dose (10 mg) pravastatin in hypercholesterolemic, hypertensive elderly subjects undergoing antihypertensive treatment, a randomized, double-blind, placebo-controlled 6-month trial was conducted. The subjects had a total plasma cholesterol of at least 250 mg/dL and had been, for at least 3 months, consuming a standard lipid-lowering diet (American Heart Association Step 1 Diet). Sixty elderly hypertensive patients randomly received placebo (n = 30) or pravastatin (n = 30) treatment. The dosage consisted of 10 mg of pravastatin daily during the 6-month trial. Over that period, in the pravastatin group, plasma levels of total cholesterol and LDL-cholesterol significantly (P < .01) dropped (-20% and -25%, respectively) compared to the placebo group. The plasma level of HDL-cholesterol increased (+5%) while triglycerides slightly decreased (-8%) (P < .05). No serious side effects occurred, and pravastatin was generally tolerated. Fasting hyperinsulinemia (11.0 +/- 0.8 v 9.3 +/- 0.7 microU/mL; P = .06) also improved, although not significantly, after 6 months of pravastatin therapy. Results from this study confirmed that a low dose (10 mg) of pravastatin daily is a safe and effective method of reducing plasma total and LDL-cholesterol in hypercholesterolemic, hypertensive elderly patients who are on concurrent antihypertensive drug therapy.",1995.0,0,0 2765,8556689,Diet in the prevention and treatment of atherosclerosis. A perspective for the elderly.,U Srinath; S S Jonnalagadda; M C Naglak; C Champagne; P M Kris-Etherton,"Atherosclerosis is the leading cause of coronary heart disease among older persons. With an increasing elderly population, cardiovascular disease has become an urgent public health concern. Diet plays an important role in atherogenesis with known beneficial effects on major risk factors among the younger population--cholesterol, hypertension, and diabetes. Intervention studies are needed to establish the benefits of diet therapy in the elderly segment of the population. Efforts are also needed to educate the elderly and health professionals about the benefits of a healthy Step I diet.",1995.0,0,0 2766,8560901,"[Effectiveness, tolerance and safety of simvastatin in comparison with bezafibrate in treatment of hypercholesterolemia].",M Lechleitner; S Sailer; H Irsigler; W Klein; J R Patsch,"The efficacy, tolerability and safety of simvastatin was compared to that of bezafibrate in a randomized placebo controlled double-blind trial including 64 patients with primary hypercholesterolemia with total cholesterol levels above 240 mg/dl and low-density lipoprotein (LDL) cholesterol above 195 mg/dl. During a placebo period of four weeks patients were counselled for a diet low in cholesterol (< 300 mg/day) and saturated fat (< 10% of calories). This period was also used for randomization of the individuals into the bezafibrate and simvastatin group, respectively. Patients assigned to bezafibrate treatment took bezafibrate at 600 mg/day throughout the entire 12 weeks of active treatment. Patients assigned to simvastatin took simvastatin at 10 mg/day when LDL-cholesterol was below 195 mg/dl, and at 20 mg/day when LDL-cholesterol was above 195 mg. To compare the lipid lowering effect of both substances total cholesterol, LDL- and high-density lipoprotein (HDL)-cholesterol were measured as well as triglycerides, very low density lipoprotein (VLDL)-cholesterol and the concentrations of apolipoproteins (apo)-AI, apo-AII and apo-B, respectively. These variables were compared between the two study groups with respect to the percentage change from baseline levels obtained during the placebo period. After a 12 week treatment period mean percent reduction of total cholesterol in the simvastatin group was 24% and that of LDL-cholesterol was 36%, both more pronounced than the respective reductions (14% and 17%) observed in the bezafibrate group. The mean percent increase in HDL-cholesterol was similar in both treatment groups (simvastation by 20% vs. bezafibrate by 17%).(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0 2767,8564589,Failure of educational videotapes to improve medication compliance in a health maintenance organization.,K M Powell; B Edgren,"The value of mailed educational videotapes as a means of enhancing compliance with drug therapy was studied. Members of a health maintenance organization with a pharmacy claim for benazepril, metoprolol, simvastatin, or transdermal estrogen were randomly assigned to a study group or a control group. Subjects in the study group were mailed one of four videotape programs giving information on the drug prescribed and the inferred disease state. Control subjects received no educational materials. Subjects were enrolled from July 1, 1993, through January 2, 1994. Refill data were collected from July 1, 1993, through April 1, 1994. The medication possession ratio (MPR) was calculated as the total number of days' supply of a drug obtained by a member divided by the number of days between the time of enrollment and April 1, 1994, or the date the member was terminated from the plan. A subject was deemed compliant if his or her MPR was > or = 0.80. There were no significant differences in mean MPRs between the study group (n = 1993) and the control group (n = 2253). None of the mean MPRs was > or = 0.80, although 44% of control subjects and 46% of study-group subjects were compliant. Of 97 respondents to a survey mailed to a randomly selected subset of the study group, almost 87% reported that they had viewed the videotapes, and of these subjects, about 88% said they found them very useful or somewhat useful. A one-time mailing of videotapes to patients, with no individual follow-up, did not increase compliance with the medications monitored.",1995.0,0,0 2768,8568017,"Effect of food on the bioavailability of atorvastatin, an HMG-CoA reductase inhibitor.",L L Radulovic; D D Cilla; E L Posvar; A J Sedman; L R Whitfield,"To determine whether atorvastatin, a new HMG-CoA reductase inhibitor, could be administered with food in Phase II and III clinical trials, a nonblind, randomized, two-way crossover study was conducted to assess the effect of food on rate and extent of atorvastatin absorption. Sixteen healthy volunteers received single 80-mg atorvastatin capsule doses on two occasions one week apart: once after an 8-hour overnight fast and once with a medium-fat breakfast. The single 80-mg atorvastatin capsule doses were well-tolerated. Mean maximum plasma atorvastatin equivalent concentration (Cmax) and area under the concentration-time curve (AUC) values with food were 47.9% and 12.7% lower, respectively, than without food. Mean time of maximum observed concentration (tmax) and elimination half-life (t1/2) values were 5.9 and 32.0 hours, respectively, with food and 2.6 and 35.7 hours, respectively, without food. A medium-fat breakfast decreased the rate of atorvastatin absorption significantly, but had little impact on extent of drug absorption. Changes in rate of atorvastatin absorption are not expected to have a clinically significant effect, as subsequent multiple-dose clinical studies have shown that dose but not plasma atorvastatin concentration profiles correlates with lipid-lowering effects.",1995.0,0,0 2769,8570427,The effect of supplemental dietary fat on plasma cholesterol levels in lovastatin-treated hypercholesterolemic patients.,J M McKenney; J D Proctor; J T Wright; R J Kolinski; R K Elswick; J S Coaker,"A validation study was conducted first to test assumptions about the effect of saturated and unsaturated dietary fat supplements. The second study was conducted to determine the effect on blood cholesterol levels of saturated and unsaturated fat supplements in patients who followed a low-fat diet and were administered lovastatin. Randomized, crossover design, with three periods in the first study and four in the second study, each lasting 6 weeks. Cholesterol Research Center. The first study evaluated adults with total cholesterol levels between 200 and 280 mg/dl (5.172 and 7.241 mmol/L). The second study included adults with low-density lipoprotein (LDL) cholesterol levels above 160 mg/dl (4.138 mmol/L). Fat supplements with either coconut or canola oil were delivered to patients in oatmeal-raisin cookies. In the validation study, patients' mean prerandomization total cholesterol level of 222 mg/dl was reduced to 213 mg/dl with canola oil and increased to 233 mg/dl with coconut oil cookies (p = 0.0038). In the second study the mean prerandomization total cholesterol level of 214 mg/dl was decreased to 199 mg/dl with canola oil and to 208 mg/dl with coconut oil cookies (p = 0.2342). The LDL cholesterol levels changed in a similar fashion in both studies. Changes in total and LDL cholesterol levels in the validation study were expected based on established effects of saturated and unsaturated fatty acids, but changes in these levels in lovastatin-cookie study were not expected. They could have occurred because lovastatin reversed the effect of saturated fats and enhanced the effect of unsaturated fats. Alternatively, they may have been due to enhanced bioavailability of lovastatin when administered with a high-fat diet. These findings must be confirmed.",2001.0,0,0 2770,8571098,Blood pressure lowering for the primary and secondary prevention of coronary and cerebrovascular disease.,S MacMahon; B Neal; A Rodgers,"An overview of the 17 completed randomised trials of antihypertensive treatment demonstrates that a 5-6 mm Hg reduction in DBP reduced stroke risk by 38% (SD 4) and CHD risk by 16% (SD 4). These results indicate that a few years' treatment with diuretic- or beta-blocker-based therapy produces most or all of the long-term stroke avoidance and much of the long-term CHD avoidance that would be predicted from observational epidemiological studies, given the blood pressure reductions that were achieved in the trials. The relative risk reductions were similar in trials of older and younger patients, although the absolute reduction in events was more than twice as great in the trials in older patients. From these results it can be estimated that in fully compliant patients at similar risk of vascular disease to those included in the trials, antihypertensive treatment for 5 years would prevent one major vascular event among every 20 older patients and one major vascular event among every 60 younger patients. Obviously the benefits of treatment will be greater among those at higher risk than the patients included in the previous trials. The greatest benefits are likely to be achieved in those with a history of vascular disease since their risk of future events is particularly high. Among such patients it is possible that blood pressure reduction will confer worthwhile benefits in those without hypertension, as well as those with hypertension. It is also possible that the benefits of treatment will be determined by the size of the blood pressure reduction and by the choice of the anti-hypertensive agent. However, each of these possibilities requires confirmation in large scale randomised controlled trials.",1995.0,0,0 2771,8575912,Secondary prevention in coronary heart disease. Fact: lowering cholesterol saves lives.,C J McKenna; D D Sugrue,,1995.0,0,0 2772,8580613,The detection and management of dyslipidaemia in children and adolescents.,L Ose; S Tonstad,"Previous algorithms regarding treatment of children with dyslipidaemia do not distinguish sufficiently between children at very high risk for cardiovascular disease and those with less exceptional risk. We propose that physicians assess risk, taking into consideration the nature of the genetic disorder, the severity of hypercholesterolaemia and the family history. Screening should be limited to children with suspected familial hypercholesterolaemia. Guidelines for individualized dietary and drug therapy are suggested.",1995.0,0,0 2773,8584066,Treating hypercholesterolemia aggressively.,C S Wilson,,1996.0,0,0 2774,8585875,[Comparison of pravastatin and diet in the treatment of hypercholesterolemia].,V Palazzuoli; S Mondillo; S Faglia; N D'Aprile; L Mangiacotti,"Aim of this study is to point out a correct therapy for the treatment of poligenic hypercholesterolemia resistant to dietetic treatment. There have been studied 40 patients which, after repeated haematochemical controls, resulted affected by dyslipidaemia with prevalent increase of the cholesterol levels. After 30 days of standard hypo-caloric dietetic treatment were enrolled 23 patients, 13 males and 10 females, who presented a plasmatic cholesterol level superior to 250 mg% and LDL superior to 160 mg%. All the patients continued the dietetic treatment; 10 patients began pravastatin therapy at a dose of 20 mg/die while to the rest of them was given placebo. The 30th, 60th, 120th day were controlled the following haematochemical parameters: lipidic frame haematology, hepatic and renal function, glycemia and CPK. After 4 months of treatment the average plasmatic levels of cholesterol resulted different in the two groups: mg% (p < 0.001) in the pravastatin group and 262 mg% (P = ns) in the control group. Then, the pravastatin therapy was suspended and all 23 patients continued for 30 days, dietetic treatment and placebo. After 6 months a new control of the lipidic frame was performed. Our results showed that the hypocholesterolic therapy must be continued for ever. In fact, the suspension of the treatment is followed by an immediate rebound of the dislipidaemia which plasmatic cholesterol levels even superior to the basic levels with probable negative repercussion on the cardiovascular system.",1995.0,0,0 2775,8590530,Comparison of the efficacy of simvastatin and standard fibrate therapy in the treatment of primary hypercholesterolemia and combined hyperlipidemia.,E Bruckert; J L De Gennes; W Malbecq; F Baigts,"Five multicenter, randomized, double-blind, placebo-controlled studies were conducted in France to compare the efficacy and safety of once-daily simvastatin treatment (10-40 mg/day) with conventional therapy with gemfibrozil 900 mg/day, ciprofibrate 100 mg/day, bezafibrate 400 mg/day, and fenofibrate 300 or 400 mg/day in a total of 800 patients with hypercholesterolemia. Simvastatin was associated with statistically significantly greater (p < or = 0.01) mean percent reductions in plasma low-density lipoprotein (LDL) cholesterol compared with each of the five fibrate regimens, even when administered at its recommended starting dose of 10 mg/day. Furthermore, approximately 90% of patients treated once daily with simvastatin experienced an at least 20% decrease in plasma LDL cholesterol compared with only 36 to 68% of patients treated with the individual fibrate agents (p < or = 0.05). The effectiveness of simvastatin in reducing LDL cholesterol did not differ as a function of the baseline plasma concentrations of total cholesterol or triglycerides. In contrast, the effectiveness of fibrate therapy in lowering plasma LDL cholesterol levels was significantly diminished (p < or = 0.05) among patients with triglyceride concentrations > 1.7 mmol/l. Plasma high-density lipoprotein (HDL) cholesterol levels were increased by approximately 10% after treatment with simvastatin or the fibrates. Although fibrate therapy was more effective overall in lowering plasma triglyceride levels, the effectiveness of simvastatin in reducing plasma triglyceride levels was generally 2- to 4-fold greater in patients with hypercholesterolemia associated with triglyceride levels > or = 2.3 mmol/l than in those with hypercholesterolemia associated with triglyceride levels < 2.3 mmol/l. The results of these studies confirm the superiority of simvastatin to standard fibrate therapy in reducing plasma levels of total and LDL cholesterol. They further indicate that once-daily treatment with simvastatin is effective in patients with isolated hypercholesterolemia or hypercholesterolemia associated with elevated triglyceride levels.",1995.0,0,0 2776,8595642,"A comparison of lovastatin, an HMG-CoA reductase inhibitor, with gemfibrozil, a fibrinic acid derivative, in the treatment of patients with diabetic dyslipidemia.",D S Bell,"Hyperlipidemia associated with non-insulin-dependent diabetes mellitus (NIDDM) and insulin resistance is characterized by high triglyceride levels; raised levels of total low-density lipoprotein (LDL), which is made up of small, dense, cholesterol-rich particles; low levels of high-density lipoprotein (HDL); and glycosylation of apolipoproteins. Optimal drug therapy for this lipid profile is controversial. To test whether a fibrinic acid derivative (gemfibrozil) or a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (lovastatin) would produce better results in these patients, a crossover study was performed. Gemfibrozil 600 mg twice daily and, after a washout period, lovastatin 20 to 40 mg twice daily were administered to nine patients with NIDDM. Gemfibrozil significantly decreased triglyceride, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) levels, the total cholesterol:HDL ratio, and the IDL plus VLDL;HDL ratio, and significantly increased levels of HDL, HDL2, and HDL3. Lovastatin significantly decreased levels of total cholesterol, calculated LDL, directly measured LDL, IDL, total triglycerides, VLDL, and the ratios of LDL:HDL, total cholesterol:HDL, and directly measured LDL:HDL and significantly increased total HDL and HDL3 levels. Gemfibrozil was significantly more effective than lovastatin in raising total HDL and HDL3 levels and in lowering the IDL plus VLDL:HDL ratio. Lovastatin was significantly more effective than gemfibrozil in lowering total cholesterol, LDL, directly measured LDL, and the LDL:HDL and directly measured LDL:HDL ratios. In the absence of malignant hypertriglyceridemia, an HMG-CoA reductase inhibitor, rather than a fibrinic acid derivative, is indicated for the treatment of patients with dyslipidemia associated with NIDDM and insulin resistance.",1995.0,0,0 2777,8597317,Reduction in carotid arterial wall thickness using lovastatin and dietary therapy: a randomized controlled clinical trial.,H N Hodis; W J Mack; L LaBree; R H Selzer; C Liu; C Liu; P Alaupovic; H Kwong-Fu; S P Azen,"To assess the effects of lipid-lowering therapy on the progression of early, preintrusive carotid arterial atherosclerosis. Randomized, double-blind, placebo-controlled, serial carotid arterial imaging trial. University Atherosclerosis Research Unit. 188 patients from the Monitored Atherosclerosis Regression Study who were 37 to 67 years of age and had angiographically defined coronary artery disease. Cholesterol-lowering diet plus placebo or lovastatin, 80 mg/d. High-resolution B-mode ultrasonographic quantification of the combined thickness of the distal common carotid arterial far wall intima-media complex (carotid arterial intima-media thickness) at baseline and every 6 months for as long as 4 years. The annual rate of change in carotid arterial intima-media thickness differed significantly between the lovastatin group and the placebo group at 2 and 4 years (P < 0.001). Lipid-lowering therapy reverses the progression of early, preintrusive atherosclerosis of the carotid artery. Both cholesterol-rich and triglyceride-rich lipoproteins correlate with the progression of early, preintrusive atherosclerosis of the carotid artery. These findings, together with earlier reports of the effects of lovastatin therapy on the progression of atherosclerosis of the coronary arteries, indicate that carotid arterial far wall intima-media thickness is a useful end point for anti-atherosclerosis trials.",1996.0,0,0 2778,8602715,"Cholesterol screening in asymptomatic adults, revisited. Part 2.",A M Garber; W S Browner; S B Hulley,"To assess the role of serum lipid levels as screening tests in adults. Pooled analysis of clinical trials, supplemented by analysis of data from the Framingham Heart Study, to estimate the effect of cholesterol reduction in patient groups stratified by cardiac risk. Published randomized controlled trials of cholesterol reduction, meta-analyses of such trials, prospective cohort studies of the association between cholesterol levels and morbidity and death related to coronary heart disease, and cost-effectiveness analyses of cholesterol reduction. Two-stage logistic regression on cardiac risk factors and outcomes in the Framingham Heart Study. The first stage predicted the risk for death from coronary heart disease using standard risk factors but not cholesterol; the second stage predicted the risk for death from coronary heart disease and all causes as functions of age and cholesterol level, stratified by the risk predicted from the first stage. Randomized clinical trials show that cholesterol reduction confers survival benefits in patients with symptomatic coronary disease. In asymptomatic middle-aged men, who are at lower risk for death from coronary disease, cholesterol reduction prevents coronary disease but has not been shown to prolong life. The risk model based on analysis of the data from the Framingham Heart Study is consistent with the randomized trial data and shows that in the demographic groups excluded from trials, the hypothetical benefits of cholesterol reduction are greatest when the underlying risk for coronary disease is greatest. Screening with total cholesterol levels is most likely to be useful when done in populations at high short-term risk for dying of coronary heart disease, such as survivors of myocardial infarction and middle-aged men with multiple cardiac risk factors. In these populations, cholesterol reduction appears to be both effective and cost-effective. In other populations, the benefits of reduction are much smaller or are uncertain.",1996.0,0,0 2779,8604188,Apparent discontinuation rates in patients prescribed lipid-lowering drugs.,L A Simons; G Levis; J Simons,"To evaluate apparent discontinuation rates in patients newly prescribed lipid-lowering drugs. A prospective survey of 12 months' dispensing data in 138 community pharmacies across metropolitan Sydney. 610 adults (49% men) with a mean age of 58 years; 91% of prescriptions were from general practitioners; prescribed drugs were simvastatin (54%), pravastatin (31%) and gemfibrozil (15%). The number of patients failing to collect prescription refills. 60% of patients (95% confidence interval [CI], 56%-64%) apparently discontinued their medication over 12 months. Half of the apparent discontinuations occurred within three months and a quarter within one month of starting treatment. The predominant reasons for discontinuation were: patient unconvinced about need for treatment (32%), poor efficacy (32%) and adverse events (7%). Only half of those experiencing poor efficacy were switched to another drug. The relative risk (RR) of discontinuation was lower in older patients (age 65+ v. <50 years: RR 0.66; 95% CI 0.47-0.93) and in those using other cardiovascular drugs (RR 0.69; CI 0.56-0.86), but was increased in those showing early evidence of poor compliance (RR 1.77; CI 1.33-2.35). Discontinuation appeared to be unrelated to sex, the source of the prescription (general practitioner or specialist), past use of lipid-lowering drugs or the cost of medication. High apparent discontinuation rates with lipid-lowering drugs suggest significant wastage of resources in treatments that are initiated but not continued and a lost opportunity for heart disease prevention. Many patients appear to discontinue therapy for illogical reasons and this may be amenable to intervention.",1996.0,0,0 2780,8609365,27th Bethesda Conference: matching the intensity of risk factor management with the hazard for coronary disease events. Task Force 4. Efficacy of risk factor management.,J S Forrester; C N Merz; T L Bush; J N Cohn; D B Hunninghake; S Parthasarathy; H R Superko,,1996.0,0,0 2781,8610621,Lovastatin plus probucol for prevention of restenosis after percutaneous transluminal coronary angioplasty.,J H O'Keefe; G W Stone; B D McCallister; C Maddex; R Ligon; R L Kacich; J Kahn; P G Cavero; G O Hartzler; B D McCallister,"Combination lovastatin and probucol reduced total cholesterol (27%) and low-density lipoprotein levels (30%), but did not prevent restenosis or clinical events during the first 6 months after percutaneous transluminal coronary angioplasty.",2001.0,0,0 2782,8610922,Cholesterol reduction: weighing the benefits and risks.,J M Gaziano; P R Hebert; C H Hennekens,"The National Cholesterol Education Program recommends reducing total and low-density lipoprotein cholesterol levels to decrease the risk for coronary heart disease. The available evidence clearly indicates that higher cholesterol levels increase the risk for coronary heart disease and that cholesterol reduction results in corresponding decreases in risk. In contrast, existing data do not strongly support the idea that cholesterol reduction causes increases in any specific nonvascular cause of death. The outcomes of ongoing, large-scale trials will enable existing guidelines to be refined. However, current recommendations, which encourage nonpharmacologic interventions for about 30% of U.S. adults and cholesterol-reducing drugs for about 7% of U.S. adults, seem both justified and warranted.",1996.0,0,0 2783,8614809,Heart attacks: gone with the century?,M S Brown; J L Goldstein,,1996.0,0,0 2784,8615304,Pharmacologic profile of survivors of acute myocardial infarction at United States academic hospitals.,B G Phillips; J M Yim; E J Brown; N Bittar; T J Hoon; C Celestin; P H Vlasses; J L Bauman,"Optimal drug therapy for patients with acute myocardial infarction (AMI) is well described in the medical literature. However, data on the actual pharmacologic management of patients surviving AMI at academic hospitals is unavailable. The purpose of this study was to document treatment profiles in 500 patients surviving AMI at 12 academic hospitals in the United States. These profiles were compared with established guidelines and were evaluated for trends. Overall, thrombolytics (streptokinase > or = tissue-type plasminogen activator) were administered in 29% of the patients, with a greater proportion of patients receiving beta-blockers than calcium channel antagonists in the initial 72 hours (61% vs 40%; p < 0.005) and at discharge (51% vs 35%; p < 0.005). Further, women were less likely than men to receive thrombolytic therapy (odds ratio [OR] = 0.61; confidence interval [CI], 0.54 to 0.69) or beta-blocker therapy within the first 72 hours (OR = 0.61; CI, 0.55 to 0.67) or at hospital discharge (OR = 0.53; CI, 0.48 to 0.58). Overall, improvements could still be made in the number of patients who receive thrombolytic and acute and chronic beta-blocker therapies after AMI, particularly in women. Changes in treatment profiles may be a reflection of the publication of large clinical trials.",2001.0,0,0 2785,8615705,Cholesterol-reduction intervention study (CRIS): a randomized trial to assess effectiveness and costs in clinical practice.,G Oster; G M Borok; J Menzin; J F Heyse; R S Epstein; V Quinn; V Benson; R J Dudl; A M Epstein,"The 1988 US National Cholesterol Education Program Expert Panel Report recommended initial treatment with niacin or bile acid sequestrants, followed by other agents if needed, to lower low-density lipoprotein cholesterol (LDL-C) levels in hypercholesterolemic patients who require drug therapy. It is unknown how the effectiveness and costs of such an approach (""stepped care"") compare in typical clinical practice to those of initial therapy with lovastatin. We randomly assigned 612 patients, aged 20 to 70 years, who met 1988 National Cholesterol Education Program guidelines for drug treatment of elevated LDL-C level and had not previously used cholesterol-lowering medication, to either a stepped-care regimen or initial therapy with lovastatin (both n=306). The study, conducted at Southern California Kaiser Permanente, was designed to approximate typical practice: provider compliance with treatment plans was encouraged but not enforced, and patients paid for medication as they customarily would. At 1 year, the decline in mean LDL-C level was significantly greater among patients assigned to initial treatment with lovastatin (22% vs 15% for stepped care; P<.001), as was the number who attained goal LDL-C level (0.92). To study the difference between methodologies on QCA results as influenced by the choice of frame and normal segment analyzed, the patient films were analyzed independently in 3 separate rounds of interpretation. In round 1, each system's operator individually chose frames and normal segments for analysis. In round 2, both systems analyzed the same preselected frames, but independently chose normal segments. In round 3, both systems analyzed the same preselected normal segments and frames. The intersystem correlations between visual and automatic systems for rounds 1, 2, and 3 were: normal diameter, r = 0.25, r = 0.37, and r = 0.75, respectively; minimal lumen diameter, r = 0.79, r = 0.86, and r = 0.85, respectively; and diameter stenosis, r = 0.65, r = 0.73, and r = 0.87, respectively. The manual edge-detection and automated edge-detection systems used in this study are reasonably accurate and consistent on phantom studies. In patient studies, the nonautomated processes (choice of frame and normal segment for analysis) produced significant differences in the QCA results, thus illustrating that operator-dependent factors other than edge detection are very important in QCA.",1996.0,0,0 2789,8626228,Osteopathic medicine: an inherently natural approach to cholesterol reduction.,F J Rogers,,1996.0,0,0 2790,8628597,Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Canadian Lovastatin in Children Study Group.,M Lambert; P J Lupien; C Gagné; E Lévy; S Blaichman; S Langlois; M Hayden; V Rose; J T Clarke; B M Wolfe; C Clarson; H Parsons; D K Stephure; D Potvin; J Lambert,"Familial hypercholesterolemia (FH), an inherited autosomal dominant disorder of lipoprotein metabolism, is associated with premature atherosclerosis. The recommended pediatric therapy consists of dietary intervention and, when necessary, treatment with bile acid-binding resins. However, compliance has been poor in many children. Therefore, our objectives were to determine the efficacy, safety, and tolerance of the short-term use of lovastatin, a 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitor, in the control of severe FH in a male pediatric population and to evaluate the dose-response relationship. Sixty-nine male patients with FH 12.9 +/- 2.4 years of age (mean +/- SD) participated in this multicenter, randomized, double-blind trial. After a 4-week placebo period, the patients were allocated to four treatment groups (lovastatin 10, 20, 30, 40 mg/d) for 8 weeks. Plasma lipid and apolipoprotein (Apo) concentrations were measured every 2 weeks. Clinical and laboratory evidence of adverse events was monitored periodically throughout the study. All lovastatin doses reduced total cholesterol (-17% to -29%), low density lipoprotein cholesterol (-21% to -36%), and ApoB (-19% to -28%) concentrations. A dose-response relationship was seen, and between-group comparisons showed that results were significantly improved up to a dose of 30 mg/d. We observed a 7% increase in high-density lipoprotein cholesterol and a 4% increase in ApoA1 concentrations. The medication was well tolerated by all patients. No serious clinical adverse experience was reported. Lovastatin increased aspartate aminotransferase concentrations, but there was no evidence of a dose-response relationship, and no value exceeded two times the upper limit of normal. No significant change in alanine aminotransferase was observed. Three patients had marked (more than three times the upper limit of normal) asymptomatic elevations in their creatine kinase values, which returned spontaneously to normal, and no action was required regarding the drug.",1996.0,0,0 2791,8629587,Comparison of the effects on quality of life and of the efficacy and tolerability of lovastatin versus pravastatin. The Quality of Life Multicenter Group.,M R Weir; M L Berger; M L Weeks; C L Liss; N C Santanello,"This multicenter study compared the effects of lovastatin (40 mg) and pravastatin (40 mg) on quality of life. Men, aged 20 to 65 years old, with primary hypercholesterolemia (types IIa and IIb) were eligible for enrollment if baseline low-density lipoprotein cholesterol met the first National Cholesterol Education Program adult treatment guidelines. Eligible patients were enrolled into a 6-week diet baseline period, followed by a 6-week diet-plus-placebo period. Patients whose low-density lipoprotein cholesterol still met National Cholesterol Education Program guidelines for drug therapy were randomized into the double-blind, active-treatment period to receive either lovastatin 40 mg or pravastatin 40 mg/day for 12 weeks. Clinic visits were scheduled every 4 weeks and included complete serum lipid profiles, monitoring of adverse experiences, and patient completion of health-related quality-of-life questionnaires. The primary end point of the study was the change in quality of life, as measured by the Nottingham Health Profile (part 1) after 12 weeks of treatment. Secondary end points included responses to a general health question from the National Health and Nutrition Examination Survey, sexual function questions from the Medical Outcomes Study, and stress/life event questions from the National Institutes of Health Post-Coronary Artery Bypass Grafting Study. No significant differences between the 2 groups were observed in tolerability, health-related quality-of-life measures, or changes in lipid profiles.",1996.0,1,1 2792,8629655,Drug therapy for hypercholesterolemia in patients with cardiovascular disease: factors limiting achievement of lipid goals.,G Schectman; J Hiatt,"To determine the extent that goal lipid levels derived from the National Cholesterol Education Program (NCEP) are achievable in clinical practice, and to identify factors associated with the achievement of these goals. We conducted a retrospective cohort study consisting of a consecutive sample of 244 patients with either coronary artery disease or peripheral vascular disease treated for hypercholesterolemia at a large Veterans Affairs medical center. Primary outcomes, recorded prospectively, were lipid levels and lipoprotein cholesterol response, and tolerance and compliance to drug therapy. Goal lipid levels were defined as low-density lipoprotein cholesterol (LDL-C) < or = 130 mg/dL and triglyceride (TG) < or = 200 mg/dL. Lipid-lowering drug therapy reduced LDL-C from 25% to 42% below baseline in patients with hypercholesterolemia varying from mild (130 to 160 mg/dL) to severe ( > 220 mg/dL), respectively. Approximately 75% of patients with LDL-C < or = 160 mg/dL ultimately achieved their lipid goal with drug therapy; however, less than half of patients with baseline LDL-C > 160 mg/dL achieved target lipid values. Multivariate analysis indicated that lower baseline LDL-C and triglycerides, use of combinations of drug therapy rather than monotherapy, and patient adherence to treatment predicted the achievement of goal lipid levels. Successful implementation of NCEP guidelines, frequently requires combination drug therapies, and is limited by poor patient tolerance and acceptance of niacin and the sequestrants.",1996.0,0,0 2793,8633373,The effect of pravastatin on acute rejection after kidney transplantation--a pilot study.,S Katznelson; A H Wilkinson; J A Kobashigawa; X M Wang; D Chia; M Ozawa; H P Zhong; M Hirata; A H Cohen; P I Teraski,"Hyperlipidemia is an important complication of kidney transplantation affecting up to 74% of recipients. HMG-CoA reductase inhibitors are reported to provide safe and effective treatment for this problem. A recent study suggests that pravastatin, an HMG-CoA reductase inhibitor, also decreases the incidence of both clinically severe acute rejection episodes and natural killer cell cytotoxicity after orthotopic heart transplantation. We have performed a prospective randomized pilot study of the effect of pravastatin on these same parameters after cadaveric kidney transplantation. Graft recipients were randomized to receive pravastatin after transplantation or no pravastatin (24 patients in each group) in addition to routine cyclosporine and prednisone immunosuppression. Lipid levels, acute rejection episodes and serial natural killer cell cytotoxicities were followed for 4 months after the transplant. At the end of the study period, pravastatin had successfully controlled mean total cholesterol levels (202.6 +/- 9.3 vs. 236.5 +/- 11.9 mg/dl, P < 0.02), LDL levels (107.9 +/- 6.6 vs.149.6 +/- 10.7 mg/dl, P < 0.002), and triglyceride levels (118.8 +/- 14.2 vs. 157.2 +/- 13.8 mg/dl, P < 0.05). In addition, the pravastatin-treated group experienced a reduction in the incidence of biopsy-proven acute rejection episodes (25% vs. 58%, P = 0.01), the incidence of multiple rejections episodes (P < 0.05), and the use of both pulse methylprednisolone (P = 0.01) and OKT3 (P = 0.02). Mean natural killer cell cytotoxicity was similarly reduced (11.3 +/- 1.6 vs. 20.0 +/- 2.0% lysis of K562 target cells, P < 0.002). These data suggest that pravastatin exerts an additional immunosuppressive effect in kidney transplant recipients treated with cyclosporine-based immunosuppression.",1996.0,0,0 2794,8635258,Cholesterol lowering and the use of healthcare resources. Results of the Scandinavian Simvastatin Survival Study.,T R Pedersen; J Kjekshus; K Berg; A G Olsson; L Wilhelmsen; H Wedel; K Pyörälä; T Miettinen; T Haghfelt; O Faergeman; G Thorgeirsson; B Jönsson; J S Schwartz,"Advances in the treatment of cardiovascular disease have increased costs; annual cardiovascular healthcare expenditure in the United States currently exceeds $100 billion. Physicians and third-party payers need to assess the economic impact of treatments that reduce cardiovascular morbidity and mortality. The Scandinavian Simvastatin Survival Study is a randomized, double-blind, placebo-controlled trial in which simvastatin reduced the risk of death by 30% (P=.0003) over the median follow-up period of 5.4 years in patients with previous myocardial infarction or stable angina pectoris as a result of a 42% reduction in the risk of coronary deaths (P=.00001). In the present report, data prospectively collected from hospital admissions were analyzed to evaluate the impact of simvastatin on healthcare resource use and perform a cost-minimization analysis. In the placebo group (n=2223), there were 1905 hospitalizations (average duration, 7.9 days) for acute cardiovascular events or coronary revascularization procedures among 937 patients, whereas in the simvastatin group (n=2221), there were 1403 such hospitalizations (average duration, 7.1 days) among 720 patients (all differences, P<.0001). The corresponding number of hospital days was 15089 and 9951 in the two groups, respectively (34% reduction,P<.0001). In the United States, the resulting reduction in hospitalization costs over the 5.4 years of the trial would be $3872 per patient, reducing the effective cost of simvastatin by 88% to $0.28 per day. In addition to reducing mortality and morbidity in coronary heart disease patients, simvastatin markedly reduces use of hospital services, thus offsetting most of its cost.",1996.0,0,0 2795,8635262,LDL-Apheresis Atherosclerosis Regression Study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis.,A A Kroon; W R Aengevaeren; T van der Werf; G J Uijen; J H Reiber; A V Bruschke; A F Stalenhoef,"Intensive lipid lowering may retard the progression of coronary atherosclerosis. LDL-apheresis has the potential to decrease LDL cholesterol to very low levels. To assess the effect of more aggressive lipid lowering with LDL-apheresis, we set up a randomized study in men with hypercholesterolemia and severe coronary atherosclerosis. For 2 years, 42 men were treated with either biweekly LDL-apheresis plus medication or medication alone. In both groups a dose of simvistatin of 40 mg per day was administered. Baseline (mean+/-SD) LDL cholesterol was 7.8+/-1.9 mmol x L(-1) and 7.9+/-2.3 mmol x L(-1) in the apheresis and medication groups, respectively. The mean reduction in LDL cholesterol was 63% (to 3.0 mmol x L(-1)) and 47% (to 4.1 mmol x L(-1)), respectively. Primary quantitative coronary angiographic end points were changes in average mean segment diameter and minimal obstruction diameter. No differences between the apheresis and medication groups were found in mean segment diameter (-0.01+/-0.16 mm versus 0.03+/-0.16 mm, respectively) or in minimal obstruction diameter (0.01+/-0.13 mm versus 0.01+/-0.11 mm, respectively), expressed as means per patient. On the basis of coronary segment, mean percent stenosis of all lesions showed a tendency to decrease; only in the apheresis group more minor lesions disappeared in comparison to the medication group. On bicycle exercise tests, the time to 0.1 mV ST-segment depression increased significantly by 39% and the maximum level of ST depression decreased significantly by 0.07 mV in the apheresis group versus no changes in the medication group. Two years of lipid lowering both with medication alone or LDL-apheresis with medication showed angiographic arrest of the progression of coronary artery disease. However, more aggressive treatment induced functional improvement, which may precede anatomic changes.",1996.0,0,0 2796,8636668,Cholesterol-lowering agent in men without CHD.,P Millard; K H Johnson,,1996.0,0,0 2797,8637293,[Treatment of hyperlipemia: opinions of primary care physicians of the La Rioja region].,A J Brea Hernando; M A Villar Arias; J D Mosquera Lozano; M V Ramírez Alesón,"Primary health care physicians (PHCP) play a fundamental role in the detection and treatment of hyperlipemias in a general population. The aim of this study was to estimate the opinion of the PHCP in the Autonomic Community of La Rioja, Spain, regarding desirable lipemic values and treatment of hyperlipemias. A survey with personal interview was carried out to all the PHCP in the Spanish National Health Care (INSALUD) in La Rioja in May and June 1994. Of the 177 PHCP included 97% completed the questionnaire. The main coronary risk factor for 46% of physicians was high blood pressure followed by serum cholesterol (30%). Fifty-six percent of the physicians believed that the desired populational cholesterolemia should be less than 200 mg/dl and this percentage rose if the physician worked in an urban environment (p < 0.01). Sixty-six percent considered 200 mg/dl as the desired triglyceridemia. For treatment and follow-up of hyperlipemia, 78% of physicians use cholesterol linked to low density lipoproteins (cLDL). This use of cLDL increased among those who were familiar with the recommendations of the Spanish Society of Arteriosclerosis (p < 0.002) or who worked in health care centers (p < 0.02). Regarding initiation of dietetic treatment most chose cholesterolemia between 200-250 mg/dl, a cLDL value between 150-185 mg/dl and triglyceridemia between 200-250 mg/dl. For the use of pharmacologic treatment these levels were 250-300 mg/dl, 150-185 mg/dl and 250-300 mg/dl, respectively. Ninety-nine percent of physicians indicated diet as the first therapeutic measure. In isolated hypercholesterolemia the resins were most used by the Family Medicine specialists (p < 0.002) and fibrates (p < 0.03) and statins (p < 0.02) the least used. The use of statins was lower in the physicians working in health care centers (p < 0.03). Knowledge of theshold values of serum cholesterol and triglicerides levels and the use of drugs among the primary health care physicians from La Rioja, Spain, are generally correct. The physicians with good knowledge of the National Consensus Guides on hyperlipemias had the most adequate opinion.",1996.0,0,0 2798,8637349,Statins and coronary heart disease.,R Fey; N Pearson,,1996.0,0,0 2799,8639010,"Meta-analysis, clinical trials, and transferability of research results into practice. The case of cholesterol-lowering interventions in the secondary prevention of coronary heart disease.",R Marchioli; R M Marfisi; F Carinci; G Tognoni,"To evaluate, in the comprehensive scenario of ""evidence-based"" medicine, the transferability of the results of published randomized clinical trials and meta-analyses on cholesterol-lowering interventions to clinical practice. Overview of randomized clinical trials on cholesterol-lowering interventions in the secondary prevention of coronary heart disease. The present overview on secondary prevention of coronary heart disease included 34 trials with cholesterol-lowering interventions in 24968 individuals. There was a 12.5% mortality in the group that was allocated active intervention and a 17.2% mortality in the control group (risk reduction, 13%; 95% confidence interval, -19% to -6%). Coronary and cardiovascular odds of deaths were significantly reduced. No clear association was found between noncoronary mortality and cholesterol-lowering interventions. Baseline total cholesterol levels had no clear influence on total mortality. Intermediate (10%-20%) and high ( > 20%) total cholesterol reductions were associated with similar reductions in the odds of death (-23% and -30%, respectively). No conclusion could be reached for patients who were less represented in the studies (ie, women and elderly persons). Patients with more complicated baseline clinical conditions (eg, congestive heart failure) had little nonsignificant benefit from cholesterol-lowering interventions. The effect of cholesterol-lowering interventions at least in the secondary prevention of coronary heart disease can be considered as established, but the transferability of such results to real-life patients remains the critical, unanswered question.",1996.0,0,0 2800,8641021,Levels of soluble cell adhesion molecules in patients with dyslipidemia.,A Hackman; Y Abe; W Insull; H Pownall; L Smith; K Dunn; A M Gotto; C M Ballantyne,"Increased expression of cell adhesion molecules (CAMs) on the vascular endothelium has been postulated to play an important role in atherogenesis. Both in vitro and in vivo studies have suggested that dyslipidemia may increase expression of CAMs. To determine whether dyslipidemia is associated with increased expression of CAMs, we examined the levels of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and soluble E-selectin (sE-selectin) in individuals with either hypercholesterolemia or hypertriglyceridemia and in control subjects matched for age and sex. Patients with hypertriglyceridemia had significantly higher levels of sVCAM-1 (739 +/- 69 ng/mL) compared with patients with hypercholesterolemia (552 +/- 63 ng/mL) and control subjects (480 +/- 56 ng/mL). Levels of sICAM-1 were significantly increased in both the hypercholesterolemic and hypertriglyceridemic groups (298 +/- 29 and 342 +/- 31 ng/mL, respectively) compared with the control group (198 +/- 14 ng/mL). Levels of sE-selectin were significantly increased in hypercholesterolemic patients (74 +/- 9 ng/mL) compared with control subjects (48 +/- 5 ng/mL). Ten hypercholesterolemic patients were treated aggressively with atorvastatin alone or a combination of colestipol and either atorvastatin or simvastatin for a mean of 42 weeks and had an average LDL cholesterol reduction of 51%. Comparison of soluble CAMs before and after treatment showed a significant reduction only in sE-selectin (77 +/- 11 versus 56 +/- 6 ng/mL, P < or = .03) but not for sVCAM-1 or sICAM-1. Although severe hyperlipidemia is associated with increased levels of soluble CAMs, aggressive lipid-lowering treatment had only limited effects on the levels. Increased levels of soluble CAMs in patients with hyperlipidemia may be a marker for atherosclerosis.",2001.0,0,0 2801,8642715,Cardiovascular disease.,J M Gore; J E Dalen,,1996.0,0,0 2802,8642723,General internal medicine.,L A Petersen; J Daley,,1996.0,0,0 2803,8644987,Update in cardiology.,J S Alpert; M D Cheitlin,,1996.0,0,0 2804,8650428,Fish oil supplementation in patients with heterozygous familial hypercholesterolemia.,G P Balestrieri; V Maffi; I Sleiman; S Spandrio; O Di Stefano; A Salvi; T Scalvini,"Familial hypercholesterolemia is associated with premature coronary heart disease. In patients with familial hypercholesterolemia, monotherapy with hydroxymethylglutaril coenzyme. A reductase inhibitors rarely achieves the goal of desirable low-density lipoprotein levels. Epidemiological studies suggest that populations with a high dietary intake of marine n3 fatty acids are protected against coronary heart disease. Hepatic synthesis and secretion of very low density lipoproteins are reduced during fish oil supplementation while other effects on lipid and lipoprotein metabolism are controversial. Fourteen patients affected by familial heterozygous hypercholesterolemia on chronic treatment with simvastatin were enrolled in a double blind, placebo controlled, randomized crossover trial that evaluated the effect of fish oil ethyl ester (Esapent, 5.1 g/day) on lipid and lipoprotein serum concentrations. Total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, apoprotein B, apoprotein AI, lipoprotein (a) did not show any significant variation during the four week treatment period with fish oil ethyl ester. The present data suggest that the possible favourable influence of fish oil on the progression of atherosclerosis in these high-risk patients might involve mechanisms which are different from lipid metabolism.",1996.0,0,0 2805,8650638,[Statin therapy of individuals with high risk for coronary disease].,I Holme,"After the release of the results from the West of Scotland Prevention study (WOSCOPS) some questions have been raised with respect to validity of its finding on all cause mortality, which was reduced by 22% with pravastatin treatment (p = 0.051) compared with placebo. Also, since WOSCOPS was a primary preventive study its results could affect a large proportion of Norwegian men. Thus, it can also be asked whether statin treatment should be preferred to standard, specific treatment for certain diseases, e.g. hypertension, if economic restrictions by the government make it necessary to make priorities. For example, expensive drugs are now given free to many diabetics and hypertensives, who should probably be treated with statins, almost regardless of their cholesterol level. The total social costs of medication could then exceed accepted budgets and could lead to restrictions. The author discusses the validity of the WOSCOPS findings on all cause mortality, and compares the results obtained in this study with those randomised trials and other statin trials. Finally, a comparison is made between results from two metaanalyses: one of randomised hypertension trials and one of all randomised statin trials. It is concluded that more favourable results are obtained from the latter. Caution should be shown, however, when interpreting such a comparison.",1996.0,0,0 2806,8651835,Beyond low-density lipoprotein cholesterol. A perspective on low high-density lipoprotein disorders and Lp(a) lipoprotein excess.,R S Rosenson,"Evidence supports the involvement of 2 common dyslipidemias---low high-density lipoprotein disorders and Lp(a) lipoprotein excess--in coronary heart disease. Until clinical trials determine whether specific therapeutic interventions can prevent the occurrence and recurrence of coronary heart disease in patients with these dyslipidemias, the implementation of cholesterol-lowering guidelines can provide a reasonable way to manage low high-density lipoprotein disorders and to identify specific categories of patients who may be at particularly high risk for premature coronary heart disease. Empiric treatment guidelines are suggested for low high-density lipoprotein disorders and Lp(a) lipoprotein excess in order to foster further discussion and validation by clinical trial data.",1996.0,0,0 2807,8653869,Endothelium-dependent coronary vasomotion relates to the susceptibility of LDL to oxidation in humans.,T J Anderson; I T Meredith; F Charbonneau; A C Yeung; B Frei; A P Selwyn; P Ganz,"Oxidatively modified LDL has been shown to markedly impair endothelium-dependent dilation in experimental studies. The aim of the present study was to determine the relationship between the coronary vasomotor response to the endothelium-dependent agonist acetylcholine and the in vitro susceptibility of LDL to oxidation in patients. Endothelium-dependent coronary vasomotion in response to acetylcholine (10(-8) to 10(-6) mol/L) was assessed in 23 patients with hypercholesterolemia (mean age, 56 +/- 9 years) after 1 year of therapy with either an American Heart Association Step 1 diet (seven patients), lovastatin and cholestyramine (seven patients), or lovastatin and probucol (nine patients). The susceptibility of LDL to oxidation was determined by measuring the lag phase of conjugated diene formation induced by Cu2+. Patients treated with lovastatin and probucol had prolongation of the lag phase (263 +/- 64 minutes) compared with diet- (91 +/- 22 minutes) or lovastatin and cholestyramine-(118 +/- 57 minutes) treated patients (P<.0001). By univariate analysis, the coronary vasomotor response to acetylcholine was significantly related to the lag phase of conjugated diene formation (P=.002), cholesterol-lowering therapy (P=.002), and serum cholesterol (P=.02). By multivariate analysis, the lag phase remained a significant predictor of the acetylcholine vasomotor response, independent of the effect of cholesterol-lowering treatment. In patients treated with lipid-lowering agents, the vasodilator response to acetylcholine is related to the susceptibility of LDL to oxidation. These findings suggest that oxidative stress is an important determinant of the coronary endothelial dysfunction observed in patients with atherosclerosis and hypercholesterolemia.",1996.0,0,0 2808,8654109,Lens opacity increase in a longitudinal study: comparison of the lens opacities classification system II and lensmeter 701.,P Rouhiainen; H Rouhiainen; J T Salonen,"We evaluated the ability of Lensmeter 701 (LOM) to detect changes in the transparency of the lens graded with the Lens Opacities Classification System II (LOCS II). In this prospective study 410 middle-aged Eastern Finnish men participating in the Kuopio Atherosclerosis Prevention Study were examined three times at eighteen month intervals, and lens opacities were graded with both LOM and LOCS II, the latter serving as the standard. Majority of the change in the LOM reading during the follow-up fell within the 95% tolerance interval of the apparatus (3.08 units). Only four eyes showing progression by LOCS II were detected by LOM. The association between LOM change and the change observed by LOCS II was not statistically significant, and the correspondence of the two methods was weak. It seems that the sensitivity of the LOM is not sufficient to detect small changes in the transparency of the lens over time.",1996.0,0,0 2809,8656168,Number-needed-to-treat analysis of the prevention of myocardial infarction and death by antidyslipidemic therapy.,C M Rembold,"Atherosclerosis of the coronary arteries is the most common cause of death in the United States for persons over the age of 45. Dyslipidemia is one of the risk factors for the development of coronary atherosclerosis. Recent studies suggest that treating dyslipidemia in persons with coronary atherosclerosis may decrease morbidity and mortality. A meta-analysis of 33 studies on the clinical and angiographic benefits of treating dyslipidemia in the prevention of morbidity and mortality from cardiovascular disease was performed. These benefits are quantitated in the form of ""number needed to treat"" (NNT) as an estimate of the public health benefit. The NNT is defined as the number of people that need to be treated to prevent one event. Treatment of dyslipidemia in persons with multiple atherosclerosis risk factors alone, ie, primary prevention, was effective in preventing myocardial infarction and all-cause death. In six trials of primary prevention, excluding the British cooperative trial using clofibrate, the NNT was 53 to prevent a nonfatal MI and 190 to prevent all-cause death (4.8 years treatment with total cholesterol reduction of 15%). Treatment of dyslipidemia in people with known atherosclerosis, ie, secondary and tertiary prevention, was also effective in preventing myocardial infarctions and death from all causes. For 23 trials of secondary and tertiary prevention, the NNT was 37 to prevent death from any cause (4.9 years treatment with total cholesterol reduction of 18%). In the trials with quantitative angiography, the NNT was 7 to prevent progression of coronary atherosclerosis and 10 to induce regression of coronary atherosclerosis (2.5 years treatment with a low-density lipoprotein cholesterol reduction of 28%). Similar benefits were observed in those trials employing HMG CoA reductase inhibitors. Benefits may be similar with niacin or dietary therapy, but these therapies did not reach significance in all categories of benefits, potentially due to beta error. These treatment benefits are comparable to other secondary prevention measures such as aspirin or beta blockers. The benefits appeared to extend to persons over 65, with less clearly defined benefits for women. These results support the overall clinical benefit of treating dyslipidemia, both in persons with and without known atherosclerosis.",1996.0,0,0 2810,8658343,Cholesterol and cataracts.,R J Cenedella,"Inherited defects in enzymes of cholesterol metabolism and use of drugs which inhibit lens cholesterol biosynthesis can be associated with cataracts in animals and man. The basis of this relationship apparently lies in the need of the lens to satisfy its sustained requirement for cholesterol by on-site synthesis, and impairing this synthesis can lead to alteration of lens membrane structure. Lens membrane contains the highest cholesterol content of any known membrane. The Smith-Lemli-Opitz syndrome, mevalonic aciduria, and cerebrotendinous xanthomatosis all involve mutations in enzymes of cholesterol metabolism, and affected patients can develop cataracts. Two established models of rodent cataracts are based on treatment with inhibitors of cholesterol biosynthesis. The long-term ocular safety of the very widely used vastatin class of hypocholesterolemic drugs is controversial. Some vastatins are potent inhibitors of cholesterol biosynthesis by animal lenses, can block cholesterol accumulation by these lenses and can produce cataracts in dogs. Whether these drugs inhibit cholesterol biosynthesis in human lenses at therapeutic doses is unknown. Results of clinical trials of 1-5 years duration in older patient populations indicate high ocular safety. However, considering the slow life-long growth of the lens and its continuing need for cholesterol, longterm safety of the vastatins should perhaps be viewed in units of 10 or 20 years, particularly with younger patients.",1996.0,0,0 2811,8663599,Molecular cloning of human phosphomevalonate kinase and identification of a consensus peroxisomal targeting sequence.,K L Chambliss; C A Slaughter; R Schreiner; G F Hoffmann; K M Gibson,"Two overlapping cDNAs which encode human liver phosphomevalonate kinase (PMKase) were isolated. The human PMKase cDNAs predict a 191-amino acid protein with a molecular weight of 21,862, consistent with previous reports for mammalian PMKase (Mr = 21,000-22,500). Further verification of the clones was obtained by expression of PMKase activity in bacteria using a composite 1024-base pair cDNA clone. Northern blot analysis of several human tissues revealed a doublet of transcripts at approximately 1 kilobase (kb) in heart, liver, skeletal muscle, kidney, and pancreas and lower but detectable transcript levels in brain, placenta, and lung. Analysis of transcripts from human lymphoblasts subcultured in lipid-depleted sera (LDS) and LDS supplemented with lovastatin indicated that PMKase gene expression is subject to regulation by sterol at the level of transcription. Southern blotting indicated that PMKase is a single copy gene covering less than 15 kb in the human genome. The human PMKase amino acid sequence contains a consensus peroxisomal targeting sequence (PTS-1), Ser-Arg-Leu, at the C terminus of the protein. This is the first report of a cholesterol biosynthetic protein which contains a consensus PTS-1, providing further evidence for the concept that early cholesterol and nonsterol isoprenoid biosynthesis may occur in the peroxisome.",1996.0,0,0 2812,8667843,[A new study on hypercholesterolemia. Statin is effective against heart disease].,A G Olsson,,1996.0,0,0 2813,8672984,Genetic and cellular changes in colorectal cancer: proposed targets of chemopreventive agents.,P Greenwald; G J Kelloff; C W Boone; S S McDonald,"Progress in development of a genetic model for colorectal tumorigenesis and human chemoprevention research may allow the mechanism-based identification of targets and chemopreventive agents that will protect against colorectal cancer. For example, numerous mutagenic events can occur throughout colorectal carcinogenesis, including loss of heterozygosity in tumor suppressor genes such as APC, MCC, DCC, and p53, as well as in oncogenes such as K-ras. Chemopreventive agents that inhibit mutagenic activity such as N-acetyl-l-cysteine, oltipraz, and nonsteroidal anti-inflammatory drugs may protect against these mutations. Also, agents such as perillyl alcohol and lovastatin that interfere with protein isoprenylation and, hence, inhibit oncogene activation may protect against aberrant K-ras expression. Hyperproliferation in normal mucosa, leading to growth and progression of neoplasia, are also aspects of colorectal carcinogenesis that can be controlled by chemopreventive agents. Calcium is a chemopreventive agent for which there is both clinical and experimental evidence of inhibition of cell proliferation in colon mucosa. Other examples of antiproliferative agents with potential chemopreventive efficacy in colon are 2-difluoromethylornithine, dehydroepiandrosterone, and selenium. Differentiating agents such as retinoids and deltanoids also may slow proliferation and progression. Antioxidants have potential for interfering with both mutagenicity and proliferation (e.g., by preventing oxidative activation of carcinogens and scavenging activated oxygen species generated during inflammation). The same mechanistic principles apply to identification of dietary chemopreventive intervention for colorectal carcinogenesis. For example, lowering dietary fat and increasing dietary fiber lead to lower colorectal mucosal proliferation, and cruciferous vegetables contain agents such as indoles and dithiolthiones that have shown antimutagenic activity.",1995.0,0,0 2814,8678079,Inadequate treatment with HMG-CoA reductase inhibitors by health care providers.,J J Marcelino; K R Feingold,"To determine if patients treated with HMG-CoA reductase inhibitors have their LDL cholesterol levels at or below the levels recommended by the National Cholesterol Education Program (NCEP) and if patients on these medications are monitored for potential toxicity. Ninety patients from the VA Medical Center in San Francisco were randomly selected in this retrospective analysis. All patients were taking a HMG-CoA reductase inhibitor as monotherapy for treatment of high blood cholesterol for a minimum of 1 year. Medical charts and laboratory and pharmacy computer databases were utilized to gather information regarding the patients' medical history, treatment history, relevant laboratory tests, and medication refill profile. The majority of patients, 73%, were secondary prevention patients. Only 33% of the 90 subjects met the LDL cholesterol goal recommended by the NCEP. For the secondary prevention patients, only 24% met goal LDL. Even when the stringency of the NCEP guidelines was reduced by 20% (goal LDL < 120 mg/dL), 50% of the secondary prevention patients were still inadequately treated. Only 2 of the 90 patients were on maximal dosage regimens. Sixty-seven percent of patients had annual lipid panels and 49% had annual liver panels. Forty-five percent of patients followed by nonphysicians met goal LDL while only 29% and 31% of patients followed by attending physicians and residents/fellows met goal LDL, respectively. In addition, patients followed by nonphysicians were monitored more closely for efficacy and toxicity of the medications. Based on the current NCEP recommendations, patients on monotherapy with HMG-CoA reductase inhibitors are often inadequately treated. Only 33% of the patients evaluated at our institution were at or below the NCEP recommended LDL cholesterol levels and less than half of the patients were adequately monitored for hepatotoxicity.",1996.0,0,0 2815,8678327,Prevalence and correlates of symptomatic peripheral atherosclerosis in individuals with coronary heart disease and cholesterol levels less than 240 mg/dL: baseline results from the Cholesterol and Recurrent Events (CARE) Study.,T J Wilt; B R Davis; D G Meyers; J L Rouleau; F M Sacks,"To determine the prevalence and correlates of symptomatic peripheral atherosclerosis in individuals with a history of myocardial infarction (MI) and cholesterol levels lower than 240 mg/dL. A cross-sectional analysis was conducted at baseline of 4159 participants in the Cholesterol and Recurrent Events (CARE) Study. Symptomatic diffuse atherosclerosis was defined as a history of MI plus lower extremity or cerebrovascular atherosclerosis or claudication by Rose questionnaire. The prevalence of symptomatic diffuse atherosclerosis was 12.9%; 353 participants (8.5%) had lower extremity disease and 219 (5.3%) had cerebrovascular disease. After controlling for other variables, diffuse atherosclerosis was associated with age (Odds Ratio [OR] = 1.44 per ten-year increase), systolic blood pressure (OR = 1.13 per 10 mm Hg increase), a history of multiple myocardial infarctions (OR = 1.76), diabetes (OR = 1.76), hypertension (OR = 1.38), reduced exercise performance (OR = 1.55), current smoking status (OR = 2.87), and lower alcohol intake (OR = 0.97 per drink per week). There was no association with race, gender, or lipid levels. The presence of clinically evident diffuse atherosclerosis is common and is associated with several modifiable risk factors. Early identification of these individuals could affect treatment and clinical outcomes.",1996.0,0,0 2816,8686314,Cost effectiveness of cholesterol-lowering drugs: a review of the evidence.,E Thorvik; I Aursnes; I S Kristiansen; H T Waaler,"Four studies of the cost per life year saved through lipid lowering with lovastatin or simvastatin showed considerable variation in the results. For example, the cost per life year saved on administration of simvastatin 20 mg/day for primary prevention in men 42 years old at the start of therapy and with an initial cholesterol level of 8 mmol/L, was 19,000 1994-US dollars according to one study, and 55,000 according to another. Both when the differences were due to different cost estimates and when they were due to different estimates of the number of life years saved, plausible explanations for the discrepancies between the cost-effectiveness ratios were generally found. The cost per life year saved through primary prevention was about three times greater among women than men at age 40, twice greater at age 60, an 1.3 times greater at age 70. The accordance between the studies was not good regarding how cost per life year saved varies with age at the start of drug therapy. According to one study, the cost per life year saved for secondary prevention is generally low. We also compared the estimates for statins with estimates for several other life-extending health interventions. Given current guidelines for the prescription of cholesterol-lowering drugs, primary prevention with statins seems generally to be one of the less cost-effective life extending health interventions, especially for women. The cost effectiveness of statins is likely to become more favorable, though, when the patients on these drugs expire.",1996.0,0,0 2817,8686956,The influence of angiographic endpoints on the outcome of lipid intervention studies. A proposal for standardization. REGRESS study group.,J W Jukema; A J van Boven; A H Zinderman; E T Bal; J H Reiber; A V Bruschke,"The aims of this study were to evaluate the influence of different coronary angiographic endpoints on the outcome of lipid intervention studies and to formulate a proposal for angiographic endpoint standardization. In recent angiographic intervention studies a confusing diversity in angiographic endpoints has been used to determine the outcome. In addition, differences in study populations (eg, bypass patients included or not) could influence results. This makes comparisons between studies cumbersome and raises the question to what extent the results of various studies may be subject to the selection of angiographic endpoints. The investigators compared three frequently used endpoints (mean segment diameter, minimum obstruction diameter, and % stenosis) in a group of 505 patients who had just finished a trial designed to assess the effect of cholesterol lowering by pravastatin. To exclude a potential bias this analysis was carried out at the time that the study was still blinded. They found poor intercorrelation coefficients for mean segment diameter calculated in different ways, ranging from 0.55 to 0.95, dependent on inclusion or exclusion of segments influenced by coronary angioplasty or bypass grafting and on whether or not a value of 0 was assumed for occluded segments and segments distal to occlusions. The correlation between mean segment diameter and minimum obstruction diameter was 0.79; between minimum obstruction diamete and % stenosis, 0.85; and between mean segment diameter and % stenosis, only 0.64. Different endpoints sometimes correlate poorly. This may lead to differences in results of angiographic intervention trials. The authors propose standardization by (1) using both mean sement diameter and minimum obstruction diameter as endpoints and (2) excluding from the primary analysis segments influenced by mechanical interventions.",1996.0,0,0 2818,8688757,Randomised placebo controlled trial of effect on mood of lowering cholesterol concentration. Oxford Cholesterol Study Group.,J Wardle; J Armitage; R Collins; K Wallendszus; A Keech; A Lawson,"To evaluate the effects on mood of a substantial and prolonged reduction in total cholesterol concentration. Randomised placebo controlled comparison of patients who had been allocated to receive simvastatin 20 mg or 40 mg daily versus those allocated matching placebo in a ratio of 2:1. Follow up at an average of 152 weeks after randomisation. Men and women aged between 40 and 75 years at entry with blood total cholesterol of 3.5 mmol/l or greater, who were considered to be at higher than average risk of coronary heart disease based on medical history. The shortened profile of mood states questionnaire, reported use of psychotropic medication, and symptoms possibly related to mood. Simvastatin reduced total cholesterol by 1.9 mmol/l (26.7%) at the time of follow up. Among all 621 patients randomised to simvastatin (414 patients) or placebo (207 patients) there were no significant differences in the use of psychotropic medication or in reports of symptoms possibly related to mood. Of these patients, 491 (334 simvastatin, 157 placebo) completed the mood questionnaire, and there were no significant differences between the treatment groups in total or subscale scores, even when patients with low baseline cholesterol concentrations or elderly subjects were considered separately. These results do not support the hypothesis that treatment to lower cholesterol concentration causes mood disturbance.",1996.0,0,0 2819,8690811,Treating elevated cholesterol levels: the great Satan in perspective.,M Gibaldi; W Kradjan,"The purpose of this review is to provide perspective on the developments leading to the recognition of high cholesterol levels as a risk factor for coronary heart disease (CHD). Another objective is to consider the unfolding controversies regarding the relative value of cholesterol-lowering drug therapy in primary and secondary prevention. Should physicians use lipid-lowering drugs to treat patients with elevated cholesterol levels but no clinical evidence of coronary disease, or limit intervention to patients with a previous history of angina, coronary angioplasty, coronary artery bypass surgery, or myocardial infarction? This review finds inadequate data to support a recommendation for screening large populations for the presence of elevated cholesterol levels or for primary prevention in those known to have high cholesterol. On the other hand, there is mounting evidence to support vigorous intervention in those with known coronary disease. Further study is needed to determine whether a subset of patients with one or more well-defined risk factors would benefit from primary prevention.",1996.0,0,0 2820,8690818,Effect of age and gender on pharmacokinetics of atorvastatin in humans.,D M Gibson; N J Bron; A Richens; N J Hounslow; A J Sedman; L R Whitfield,"Atorvastatin is a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor that reduces plasma cholesterol by inhibiting cholesterol synthesis and increasing cellular uptake of low density lipoproteins. The effects of age and gender on the pharmacokinetics of atorvastatin after administration of single 20-mg tablets of atorvastatin were studied in 16 young and 16 elderly volunteers (8 men and 8 women in each age group). Plasma equivalent concentrations of atorvastatin were quantitated by a validated enzyme inhibition bioassay. Atorvastatin was well tolerated by the participants. The equivalent maximum concentration (Cmax) of atorvastatin was 42.5% higher in elderly participants (age, 66-92 years) than in young participants (age, 19-35 years) and 17.6% higher in women than in men. In addition, mean area under the concentration-time curve (AUC0-infinity) and half-life (t1/2) were 27.3% greater and 36.2% longer, respectively, in elderly adults than in young adults and 11.3% lower and 19.9% shorter, respectively, in women than in men. Because the primary site of action for HMG-CoA reductase inhibitors is the liver and atorvastatin is subject to extensive first-pass hepatic metabolism, it is unclear whether these age- and gender-related differences in the pharmacokinetics of atorvastatin will be clinically important. Results of subsequent safety and efficacy trials should help clarify the clinical significance of these pharmacokinetic differences.",1996.0,0,0 2821,8706591,The 4S study. Implications for prescribing.,A J van Boven; J Brügemann; P A de Graeff; J F May; H J Crijns,"This article discusses various aspects of cholesterol-lowering therapy using the HMG-CoA reductase inhibitor simvastatin in the light of the large Scandinavian Simvastatin Survival Study (4S). In 4S, patients with proven coronary heart disease (CHD) and plasma total cholesterol > 5.5 mmol/L (212 mg/dl) despite dietary measures received statin therapy or placebo for > or = 5 years. A significant mortality reduction was accomplished in those receiving the statin. Moreover, a significant decrease of nonfatal myocardial infarction and requirement for coronary bypass surgery or angioplasty was demonstrated, which will contribute to the cost-effectiveness of this well tolerated therapy. Plaque stabilisation and improvement of endothelial function are thought to be mediators of this therapeutic success. Responsible drug prescription in the post-4S era may result in the recognition and treatment of more patients with CHD. This is likely to be more beneficial than exhaustive efforts to completely achieve the goals of the most strict guidelines in the individual patient. In patients who carry the highest absolute risk for a recurrent event, aggressive drug therapy may be most justified. Reluctance to initiate lipid lowering drug therapy in patients with proven CHD should now be disputed.",1996.0,0,0 2822,8706596,Itraconazole. A reappraisal of its pharmacological properties and therapeutic use in the management of superficial fungal infections.,M Haria; H M Bryson; K L Goa,"Itraconazole is an orally administered triazole antifungal agent. Its spectrum of activity includes dermatophyte, dimorphic and dematiaceous fungi, yeasts, and some moulds. In clinical trials, mycological cure was attained in approximately 70 to 80, > or = 70 and > or = 80% of patients with, respectively, fingernail and toenail onychomycosis (200 mg/day for 3 months), dermatophytosis (100 mg/day for 2 to 4 weeks) and vaginal candidiasis (400 mg/day for 1 day or 200 mg/day for 3 days). Approximately 20 to 30% of patients with onychomycosis may relapse after completion of therapy; relapse rate data are limited for the other indications. Recently developed intermittent regimens of itraconazole (400 mg/day for 1 week per month for 3 to 4 months) appear to have similar efficacy to standard regimens in the treatment of onychomycosis. Shorter, higher dosage itraconazole treatment regimens (200 or 400 mg/day for 1 week) are also beneficial in dermatomycoses. Discrepancies and limitations of study design hamper conclusions about efficacy relative to other antifungal drugs. Newer intermittent and short course higher dosage itraconazole regimens have also not been evaluated in comparative studies. Available studies show that the efficacy of itraconazole appears to be greater than that of griseofulvin, but similar to or lower than that of terbinafine in patients with dermatophyte onychomycosis or cutaneous fungal infections. Moreover, the efficacy of itraconazole may be similar to or lower than that of fluconazole in the treatment of cutaneous mycoses. Comparative data from patients with acute vaginal candidiasis suggest that itraconazole is at least as effective as intravaginal clotrimazole and oral fluconazole, and superior to intravaginal econazole. These results require confirmation. Prescription-event monitoring data indicate that itraconazole is generally well tolerated. Gastrointestinal disturbances, dizziness and headache occur most commonly; liver toxicity has been rarely described. Its usefulness in some clinical situations may be limited because of its ability to interact with various therapeutic agents. In conclusion, itraconazole along with other established agents should be considered a first-line treatment for patients with extensive or recalcitrant cutaneous fungal infections, mixed dermatophyte and Candida onychomycosis or vaginal candidiasis. It is currently considered a second-line drug for dermatophyte onychomycosis; the use of newer intermittent itraconazole treatment regimens may, however, extend its role in the management of this condition. Although itraconazole offers greater benefit than conventional therapies (griseofulvin and ketoconazole) in terms of efficacy and tolerability, wider clinical experience is required to determine its merits relative to the newer agents, terbinafine and fluconazole.",1996.0,0,0 2823,8707385,Attenuation of hypertension by insulin-sensitizing agents.,T A Kotchen,,1996.0,0,0 2824,8708586,Changes in cardiovascular risk factors by combined pharmacological and nonpharmacological strategies: the main results of the CELL Study.,L H Lindholm; T Ekbom; C Dash; A Isacsson; B Scherstén,"The objectives of the Cost Effectiveness of Lipid Lowering (CELL) study were twofold: (i) to evaluate the effect on overall cardiovascular risk of two types of health care advice (""usual' and ""intensive') given in primary care, with or without pharmacological medication, with the target being to attain a moderate decrease in cholesterol; (ii) to evaluate the ritual of daily medication on compliance with the health care advice. A prospective, double-blind, randomized, controlled trial of 18 months' duration. The study was carried out in 32 health centres (out of a total of approximately 850) in Sweden. In all, 681 subjects, aged 30-59 years, were randomized. They had at least two cardiovascular risk factors in addition to moderate primary hyperlipidaemia (total cholesterol of at least 6.50 mmol L-1 on three occasions measured by Reflotron triglycerides less than 4.0 mmol L-1 and an LDL:HDL cholesterol ratio of more than 4.0). Most (87%) of the subjects were males; 626 subjects (92%) completed the 18-month follow-up. Half the subjects were randomized to 'intensive advice' given in group sessions led by doctors and nurses in primary care. The other half received 'usual advice'. In each of the two advice groups, one-third received an active lipid-lowering drug (pravastatin), one-third placebo, and one-third no drug at all. The tablets were titrated to achieve a 15% reduction in cholesterol. Changes in the overall Framingham risk score, and the development of adverse events in each group. The change in Framingham risk score was significantly reduced only in subjects taking lipid-lowering medication (together with intensive advice -0.13; 95% CI-0.20, -0.06, and together with usual advice -0.16; 95% CI -0.23, -0.09). The other subjects receiving intensive advice tended to fare better than those on usual advice. Lifestyle was not influenced significantly over the study period. The ritual of daily medication did not affect the outcome. As expected, lipid-lowering medication reduced serum cholesterol as well as overall cardiovascular risk in subjects with several risk factors for cardiovascular disease. There was no additive effect of intensive advice to these subjects. However, there was a meagre but significant effect of intensive advice in subjects not receiving active lipid-lowering drugs. One explanation for this difference may be that those on active lipid-lowering medication who had substantial drops in cholesterol might have felt less inclined to change their lifestyle compared with those on other treatment regimens who had less successful drops in cholesterol. There was no benefit from the ritual of taking daily medication.",1996.0,0,0 2825,8708587,The cost effectiveness of lipid lowering in Swedish primary health care. The CELL Study Group.,M Johannesson; L Borgquist; B Jönsson; L H Lindholm,"To evaluate the cost-effectiveness of two types of advice (usual and intensive) to lower cardiovascular risk, with or without pharmacological medication aimed at lowering cholesterol levels. Prospective, randomized, controlled clinical study of 18 months' duration. Thirty-two primary health care centres in Sweden. A total of 384 males, aged 30-59 years, with at least one cardiovascular risk factor in addition to moderate primary hyperlipidaemia; of these, 355 completed the 18-month follow-up. Intensive advice consisted of group sessions led by a health care professional; the usual level of advice was given at follow-up visits. The pharmacological intervention consisted of pravastatin. The goal was to achieve a 15% reduction in cholesterol. Cost per life-year gained based on the change in serum cholesterol and the net intervention cost of the four treatment options. The usual level of advice and intensive advice in combination with pharmacological treatment achieved no incremental effects and were not considered in the cost-effectiveness analysis. The cost per life-year gained of pharmacological treatment compared with intensive advice decreased. The cost per life-year gained of pharmacological treatment compared with no treatment was about $61,000, if no adverse consequences on noncardiovascular mortality were assumed. According to the results of the CELL trial, intensive advice is not a cost-effective strategy compared with lipid-lowering drug treatment. However, it is also doubtful whether drug treatment as primary prevention is cost-effective compared with no treatment in the studied patient population.",1996.0,0,0 2826,8712148,,,,,0,0 2827,8713484,HMG-CoA reductase inhibitors: issues in assessing their benefits in coronary heart disease.,A M Gotto,,2001.0,0,0 2828,8713485,Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: a reappraisal.,T R Pedersen; J A Tobert,"Although several cholesterol-lowering interventions have reduced coronary heart disease (CHD) events in clinical trials, drug therapy for hypercholesterolaemia has not been as widely used as the US and European guidelines recommend, mainly because until recently there was insufficient clinical trial evidence for improved survival. The Scandinavian Simvastatin Survival Study (4S) is the first trial of lipid-lowering therapy to demonstrate an unequivocal reduction in total mortality. Largely as a result of this study, there is now little disagreement on the necessity to reduce low density lipoprotein (LDL) cholesterol effectively in hypercholesterolaemic patients with CHD. Many physicians believe it is also important to reduce elevated levels of LDL cholesterol in patients without overt coronary disease, but more clinical trial evidence will be required before this is universally accepted. Inhibitors of HMG-CoA reductase are the most effective class of agents for this purpose, and have become widely used. It is likely that the magnitude of risk reduction produced by lipid-lowering therapy is proportional to the degree of cholesterol lowering achieved, which is an important consideration when selecting an agent and deciding the dosage to use. The results of several multicentre comparative trials have clearly established that the 4 members of the class are not all equipotent on a mg basis in terms of their effects on lowering LDL cholesterol. They have shown that the hypolipidaemic effect of simvastatin 5 mg approximately equals that of pravastatin 15 mg and lovastatin 15 mg and that of fluvastatin 40 mg, all given once daily. The tolerability profiles of HMG-CoA reductase inhibitors are excellent. Five-year data are available for simvastatin and lovastatin, and to date there is no good evidence for important differences in safety or tolerability among the class.",1996.0,0,0 2829,8718452,Cardiovascular disease and diabetes: issues raised at The European Association for the Study of Diabetes annual meeting.,Z T Bloomgarden,,1996.0,0,0 2830,8719939,Is responsiveness to lovastatin in familial hypercholesterolaemia heterozygotes influenced by the specific mutation in the low-density lipoprotein receptor gene?,T P Leren; I Hjermann,"Lovastatin is one of the most commonly used lipid-lowering drugs in familial hypercholesterolaemia (FH) heterozygotes. In order to study whether the response to lovastatin is influenced by the underlying mutation in the low-density lipoprotein (LDL) receptor gene, the authors compared the response in 24 heterozygotes in whom the mutation has been classified and in 34 heterozygotes in whom the mutation has not been classified. Those possessing a classified mutation had significantly higher pre-trial values of LDL-cholesterol than those possessing an unclassified mutation. However, no difference was found in the response to lovastatin. Nor were there any differences in the response between subjects possessing one of the three different classified mutations. Furthermore, irrespective of whether or not the mutation had been classified, no difference in the response was found between subjects in the upper and lower quartile with respect to pre-trial values of LDL-cholesterol. The authors conclude that the response to lovastatin is independent of both the specific mutation in the LDL receptor gene and the actual cholesterol level in FH heterozygotes.",1995.0,0,0 2831,8721786,Cholesterol-lowering therapy may retard the progression of diabetic nephropathy.,H H Parving,,1996.0,0,0 2832,8721787,The effect of cholesterol-lowering therapy on the progression of diabetic nephropathy is unproved.,R Bender,,1996.0,0,0 2833,8721797,Assessing the quality of reports of randomized clinical trials: is blinding necessary?,A R Jadad; R A Moore; D Carroll; C Jenkinson; D J Reynolds; D J Gavaghan; H J McQuay,"It has been suggested that the quality of clinical trials should be assessed by blinded raters to limit the risk of introducing bias into meta-analyses and systematic reviews, and into the peer-review process. There is very little evidence in the literature to substantiate this. This study describes the development of an instrument to assess the quality of reports of randomized clinical trials (RCTs) in pain research and its use to determine the effect of rater blinding on the assessments of quality. A multidisciplinary panel of six judges produced an initial version of the instrument. Fourteen raters from three different backgrounds assessed the quality of 36 research reports in pain research, selected from three different samples. Seven were allocated randomly to perform the assessments under blind conditions. The final version of the instrument included three items. These items were scored consistently by all the raters regardless of background and could discriminate between reports from the different samples. Blind assessments produced significantly lower and more consistent scores than open assessments. The implications of this finding for systematic reviews, meta-analytic research and the peer-review process are discussed.",1996.0,0,0 2834,8722437,Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Research Group.,B R Davis; J A Cutler; D J Gordon; C D Furberg; J T Wright; W C Cushman; R H Grimm; J LaRosa; P K Whelton; H M Perry; M H Alderman; C E Ford; S Oparil; C Francis; M Proschan; S Pressel; H R Black; C M Hawkins,"Are newer types of antihypertensive agents, which are currently more costly to purchase on average, as good or better than diuretics in reducing coronary heart disease incidence and progression? Will lowering LDL cholesterol in moderately hypercholesterolemic older individuals reduce the incidence of cardiovascular disease and total mortality? These important medical practice and public health questions are to be addressed by the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind trial in 40,000 high-risk hypertensive patients. ALLHAT is designed to determine whether the combined incidence of fatal coronary heart disease (CHD) and nonfatal myocardial infarction differs between persons randomized to diuretic (chlorthalidone) treatment and each of three alternative treatments--a calcium antagonist (amlodipine), an angiotensin converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin). ALLHAT also contains a randomized, open-label, lipid-lowering trial designed to determine whether lowering LDL cholesterol in 20,000 moderately hypercholesterolemic patients (a subset of the 40,000) with a 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor, pravastatin, will reduce all-cause mortality compared to a control group receiving ""usual care."" ALLHAT's main eligibility criteria are: 1) age 55 or older; 2) systolic or diastolic hypertension; and 3) one or more additional risk factors for heart attack (eg, evidence of atherosclerotic disease or type II diabetes). For the lipid-lowering trial, participants must have an LDL cholesterol of 120 to 189 mg/dL (100 to 129 mg/dL for those with known CHD) and a triglyceride level below 350 mg/dL. The mean duration of treatment and follow-up is planned to be 6 years. Further features of the rationale, design, objectives, treatment program, and study organization of ALLHAT are described in this article.",2001.0,0,0 2835,8723592,Restenosis--an open file.,M Gottsauner-Wolf; D J Moliterno; A M Lincoff; E J Topol,"The main procedural drawback to percutaneous coronary angioplasty is restenosis of the treated site within 6 months. Despite advances in equipment, technique, and adjunctive therapies, restenosis has occurred in approximately one-third to one-half of all patients. The biology of restenosis can be divided into plaque persistence and recoil, thrombus formation and transformation, and cellular proliferation and vascular remodeling. Animal models of restenosis have helped to elucidate these mechanisms of restenosis and provide a means to test pharmacologic and mechanical strategies to reduce stenosis recurrence. While numerous agents have been tested in animal models, until recently none has translated into benefit in large-scale clinical trials. Two therapeutic ""hopefuls"" which have recently emerged in clinical practice are the potent platelet inhibitors, glycoprotein IIb/IIIa receptor antagonists, and intracoronary metallic stents. The IIb/IIIa receptor antagonists target thrombus formation at the angioplasty site, thereby minimizing abrupt vessel closure acutely and neointimal growth chronically, while intracoronary stents safely produce a large coronary arterial lumen acutely and prevent vessel recoil. Separately, these therapeutic strategies have been shown to reduce clinical restenosis 20-30% at 6-month follow-up. With these encouraging results, the future will certainly provide more pharmacologic and mechanical therapies targeting restenosis. With increased understanding of the restenotic process and continued refinement of effective treatments, it may be possible one day to prevent stenosis recurrence.",1996.0,0,0 2836,8725976,Physician extenders for cost-effective management of hypercholesterolemia.,G Schectman; N Wolff; J C Byrd; J G Hiatt; A Hartz,"Treatment of elevated cholesterol levels reduces morbidity and mortality from coronary heart disease in high-risk patients, but can be costly. The purpose of this study was to determine whether physician extenders emphasizing diet modification and, when necessary, effective and inexpensive drug algorithms can provide more cost-effective therapy than conventional care. Randomized controlled trial. A Department of Veterans Affairs Medical Center. Two hundred forty-seven veterans with type IIa hypercholesterolemia. Patients assigned to either a cholesterol treatment program (CTP) or usual health care provided by general internists (UHC). CTP included intensive dietary therapy administered by a registered dietitian utilizing individual and group counseling and drug therapy initiated by physician extenders for those failing to achieve goal low-density lipoprotein (LDL) levels with diet alone. A drug selection algorithm for CTP subjects utilized niacin as initial therapy followed by bile acid sequestrants and lovastatin. Subjects were followed prospectively for 2 years. Primary outcome measurements were effectiveness of therapy defined as reductions in LDL cholesterol (LDL-C), and whether goal LDL-C levels were achieved; costs of therapy; and cost-effectiveness defined as the cost per unit reduction in the LDL-C. Total program costs were higher for CTP patients than for UHC patients ($659 +/- $43 vs $477 +/- $42 per patient, p < .001). However, at 24 months the patients in CTP were more likely to achieve LDL goal levels (65% vs 44%, p < .005), and also achieved greater reductions in LDL-C 27% +/- 2% vs 14% +/- 2% at 24 months, p < .001). Program costs per unit (mmol/L) reduction in the LDL-C, a measure of cost-effectiveness, was significantly lower for CTP ($758 +/- $58 vs $1,058 +/- $70, p = .002). Although more expensive than usual care, the greater effectiveness of physician extenders implementing cholesterol treatment algorithms resulted in more cost-effective therapy.",1996.0,0,0 2837,8726243,Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia.,H C Knipscheer; C C Boelen; J J Kastelein; D E van Diermen; B E Groenemeijer; A van den Ende; H R Büller; H D Bakker,"The safety, tolerability, and efficacy of a 12-wk treatment with pravastatin, 5, 10, and 20 mg/d, was evaluated in 72 children with heterozygous familial hypercholesterolemia (FH) in a double-blind, randomized and placebo-controlled study. The results show that pravastatin was well tolerated and that adverse events were mild and equally distributed among the three treatment groups. Plasma total and LDL cholesterol levels were significantly reduced in all pravastatin treatment groups, in comparison with the control group; -24.6% (-28.1 to 21.0) and -32.9% (-37.0 to -28.6), for mean change and 95% confidence interval, respectively. In four children plasma LDL cholesterol levels were reduced within normal limits for sex and age. HDL cholesterol increased in the pravastatin 20-mg group, +10.8% (+3.4 to +18.8), whereas plasma apo B100 and very LDL (VLDL) cholesterol levels were reduced within all pravastatin-treated groups -26.8% (-31.2 [corrected] to -21.7) and -24.5% (-35.0 to -12.3). These data show that short-term pravastatin treatment of children with FH is safe and effective, although long-term dose titration studies with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors need to be performed, to reduce plasma LDL cholesterol levels below a predefined level. The results of these studies have to be awaited before new treatment strategies are to be considered in these children.",1996.0,0,0 2838,8726600,Combination therapy with low-dose lovastatin and niacin is as effective as higher-dose lovastatin.,S F Gardner; E F Schneider; M C Granberry; I R Carter,"To determine if low-dose lovastatin in combination with niacin causes a greater percentage reduction in low-density lipoprotein (LDL) cholesterol than lovastatin alone, and to determine if the combination increases the risk of serious adverse effects. design. Prospective, randomized, open-label, clinical trial. setting. Family medicine clinic of a university-affiliated hospital. Patients. Patients with fasting LDL cholesterol concentrations of at least 150 mg/dl after 4 weeks of dietary stabilization and washout of any cholesterol-lowering drugs. Twenty-eight patients received lovastatin 20 mg/day for 4 weeks after dietary stabilization and washout. If LDL cholesterol remained above 130 mg/dl (100 mg/dl in patients with coronary artery disease), they were randomized to receive either lovastatin 40 mg/day or a combination of lovastatin 20 mg/day and niacin 500 mg 3 times/day. There was no difference in actual or percentage reductions of LDL cholesterol, total cholesterol, and triglycerides between the groups. A greater increase in high-density lipoprotein (HDL) cholesterol occurred with combination therapy (p = 0.024). There was no difference in liver function tests, glucose, or uric acid between the therapies. Based on drug-acquisition cost, combination therapy is approximately 40% less expensive than monotherapy. Low-dose niacin plus low-dose lovastatin was as effective as higher-dose lovastatin in lowering total cholesterol, LDL cholesterol, and triglyceride levels. The combination may offer benefit in raising HDL cholesterol levels.",1996.0,0,0 2839,8728350,"Effects of atorvastatin, an HMG-CoA reductase inhibitor, on hepatic oxidative metabolism of antipyrine.",B B Yang; N J Hounslow; A J Sedman; S T Forgue,"Possible effects of multiple-dose administration of atorvastatin on the pharmacokinetics of single-dose antipyrine were evaluated in this drug-drug interaction study. Twelve healthy male volunteers received three 200-mg capsules of antipyrine on days 1 and 22, and two 40-mg atorvastatin tablets in the morning on days 8 through 23. Serial blood and urine samples were collected after administration of each antipyrine dose. Plasma was analyzed for antipyrine, and urine samples were analyzed for antipyrine, 4-hydroxyantipyrine, and norantipyrine by validated high-performance liquid chromatography with ultraviolet detection. Overall, antipyrine and atorvastatin doses were well tolerated in healthy volunteers. Mean antipyrine concentrations in plasma after administration of a single, oral dose of antipyrine during coadministration of multiple doses of atorvastatin were nearly superimposible on concentrations after administration of antipyrine alone. Individual and mean parameter values for plasma pharmacokinetics of antipyrine were similar in both treatment periods. Atorvastatin did not significantly alter the fraction of clearance of antipyrine in plasma that occurred by urinary excretion of 4-hydroxyantipyrine and norantipyrine. These results indicate that the recommended highest daily dose of atorvastatin has negligible effects on antipyrine pharmacokinetics and on oxidative pathways responsible for the metabolism of antipyrine.",1996.0,0,0 2840,8729585,Treatment of dyslipidaemias with fluvastatin.,T K Peters,"In many patients with primary hyperlipidaemia the statins have become the drugs of choice when diet alone has failed. The usual dosages of statins prescribed in most countries appear to be aimed at producing a reduction in levels of low-density lipoprotein cholesterol (LDL-C) of about 25%. Fluvastatin is the newest member of this class of agent and the first completely synthetic compound. In dose-finding studies, fluvastatin has produced statistically significant (P < 0.001) reductions in LDL-C levels when used in dosages of 20 mg (21%) and 40 mg (27.4%), thus placing it within the range generally expected with usual dosages of other statins; additional studies have shown that the efficacy of fluvastatin is unaffected by gender and age. Moreover, fluvastatin produces the maximum reduction in LDL-C levels within 6 weeks and maintains this efficacy during long-term treatment (LDL-C levels have been reported to fall by 27.4% over 2 years with fluvastatin 40 mg/day). In high-risk patients the LDL-C-lowering effect of fluvastatin 40 mg/day is maintained when compared with low-risk patients (26.6% vs 24.8%). A similar pattern has been observed in hypertensive patients, irrespective of the antihypertensive agent used to control blood pressure. Fluvastatin has been found to produce better LDL-C-lowering effects than bezafibrate. In addition to lowering LDL-C levels by the required amount, 20 and 40 mg (the equivalent of pravastatin 20 mg) dosages of fluvastatin significantly reduce levels of total cholesterol and triglycerides and increase high-density lipoprotein cholesterol levels.",1996.0,0,0 2841,8729586,Safety profile of fluvastatin.,T K Peters,"Statins are regarded as a well-tolerated class of drugs, particularly when compared with some of the older lipid-modifying agents, which have poor rates of compliance. Despite some early concern, the incidence of lens opacities observed in clinical studies involving statin use is no different from that in a normal ageing population. Similarly, the occurrence of insomnia with lipophilic agents appears to have been overemphasised and is not a clinically significant problem, irrespective of the statin under study. Fluvastatin is the newest representative of this class of agents; it has already been evaluated in thousands of patients who have hyperlipidaemia with and without additional risk factors. In controlled clinical studies, the incidence of the majority of adverse events observed with fluvastatin therapy is no higher than that seen with placebo, with the exception of gastrointestinal disturbances (known to be common to all stains). Nonetheless, the incidence of these effects seen with fluvastatin treatment is noted to be lower than that associated with cholestyramine or fibrate use. Elevations in levels of liver transaminases (aspartate aminotransferase and alanine aminotransferase) have been reported with fluvastatin therapy but have led to discontinuation of treatment with the same frequency as with placebo. Elevations in creatine kinase levels as a cause of discontinuing fluvastatin are not more frequent than with placebo. Drug-related myopathy and rhabdomyolysis have not been reported with fluvastatin therapy, and myalgia does not occur more frequently than with placebo. In terms of drug interactions, fluvastatin does not interfere with the efficacy of antihypertensive agents. In controlled clinical trials, the overall reported discontinuation rate due to adverse events noted with fluvastatin therapy is not significantly distinguishable from the rate associated with placebo.",1996.0,0,0 2842,8729587,The patient at risk: who should we be treating?,I Shviro; E Leitersdorf,"Both the European Atherosclerosis Society and the US National Cholesterol Education Program have issued revised guidelines for the prevention of coronary heart disease (CHD), based on a multitude of recent epidemiological and angiographic studies. Both authorities agree that a target plasma low-density lipoprotein cholesterol (LDL-C) level is the single most important parameter, this target level being different for primary and secondary prevention. The introduction of statins for the treatment of hypercholesterolaemia provides an important tool to enable target LDL-C levels to be reached in most cases of primary prevention. For secondary prevention, however, the target LDL-C levels--2.6 mmol/l (100 mg/dl)--may be achieved in only a fraction of cases. Others may require the concomitant administration of other cholesterol-lowering drugs, such as bile-acid sequestrants (resins) and/or derivatives of fibric acid (fibrates). The use of statin-fibrate combinations has been discouraged since the report by the US Food and Drug Administration of 12 sporadic cases of myositis or rhabdomyolysis. During the past 7 years, however, 21 clinical trials have examined the efficacy and safety of statin-fibrate combinations in a total of 486 patients with a variety of dyslipidaemias. Overall, the combinations were proven to be effective and safe, and the incidence of abnormalities in liver function tests and levels of creatine kinase (CK) was low. A double-blind study has been carried out at the Hadassah University Hospital to examine the efficacy and safety of fluvastatin when combined with either cholestyramine (group 1) or bezafibrate (group 2) for the treatment of 38 patients with heterozygous familial hypercholesterolaemia (FH). Patients in group 2 showed a reduction in plasma LDL-C levels of 35% and in LDL-C to high-density lipoprotein cholesterol (HDL-C) ratio of 45% compared with 32% and 38% respectively in group 1. Both cholestyramine and bezafibrate produced an additional benefit of a 13% reduction in LDL-C levels in comparison with fluvastatin as monotherapy. An open-label ongoing study on a larger cohort of FH patients reveals that a decrease in plasma LDL-C levels of up to 38.5% may be achieved with a combination of fluvastatin 80 mg/day and bezafibrate 400 mg/day. In both studies, biochemical safety analyses revealed no notable abnormalities in liver function tests or levels of CK. It was concluded that fluvastatin-bezafibrate is a very effective synergistic therapy for heterozygous FH and is superior to a fluvastatin-cholestyramine combination.",1996.0,0,0 2843,8729588,Fluvastatin in combination with other lipid-lowering agents.,L A Jokubaitis,"Fluvastatin, a new synthetic inhibitor of HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, has been studied in several models to examine its effects when used in combination with other lipid-modifying agents such as derivatives of fibric acid (bezafibrate), resins (cholestyramine), and niacin. The combination of fluvastatin with bezafibrate has been studied in a double-blind trial involving patients with well-documented familial hypercholesterolaemia. Fluvastatin 40 mg/day, combined with either bezafibrate 400 mg/day or cholestyramine 8 g/day, resulted in reductions in levels of low-density lipoprotein cholesterol (LDL-C), these being indistinguishable between the groups; however, significantly greater increases in levels of high-density lipoprotein cholesterol (21.3%) and reductions in levels of triglycerides (25.1%) were seen with the fluvastatin-bezafibrate combination. No notable increases were seen in levels of serum creatine kinase, aspartate aminotransferase, or alanine aminotransferase, and no cases of myopathy were observed. In a study model that examined low-dose combinations of fluvastatin with cholestyramine, reductions in levels of LDL-C of 15.8% and 19.3% were seen with fluvastatin 10 mg and 20 mg, respectively. After an 8-week interval in which a daily dosage of cholestyramine 8 g was added, from baseline, reductions of 26.3% in the 10 mg fluvastatin-cholestyramine group and 31.2% in the 20 mg fluvastatin-cholestyramine group were observed, whereas the placebo-cholestyramine group displayed a reduction of 14.9%. Doubling the resin dosage to 16 g/day for the final 8 weeks of the study provided little additional benefit. Myotoxicity has been observed when lovastatin is coadministered with niacin, and so the combination of niacin with fluvastatin has also been studied to examine the possibility of this effect occurring. Patients were randomised to either fluvastatin 20 mg or placebo for 6 weeks, after which time open-label niacin was administered to all patients and titrated to a final dosage of 3 g/day. After 6 weeks, fluvastatin produced a 20.8% reduction in LDL-C levels from baseline. When combined with niacin, a 43.7% reduction was noted at the week 15 endpoint, against the 26.5% reduction seen with niacin monotherapy. The combination was well tolerated, with no reports of myopathy or of significant elevations in creatine kinase or liver transaminase levels. Combinations of fluvastatin with a variety of other agents have been shown to have significant effects on lipid profiles, with no evidence to date of clinically remarkable safety findings. Thus, the use of combination therapies may result in optimal management of patients with moderately severe hypercholesterolaemia and mixed dyslipidaemic profiles.",1996.0,0,0 2844,8729590,Fluvastatin for the prevention of restenosis after coronary balloon angioplasty: angiographic and methodological background of the fluvastatin angioplasty restenosis trial.,D P Foley; P W Serruys,"Luminal renarrowing (restenosis) is the major limitation of percutaneous transluminal coronary angioplasty (PTCA), and the search for a 'magic bullet' to prevent this apparent biological healing response to vessel injury has thus far been unsuccessful. Large clinical trials using serial quantitative coronary angiography have, however, provided some valuable insight into this area. In particular, the restenosis process may be measured as the loss in minimal luminal diameter from post-PTCA to follow-up angiography, and is essentially ubiquitous and normally distributed. The angiographic outcome of clinical trials can thus be appropriately evaluated using a continuous rather than a categorical approach, which also considerably reduces the number of patients required. Fluvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been shown experimentally to reduce the neointimal proliferative response after PTCA, independent of its lipid-lowering action. The FLuvastatin Angioplasty REstenosis trial was designed to evaluate whether fluvastatin 40 mg twice daily, commencing at least 2 weeks before planned PTCA, can reduce luminal loss by 30% from successful PTCA to follow-up angiography at 26 +/- 2 weeks in 730 evaluable patients.",1996.0,0,0 2845,8729591,Lipoprotein(a) as a marker for coronary heart disease.,P Duriez; J Dallongeville; J C Fruchart,"Lipoprotein(a) (Lp(a)) resembles a low-density lipoprotein (LDL) particle, but with the addition of apolipoprotein(a). Apolipoprotein(a) (apo(a)) is homologous to plasminogen, and its similarity to plasminogen indicates a prothrombogenic role for Lp(a), whereas the similarity of Lp(a) to LDL suggests a proatherogenic role. Thus, Lp(a) is a link between atherosclerosis and thrombosis. The apo(a) gene is highly polymorphic, and a relationship exists between the different apo(a) alleles and plasma Lp(a) levels. There is also evidence to suggest an association between serum Lp(a) concentration and the frequency of cardiovascular atherosclerosis, particularly myocardial infarction in men, although some of the recently published epidemiological studies have been controversial. The heightened awareness of increased Lp(a) levels being a risk factor for coronary artery disease has led to the evaluation of the effects of lipid-lowering agents on Lp(a) levels. The data that have emerged, however, are conflicting, and are derived mostly from short-term studies involving the use of statins. Our group has studied the short- and long-term effect of fluvastatin on Lp(a) in hypercholesterolaemic patients; fluvastatin was found to have no effect in such patients as observed in the short-term studies, but significant reductions in Lp(a) levels were noted during long-term treatment. Although our findings are in agreement with those of a previously published report, there is still a great need to confirm the data that have been reported in separate studies.",1996.0,0,0 2846,8729902,More on comparison of HMG-CoA reductase inhibitors.,I Hsu; S A Spinler,,1996.0,0,0 2847,8730343,Cerebrotendinous xanthomatosis: a family study of sterol 27-hydroxylase mutations and pharmacotherapy.,G F Watts; W D Mitchell; J J Bending; A Reshef; E Leitersdorf,"We examined the phenotypic characteristics, molecular genetics and optimal pharmacological treatment of cerebrotendinous xanthomatosis (CTX) in an English family with combined hyperlipidaemia. The proband presented in adulthood with classical clinical characteristics of CTX, a greater than tenfold elevation in plasma cholestanol and combined hyperlipidaemia. His brother also had typical features of CTX without the presence of dyslipidaemia. Genotyping revealed that the two brothers were compound heterozygotes for a novel missense mutation in exon 2 (R94Q) and for a recently described nonsense mutation in exon 5, of the sterol 27-hydroxylase gene (CYP27). Analysis of all available family members revealed that hyperlipidaemia did not co-segregate with the presence of a CYP27 mutant allele. Trial of therapy showed that the lowest plasma sterol and triglyceride concentrations and cholestanol:cholesterol ratio were achieved with the combination of chenodeoxycholic acid (CDCA) 750 mg/day, a primary bile acid, and simvastatin 40 mg/day, an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase. CDCA alone and simvastatin alone significantly lowered plasma cholestanol concentration, but the decrease was greater with the former. After 1 year there was significant improvement in both cognitive and motor function with regression of tendon xanthomata on computerized tomography. We conclude that CTX in this English pedigree is probably due to compound mutant alleles in CYP27, that combined hyperlipidaemia in this family is unrelated to CTX, and that this complicated condition responds optimally to the combination of CDCA and simvastatin.",1996.0,0,0 2848,8735678,A comparison of the effects of fluvastatin and bezafibrate on exercise metabolism: a placebo-controlled study in healthy normolipidaemic subjects.,C J Eagles; M J Kendall; S Maxwell,"1. We have examined the interaction between aerobic exercise and lipid-lowering drugs in a crossover study of 16 healthy normolipidaemic volunteers who each received 21 days' treatment with bezafibrate (400 mg), fluvastatin (40 mg), and placebo, in random order. 2. Fluvastatin treatment reduced pre-exercise total cholesterol (TC) by 23% (P < 0.0001), low-density lipoprotein cholesterol (LDL-C) by 33% (P < 0.0001), and plasma triglycerides by 11%, compared with pre-treatment values. Bezafibrate reduced TC by 11% (P < 0.01); LDL-C by 9%; and plasma triglycerides by 40% (P < 0.01), compared with pre-treatment values. 3. During exercise, in comparison with placebo, and fluvastatin treatment, respectively, bezafibrate significantly reduced mean fat oxidation: 31% vs 39%, P = 0.035, 31% vs 39%, P = 0.002, plasma free fatty acid (FFA) availability, e.g. after 90 min of exercise: (t90) 520 vs 662 mumol 1(-1), P = 0.054, 520 vs 725 mumol 1(-1), P = 0.016, and plasma levels of glycerol (t90): 59 vs 74 mumol 1(-1), P = 0.037, 59 vs 73 mumol 1(-1), P = 0.016. Fluvastatin had no impact on fat metabolism in comparison with placebo. 4. Reduced plasma FFA concentration and lower fat oxidation during prolonged exercise on bezafibrate treatment may be due to an inhibition of hepatic acetyl coenzyme A carboxylase, resulting in reduced FFA release from adipose tissue. 5. The possibility that impaired fat metabolism on fibrates could induce premature fatigue during exercise of moderate duration and intensity should be examined in hyperlipidaemic patients.",1996.0,0,0 2849,8736620,Gemfibrozil. A reappraisal of its pharmacological properties and place in the management of dyslipidaemia.,C M Spencer; L B Barradell,"Gemfibrozil improves lipid and apolipoprotein profiles, particularly very low density lipoprotein (VLDL) triglyceride and high density lipoprotein (HDL) cholesterol levels, in patients with dyslipidaemia when administered at a total daily dose of 900 or 1200 mg. As demonstrated by the Helsinki Heart Study, these effects result in a reduction in some risk factors for coronary heart disease (CHD) and also a 34% reduction in the incidence of this disease after 5 years compared with placebo. Limited data suggest that gemfibrozil has beneficial effects on the fibrinolytic system and may slow the progression of atherosclerosis. Gemfibrozil has shown efficacy in the treatment of patients with type IIa, IIb, III, IV or V dyslipidaemia or hypoalphalipoproteinaemia, especially in patients with elevated triglyceride and low HDL cholesterol levels. It is also effective in patients with non-insulin-dependent diabetes mellitus (NIDDM) and dyslipidaemia and has no detrimental effects on glycaemic control. A small number of studies also showed gemfibrozil to be effective for the control of dyslipidaemia associated with renal failure, transplantation, nephrotic syndrome, arterial occlusive disease or systemic lupus erythematosus. However, patients with pre-existing CHD do not appear to derive the same benefits (reduced CHD mortality) from gemfibrozil therapy as these other patients, although results are based on studies of limited size and number. In general, gemfibrozil has at least similar efficacy to bile acid sequestrants and other fibric acid derivatives. Comparisons with HMG-CoA reductase inhibitors show these agents to produce different effects on lipid profiles from gemfibrozil. Thus, gemfibrozil would be expected to be superior in some patients (those with elevated triglyceride or VLDL cholesterol levels), but HMG-CoA reductase inhibitors should have greater benefits in those with elevated low density lipoprotein cholesterol levels. Thus, in patients with elevated triglyceride levels and low HDL cholesterol levels, and, particularly in patients with NIDDM, gemfibrozil is a useful treatment option, which has been shown to reduce the risk of CHD in middle aged men. However, limited available data prevents the accurate comparison of this agent with HMG-CoA reductase inhibitors in patients with this lipid profile.",1996.0,0,0 2850,8737199,Can improved quality of care reduce the costs of managing angina pectoris?,J G Cleland,"Angina pectoris is a common symptom in patients over 50 years and is usually secondary to myocardial ischaemia resulting from coronary artery disease. The management of angina should be aimed at the maintenance or improvement of quality of life and delaying death. There are three strategies that may be adopted: medical, percutaneous transluminal coronary angioplasty and surgery. The majority of patients with angina can be controlled symptomatically most of the time by medical treatment alone. Any assessment of cost of treatment must take into account the cost of investigation, treatment, the morbidity associated with procedures or side effects of drugs, together with that of recurrent hospitalization, prolonged life and premature death. In addition, the duration of treatment has a major bearing on cost. Taking these factors into account, medical therapy is the least expensive short- and long-term treatment for angina pectoris. A medical approach to treatment also has considerable advantages over an interventional approach in terms of major morbidity. Only one of six surgical trials has demonstrated a survival benefit.",1996.0,0,0 2851,8737761,"In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors.",C Transon; T Leemann; P Dayer,"The affinity of (+)-, (-)- and (+/-)- fluvastatin, a new synthetic HMG-CoA reductase inhibitor developed as a racemate, for specific human P450 monooxygenases in liver microsomes was compared with that of the pharmacologically active acidic forms of lovastatin, pravastatin and simvastatin. Affinity was determined as the inhibitory potency for prototype reactions for 3 major drug metabolising enzymes: diclofenac 4'-hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), and midazolam 1'-hydroxylation (CYP3A4). Lovastatin acid, pravastatin and simvastatin acid displayed moderate affinity for all three P450 isozymes (estimated Ki > 50 micromol.1(-1)). Racemic and (+)- and (-)-fluvastatin showed moderate affinity (estimated Ki > 50 micromol.1(-1)) for CYP2D6 and CYP3A4, whereas their affinity for CYP2C9 was high (estimated Ki < 1 micromol.1(-1)). Diclofenac 4'-hydroxylation was competitively and stereoselectively inhibited, with measured Ki's of 0.06 and 0.28 micromol.1(-1) for (+)- and (-)- fluvastatin, respectively. Fluvastatin selectively inhibits a major drug metabolising enzyme (CYP2C9), the (+)-isomer (pharmacologically more active) showing 4-5 fold higher affinity. As already reported for lovastatin and simvastatin, in vivo drug interactions by inhibition of liver oxidation of CYP2C9 substrates (e.g. hypoglyceamic sulphonylureas and oral anticoagulants) may be expected.",1996.0,0,0 2852,8739021,"Effectiveness and safety of low-dose pravastatin and squalene, alone and in combination, in elderly patients with hypercholesterolemia.",P Chan; B Tomlinson; C B Lee; Y S Lee,"A double-blind, placebo-controlled study was conducted to compare the efficacy and safety of low-dose (10 mg) prevastatin and squalene (860 mg), either alone or in combination therapy, with placebo in the treatment of elderly patients with hypercholesterolemia. Ambulatory elderly patients (N = 102) were assigned in randomized fashion to receive active treatment or placebo for 20 weeks after a single-blind placebo lead-in period of 8 weeks. Total cholesterol and triglyceride levels in plasma were at least 250 mg/dL and less than 300 mg/dL, respectively. Concentrations of lipids and lipoproteins were measured, and clinical laboratory tests included liver function and creatine kinase determinations. Pravastatin 10 mg daily was more effective than squalene in reducing total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides and in increasing levels of high-density lipoprotein (HDL) cholesterol. Combination therapy significantly reduced total cholesterol and LDL cholesterol and increased HDL cholesterol to a greater extent than either drug alone. Adverse events and clinical laboratory abnormalities were generally mild and transient in all groups, and all but two patients finished the study. The incidence of side effects was low; myopathy did not occur. Coadministration of pravastatin and squalene combined the specific effects of the two drugs on lipoprotein concentrations. This combination may be useful and more cost-effective in elderly patients with hypercholesterolemia, who might have a higher incidence of side effects when using larger doses of pravastatin alone.",1996.0,0,0 2853,8743904,Adenovirus-mediated gene transfer: strategies and applications in lipoprotein research.,R D Gerard; L Chan,"Adenovirus-mediated gene transfer into mammalian liver is a highly efficient process that can result in transduction frequencies approaching 100%. Coupled with efficient expression levels from these vectors, the transfer of genes encoding a variety of enzymes, ligands and receptors has resulted in physiologically significant effects on lipoprotein metabolism. Adenovirus vectors have not only proved useful in the study of lipoprotein metabolism, they may also ultimately be used for hepatic gene therapy of inherited monogenic and polygenic disorders. The main hurdle to overcome before this technology can be therapeutically applied is the relatively short duration of expression in immunocompetent hosts. Apparently, cytolytic T-lymphocyte-mediated rejection of the transduced hepatocytes is caused by low-level expression of adenovirus genes. Several strategies have been recently employed in an attempt to circumvent this immune response and prolong transgene expression.",1996.0,0,0 2854,8744535,Hyperlipidemia and its management in renal disease.,Z A Massy; B L Kasiske,"Dyslipidemia is common in patients with renal disease, may contribute to the high incidence of cardiovascular disease, and may play a role in progressive renal injury. Recent studies have shown that newer antilipemic agents appear to be safe and effective in patients with renal disease. This should make it possible to conduct large, controlled clinical trials examining the effect of lipid-lowering strategies on cardiovascular disease, and on renal disease progression.",1996.0,0,0 2855,8746603,"Combined treatment with captopril, hydrochlorothiazide and pravastatin in dyslipidemic hypertensive patients.",B Waeber; P Greminger; W Riesen; R Darioli; D Simeon-Dubach; R Wunderlin,"Hypertension and hypercholesterolemia frequently coexist, necessitating concurrent treatments for both disorders. The present study aimed at evaluating the efficacy, the safety, and the toleration of captopril, an ACE inhibitor, hydrochlorothiazide, a diuretic, and pravastatin, a HMG-CoA reductase inhibitor co-administered in hypertensive patients in general practice. The patients were followed for 16 weeks and asked to comply with a lipid lowering diet for the whole period. Captopril, 50 mg/once daily, was administered alone for the first 4 weeks. Hydrochlorothiazide, 25 mg/day, was added after 4 weeks if required. Pravastatin treatment (20 mg/day) was started at the 8th week of the study and its dose was doubled 4 weeks later if needed. A total of 603 patients with hypertension (diastolic blood pressure > or = 95 mmHg) and dyslipidemia (total cholesterol > 6.5 mmol/l) were included. The study was performed in general practice by 230 physicians. Determination of blood pressure, circulating levels of total cholesterol, HDL-cholesterol and triglycerides, and blood chemistry for safety monitoring. At the end of the trial 75.1% of patients had their diastolic blood pressure < or = 90 mmHg and 43.5% a total cholesterol level < 6.5 mmol/l. The overall incidence of adverse events was 21.7%, leading to withdrawal in 10.9% of the total number of patients. The combined treatments had no deleterious effect on safety variables. Captopril, hydrochlorothiazide and pravastatin are effective and well tolerated medications to treat dyslipidemic hypertensive patients.",1995.0,0,0 2856,8750244,Effects of pravastatin in heart transplant recipients: implications of Kobashigawa et al.,A M Gotto,The recently published article by Kobashigawa et al. [1] regarding the benefit of using pravastatin in treating hypercholesterolemia in heart transplant recipients is reviewed. A comment on the implications of the researchers' findings follows.,2001.0,0,0 2857,8750245,Reduction of coronary events: evidence from clinical trials.,A M Gotto,,2001.0,0,0 2858,8750248,Selection of appropriate type and intensity of lipid-lowering therapy.,M J Tikkanen,"A wide consensus has been reached concerning the importance of lipid-lowering drug therapy in patients with dyslipidaemia with overt coronary heart disease. This consensus is also likely to be reflected in the more active treatment of other high-risk patient groups. The statin family of drugs has been tested in a large secondary prevention study, the Scandinavian Simvastatin Survival Study, and in angiographic trials. Their role in the treatment of hypercholesterolaemia and mixed hyperlipidaemia is increasing, whereas fibrates are increasingly limited to hypertriglyceridaemia.",1995.0,0,0 2859,8750249,,,,,0,0 2860,8750250,Trials of lipid-lowering therapy in secondary prevention of coronary heart disease.,A G Olsson; T Pedersen; B Bergdahl,The Scandinavian Simvastatin Survival Study showed that a 35% decrease in LDL-cholesterol was accompanied by a 42% reduction in coronary mortality. Even if the period of time is longer than 1 year for the divergence of survival curves in the simvastatin and placebo groups there are reasons to believe that the beneficial effect of lipid lowering is rapid. The effect may be mediated by stabilization of lipid-rich coronary lesions or by effects on endothelium. Lipid-lowering studies in the acute stage of coronary heart disease are suggested.,1995.0,0,0 2861,8750251,Effects of lipid-lowering therapy on total and coronary mortality.,I Holme,"The results of several lipid-lowering randomized trials were released during the past year. The Scandinavian Simvastatin Survival Study has contributed significantly to the understanding of lipid-lowering on all-cause and coronary mortality outcome. An approximate 25% net difference in cholesterol between the simvastatin and placebo group produced a 30% reduction in total mortality in the simvastatin group (P < 0.01). No increase in noncardiovascular mortality or nonfatal diseases was observed. Although angiographic trials that study atherosclerosis are not designed to show the effect on clinical outcome, several new trials such as the Asymptomatic Carotid Artery Progression Study, the Multicentre Anti-Atheroma Study, the Canadian Coronary Atherosclerosis Intervention Trial and the Stanford Coronary Risk Intervention Project all add information that is consistent with the results from the Scandinavian Simvastatin Survival Study. The meta-analysis of randomized cholesterol-lowering trials also indicates that no excess of all-cause mortality is present when the degree of cholesterol reduction and treatment modality is adjusted. It is probable that the excess mortality from noncardiovascular causes found in unadjusted analyses is due to specific effects of hormones and fibrate drug treatments to reduce cholesterol. It is concluded that the lipid hypothesis is confirmed more solidly than ever before.",1995.0,0,0 2862,8750252,Angiographic trials of lipid-lowering therapy: an update.,G B Mancini,"The value of specific LDL apheresis in drug-resistant cases of hyperlipidaemia is reviewed, as well as new data on the prevention of new lesion formation, efficacy of therapy based on initial lipid levels, and the consequences of lipid lowering in the angioplasty setting. Studies undertaken in the carotid and femoral bed are included, as is a brief discussion of the use of probucol as an adjunct to lipid-lowering therapy. These studies have emerged on a backdrop of data focused more on reduction of clinical events than on morphologic changes. Studies on the clinical impact of lipid-lowering therapy are included to provide a linkage between the rationale and conclusions of the angiographic trials with the emerging demonstration that cholesterol lowering does indeed reduce both cardiovascular and total mortality without inducing significant noncardiovascular morbidity or mortality.",1995.0,0,0 2863,8752184,Cost-effectiveness of pravastatin in secondary prevention of coronary artery disease.,T Ashraf; J W Hay; B Pitt; E Wittels; J Crouse; M Davidson; C D Furberg; L Radican,"This study analyzed the cost-effectiveness of pravastatin in secondary prevention of coronary artery disease (CAD). The projected risk model in 445 male patients with established CAD and moderately elevated serum low-density lipoprotein cholesterol used results data from 2 placebo-controlled plaque regression trials: Pravastatin Limitation of Atherosclerosis in the Coronary Arteries and Pravastatin, Lipids, and Atherosclerosis in the Carotids. Framingham Heart Study data were used to project the risk of mortality 10 years after myocardial infarction (MI) for incremental male patients in the placebo group who had MI. A Markov process was used to estimate life-years saved, and decision analysis was used to estimate cost. Depending on the patient-risk profile, the midrange estimated cost per life-year saved with pravastatin in secondary prevention of CAD varied from $7,124 to $12,665, which is favorable compared with other widely accepted medical interventions.",1996.0,0,0 2864,8752186,Efficacy and tolerability of lovastatin in 459 African-Americans with hypercholesterolemia.,L M Prisant; M Downton; L O Watkins; H Schnaper; R H Bradford; A N Chremos; A Langendörfer,"A paucity of substantive data from clinical drug trials is available specifically evaluating the effects of therapy for hypercholesterolemia in African-Americans, even though a substantial number are candidates for medical advice and intervention for high blood cholesterol. The efficacy and safety of lovastatin in 459 African-Americans with hypercholesterolemia were studied in the Expanded Clinical Evaluation of Lovastatin study, a multicenter, double-blind, diet- and placebo-controlled trial. This trial involved 8,245 patients who were randomly assigned, regardless of race, to receive placebo or lovastatin at doses of 20 mg once daily, 40 mg once daily, 20 mg twice daily, or 40 mg twice daily for 48 weeks. Among African-Americans, lovastatin produced sustained, dose-related (p <0.001) decreases in low-density lipoprotein cholesterol (20% to 38%), total cholesterol (14% to 28%), and triglycerides (8% to 15%). From 75% to 96% of African-Americans treated with lovastatin achieved the National Cholesterol Education Program goal of low-density lipoprotien cholesterol <160 mg/di, and from 33% to 71% achieved the goal <130 mg/di. The safety profile of lovastotin in African-Americans was generally favorable. A relatively high incidence of creatine kinase levels greater than the upper limit of normal was observed in African-Americans during the study, i.e., 63% in the placebo group and similar levels in lovastatin treatment groups. Lovastatin is highly effective and generally well tolerated as therapy for primary hypercholesterolemia in African-Americans.",1996.0,1,1 2865,8769685,Effects of pravastatin sodium and simvastatin on plasma fibrinogen level and blood rheology in type II hyperlipoproteinemia.,Y Tsuda; K Satoh; M Kitadai; T Takahashi; Y Izumi; N Hosomi,"Elevated plasma fibrinogen level is known to progress atherosclerosis and to be one of the risk factors for the occurrence of cardiovascular diseases. The objective of this study is to evaluate the changes in plasma fibrinogen level and blood rheology in patients with type II hyperlipoproteinemia before and after random administrations of HMG-CoA (3-hydroxy-e-methylglutaryl-cocarboxylase-A) reductase inhibitors, pravastatin sodium and simvastatin, and compare with results in normal subjects. Of a total of 28 patients with type II primary hyperlipoproteinemia with > 230 mg/dl fasting total plasma cholesterol, 16 patients (mean, 59.7 years old) were administered 10-15 mg/day of pravastatin sodium for an average of 10.2 weeks, and 12 patients (mean, 62.0 years old) were administered 5-10 mg/day of simvastatin for an average of 13.9 weeks. Patients were evaluated before and after drug administration and results were compared with those of 16 normal subjects of similar age (mean, 56.9 years old). Blood viscosities were measured using a cone-plate viscometer (Biorheolizer, BRL-1000, Japan). The following were measured before and after drug administration: whole blood viscosity at shear rates of 75-375 s-1, corrected blood viscosity at low (112.5 s-1) and high (225.0 s-1) shear rates for the standard hematocrit of 45%, plasma viscosity, hematocrit, total protein, serum albumin, and plasma fibrinogen. Total cholesterol level was significantly decreased (from 270 to 225, mg/dl, mean values; P < 0.0007) an average of 10.2 weeks after start of pravastatin sodium administration. In addition to the reductions of whole blood viscosity, at every shear rate examined, corrected blood viscosity, and plasma viscosity, plasma fibrinogen levels were significantly decreased (from 354 to 309 mg/dl, mean values; P < 0.0007) after start of pravastatin sodium administration. Fibrinogen level and blood rheology were not significantly changed after start of simvastatin administration despite similar significant reductions in total cholesterol level (from 260 to 207 mg/dl, mean values; P < 0.0001) to those in the case of pravastatin sodium. From the results, we conclude that administration of pravastatin sodium, but not simvastatin, reduced the plasma fibrinogen level and blood viscosities to normal levels in type II hyperlipoproteinemic patients while both drugs reduced total cholesterol level. The hydrophilicity and a small binding capacity with plasma protein of pravastatin sodium may be responsible in part for the beneficial hemorheologic effects observed in the patients with type II hyperlipoproteinemia. Further investigations should be conducted to confirm the findings observed.",1996.0,0,0 2866,8770319,Comparative effects of simvastatin and pravastatin on cholesterol synthesis in patients with primary hypercholesterolemia.,C Feillet; M Farnier; L H Monnier; C Percheron; C Colette; B Descomps; A Crastes De Paulet,"The effects of simvastatin and pravastatin on cholesterol biosynthesis were compared in 26 hypercholesterolemic patients who were randomly allocated to either simvastatin or pravastatin treatment (20 mg once daily) for 6 weeks in a crossover trial. Serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) lathosterol (latho) concentrations and lathosterol/cholesterol (latho/chol) ratios (the latter two are considered as reliable indices of whole body cholesterol synthesis) were evaluated at the beginning and end of each therapeutic sequence. Reductions in TC and LDL-C were more pronounced (P < 0.001) with simvastatin (TC = -28.0%, LDL-C = -35.6%) than with pravastatin (TC = -19.6%, LDL-C = -25.2%). These results were associated with concomitant decreases in both latho concentrations (-59.0% with simvastatin and -37.0% with pravastatin) and latho/chol ratios (-43.0% with simvastatin and -20.3% with pravastatin). Simvastatin resulted in more marked diminutions of latho concentrations (P < 0.01) and latho/chol ratios (P < 0.05) than pravastatin. These results suggest that the better efficacy of simvastatin on serum cholesterol and LDL cholesterol might result in part from a greater inhibitory action of simvastatin on cholesterol synthesis compared with that of pravastatin.",1995.0,0,1 2867,8772621,Metformin improves blood lipid pattern in nondiabetic patients with coronary heart disease.,S M Carlsen; O Rossvoll; K S Bjerve; I Følling,"To study whether the addition of metformin further improves the blood lipid pattern in non-diabetic patients with coronary heart disease already treated with lovastatin, diet and lifestyle advice. An open, prospective, randomized study in a university hospital setting. Sixty non-diabetic male patients previously treated with coronary artery bypass surgery or angioplasty and with serum cholesterol > or = 6.0 mmol L-1 and/or HDL-cholesterol < or = 1.2 mmol L-1. After a 4-week run-in period with lovastatin (40 mg day-1), and diet and lifestyle advice, patients were randomized into two groups, both continuing the run in treatment. One group received metformin up to 2000 mg day-1; the control group got no additional treatment. Fasting serum lipids, glucose and weight were registered at entrance (= week-4), and at weeks 0, 4 and 12. Changes from week 0 to week 4 and from week 0 to week 12 were compared. Side-effects of the treatment were also registered. Metformin lowered the LDL/HDL-cholesterol ratio by 12 and 6% at weeks 4 and 12, respectively, and reduced body weight by 1.8 kg at week 12. There was also a transient lowering effect on LDL-cholesterol and apolipoprotein B. In the normal weight subgroup of patients (body mass index < 27 kg m-2), metformin induced a decrease in total cholesterol (-9%). LDL-cholesterol (-12%). LDL/HDL-cholesterol ratio (-10%) and apolipoprotein B (-7%), as compared to the control group. In this subgroup, body weight and fasting glucose were unaffected by metformin. Thus, the lipid lowering effect in normal weight patients was not secondary to changes in body weight or fasting glucose. In overweight patients (body mass index > 27 kg m-2), metformin had no significant effects on blood lipids, but induced a weight loss of -3.0 kg and a transient reduction of fasting glucose. No side-effects were registered apart from those expected from each individual drug. Metformin given for 12 weeks as a supplement to lovastatin, diet and lifestyle advice to non-diabetic male patients with coronary heart disease further improves the lipid pattern in normal weight patients, and reduces weight in the overweight patients. Because metformin is cheap and other lipid lowering drugs are expensive, the potential of metformin as a lipid lowering agent should be further investigated.",1996.0,0,0 2868,8772679,Effects of cigarette smoking on the angiographic evolution of coronary atherosclerosis. A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) Substudy. CCAIT Study Group.,D Waters; J Lespérance; P Gladstone; S J Boccuzzi; T Cook; R Hudgin; G Krip; L Higginson,"Although smoking increases both the risk of developing coronary disease and the risk of coronary events in patients with known coronary atherosclerosis, the effect of smoking on the evolution of coronary atherosclerosis as assessed by serial angiography is poorly defined. Ninety smokers with coronary atherosclerosis shown on a recent angiogram and with fasting cholesterol levels between 220 and 300 mg/dL were enrolled in a randomized, double-blind, placebo-controlled trial of cholesterol-lowering therapy, along with 241 nonsmokers and exsmokers. Lovastatin at a mean dose of 36 mg/d lowered total and LDL cholesterol by 21 +/- 11% and 29 +/- 11%, respectively, but these levels changed by < 2% in placebo-treated patients. Coronary arteriography was repeated after 2 years in 72 smokers and their 557 lesions were measured blindly with an automated quantitative system, along with 1752 lesions in 227 nonsmokers. Coronary change score, the per-patient mean of the minimal lumen diameter changes for all qualifying lesions, worsened by 0.16 +/- 0.16 mm in smokers and by 0.07 +/- 0.15 mm in nonsmokers in the placebo group (P < .001). Lovastatin-treated smokers had less worsening (0.07 +/- 0.15 mm) than placebo-treated smokers (P = .024). One or more coronary lesions progressed in 16 of 34 lovastatin-treated smokers and in 28 of 38 placebo-treated smokers (47% versus 74%, P < .001). In the placebo group, new coronary lesions developed in 21 of 38 smokers and in 28 of 115 nonsmokers (55% versus 24%, P < .001); fewer lovastatin-treated smokers developed new lesions (15% versus 55%, P < .001). Smoking accelerates coronary progression and new lesion formation as assessed by serial quantitative coronary arteriography. Lovastatin slows the progression of coronary atherosclerosis and prevents the development of new coronary lesions in smokers.",1996.0,0,0 2869,8773342,Prospective case control study to determine the effect of lovastatin on serum testosterone and cortisol concentrations in hyperlipidemic nephrotic patients with chronic renal failure.,A Segarra; P Chacón; M Vilardell; L L Piera,"In order to investigate the effects of lovastatin on adrenal and gonadal function, we prospectively determined the basal and gonadorelin-stimulated concentrations of testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and the cortisol response to adrenocorticotropic hormone (ACTH) in a sample of 25 male patients with advanced chronic renal failure, hypercholesterolemia and proteinuria. Hormone studies were done prior to and after lovastatin treatment. The values of these patients were compared with those of a matched healthy control group. Before starting treatment with lovastatin, the patients showed significantly lower testosterone concentration and higher LH concentration than the control group. After stimulation with gonadorelin, they also showed a lower increase in testosterone and LH. After 12 months of lovastatin treatment, a significant decrease in the concentration of cholesterol, LDL C, VLDL C and apo B was observed, but neither the basal testosterone concentration nor the response to gonadorelin stimulation was modified. Before treatment, basal and ACTH-stimulated serum cortisol levels did not differ from those of the control group. After lovastatin treatment, neither the basal serum cortisol levels nor the response to ACTH was modified. We conclude that in the patients studied, although the decrease in testosterone concentration may be partially attributable to a decrease in its synthesis, lovastatin treatment does not increase testosterone deficit. This is either because this drug does not inhibit gonadal hydroxymethylglutaryl CoA reductase at the does given or because the cholesterol which LDL C provides the cell with is enough to maintain testosterone synthesis.",1996.0,0,0 2870,8774625,Effectiveness of probucol in preventing restenosis after percutaneous transluminal coronary angioplasty.,Y J Lee; H Daida; H Yokoi; H Miyano; J Takaya; H Sakurai; H Mokuno; H Yamaguchi,"Lipid lowering therapies were employed to prevent restenosis following elective percutaneous transluminal coronary angioplasty (PTCA). The effect of probucol was compared to that of Pravastatin in 141 coronary atherosclerosis patients. Probucol (750 mg/day) was administered for at least 30 days prior to PTCA (34 patients, group P-1) or less than 14 days prior to PTCA (27 patients, group P-2). Pravastatin (10 mg/day) was administered for at least 30 days prior to PTCA (38 patients, group V-1) or less than 14 days prior to PTCA (42 patients, group V-2). In group P-1, the patient restenosis rate was 17.6% and lesion restenosis rate was 14%. These rates were significantly lower than those of group V-1, which were 44.7% and 40.4% respectively (p < 0.05). The respective values were 48.1% and 51.8% in group P-2 (p < 0.05, vs group P-1) and 35.7% and 34% (p < 0.05, vs group P-1) in group V-2. Probucol seems to work, not only by lowering cholesterol but also by its antioxidative properties when administered for a sufficient period prior to PTCA.",1996.0,0,0 2871,8775472,"Changes in biliary lipid secretion and cholic acid kinetics induced by diet, diet plus simvastatin and diet plus ursodeoxycholic acid in obese subjects.",G Mazzella; A Cipolla; N Villanova; C Polimeni; A Sipahi; P Parini; P Fusaroli; D Festi; E Roda,"The aim of this work was to evaluate and compare the effects of a low calorie diet (1026 kcal), simvastatin and ursodeoxycholic acid administration on biliary lipid secretion and cholic acid kinetics in dieting obese subjects. We studied 6 obese subjects before and after four weeks of a hypocaloric diet alone, after four weeks of diet plus ursodeoxycholic acid (900 mg/day) and after four weeks of diet plus simvastatin (40 mg/day), according to a Latin square design. The cholesterol saturation index was increased after diet alone, significantly reduced with diet plus ursodeoxycholic acid (p < 0.01), and unchanged during simvastatin administration. While the cholesterol output was reduced by all three regimens, diet plus ursodeoxycholic acid caused a significantly greater decrease than diet alone (p < 0.01). Cholic acid synthesis and bile acid secretion were decreased by diet and diet plus simvastatin (p < 0.05), but neither was affected by ursodeoxycholic acid. For cholic acid, all three treatments, but especially diet alone and diet plus simvastatin (p < 0.05), reduced the pool size; all three regimens also increased the turnover rate, but this was significant only for ursodeoxycholic acid (p < 0.01). Our study shows that, in obese patients, a hypocaloric diet reduces cholesterol-holding biliary lipid output and consequently increases the cholesterol saturation index. The addition of simvastatin to a hypocaloric dietary regimen reduces cholesterol secretion, but without variation in bile acid and phospholipid output thus the cholesterol saturation index remains unchanged. When ursodeoxycholic acid is added to the dietary regimen, it reduces cholesterol secretion, while maintaining bile acid output and, thus, lowers the cholesterol saturation index. Unlike simvastatin, ursodeoxycholic acid prevents the drop in cholic acid synthesis induced by a low calorie diet.",1995.0,0,0 2872,8781465,Association between low plasma vitamin E concentration and progression of early cortical lens opacities.,P Rouhiainen; H Rouhiainen; J T Salonen,"The authors evaluated the association between plasma vitamin E content and progression of eye lens opacities. A total of 410 hypercholesterolemic eastern Finnish men participated in the study from January 1990 to September 1993 in Kuopio, Finland. Lens opacities were classified three times at 18-month intervals using the Lens Opacities Classification System II. A low plasma vitamin E level (lowest quartile) was associated with a 3.7-fold excess risk (95% confidence interval 1.2-11.8) of the progression of early cortical lens opacities compared with the highest quartile (p = 0.028). In addition, the number of cigarettes smoked daily was a significant predictor of the progression of cortical lens opacity (relative risk = 1.06 per cigarette, 95% confidence interval 1.003-1.12). The progression of nuclear lens opacities was not associated with either the plasma vitamin E content or smoking. The data suggest that low plasma vitamin E content may be associated with increased risk of the progression of early cortical lens opacity.",1996.0,0,0 2873,8782844,Effect of withdrawal of pravastatin on biliary lipid composition in humans.,M Muraca; G Baggio; M T Vilei; S Martini; V Cianci; G Crepaldi,"Abrupt withdrawal of HMG-CoA reductase inhibitors is associated with increased excretion of cholesterol into bile, but this phenomenon has not been investigated in humans. In order to evaluate whether patients interrupting these hypolipidemic drugs are at increased risk of forming gallstones, pravastatin (40 mg twice a day) or placebo was randomly administered to 16 bile fistula patients for 5 days. Biliary lipid composition was determined in basal conditions and for 5 consecutive days after drug withdrawal. Both biliary cholesterol concentration and saturation increased significantly on the second day after pravastatin withdrawal, but tended to decrease thereafter. Biliary bile acids and phospholipids were not affected. This short-lasting effect on biliary cholesterol excretion was probably the result of a transient increase of hepatic cholesterol synthesis by the up-regulated HMG-CoA reductase in the absence of the inhibitory drug. These results are consistent with the hypothesis that, also in humans, biliary cholesterol excretion could be dependent on the hepatic free cholesterol pool.",1996.0,0,0 2874,8795167,Assessment of temporal bias in longitudinal measurements of carotid intimal-medial thickness in the Asymptomatic Carotid Artery Progression Study (ACAPS). ACAPS Research Group.,W A Riley; T Craven; A Romont; C D Furberg,"A randomly selected subset of 100 pairs of baseline and 36-month follow-up carotid B-mode ultrasound examinations from the 919 patients participating in the Asymptomatic Carotid Artery Progression Study (ACAPS) were subjected to a blinded rereading at the conclusion of the trial to assess temporal bias in the measurement of carotid artery intimal-medial thickness (IMT). The original measurements of the primary outcome variable and five secondary outcome variables at baseline and 36 months, respectively, and the 3-year change in each of these variables, were compared with those obtained from the rereadings. For the primary outcome variable, the mean value of 12 IMT measurements obtained from predefined carotid segments, the mean difference (original-rereading) and the 95% confidence interval which resulted from the rereadings were -0.005 (-0.033, 0.023) mm at baseline and -0.009 (-0.031, 0.013) mm at 36 months. The difference in the 3-year change was -0.004 (-0.038, 0.028) mm. The 95% confidence interval for the mean difference between the rereadings and the original readings for the baseline and the 36-month follow-up examinations included zero for all of the six outcome variables as was also the case for the 3-year change in each variable. The magnitude of the mean differences for these 18 variables ranged from 0.004 to 0.034 mm. Intraclass correlation coefficients between the original readings and rereadings ranged from 0.56 to 0.87 with the 3-year changes in outcome variables tending to have lower correlations and the 36-month examinations higher correlations. The carotid IMT measurement process, when combined with uniform reader training, certification and monitoring of reading performance throughout the course of the study, can avoid the temporal bias observed in other studies.",1996.0,0,0 2875,8800496,Increased oxidation resistance of atherogenic plasma lipoproteins at high vitamin E levels in non-vitamin E supplemented men.,E Porkkala-Sarataho; K Nyyssönen; J T Salonen,"The oxidative modification of human low density lipoprotein (LDL) has been widely investigated. However, there are no data concerning the oxidation susceptibility of combined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein fraction, although all of them are atherogenic and contain antioxidants such as alpha-tocopherol. We investigated the oxidation susceptibility and oxidation resistance of VLDL + LDL (including IDL) fraction by induction with CuCl2 and its relation to plasma alpha-tocopherol concentration and lipid standardised alpha-tocopherol concentration in 406 non-vitamin E-supplemented men from eastern Finland. Even thought we did not give oral vitamin E or any other antioxidant supplementation to our study participants, we observed a significant, consistent relationship between measurements of oxidation resistance and plasma content of vitamin E. In the multivariate regression model, a high plasma content of vitamin E or lipid standardised vitamin E concentration were the most important determinants of lag time to maximal oxidation rate (standardised regression coefficient = 0.244, P < 0.0001 for vitamin E and 0.211, P < 0.0001 for lipid standardised vitamin E). After statistical adjustment for age, use of cigarettes, hypolipidemic medication (yes vs. no), month of the measurements, plasma concentrations of total ascorbic acid (ascorbic acid + dehydroascorbic acid), beta-carotene and phospholipids, serum concentrations of LDL cholesterol and triglycerides and dietary intake of linoleic acid, the lag time to maximal oxidation rate was 10% (95% C.I. 6.0-13.5%) longer in men in the highest fifth than in the lowest fifth of plasma vitamin E content (P < 0.0001 for trend). When the fifths of lipid standardised vitamin E were compared, the lag time to maximal oxidation rate was 6% (95% C.I. 1.8-10.1%) longer in men in the highest than in the lowest fifth (P < 0.0001 for trend). Our data suggest that alpha-tocopherol is an important antioxidant preventing the in vitro oxidation of VLDL + LDL fraction even in non-supplemented subjects.",1996.0,0,0 2876,8801396,"[Multicenter comparative study on safety, tolerance, and effectiveness of lovastatin combined or not with cholestyramine, and gemfibrozil combined or not with cholestyramine in the treatment of primary hypercholesterolemia].",E Jover; J L Aranda; X Nogués; A del Palacio; J Rubiés-Prat,"The well-known relationship between high plasma cholesterol levels and coronary heart disease makes the treatment of primary hypercholesterolemia an important issue. A randomized, double-blind 12 week study to compare lovastatin (20-80 mg/day) and gemfibrozil (600 mg b.i.d.) was performed in 59 patients with primary hypercholesterolemia. Resincholestyramine was started on week 12, at a dose of 8-16 g/day for the next 12 weeks in any patient whose LDL-cholesterol exceeded 165 mg/dl at week 12. Total cholesterol, triglycerides and LDL-cholesterol decreased significantly (23.8%, 16.4% and 30.9%, respectively) after lovastatin therapy, whereas HDL-cholesterol increased (13.9%). The figures for the group treated with gemfibrozil were 12.8%, 30.3%, 17.2% and 14.6%, respectively. Mean changes between the two groups were statistically significant for all parameters except for HDL-cholesterol. LDL-cholesterol decreased below 165 mg/dl in 69% of patients receiving lovastatin and 36.7% of patients treated with gemfibrozil (p < 0.05). During the second phase there were no additional significant changes in the 9 patients of the lovastatin group and the 20 patients of the gemfibrozil group after cholestyramine, but LDL-cholesterol decreased below 165 mg/dl in 5 patients (55%) and 6 patients (30%), respectively. Side-effects were more prevalent in patients treated with gemfibrozil alone or in combination with cholestyramine. In patients with primary hypercholesterolemia, lovastatin alone or in combination with cholestyramine was more effective than gemfibrozil alone or in combination with cholestyramine to lower total cholesterol and LDL-cholesterol. The effect of both drugs on HDL-cholesterol was similar.",1996.0,0,0 2877,8801446,The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.,F M Sacks; M A Pfeffer; L A Moye; J L Rouleau; J D Rutherford; T G Cole; L Brown; J W Warnica; J M Arnold; C C Wun; B R Davis; E Braunwald,"In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear. In a double-blind trial lasting five years we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 percent of the patients in the pravastatin group and 10 percent of those in the placebo group, a 26 percent reduction (P=0.005), and coronary angioplasty was needed in 8.3 percent of the pravastatin group and 10.5 percent of the placebo group, a 23 percent reduction (P=0.01). The frequency of stroke was reduced by 31 percent (P=0.03). There were no significant differences in overall mortality or mortality from noncardiovascular causes. Pravastatin lowered the rate of coronary events more among women than among men. The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol. These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels.",1996.0,1,1 2878,8801868,Intima-media thickness after cholesterol lowering in familial hypercholesterolemia. A three-year ultrasound study of common carotid and femoral arteries.,I Wendelhag; O Wiklund; J Wikstrand,"Patients with familial hypercholesterolemia (FH) (n = 53) were examined with B-mode ultrasound before and after 3 years of cholesterol-lowering therapy with pravastatin, cholestyramine, or a combination. The aim was to measure the progression rate of intima-media thickening during follow-up in the common carotid and common femoral arteries. Since for ethical reasons it was not possible to perform a randomized placebo controlled study in patients with FH, we chose to recruit an untreated control group with lower risk, matched for sex, age, height and weight, and with serum cholesterol below 6.5 mmol/l. At baseline, intima-media thickness was larger in the hypercholesterolemic group than in the control group in both the common carotid and common femoral arteries. The difference between the change over 3 years observed in the control group and the change observed in the hypercholesterolemic group was calculated and defined as 'net difference'. There was a -32% net difference in low density lipoprotein (LDL) in the hypercholesterolemic group during follow-up. The ultrasound investigation showed a concomitant net difference of -0.06 mm in mean carotid intima-media thickness (95% confidence interval, -0.11 to -0.01 mm) and of -0.09 mm in maximum carotid intima-media thickness (P < 0.05, 95% confidence interval, -0.16 to -0.01 mm), with no net change in lumen diameter. No decrease was recorded in common femoral intima-medial thickness. Seventeen of the patients with FH had a positive history of myocardial infarction (MI) and this subgroup had a significantly larger decrease in mean carotid intima-media thickness during follow-up than the subgroup of patients with a negative history of MI (P < 0.01). In conclusion, the results showed a reduction in common carotid intima-media thickness after long-term cholesterol-lowering therapy in patients with FH. This finding may indicate a beneficial effect on atherosclerosis development in these patients.",1995.0,0,0 2879,8806337,Treatment of hyperlipidemia after heart transplantation and rationale for the Heart Transplant Lipid Registry.,C M Ballantyne; R C Bourge; L J Domalik; H J Eisen; D P Fishbein; S H Kubo; K D Lake; B Radovancevic; D O Taylor; H O Ventura; C W Yancy; J B Young,"Hyperlipidemia occurs frequently after heart transplantation, and accelerated coronary artery disease remains the major cause of morbidity and mortality in patients who survive more than 1 year after heart transplantation. However, the risks and benefits of lipid-lowering therapy after heart transplantation remain poorly defined, and national guidelines for lipid-lowering drug therapy do not specifically address treatment of dyslipidemia in transplant recipients. Since the initial reports in the 1980s of rhabdomyolysis in heart transplant patients receiving high-dosage lovastatin, results of 11 post-transplantation series that used lovastatin, simvastatin, or pravastatin at lower dosages as drug monotherapy have been published. These studies have shown an overall 1% incidence of rhabdomyolysis, defined as creatine kinase > 10 times the upper limit of normal plus muscle symptoms. One randomized, controlled prospective trial has investigated the effects of lipid-lowering pharmacotherapy on patient outcome in cardiac transplant recipients. At 1-year follow-up in this nonblinded, single-center trial, patients treated with pravastatin (20 or 40 mg/day) initiated within 2 weeks of transplantation had a significant reduction in mortality rate and a significantly lower incidence of transplant arteriopathy. A number of important issues remain unanswered regarding treatment guidelines in patients with hyperlipidemia after heart transplantation. In January 1995 we began the Heart Transplant Lipid Registry, with 12 participant centers, to gather data prospectively on the efficacy and safety of lipid-lowering drugs in the treatment of dyslipidemia after heart transplantation.",2001.0,1,1 2880,8808497,"Plasma mevalonic acid, an index of cholesterol synthesis in vivo, and responsiveness to HMG-CoA reductase inhibitors in familial hypercholesterolaemia.",R P Naoumova; A D Marais; J Mountney; J C Firth; N B Rendell; G W Taylor; G R Thompson,"Fasting plasma mevalonic acid (MVA), an indicator of in vivo cholesterol synthesis, was measured in 35 patients with familial hypercholesterolaemia (FH) of whom 7 were treated with pravastatin 10-40 mg/day, 7 with simvastatin 10-40 mg/day and 21 with atorvastatin 80 mg/day. Reductions in low density lipoprotein (LDL) cholesterol and MVA on maximal dose therapy differed significantly between the three drugs: 34.7%, 42.9% and 54.0% (P = 0.0001), and 31.6%, 48.9% and 58.8% (P = 0.004), respectively. Patients on atorvastatin were subdivided according to whether their reduction in LDL cholesterol on treatment was above or below the mean percentage change for the whole group. Basal values of LDL cholesterol did not differ significantly, but above average responders had a significantly higher mean pre-treatment level of MVA (6.2 +/- 0.60 vs. 4.3 +/- 0.61 ng/ml, P < 0.05) than below average responders. When all three drug groups were pooled above average responders showed a significantly greater absolute decrease in MVA on treatment than below average responders (3.85 +/- 0.48 vs. 2.33 +/- 0.40 ng/ml, P < 0.05). However, there was no significant correlation between the magnitude of the decreases in LDL cholesterol and MVA. These findings suggest that FH patients who responded well to statins had a higher basal level of plasma MVA, i.e. a higher rate of cholesterol synthesis, which was more susceptible to pharmacological inhibition. The more marked cholesterol lowering effect of atorvastatin 80 mg/day presumably reflects, at least in part, its ability to inhibit HMG-CoA reductase to a greater extent than maximal recommended doses of pravastatin and simvastatin of 40 mg/day.",1996.0,0,0 2881,8809507,Cost-benefit analysis of lipid lowering therapy.,A P Davie; J J McMurray,,1996.0,0,0 2882,8809516,Cost-effectiveness of cholesterol lowering. Results from the Scandinavian Simvastatin Survival Study (4S),B Jönsson; M Johannesson; J Kjekshus; A G Olsson; T R Pedersen; H Wedel,"An analysis of the cost-effectiveness of simvastatin was conducted, based on the Scandinavian Simvastatin Survival Study (4S). The total cost of hospitalization in the placebo group was 52.8 million Swedish kronor (SEK) (5.15 million pounds), compared with SEK 36.0 million (3.51 million pounds) in the simvastatin group. This amounts to a 32% reduction, or a saving of SEK 16.8 million (1.6 million pounds) or SEK 7560 (738 pounds) per patient. The net cost per patient for the duration of the study (5.4 years) was SEK 13,540 (1324 pounds). Simvastatin treatment saved an estimated 0.377 undiscounted life years (0.240 life years discounted at 5% per annum). The cost of simvastatin therapy per discounted life-year saved was therefore SEK 56,400 (5502 pounds). Sensitivity analysis, examining the effect of different life expectancies, costs of initiation and monitoring of simvastatin therapy, and discount rates, showed the results to be stable. Conclusion. The cost per life-year saved of simvastatin in the treatment of post-myocardial infarction and angina patients, as determined from 4S data, is well within the range normally considered cost-effective.",1996.0,0,0 2883,8815751,"Effect of combination therapy with lipid-reducing drugs in patients with coronary heart disease and ""normal"" cholesterol levels. A randomized, placebo-controlled trial. Harvard Atherosclerosis Reversibility Project (HARP) Study Group.",R C Pasternak; L E Brown; P H Stone; D I Silverman; C M Gibson; F M Sacks,"Combination drug therapy has been shown to decrease cholesterol levels in hyperlipidemic patients. However, its efficacy has not been well studied in patients previously considered to be normolipidemic, many of whom are now candidates for this therapy. To determine the efficacy and tolerability of multidrug therapy designed to improve low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels in patients with coronary heart disease and average lipid levels. Randomized, placebo-controlled, 2.5-year trial comparing patients receiving usual care with patients receiving stepped-care drug therapy. Stepped-care therapy (pravastatin, nicotinic acid, cholestyramine, and gemfibrozil) to decrease total cholesterol levels to less than 4.1 mmol/L (160 mg/dL) and the ratio of LDL cholesterol to HDL cholesterol to less than 2.0. 2 academic, urban, tertiary care hospitals. 91 patients (80 men and 11 women) with coronary heart disease, a mean age of 60 years, total cholesterol levels less than 6.4 mmol/L (250 mg/dL) at baseline, and ratios of total cholesterol to HDL cholesterol greater than 4.0 at baseline. Fasting serum lipoprotein profile, fasting apolipoprotein levels, and frequency of adverse effects. Patients were assessed every 6 weeks during drug titration and every 3 months thereafter. Mean lipid levels at baseline were as follows: total cholesterol, 5.5 mmol/L (214 mg/dL); LDL cholesterol, 3.6 mmol/L (140 mg/dL); HDL cholesterol, 1.1 mmol/L (42 mg/dL); and triglycerides, 1.8 mmol/L (159 mg/dL). With pravastatin, changes in levels from baseline were -22% for total cholesterol, -32% for LDL cholesterol +8% for HDL cholesterol, and -15% for triglycerides (P < 0.001 for all comparisons). With the addition of 1.5 g of nicotinic acid, additional changes were -6% for total cholesterol (P < 0.002). -11% for LDL cholesterol, +8% for HDL cholesterol, and -10% for triglycerides (P < 0.001 for all comparisons). With 2.25 to 3 g of nicotinic acid, these changes were -7% for total cholesterol (P = 0.007), -14% for LDL cholesterol (P < 0.001), +6% for HDL cholesterol (P = 0.02), and -13% for triglycerides (P = 0.03). With cholestyramine, total cholesterol and LDL cholesterol levels were unchanged compared with the previous step; the change in HDL cholesterol level was -8% (P = 0.03); and the change in triglyceride level was +46% (P < 0.001). With gemfibrozil, total cholesterol level was unchanged; the additional change in LDL cholesterol level was +12% (P = 0.09); the change in HDL cholesterol level was +12% (P = 0.03); and the change in triglyceride level was -37% (P < 0.001). Apolipoprotein B levels decreased by 25% overall (P < 0.001); lipoprotein(a) levels did not change significantly. Adverse effects were primarily attributable to nicotinic acid or cholestyramine. In 18 of the 35 patients (50%) whose baseline LDL cholesterol levels were greater than 3.35 mmol/L (130 mg/dL), pravastatin decreased LDL cholesterol levels to 2.6 mmol/L (100 mg/dL) or less by 6 weeks; 70% of patients needed combination therapy to reach this National Cholesterol Education Program goal during the 2.5 years of the study. Adding nicotinic acid to pravastatin produced LDL cholesterol levels of 2.6 mmol/L or less in 15 more of these 35 patients, so that 94% (n = 33) of the patients receiving these two drugs reached this goal. To reach current goals for LDL cholesterol levels, most normolipidemic patients with coronary heart disease in this study needed combination therapy. Pravastatin with nicotinic acid and pravastatin with gemfibrozil are well-tolerated combinations that can maintain target LDL cholesterol levels, decrease triglyceride levels, and increase HDL cholesterol levels. Adding resin to these combinations produced no further benefit.",1996.0,0,0 2884,8816723,Pravastatin and risk factor modification in patients with moderate primary hypercholesterolaemia.,R Morris; G Robinson; M Tilyard; E Gurr,"To evaluate the efficacy and safety of pravastatin 20mg at night, versus placebo, in combination with dietary, smoking cessation, and other lifestyle advice in general practice. This was a multicentre, randomised double blind placebo controlled trial carried out in thirty general practices in three New Zealand centres. Patients with moderate primary hypercholesterolaemia (5.2-6.7 mmol/L) and two or more risk factors for coronary heart disease were enrolled. After a minimum of 6 weeks lifestyle changes, 95 patients (aged 18-70 years) were randomised to active or placebo therapy. They continued to receive advice and encouragement in maintaining dietary, exercise or smoking cessation changes. Seventy eight patients, pravastatin (n = 39) and placebo (n = 39), completed the treatment phase of the study. After 6 weeks on 20 mg pravastatin, total cholesterol decreased by 18% (0.9 mmol/L, p < 0.0001), triglycerides decreased by 6% (0.1 mmol/L ns), LDL-cholesterol decreased by 23% (1.1 mmol/L, p < 0.0001), and HDL-cholesterol increased by 8% (0.1 mmol/L, ns). A similar effect was also observed after 26 weeks of therapy. These effects were also significant when compared with the placebo group. In 61% of patients treated with pravastatin there was a reduction in cholesterol to less than 5.2 mmol/L, and no real change in lipid levels in patients receiving placebo. No significant differences were observed between the active and placebo groups with regard to patient withdrawal, compliance, or adverse reactions. In general practice pravastatin is a well tolerated and safe drug that induces a favourable effect on lipid profile in patients with primary moderate hypercholesterolaemia and two or more other risk factors for coronary artery disease.",1996.0,0,0 2885,8819689,Cholesterol lowering: perspectives on the 4S and West of Scotland studies.,J W Olin,,1996.0,0,0 2886,8820097,Inhibition of acyl-CoA: cholesterol acyltransferase decreases apolipoprotein B-100-containing lipoprotein secretion from HepG2 cells.,R Musanti; L Giorgini; P P Lovisolo; A Pirillo; A Chiari; G Ghiselli,"There is evidence that the overproduction of apoB-100-containing lipoproteins by the liver is the underlying event in some forms of dyslipoproteinemia. This metabolic status is associated to an increased risk of developing premature coronary artery disease CAD. The conclusions from previous studies suggested that the availability to the hepatocytes of cholesterol that is readily esterified is an important determinant for VLDL and LDL secretion. In the present study, we set out to investigate the effect of the specific stimulation and inhibition of the rate-limiting enzyme of the cholesterol esterification, acyl-CoA:cholesterol acyltransferase (ACAT, E.C. 2.3.1.26), on the lipid and on the apoB-100 secretion rate from a human hepatoma cell line (HepG2). When the specific ACAT inhibitor FCE 27677 (10-5 M) was added to the cultures, a decrease of the cellular cholesteryl ester content and at the same time a significant reduction of the neutral lipids and of the apoB-100 secretion rate were noticed. The stimulation of ACAT by 25-hydroxycholesterol (20 microgram/ml) caused a 4-fold increase of the cellular cholesteryl ester content and a 2-fold increase of the lipoprotein secretion rate. FCE 27677 (10-5 M to 10-7 M) prevented the effects elicited by the oxysterol. On the contrary, lovastatin (10-6 M) and gemfibrozil (10-6 M) had no effect. The analysis of the lipid and of the apolipoprotein composition of the lipoproteins secreted in the medium revealed that ACAT inhibition had the dual effect of both decreasing the number of apoB-100-containing lipoproteins secreted as well as their cholesteryl ester load. Altogether, these data support the idea of a close relationship between ACAT activation, leading to increased cholesteryl ester availability, and apoB-100-containing lipoprotein secretion. It is speculated that ACAT inhibitors may prove useful for the treatment of human dyslipoproteinemias caused by the hepatic overproduction of apoB-100-containing lipoproteins.",1996.0,0,0 2887,8820770,"The new paradigm for coronary artery disease: altering risk factors, atherosclerotic plaques, and clinical prognosis.",J H O'Keefe; R D Conn; C J Lavie; T M Bateman,"The old paradigm states that the greater the stenosis, the greater the risk of cardiac events. Revascularization procedures are the only effective approach to improving prognosis associated with coronary artery disease. In contrast, on the basis of the new paradigm, the nature of the plaque determines the risk of acute cardiovascular events. Dangerous plaques have a lipid-rich core with surrounding inflammation and a thin friable overlying fibrous cap, but they usually appear innocuous on angiography. Effective risk factor modification stabilizes the dangerous plaques and is associated with prompt improvement in endothelial dysfunction and a substantial decrease in the risk of acute cardiovascular events and death.",2001.0,0,0 2888,8824106,"Effects of gemfibrozil or simvastatin on apolipoprotein-B-containing lipoproteins, apolipoprotein-CIII and lipoprotein(a) in familial combined hyperlipidaemia.",S J Bredie; H T Westerveld; H C Knipscheer; T W de Bruin; J J Kastelein; A F Stalenhoef,"Familial combined hyperlipidaemia (FCH), characterized by elevated very-low-density lipoprotein (VLDL) and/or low-density lipoprotein (LDL), is associated with an increased prevalence of premature cardiovascular disease. Therefore, lipid-lowering is frequently indicated. We evaluated in a parallel, double-blind randomized fashion the effect of gemfibrozil (1200 mg/day) (n = 40) or simvastatin (20 mg/day) (n = 41) on lipids, apolipoprotein-B (apo-B)-containing lipoproteins, apo-CIII and lipoprotein(a) [Lp(a)], in 81 well-defined FCH patients. While both drugs lowered plasma cholesterol and triglyceride levels, gemfibrozil lowered plasma triglycerides more effectively by reduction of triglycerides in VLDL and LDL, whereas simvastatin was more effective in its reduction of total plasma cholesterol by exclusively decreasing LDL cholesterol. High-density lipoprotein (HDL) increased to an equal extent on both therapies. Total serum apo-B levels were reduced with both drugs; however, gemfibrozil decreased apo-B only in VLDL + IDL, whereas simvastatin decreased apo-B in both VLDL + IDL and LDL. In keeping with a more effective reduction of VLDL particles, a more pronounced reduction of apo-CIII also was observed after gemfibrozil, which correlated with the reduction in plasma triglycerides. Baseline concentrations of Lp(a) showed a wide range in both treatment groups. Median Lp(a) levels increased after simvastatin, but were not affected by gemfibrozil. Both therapies exhibited their specific effects, although none of the drugs alone completely normalized the lipid profiles of these patients with FCH. Therefore, the choice of treatment should be based on the most elevated lipoprotein fraction, and in some cases a combination of the two drugs may be indicated.",1996.0,0,0 2889,8829016,Clinical pharmacologic concepts for the rational selection and use of drugs for the management of dyslipidemia.,C A Dujovne; P M Moriarty,"The long-term clinical benefits of lowering serum lipid levels have been demonstrated in multiple clinical trials in recent years. These include coronary artery disease regression and decreases in the incidence of adverse clinical events, such as myocardial infarction or refractory ischemia. Reductions in overall mortality have also been demonstrated. The health risk of dyslipidemia led the National Cholesterol Education Program expert panel to recommend intervention to bring low-density lipoprotein cholesterol values to within certain goal levels through a variety of interventions. This article reviews the available pharmacologic agents and compares their efficacy, safety, and cost-effectiveness.",1996.0,0,0 2890,8829023,Effects of antihyperlipidemic drugs and diet plus exercise therapy in the treatment of patients with moderate hypercholesterolemia.,H Nomura; Y Kimura; O Okamoto; G Shiraishi,"We compared the efficacy of two antihyperlipidemic drugs and the efficacy of diet plus exercise therapy in the treatment of patients with moderate hypercholesterolemia. The study included 48 patients with moderate hypercholesterolemia (serum total cholesterol [TC], 250 to 320 mg/dL). Patients were divided into three groups: group A--patients administered 10 mg/d of pravastatin; group B--patients administered 500 mg/d of probucol and 600 mg/d of pantethine; and group C--patients administered diet plus exercise therapy. The serum TC and serum high-density lipoprotein cholesterol (HDL-C) values were determined via enzymatic methods before initiation of each therapy and after 4 and 8 weeks of therapy. An atherogenic index (AI) was also calculated. The results indicated that TC showed a statistically significant decrease in all three groups at 4 and 8 weeks (P < 0.001 and P < 0.05, respectively); the HDL-C value did not change significantly in groups A and C, but it had a statistically significant decrease in group B at 4 and 8 weeks. The AI showed a statistically significant decrease in group A at 4 and 8 weeks of treatment and group C at 8 weeks; there were no significant changes in AI in group B. It may be concluded that as an antihyperlipidemic agent, pravastatin is more useful than probucol and that appropriate exercise and strict dietary management for 8 weeks achieve an efficacy close to that achieved by drug therapy.",1996.0,0,0 2891,8829110,Post-transplant hyperlipidemia: mechanisms and management.,Z A Massy; B L Kasiske,"Hyperlipidemia is common after renal transplantation. In recent years, much progress has been made in understanding the causes and treatment of lipid abnormalities in renal transplant patients. Recently, short-term studies have shown that newer antilipemic agents appear to be safe and effective in treating hyperlipidemia in this population. Despite the absence of large, controlled clinical trials examining the effect of lipid-lowering strategies on cardiovascular disease and chronic renal allograft rejection, therapy appears to be warranted in renal transplant patients with an atherogenic lipid profile and multiple risk factors.",1996.0,0,0 2892,8830937,,,,,0,0 2893,8831932,Familial defective apolipoprotein B-100 (FDB): effect of simvastatin therapy on LDL-receptor binding.,C D Mamotte; M Sturm; J I Foo; F M van Bockxmeer; R R Taylor,"Heterozygotes for familial defective apolipoprotein B-100 (FDB) have two populations of low density lipoprotein (LDL), one bearing normal apolipoprotein B-100 (apo B) and the other bearing defective apo B which exhibits a much lower affinity for the LDL-receptor. If HMGCoA reductase inhibitors such as simvastatin lowered LDL mainly by up-regulating LDL-receptor mediated clearance, they should decrease the overall binding affinity of LDL from an FDB heterozygote by selectively decreasing LDL bearing normal apo B. We compared how LDL from FDB heterozygotes competed with normal 125I-labelled LDL for binding to LDL-receptors while on and off therapy with simvastatin. The LDL of FDB heterozygotes had 40% (n = 10) the affinity of normal LDL (n = 12) for the LDL receptor on cultured fibroblasts, and 55% (n = 6) of normal LDL (n = 6) for that on HepG2 cells. Treatment of FDB subjects with simvastatin (n = 10) decreased serum LDL by 22% but had no effect on its binding affinity for LDL receptors, indicative of lowering of LDL containing both normal and defective apo B. This is consistent with the major LDL lowering effect being associated with decreased synthesis of LDL, rather than enhanced LDL-receptor clearance.",1996.0,0,0 2894,8832603,Effects of hypercholesterolemia of renal hemodynamics: study in patients with nephrotic syndrome.,G Fuiano; C Esposito; V Sepe; G Colucci; M Bovino; M Rosa; M Balletta; G Bellinghieri; G Conte; B Cianciaruso; A Dal Canton,"Experimental and clinical studies have demonstrated a positive relationship between hyperlipidemia and rate of progression of renal disease, suggesting that lipids can induce or aggravate glomerular injury mainly by interacting with mesangial cells. Nevertheless, recently has been demonstrated that increased cholesterol levels can also induce endothelial cell dysfunction. Thus, since endothelium is known to play a major role in modulating the vascular tone, we have tested the possibility that hypercholesterolemia impairs the renal hemodynamics in patients with active nephrotic syndrome and elevated serum cholesterol levels. In this single-blind, nonrandom study, 12 patients were treated with pravastatin (group T, treated, n = 12) and 8 with placebo (group C, controls, n = 8). The controls were studied after the pravastatin group had been completed. Before starting the treatment the patients underwent basal determinations including routine laboratory investigations and PAH and inulin clearances. The same determinations were repeated after 48 h, and 6 and 12 weeks from the beginning of the treatment. The study at 48 h was performed to see if pravastatin had a direct, cholesterol-independent effect on renal function. The following basal results were reported (mean +/- SEM; group T vs. group C): serum cholesterol (mmol/l) 9.7 +/- 0.4 vs. 9.1 +/- 0.3 (NS); proteinuria (g/24 h): 6.2 +/- 0.2 vs. 7.0 +/- 0.7 (NS); PAH clearance (ml/min): 353 +/- 21 vs. 385 +/- 31 (NS); inulin clearance (ml/min): 62.5 +/- 7.7 vs. 67 +/- 9.3 (NS). After 48 h, no changes were observed in both groups. Subsequently, in group T, the following percentage changes of basal levels were observed: serum cholesterol -21.4 +/- 3.2% at 6 weeks (p < 0.05) and -34.9 +/- 3.2% at 12 weeks (p < 0.01); inulin clearance +3 +/- 3.7% at 6 weeks (NS) and +9.3 +/- 2.9% at 12 weeks (p < 0.05); PAH clearance +7 +/- 3.1% at 6 weeks (p < 0.05) and +21.2 +/- 5.5% at 12 weeks (p < 0.01). By contrast, no significant changes of these parameters occurred in group C at any time, so that the percent changes of baseline values of CPAH were significantly greater in group T (at 6 weeks: p < 0.05; at 12 weeks p < 0.005). These results indicate that the reduction of cholesterol is associated with a significant increase in renal plasma flow, thus, suggesting that hypercholesterolemia may actually impair the renal hemodynamics. We speculate that this effect may contribute to increase the risk of ischemic acute renal failure in nephrotic patients and, along with changes induced in the mesangium by other mechanisms, to contribute to the progression of renal disease.",1996.0,0,0 2895,8840302,Will angiotensin II receptor antagonists be renoprotective in humans?,I Ichikawa,,1996.0,0,0 2896,8840836,Reduction of transient myocardial ischemia with pravastatin in addition to the conventional treatment in patients with angina pectoris. REGRESS Study Group.,A J van Boven; J W Jukema; A H Zwinderman; H J Crijns; K I Lie; A V Bruschke,"Lipid-lowering therapy reduces cardiac morbidity and mortality. Less is known about its potential anti-ischemic effect. In a 2-year prospective randomized placebo-controlled study, the effect of pravastatin 40 mg on transient myocardial ischemia was assessed. Forty-eight-hour ambulatory ECGs with continuous ST-segment analysis were performed in 768 male patients with stable angina pectoris, documented coronary artery disease, and serum cholesterol between 4 and 8 mmol/L (155 and 310 mg/dL). During the trial, patients received routine antianginal treatment. In the patients randomized to pravastatin, transient myocardial ischemia was present at baseline in 28% and after treatment in 19%; in the placebo group, it was found in 20% and 23% of the patients, respectively (P = .021 for change in percentage between two treatment groups; odds ratio, 0.62; 95% CI, 0.41 to 0.93). Ischemic episodes decreased by 1.23 +/- 0.25 (SEM) episode with pravastatin and by 0.53 +/- 0.25 episode with placebo (P = .047). Under pravastatin, the duration of ischemia decreased from 80 +/- 12 minutes to 42 +/- 10 minutes (P = .017) and with placebo, from 60 +/- 13 minutes to 51 +/- 9 minutes (P = .56). The total ischemic burden decreased from 41 +/- 5 to 22 +/- 5 mm.min in the pravastatin group (P = .0058) and from 34 +/- 6 to 26 +/- 4 mm . min in the placebo group (P = .24). Adjusted for independent risk factors for the occurrence of ischemia, the effect of pravastatin on the reduction of risk for ischemia remained statistically significant (odds ratio, 0.45; 95% CI, 0.22 to 0.91; P = .026). In men with documented coronary artery disease and optimal antianginal therapy, pravastatin reduces transient myocardial ischemia.",1996.0,0,0 2897,8843892,Beneficial effects of pravastatin on fasting hyperinsulinemia in elderly hypertensive hypercholesterolemic subjects.,P Chan; B Tomlinson; C B Lee; W H Pan; Y S Lee,"We undertook this prospective double-blind, placebo-controlled study to evaluate the efficacy and safety of low-dose (15 mg) pravastatin in elderly hypercholesterolemic hypertensive subjects with concurrent antihypertensive treatment and to determine whether fasting hyperinsulinemia could also be improved. At three hypertension and lipid clinics of two medical centers, 96 elderly (49 women, 47 men) ambulatory subjects were randomized to active treatment or placebo for 12 months after a 3-month single-blind lead-in period. Hypertensive subjects with plasma total cholesterol levels of at least 6.47 mmol/L (250 mg/dL) and triglyceride levels less than 3.39 mmol/L (300 mg/dL) were treated with 15 mg pravastatin for 12 months after receiving 3 months of the American Heart Association step I diet. Lipid, glucose, and fasting insulin levels were measured; clinical laboratory tests included liver function and creatine kinase determinations. After 12 months of pravastatin therapy, plasma total cholesterol concentration decreased by 25.1% (from a mean of 7.29 to 5.47 mmol/L, P < .05), low-density lipoprotein cholesterol decreased by 30.2% (from 5.27 to 3.68 mmol/L, P < .05), and triglycerides decreased by 10.7% (from 1.68 to 1.50 mmol/L, P < .05). High-density lipoprotein cholesterol increased by 9.2% (from 1.20 to 1.31 mmol/L, P < .05). Fasting insulin levels decreased from 89.0 to 61.5 pmol/L (P < .05). All of these changes were greater (P < .05) than any tendency toward change in the placebo group. Adverse events and clinical laboratory abnormalities were generally mild and transient in both placebo and pravastatin groups. Study drugs were withdrawn from one subject in each group with asymptomatic creatine kinase elevations. We conclude that low-dose pravastatin was effective and safe in the treatment of hypercholesterolemic hypertensive subjects on concurrent antihypertensive therapy. It also improved fasting hyperinsulinemia despite the use of beta-blockers and diuretics in these hypertensive subjects.",1996.0,0,0 2898,8844442,Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening.,D D Cilla; D M Gibson; L R Whitfield; A J Sedman,"The pharmacodynamic effects and pharmacokinetics of atorvastatin, a potent investigational inhibitor of HMG-CoA reductase, were studied in 16 normolipidemic subjects after administration of 40 mg daily for 15 days in the morning or evening. Lipid and apolipoprotein parameters were determined, and plasma atorvastatin equivalent concentrations were measured according to a validated enzyme inhibition bioassay procedure. Atorvastatin was well tolerated by the participants. Overall, mean reductions of 34% in total cholesterol, 48% in low-density lipoprotein (LDL) cholesterol, 37% in very low density lipoprotein (VLDL) cholesterol, 25% in triglycerides, 6% in apolipoprotein A-I, and 34% in apolipoprotein B were observed. Changes in lipid and apolipoprotein values were similar after morning and evening administration of atorvastatin. In contrast, studies with other HMG-CoA reductase inhibitors have consistently shown that evening administration results in larger reductions in total and LDL cholesterol than does morning administration. Rate and extent of equivalent absorption of atorvastatin were lower during evening than morning administration. Mean elimination half-life values were similar, however, suggesting that there is no diurnal variation in disposition of this drug. Pharmacokinetic differences did not correlate with effects on serum lipids.",2001.0,0,0 2899,8845726,"Having too much evidence (depression, suicide, and low serum cholesterol)",M Law,,1996.0,0,1 2900,8847874,Multicenter comparison of micronized fenofibrate and simvastatin in patients with primary type IIA or IIB hyperlipoproteinemia.,A Steinmetz; T Schwartz; U Hehnke; H Kaffarnik,"In 12 weeks of active treatment, we compared the efficacy and safety of a new (micronized) formulation of fenofibrate (F) (200 mg/day) with that of simvastatin (S) (20 mg/day), an inhibitor of hydroxy-methyl-glutaryl coenzyme A (HMG-CoA)-reductase. Men and women with primary hyperlipoproteinemia (HLP) with low-density lipoprotein (LDL) cholesterol level 180-300 mg/dl and triglyceride level < 500 mg/dl had dietary treatment for 8 weeks, and 133 (2 of 3 type IIa, 1 of 3 type IIb HLP) were randomized. The decrease in total cholesterol differed between type IIa patients (F - 17.9 vs. S - 25.8%), the decrease in triglyceride levels between the type II b groups (F - 52.8 vs. S - 14%), whereas the degree of decrease in LDL cholesterol (F - 20.9 vs. S - 34.9%) differed among all patients. Despite the difference in LDL cholesterol decrease, no difference was noted in total apolipoprotein (apo) B lowering (F - 20.8 and S - 26.5%). Increases in high-density lipoprotein (HDL) cholesterol (F + 18.5 vs. S + 15%) differed specifically in type IIb patients (F + 33.6 vs. S + 11.4%), accompanied by a more pronounced increase in apo AI with fenofibrate (F + 10.5% vs. S no change). Improvement in the ratios of total cholesterol/HDL cholesterol and apo AI/apo B occurred similarly with both drugs. Only fenofibrate, not simvastatin, decreased both fibrinogen (-10.3 vs. + 3.6%) and uric acid (-25% vs. no change) in type IIa and type IIb patients. Safety parameters reflected drug-specific known side effects, underscoring the safety of both drugs in addition to their efficacy in lipid lowering. Besides its advantages in type IIb hyperlipidemia, micronized fenofibrate proved a potent drug in decreasing total and LDL cholesterol and in very effectively decreasing apo B-containing lipoproteins, which is a recommendation for its use in primary hypercholesterolemia.",1996.0,0,0 2901,8853585,New developments in the use of niacin for treatment of hyperlipidemia: new considerations in the use of an old drug.,J R Crouse,"Niacin has been used for many years to treat hyperlipidemia. It has been shown to reduce coronary death and non-fatal myocardial infarction and, in a separate analysis of long-term (15-year) follow-up, all cause mortality. It reduces total cholesterol, low density lipoprotein cholesterol (LDL-C) and triglycerides and increases high density lipoprotein cholesterol (HDL-C). Sustained-release niacin may be associated with more dramatic changes in LDL-C and triglyceride, whereas the short acting preparation causes greater increases in HDL-C. The increase of HDL-C occurs at a lower dose (1500 mg/day) than the reduction of LDL-C (> 1500 mg/day). Niacin also favorably influences other lipid parameters including lipoprotein(a) [Lp(a)], alimentary lipemia, familial defective apolipoprotein B-100 and small dense LDL. Combination of niacin with a bile acid sequestrant or a reductase inhibitor represents a powerful lipid-altering regimen. Whereas the reductase inhibitors and bile acid binding resins primarily affect LDL-C, the combined therapy has a synergistic effect to reduce LDL-C and, in addition, the niacin reduces triglycerides and increases HDL-C. The major drawback in the use of niacin is associated side effects (flushing and palpitations) and toxicity (worsening of diabetes control, exacerbation of peptic ulcer disease, gout, hepatitis). Niacin has a long history of use as a lipid lowering agent and has several attractive features. Unfortunately, the side effect profile of this agent warrants its use only in patients with marked dyslipidemia in whom side effects and potential toxicity are closely monitored.",2001.0,0,0 2902,8857479,Effects of short-term reduction in serum cholesterol with simvastatin in patients with stable angina pectoris and mild to moderate hypercholesterolemia.,M de Divitiis; P Rubba; S Di Somma; V Liguori; M Galderisi; S Montefusco; G Carreras; V Greco; A Carotenuto; G Iannuzzo; O de Divitiis,"To evaluate the effects of short-term cholesterol-lowering treatment on myocardial effort ischemia, 22 patients with stable effort ischemia and mild to moderate hypercholesterolemia (low density lipoprotein [LDL] cholesterol 160 to 220 mg/dl) were randomly allocated at baseline (TO) in 2 groups. Group A included 12 patients treated with simvastatin 10 mg bid; group B included 10 patients treated with placebo. All patients underwent a treadmill electrocardiography (ECG) test; total cholesterol, HDL and LDL cholesterol, triglycerides, plasma, and blood viscosity were measured. All tests were repeated after 4 and 12 weeks. For 18 of the same patients (11 taking simvastatin, 7 receiving placebo), forearm strain-gouge plethysmography was performed at baseline and after 4 weeks, both at rest and during reactive hyperemia. At 4 and 12 weeks, group A showed a significant reduction in total cholesterol (p <0.05) and LDL (p <0.05), with unchanged HDL, triglycerides, blood, and plasma viscosity. Effort was unmodified, ST-segment depression at peak effort and ischemic threshold were significantly improved after 4 and 12 weeks (all p <0.05) with unchanged heart rate x systolic blood pressure product. A significant increase in the excess flow response to reactive hyperemia was detected in group A (p <0.03); group B showed no changes in hematochemical and ergometric parameters. These data suggest that cholesterol-lowering treatment is associated with an improvement in myocardial effort ischemia; this might be explained by a more pronounced increase of coronary blood flow and capacity of vasodilation in response to effort.",1996.0,0,0 2903,8857853,Gender-based mortality follow-up from the Program on the Surgical Control of the Hyperlipidemias (POSCH) and meta-analysis of lipid intervention trials. Women in POSCH and other lipid trials.,H Buchwald; C T Campos; J R Boen; P Nguyen; S E Williams; J Lau; T C Chalmers,"The authors assessed the clinical results of lipid-lowering therapy in women. The Program on the Surgical Control of the Hyperlipidemias (POSCH) has demonstrated that effective lowering of total cholesterol and low-density lipoprotein cholesterol in a postmyocardial infarction population significantly reduces atherosclerotic coronary heart disease (ACHD) mortality, ACHD mortality combined with a new confirmed nonfatal myocardial infarction, and the number of coronary artery bypass grafting and angioplasty procedures performed. A review and meta-analysis were performed of the seven primary or secondary lipid/ atherosclerosis intervention trials-including POSCH-published in the English-language literature that included women and published results in women separate from the results in men or in the entire trial population. The main outcome measure analyzed was overall mortality. The Scottish Physicians Clofibrate Study, the Newcastle upon Tyne Clofibrate Study, and the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I) Trial may have demonstrated a possible benefit in ACHD prognosis from effective lipid intervention in women. The other four available trials did not. The Minnesota Coronary Survey reported a 15.6% increase in overall mortality rate and a 30.6% increase in a combined cardiovascular endpoint rate in the lipid-intervention group. The Upjohn Colestipol Study demonstrated statistically significant reductions in overall and ACHD mortality in the men, but not in the women. The Scandinavian.",1996.0,0,0 2904,8860062,Japanese and American reports of randomized trials: differences in the reporting of adverse effects.,K Hayashi; A M Walker,"We sought to identify differences in the description of adverse drug experiences in reports of randomized clinical trials (RCTs) from the United States and Japan, using diclofenac and simvastatin as test drugs. Reports were identified in Medline (Index Medicus 1966-1990), EMBASE (Excerpta Medica 1974-1990), JAPICDOC (1979-1990), and JOIS-III (JMEDICINE 1980-1990). In each search keywords describing study design were paired with the drugs' generic names, chemical names, and development numbers. Twenty-seven U.S. reports (18 for diclofenac and 9 for simvastatin) and 22 Japanese reports (17 for diclofenac and 5 for simvastatin) identified in these four databases were selected for review. For each paper we identified the relation of the article to the data (preliminary, primary, and secondary reports, reviews), the means of identifying adverse reactions, the principal outcomes of the trials, and a variety of descriptive measures relating to study design, authorship, and elements of presentation. With few exceptions, Japanese reports were not indexed in English-language databases, and studies from the United States were not carried out in the Japanese databases. The Japanese literature consisted exclusively of primary reports of clinical trials, whereas the U.S. literature was dominated by review articles and secondary reports of data from trials not fully published elsewhere. Japanese reports contained more detail on adverse experiences but reported principally those attributed to the drugs by attending clinicians. U.S. reports by contrast offered little detail but tended to include all adverse experiences, whether or not clinically attributed to drugs. A preponderance of U.S. articles reported significant differences between drugs in safety or treatment efficacy, whereas only one third of the Japanese articles did so for the same agents. Reports from both countries offered few details of the methods used to gather information on adverse drug experiences, and as a result the reported absolute frequencies of such events are difficult to compare between trials or to generalize to other settings. In conclusion, the reporting of adverse reactions in clinical trials is inadequate in both the United States and Japanese literature. The shortcomings are complementary in that reports of U.S. trials contain insufficient detail and Japanese reports do not interpret or synthesize experience. Clinical research into drug safety in both countries could be improved through the adoption of simple standards of clarity and consistency in the monitoring and reporting of drug adverse effects.",1996.0,0,0 2905,8860708,Drug therapy of severe hypercholesterolemia in patients with coronary artery disease.,K G Parhofer; W O Richter; P Schwandt,"The beneficial effect of cholesterol-lowering therapy for secondary prevention in patients with coronary artery disease (CAD) is well established. The therapeutic goal in this situation is a low-density lipoprotein (LDL) cholesterol level of 100 mg/dl. Cholesterol-lowering therapy will not only lead to a reduction in the progression of lesions but also and probably more importantly will reduce lesion activation and rupture and improve endothelial vasomotor function. Depending on the underlying hyperlipoproteinemia, the first choice for single drug therapy is a bile acid-binding resin or a hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor in isolated LDL hypercholesterolemia, and nicotinic acid, a fibric acid, or a HMG-CoA reductase inhibitor in combined hyperlipidemia. Combination therapy usually consists of a bile acid-binding resin with either an HMG-CoA reductase inhibitor, a fibric acid, or nicotinic acid in LDL hypercholesterolemia and nicotinic acid with a fibric acid in combined hyperlipidemia.",1996.0,0,0 2906,8860713,Low-density lipoprotein apheresis versus lipid lowering drugs in the treatment of severe hypercholesterolemia: four years' experience.,R Schiel; R Bambauer; U Müller,"Elevated lipoprotein concentrations seem to be linked strongly in a dose dependent manner to an increased incidence of atherosclerosis. A total of 47 patients suffering from severe hyperlipidemia were matched to treatment with LDL apheresis (Baxter, Kaneka, Lipopak; 24 patients, aged 50.2 + or - 11.5 years), diet, and/or lipid-lowering drugs or with diet and lipid-lowering drugs only (23 patients, aged 48.8 + or - 11.8 years). After treatment periods of 49.8 + or - 13.4 months (apheresis group, 2,396 treatment sessions) and 38.6 + or - 15.1 months (drug group), the ensuing results revealed significant differences (p < 0.0001): -47.3% versus -12.1% for total cholesterol, -46.9% versus -21.8% for LDL, +8.4% versus +0.9% for HDL, -52.0% versus -13.1% for the LDL/HDL ratio, -36.4% versus - 16.2% for triglycerides, and -25.9% versus + 1.5% for lipoprotein (a). In the apheresis group, one patient died of myocardial infarction; in the drug group, there was one nonfatal myocardial infarction and the manifestation of coronary heart disease in 3 cases. There were no severe side effects in either group. All patients in the apheresis group responded to therapy. The present trial suggests that a continuing reduction in serum lipid concentrations may lower, in a dose dependent manner, the risk for development and progression of coronary heart disease. Regarding clinical and laboratory results, LDL apheresis seems to be safe, effective therapy for treatment of severe hyperlipidemia.",1996.0,0,0 2907,8862101,Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study.,T R Pedersen; K Berg; T J Cook; O Faergeman; T Haghfelt; J Kjekshus; T Miettinen; T A Musliner; A G Olsson; K Pyörälä; G Thorgeirsson; J A Tobert; H Wedel; L Wilhelmsen,"Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.",1996.0,0,0 2908,8862691,Will correction of dyslipoproteinaemia reduce coronary heart disease risk in patients with non-insulin-dependent diabetes? Need for trial evidence.,K Pyörälä; G Steiner,"The incidence of atherosclerotic vascular disease is greatly increased in patients with non-insulin-dependent diabetes (NIDDM). The most frequent lipoprotein abnormalities in this type of diabetes are an increase in triglyceride-rich lipoproteins and a decrease in high-density lipoproteins. Hypertriglyceridaemia appears to be a stronger coronary heart disease risk factor in patients with NIDDM than in nondiabetic subjects. Plasma total and low-density lipoprotein cholesterol levels in NIDDM patients and nondiabetic subjects do not differ. Hypercholesterolaemia is, however, as powerful a predictor of coronary heart disease risk in diabetic patients as in nondiabetic subjects. In spite of this knowledge, there is to date no solid evidence to indicate whether correction of dyslipoproteinaemia in order to reduce coronary heart disease risk in patients with NIDDM is more, equally, or less beneficial than it is in nondiabetic subjects. The only available data come from post-hoc subgroup analyses of the Helsinki Heart Study and the Scandinavian Simvastatin Survival Study (4S). Other trials including patients with diabetes are in progress. Only one intervention trial (currently in its treatment phase), the Diabetes Atherosclerosis Intervention Study (DAIS), is specifically designed to examine the lipid hypothesis in patients with NIDDM.",1996.0,0,0 2909,8864316,Cholesterol lowering therapy inhibits the low-flow mediated vasoconstriction of the brachial artery in hypercholesterolaemic subjects.,J L Megnien; A Simon; A Andriani; P Segond; S Jeannin; J Levenson,"1. We tested whether lipid lowering treatment with HMG CoA reductase inhibitor modified the flow mediated large artery reactivity in primary pure hypercholesterolaemia. 2. Abnormalities in arterial reactivity have been described in the presence of high blood cholesterol, in particular an enhanced constriction of the brachial artery in response to acute induction of a low flow state. 3. Using pulsed-Doppler, we measured brachial artery diameter and flow velocity at rest and their changes induced by wrist occlusion before and after 3 months of double-blind treatment by pravastatin (40 mg orally) in 13 subjects and placebo in 15 others. 4. The significant decrease (P < 0.01) in diameter induced by wrist occlusion before (0.34 +/- 0.08 mm) placebo and pravastatin (0.39 +/- 0.10 mm) persisted after placebo (0.26 +/- 0.07 mm) but was abolished after pravastatin (0.07 +/- 0.05 mm). The absolute change in diameter induced by wrist occlusion was lower after than before pravastatin (P < 0.01) and lower after pravastin than after placebo (P < 0.05). Diameter during the wrist occlusion was higher after pravastatin than after placebo (4.35 +/- 0.16 vs 3.89 +/- 0.09 mm); P < 0.01). 5. These findings indicate that the lipid changes induced by pravastatin and/or some unknown but direct mechanism of the drug itself inhibit low-flow-mediated vasoconstriction associated with hypercholesterolaemia. Such effects may have important implications for the treatment of vasospasm often seen in the presence of high blood cholesterol.",1996.0,0,0 2910,8864962,Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterolemic non-insulin-dependent diabetic men.,H Gylling; T A Miettinen,"Effectiveness of a simultaneous inhibition of cholesterol absorption and synthesis, caused by sitostanol ester margarine and pravastatin, was studied to control mild hypercholesterolemia in men with non-insulin-dependent diabetes mellitus (NIDDM) (n = 8). Margarine, 24 g daily, was a basal dietary treatment. Four 7-week intervention periods included margarine, sitostanol (3 g/day) ester margarine, pravastatin (40 mg/day), and sitostanol ester margarine plus pravastatin in a random order. Pravastatin lowered serum total (-32%) and LDL cholesterol (-38%) and apolipoprotein B (-39%) because of enhanced removal (+20%) and decreased production (-26%) of LDL apolipoprotein B, and reduced synthesis (-9%) and turnover (-8%) of cholesterol, which resulted in reduced biliary cholesterol seretion (-18%). Even though serum triglycerides were lowered by 28%, VLDL, IDL, and light and dense LDL became triglyceride-enriched. Despite increasing cholesterol synthesis, sitostanol lowered LDL cholesterol (-14%) by inhibiting cholesterol absorption (-68%) and LDL apolipoprotein B production rate (-20%). Combination of pravastatin and sitostanol ester lowered serum total, VLDL, IDL, and LDL cholesterol and LDL apolipoprotein B by the highest rate, 35%, 50%, 35%, 44%, and 45% from the control margarine period, respectively, because of reduced apolipoprotein B transport rate (but unchanged removal), in both the total and dense LDL subfractions. HDL cholesterol and apolipoprotein A-I kinetics were unchanged. In spite of decreased absorption, cholesterol synthesis was not compensatorily increased. In conclusion, simultaneous inhibition of cholesterol absorption and synthesis lowers LDL cholesterol and apolipoprotein B by 44-45% solely through inhibition of LDL apolipoprotein B production rate in hypercholesterolemic NIDDM patients. A combination of statin to sitostanol ester margarine-resistant patients offers a safe and effective measure to normalize abnormally high cholesterol values, probably with a lowered statin dose.",1996.0,0,0 2911,8865302,Natural products as a resource for new drugs.,A M Clark,"Natural products have served as a major source of drugs for centuries, and about half of the pharmaceuticals in use today are derived from natural products. The aim of this review is to provide an overview of the continuing central role of natural products in the discovery and development of new pharmaceuticals. In this context, selected examples of important natural product-derived drugs are cited, focusing on some of the most recent introductions to the clinical setting, and a brief overview of some of the important recent developments and remaining challenges in the process of discovering and developing bioactive natural products is provided. Interest in natural products research is strong and can be attributed to several factors, including unmet therapeutic needs, the remarkable diversity of both chemical structures and biological activities of naturally occurring secondary metabolites, the utility of bioactive natural products as biochemical and molecular probes, the development of novel and sensitive techniques to detect biologically active natural products, improved techniques to isolate, purify, and structurally characterize these active constituents, and advances in solving the demand for supply of complex natural products. Opportunities for multidisciplinary research that joins the forces of natural products chemistry, molecular and cellular biology, synthetic and analytical chemistry, biochemistry, and pharmacology to exploit the vast diversity of chemical structures and biological activities of natural products are discussed.",1996.0,0,0 2912,8865916,Lipid-lowering effects of simvastatin and gemfibrozil in CAPD patients: a prospective cross-over study.,F Akçiçek; E Ok; S Duman; S Kürsad; A Unsal; M Alev; G Atabay; A Basçi,"We compared the lipid-lowering effects of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, and gemfibrozil, a fibric acid derivative, in 22 continuous ambulatory peritoneal dialysis patients whose serum total cholesterol and/or triglyceride levels were > or = 220 mg/dL after a standard diet for six months. The study group was first treated with gemfibrozil (600 mg/b.i.d.) for three months (stage 1). After a wash-out period of two months, during which no treatment was given, all of the patients became hyperlipidemic again and, therefore, were given simvastatin (10 mg/day) for three months (stage 2), which was followed by another two-month wash-out period. A control group, which served to evaluate the natural progression of pharmacologically untreated dyslipidemia, was followed during the same period. Blood determinations of triglyceride, total cholesterol, and high-density lipoprotein (HDL) cholesterol were performed after each step. Low-density lipoprotein (LDL) cholesterol and HDL ratio were calculated from the measured values. Both gemfibrozil and simvastatin improved all parameters of the lipid profile, but the effect of simvastatin was better than that of gemfibrozil (-69 vs -39 mg/dL for triglyceride and -95 vs -64 mg/dL for cholesterol), while their actions on LDL and HDL cholesterol were of equal magnitude. Two months after discontinuation of simvastatin, significant decreases of total cholesterol (-46 mg/dL) and triglyceride (-60 mg/dL) were still present, while these values had returned to pretreatment levels after stopping gemfibrozil. The HDL ratio remained markedlyhigher (p < 0.05) during the wash-out period after simvastatin, while it decreased to pretreatment values after gemfibrozil was stopped. The lipid profile of the control group did not change during the follow-up. Both drugs were well tolerated, and no serious side effects occurred.",1996.0,0,0 2913,8866629,,,,,0,0 2914,8872133,Relationship between prothrombin activation fragment F1 + 2 and serum cholesterol.,C Alessandri; S Basili; M Maurelli; D Bracaglia; P Andreozzi; M Pergolini; C Cordova,"Plasma levels of fibrinogen, factor VIIc and prothrombin fragment F1 + 2, a marker of thrombin generation in vivo, were studied in 68 subjects with serum total cholesterol (TC) levels between 135 and 349 mg/dl but without clinical evidence of cardiovascular disease and other atherosclerotic risk factors. F1 + 2 plasma levels were directly correlated with TC (p < 0.0004), low-density lipoprotein cholesterol (LDL-C; p < 0.0018) and factor VIIc (p < 0.024). Thirty-five subjects with TC greater than 249 mg/dl (median value of the whole group) showed higher levels of F1 + 2 (p < 0.0001) and fibrinogen (p < 0.0015) than those with TC lower than 249 mg/dl. In subjects with TC > 249 mg/dl and F1 + 2 > 1.2 nM (median value of the whole group), a cholesterol-lowering drug (simvastatin) was able to reduce F1 + 2 (p < 0.009) as well as TC and LDL-C. This study shows a relationship between serum cholesterol and the rate of thrombin generation supporting the hypothesis that a hypercoagulable state may occur in hypercholesterolemic subjects before the onset of clinical evidence of atherosclerotic cardiovascular disease.",1996.0,0,0 2915,8873668,"The Asp9 Asn mutation in the lipoprotein lipase gene is associated with increased progression of coronary atherosclerosis. REGRESS Study Group, Interuniversity Cardiology Institute, Utrecht, The Netherlands. Regression Growth Evaluation Statin Study.",J W Jukema; A J van Boven; B Groenemeijer; A H Zwinderman; J H Reiber; A V Bruschke; J A Henneman; G P Molhoek; T Bruin; H Jansen; E Gagné; M R Hayden; J J Kastelein,"Many patients suffering from premature coronary artery disease report a family history for such events. A mutation in a particular gene, which confers susceptibility for atherosclerosis, will be found more frequently in individuals suffering from coronary atherosclerosis than in the general population. We have recently reported the identification of an Asp9 Asn substitution in the lipoprotein lipase (LPL) enzyme. We analyzed the impact of this mutation on the progression of coronary atherosclerosis and the effect of pravastatin in both carriers and noncarriers. All patients were enrolled in the quantitative coronary angiographic clinical trial REGRESS, which studied the impact of pravastatin therapy on coronary atherosclerosis. The Asp9 Asn mutation was identified in 38 of 819 (4.8%) patients. Carriers of the mutation more often had a positive family history of cardiovascular disease and lower HDL cholesterol levels than noncarriers. In the placebo group, carriers showed more progression of coronary atherosclerosis than noncarriers: mean reduction of the minimum obstruction diameter of -0.25 mm versus -0.12 mm (P = .029) and increase of percentage diameter stenosis of 6.4% versus 1.4% (P = .004). Moreover, the adjusted relative risk for a clinical event for carriers was calculated at 2.16 (95% CI, 1.09 to 4.29; P = .027). Although the lipid-lowering effect of pravastatin was attenuated in carriers, it appeared that these patients showed a response similar to noncarriers in terms of less progression of atherosclerosis and event-free survival. This study shows that heterozygosity for a mutation in the LPL gene, which causes only subtle changes in fasting plasma lipids, may promote the progression of coronary atherosclerosis and diminish clinical event-free survival.",1996.0,0,0 2916,8874986,Monotherapy with HMG-CoA reductase inhibitors and secondary prevention in coronary artery disease.,C E Rackley,"Although thrombolytic drugs, percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting have provided major advances in the treatment of coronary artery disease, the use of lipid-lowering drugs for secondary prevention has significantly reduced cardiovascular events in the population with coronary artery disease. Secondary prevention trials using HMG-CoA reductase inhibitors include the Familial Atherosclerosis Treatment Study (FATS), the Monitored Atherosclerosis Regression Study (MARS), the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the Asymptomatic Carotid Artery Progression Study (ACAPS), the Multi Anti-Atheroma Study (MAAS), the Scandinavian Simvastatin Survival Study (4S), the Pravastatin Limitation of Atherosclerosis in Coronary Arteries (PLAC I), the Regression Growth Evaluation Statin Study (REGRESS), the Pravastatin Multinational Study, and the Pravastatin, Lipids, and Atherosclerosis in Carotids (PLAC II). Mean changes from baseline of lipid fractions in these trials included: total cholesterol 18 to 35% reduction; low-density lipoprotein (LDL) cholesterol 26 to 46% reduction; high-density lipoprotein (HDL) cholesterol 5 to 15% increase; and triglyceride 7 to 22% reduction. Angiographic regression or lack of progression was statistically demonstrated in the FATS, MARS, CCAIT, MAAS, PLAC I, and REGRESS trials. Cardiovascular events decreased 25 to 92% in all trials, and there was a significant reduction in both cardiovascular and total mortality in the 4S. The greater reduction in cardiovascular events than in anatomic changes suggests that the HMG-CoA reductase inhibitors stabilized the surface of plaques. Monotherapy with HMG-CoA reductase inhibitors provides the clinical opportunity to modify the natural history of coronary artery disease.",1996.0,0,0 2917,8875112,"Conference report: renal disease, metformin, and the adipocyte.",Z T Bloomgarden,,1996.0,0,0 2918,8875973,Cost-effectiveness of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor therapy in the managed care era.,T A Jacobson,"More than $100 billion is spent in the United States each year on cardiovascular disease, primarily for hospitalizations and revascularization procedures. This is more than for any other disease state. As the clinical practice of medicine shifts from the paradigm of private practice to the managed care environment, cost-effectiveness is becoming increasingly important. A primary measure in analyzing cost-effectiveness is the cost-effectiveness ratio, or the dollar cost per unit of improvement for a given expenditure. This measure allows healthcare planners to compare completely different interventions. With approximately 52 million adult U.S. citizens having elevated low-density lipoprotein (LDL) cholesterol levels, lipid-lowering therapy---with diet or 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors---is an important consideration for primary care physicians and managed care providers. The National Health and Nutrition Examination Survey (NHANES) III indicates that 75-88% of adults who have coronary artery disease (CAD) risk factors or CAD require only a moderate (20--30%) reduction in LDL cholesterol levels to reach National Cholesterol Education Program goals. The clinical literature shows that all 4 of the currently available HMG-CoA reductase inhibitors can provide appropriate, moderate LDL cholesterol reductions within their recommended dosage ranges. For the majority of patients who need a 20--30% reduction in LDL cholesterol, fluvastatin 20 or 40 mg once daily provides the most cost-effective HMG-CoA therapy, expressed as cost of therapy per 1% LDL cholesterol reduction. For patients who need a >30% LDL cholesterol reduction, a high-dose HMG-CoA reductase inhibitor (e.g., simvastatin 20 or 40 mg/day) or a combination of a lower-dose HMG-CoA reductase inhibitor and a bile acid resin is the preferred initial therapy. Although a true cost-effectiveness analysis would incorporate morbidity and mortality data from clinical trials, analysis using intermediate endpoints, such as LDL cholesterol reduction, suggests that fluvastatin is the preferred initial HMG-CoA reductase inhibitor for the treatment of moderate hyperlipidemia.",1996.0,0,0 2919,8876936,Effect of fluvastatin or bezafibrate on the distribution of high density lipoprotein subpopulations in patients with familial hypercholesterolemia.,S Hailer; O Pogarell; C Keller; G Wolfram,"In eight patients with familial hypercholesterolemia the effects of two lipid reducing drugs on subpopulations of high density lipoproteins (HDL) were examined. After a 14-week period of diet and diet/placebo a 12-week therapy followed with either bezafibrate (CAS 41859-67-0) or fluvastatin (CAS 93957-55-2). Throughout both treatments a significant decrease of total and low density lipoprotein (LDL)-cholesterol, apolipoprotein B and triglycerides during both therapies were noted as well as an insignificant increase of HDL-cholesterol during bezafibrate. The nondenaturating gradient gel electrophoresis is a valid method for the investigation of the behaviour of HDL and was therefore chosen for this investigation. The individual HDL pattern and HDL diameters did not change in these subjects. The effect on the amounts of HDL 3b and HDL 3c was significantly more extensive during fluvastatin (+2.4% resp. + 2.9%) as compared to during bezafibrate therapy (+1.7% resp. + 2.9%). The changes noted in the HDL subclasses are probably due to a variable lipoprotein metabolism, for example increased activity of lipoprotein lipase, hepatic triglyceride lipase, lecithin-cholesterol acyltransferase and cholesterol ester transfer protein.",1996.0,0,0 2920,8877024,Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio.,G De Pinieux; P Chariot; M Ammi-Saïd; F Louarn; J L Lejonc; A Astier; B Jacotot; R Gherardi,"1. Statins inhibit synthesis of mevalonate, a precursor of ubiquinone that is a central compound of the mitochondrial respiratory chain. The main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction. 2. This study was designed to evaluate the effect of lipid-lowering drugs on ubiquinone (coenzyme Q10) serum level and on mitochondrial function assessed by blood lactate/pyruvate ratio. 3. Eighty hypercholesterolaemic patients (40 treated by statins, 20 treated by fibrates, and 20 untreated patients, all 80 having total cholesterol levels > 6.0 mmol l-1) and 20 healthy controls were included. Ubiquinone serum level and blood lactate/pyruvate ratio used as a test for mitochondrial dysfunction were evaluated in all subjects. 4. Lactate/pyruvate ratios were significantly higher in patients treated by statins than in untreated hypercholesterolaemic patients or in healthy controls (P < 0.05 and P < 0.001). The difference was not significant between fibratetreated patients and untreated patients. 5. Ubiquinone serum levels were lower in statin-treated patients (0.75 mg l-1 +/- 0.04) than in untreated hypercholesterolaemic patients (0.95 mg l-1 +/- 0.09; P < 0.05). 6. We conclude that statin therapy can be associated with high blood lactate/ pyruvate ratio suggestive of mitochondrial dysfunction. It is uncertain to what extent low serum levels of ubiquinone could explain the mitochondrial dysfunction.",1996.0,0,0 2921,8877677,"Tolerance and pharmacokinetics of single-dose atorvastatin, a potent inhibitor of HMG-CoA reductase, in healthy subjects.",E L Posvar; L L Radulovic; D D Cilla; L R Whitfield; A J Sedman,"Tolerance and pharmacokinetics after single-dose administration of atorvastatin, an investigational inhibitor of HMG-CoA reductase, were examined in 22 healthy volunteers in a three-period, partially-blinded study. Participants received capsule and solution doses of atorvastatin (0.5 to 120 mg) and placebo at weekly intervals. Atorvastatin was well tolerated at doses as high as 80 mg. The adverse event profile was similar after administration of atorvastatin capsules and placebo. Atorvastatin solution was slightly less well tolerated. The most common side effect after administration of capsules and solution was headache, followed by sporadic reports of diarrhea, flatulence, and nausea. At the 120-mg solution dose, one participant experienced mild, transient restlessness, euphoria, and mental confusion that were considered to be dose-limiting side effects. Mean concentrations of atorvastatin, maximum concentration (Cmax), and area under the concentration-time curve from time 0 to the time of the last detectable concentration (AUCo-tldc) increased with increasing dose. Plasma elimination half-life (t1/2) ranged from 14.7 to 57.6 hours. The bioavailability of atorvastatin capsules was similar to that of solution. These results suggest that atorvastatin is well tolerated after single doses as high as 80 mg, and may require administration only once daily.",2001.0,0,0 2922,8878387,Hyperlipidemia after liver transplantation: natural history and treatment with the hydroxy-methylglutaryl-coenzyme A reductase inhibitor pravastatin.,D K Imagawa; S Dawson; C D Holt; P S Kirk; F M Kaldas; C R Shackleton; P Seu; S M Rudich; M M Kinkhabwala; P Martin; L I Goldstein; N G Murray; P I Terasaki; R W Busuttil,"This study was designed to determine the frequency of hyperlipidemia after orthotopic liver transplantation and whether treatment with a hydroxy-methylglutaryl coenzyme A reductase inhibitor was safe and efficacious. Cholesterol levels were assessed in 45 consecutive adult liver transplants (mean +/- SE). Four of 22 patients on cyclosporine (CsA) (18%) and three of 23 patients on FK506 (13%) had levels >225 mg/dl at 12 months (cholesterol levels for patients on CsA [total n=22]: pre-Tx = 140+/-11, 1 month = 183+/-36,3 months = 221+/-12, 6 months = 211+/-11, 12 months = 202+/-14 [P<0.01 vs. pre-Tx]; FK506 [total n=23]: Pre-Tx = 151+/-13, 1 month = 187+/-22, 3 months = 188+/-10, 6 months = 184+/-13, 12 months = 164+/-9 [P=0.02 vs. CsA]). A separate cohort of patients with stable graft function, cholesterol >225 mg/dl, and two additional risk factors for coronary artery disease were started on pravastatin. Ninety-eight patients were enrolled. Sixteen patients (16%) discontinued the drug because of subjective complaints. No episodes of rhabdomyolysis or hepatotoxicity occurred (cholesterol levels for patients on CsA [total n=65]: pretreatment = 251+/-7, 6 months = 220+/-7 [P=0.01 vs. pretreatment], 12 months = 224+/-8 [P=0.01 vs. pretreatment]; FK506 [total n=17]: pretreatment = 251+/-17, 6 months = 219+/-17, 12 months = 208+/-17 [P=0.08 vs. pretreatment]). Natural killer cells isolated from normal volunteers (n=14) exhibited 27+/-9% specific lysis. Patients on FK506 or cyclosporine-based immunosuppression alone (n=11) exhibited 20+/-4% specific lysis. Standard immunosuppression plus pravastatin (n=10) decreased lysis to 0.2+/-10% (P<0.02 vs. controls and standard immunosuppression). We conclude: (1) posttransplant hyperlipidemia occurs less frequently in liver transplant patients than in renal or cardiac transplants; (2) pravastatin is safe and efficacious for cholesterol reduction in liver transplant patients; and (3) pravastatin coadministered with standard immunosuppression reduces natural killer cell-specific lysis in these recipients.",2001.0,0,0 2923,8879334,Considerations in the formulary selection of hydroxymethylglutaryl-coenzyme A reductase inhibitors.,K McMillan,,1996.0,0,0 2924,8879953,Lipid-lowering therapy for patients with or at risk of coronary artery disease.,J Kjekshus; T R Pedersen; J A Tobert,"Several studies have shown that effective lipid-lowering therapy slows the progression of atherosclerotic lesions in the coronary and carotid arteries. Recent clinical trials have confirmed and extended previous work showing that lowering cholesterol reduces the risk of coronary events. A clear reduction in major coronary events during treatment for 5 years with the hydroxymethylglutaryl-coenzyme A reductase inhibitor pravastatin was observed in the West of Scotland study and in the preliminary results of the Cholesterol and Recurrent Events study. The Scandinavian Simvastatin Survival Study has provided the first unequivocal demonstration of improved survival as a result of lipid-lowering therapy. These three trials, which together included over 15,000 patients studied for 5 years, have provided good evidence that noncardiovascular mortality is not affected by substantial reductions in blood cholesterol.",1996.0,0,0 2925,8881840,Atherogenic risk reduction in patients with dyslipidaemia. comparison between bezafibrate and lovastatin.,H Sinzinger; C Pirich; P Kondor; H Etti,"To examine the atherogenic risk-reducing effect of bezafibrate and lovastatin. Double-blind, randomized clinical trial of male and female patients with moderate hypercholesterolaemia with or without hypertriglyceridaemia. Two months dietary treatment followed by 400 mg sustained release bezafibrate every day or 20 mg lovastatin every day for 6 months. Patients recruited (n = 561) and treated (n = 524) by primary care physicians throughout Austria. Multifactorial assessment of atherogenic risk profile. Bezafibrate increased high density lipoprotein cholesterol by 16%, lovastatin by 10% (P < 0.05). Bezafibrate decreased low density lipoprotein cholesterol by 20%, lovastatin by 27% (P < 0.001). Bezafibrate decreased total cholesterol by 15%, lovastatin by 18% (P < 0.001). Bezafibrate reduced triglycerides by 29%, lovastatin by 13% (P < 0.001); and fibrinogen by 9.4% and 3.0%, respectively. Fibrinogen reduction as a result of bezafibrate administration was dependent on starting levels. The risk ratio cholesterol:high density lipoprotein cholesterol (baseline both 6.1) reduction was 27% in both groups. The low:high density lipoprotein ratio (baseline: 4.1/4.2) reduction reached 31% and 34% respectively. Coronary events' probability (calculated from multifactorial risk functions) were greatly reduced by both agents (41%/33%). Hypertriglyceridaemic patients had a higher initial global coronary risk and profited more from treatment. Bezafibrate was significantly better tolerated (P < 0.001) than lovastatin; most events were gastrointestinal (6 vs 14, ns) or as a result of creatine phosphokinase elevations (3 vs 12, P < 0.05). Both treatments significantly reduced the risk parameters for developing coronary heart disease, and calculated multifactorial coronary risk was similarly decreased. When selecting a drug for moderate dyslipidaemia and if haemostatic regulation is disturbed, the additional effect of bezafibrate on elevated fibrinogen levels should be considered.",1995.0,0,0 2926,8882381,Fluvastatin: a review of its pharmacology and use in the management of hypercholesterolaemia.,G L Plosker; A J Wagstaff,"Fluvastatin, a member of the group of drugs known as HMG-CoA reductase inhibitors, is used in the treatment of patients with hypercholesterolaemia. In clinical trials in patients with primary hypercholesterolaemia, fluvastatin 20 or 40 mg/day achieved marked reductions from baseline in serum levels of low density lipoprotein (LDL)-cholesterol (19 to 31%) and total cholesterol (15 to 21%), along with modest declines in serum triglyceride levels (1 to 12%) and small increases in high density lipoprotein (HDL)-cholesterol levels (2 to 10%). These beneficial effects on the serum lipid profile were similar to those demonstrated with other HMG-CoA reductase inhibitors, although direct comparative trials are limited. Concomitant administration of fluvastatin plus another lipid-lowering agent, such as a bile acid sequestrant, a fibrate or nicotinic acid, usually reduced serum levels of total cholesterol and LDL-cholesterol by at least a further 5 to 10% from baseline compared with fluvastatin monotherapy. Fluvastatin has a similar tolerability profile to that of other HMG-CoA reductase inhibitors. Gastrointestinal disturbances, which are usually mild and transient, were the most frequently reported adverse events with fluvastatin in clinical trials. Persistent elevation of serum transaminase levels occurred in approximately 1% of fluvastatin recipients, which is similar to the rate for other HMG-CoA reductase inhibitors. Unlike other HMG-CoA reductase inhibitors, which have been infrequently associated with myopathy and rarely with rhabdomyolysis, these events have not been associated with fluvastatin to date, although fluvastatin has not been used as extensively as agents such as lovastatin. HMG-CoA reductase inhibitors other than fluvastatin, when given in combination with drugs such as fibrates, nicotinic acid, cyclosporin or erythromycin, can increase the risk of these potentially serious adverse events. Thus far, myopathy or rhabdomyolysis have not been reported among patients receiving fluvastatin concomitantly with any of these drugs. Therefore, fluvastatin can be given with caution in combination with fibrates, nicotinic acid, cyclosporin or erythromycin. In conclusion, fluvastatin has similar efficacy and tolerability profiles to other HMG-CoA reductase inhibitors, which are among the most effective agents available for treating patients with hypercholesterolaemia. Pharmacoeconomic studies performed to date suggest an advantage for fluvastatin over other HMG-CoA reductase inhibitors, predominantly because of its relatively low acquisition costs (at least in those countries in which the evaluations were conducted). Thus, fluvastatin is effective and well tolerated in patients with hypercholesterolaemia and appears to have an economic advantage over other HMG-CoA reductase inhibitors, primarily as a result of its relatively low acquisition costs.",1996.0,0,0 2927,8883496,Hypoalphalipoproteinemia (low high density lipoprotein) as a risk factor for coronary heart disease.,G L Vega; S M Grundy,"Low HDL levels are inversely related to risk for coronary heart disease. Several different mechanisms may account for this relationship. First, low HDL levels may be directly atherogenic; second, a low HDL often denotes high levels of other atherogenic lipoproteins (for example, remnants); and third, a low HDL frequently accompanies other coronary risk factors (for example, insulin resistance, diabetes, and raised blood pressure). This multiplicity of relationships probably explains the power of low HDL levels to predict acute coronary events.",1996.0,0,0 2928,8891888,Effect of a reduced-fat diet with or without pravastatin on glucose tolerance and insulin sensitivity in patients with primary hypercholesterolemia.,A Q Galvan; A Natali; S Baldi; S Frascerra; T Sampietro; F Galetta; G Seghieri; E Ferrannini,"Pharmacological treatment of hyperlipidemia may be associated with deterioration of glucose tolerance. We randomized 20 nonobese patients with primary familial hypercholesterolemia (serum total cholesterol 7.8 +/- 0.4 mM, triglycerides 1.4 +/- 0.2 mM) to an isocaloric, reduced fat (< 30%) low-cholesterol (200 mg/day) diet with placebo or pravastatin (40 mg/day). Oral glucose tolerance, endogenous insulin response to glucose, insulin sensitivity (determined by the euglycemic insulin clamp technique), hepatic glucose production (by the tritiated glucose technique), and substrate utilization (by indirect calorimetry) were measured at baseline and after 8 weeks of treatment. Ten normocholesterolemic healthy subjects, matched to the patients by age, sex, and body weight, served as the control group. Diet alone (with no change in body weight) was associated with a significant 15% decrease in both serum low density lipoprotein (LDL)-cholesterol and triglycerides (p < 0.001 for both), and a slight decrease in high density lipoprotein (HDL)-cholesterol concentrations, paralleled by reductions in Apo B, C2, C3, and E levels (p < 0.05 or less). The addition of pravastatin led to a significantly larger reduction in LDL-cholesterol (30%, p < 0.05) and an 8% increase (p < 0.02) in total HDL-cholesterol concentrations. Accordingly, the ratio of LDL:HDL cholesterol (which was 60% higher than in controls at baseline) remained unchanged in the placebo-diet group whereas it was restored to normal in the pravastatin-diet group. Glucose tolerance, insulin response, insulin-induced inhibition of hepatic glucose production and lipolysis, and insulin-mediated glucose uptake and oxidation were all slightly but not significantly improved after treatment, with no significant differences between pravastatin and placebo. In nonobese patients with primary hypercholesterolemia, pravastatin treatment in combination with an isocaloric, reduced-fat diet leads to a marked reduction in LDL-cholesterol and triglycerides levels and a normalization of the LDL:HDL ratio without affecting glucose tolerance or insulin sensitivity.",1996.0,0,0 2929,8904621,Absence of effects of prolonged simvastatin therapy on nocturnal sleep in a large randomized placebo-controlled study. Oxford Cholesterol Study Group.,A C Keech; J M Armitage; K R Wallendszus; A Lawson; A J Hauer; S E Parish; R Collins,"1. It has been suggested that lipophilic HMG CoA reductase inhibitors, like lovastatin and simvastatin, may cause sleep disturbance. 2. Six hundred and twenty-one patients at increased risk of coronary heart disease were randomized in a single centre to receive 40 mg daily simvastatin, 20 mg daily simvastatin or matching placebo. To assess the effects of prolonged use of simvastatin on nocturnal sleep quality and duration, a sleep questionnaire was administered to 567 patients (95% of 595 survivors) at an average of 88 weeks (range: 44-129 weeks) after randomization. 3. The main outcome measures were sleep-related problems and use of sleep-enhancing medications reported during routine study follow-up visits, and responses to the sleep questionnaire about changes in sleep duration and about various sleep events during the preceding month. 4. No differences were observed between the treatment groups in the frequency of sleep-related problems reported, in the proportion of follow-up visits at which such problems were reported, or in the use of sleep-enhancing medications. The numbers who stopped study treatment were similar in the different treatment groups, and no patient stopped principally because of insomnia. In response to the sleep questionnaire, there were no significant differences between the treatment groups in reports of various sleep events during the preceding month, except that slightly fewer patients allocated simvastatin reported waking often. No differences in sleep duration were observed. 5. This placebo-controlled trial does not indicate any adverse effects of prolonged treatment with simvastatin on systematically sought measures of sleep disturbance.",1996.0,0,0 2930,8904672,Targeted prevention of coronary artery disease: pharmacological considerations in multimodality treatment.,I Shviro; E Leitersdorf,"Treatment of hypercholesterolemia with HMG-CoA-reductase inhibitors has revolutionized medical intervention towards the prevention of coronary artery disease. There is a wide sprectrum of patients with diverse underlying clinical conditions that may benefit from treatment using these agents. These include patients with multiple risk factors, individuals following major vascular events, and those with special conditions that are associated with accelerated atherosclerosis. The latter include patients with severe, dominantly inherited hypercholesterolemia, patients with major organ dysfunction such as chronic renal failure, and individuals after transplantation. Multimodality intervention includes behavior modification and mechanical as well as pharmacological treatment. It is aimed at several important targets: cholesterol reduction, control of hypertension and diabetes, improvement of myocardial contractility, reduction of infarct size, and control of hemostasis. Most of these patients require multiple drugs, which may interact at the pharmacodynamic (efficacy and safety) as well as pharmacokinetic levels. These potential interactions should be considered while planning and implementing preventive measures for an individual as well as for the community. The beneficial effects and the potential hazardous interactions between HMG-CoA reductase inhibitors and other medications are presented and discussed using two models: heterozygous familial hypercholesterolemia and major organ transplantation. Although there is a partial overlap in the medications used for the treatment of these two conditions, some of them differ. The interaction between HMG-CoA reductase inhibitors and other cholesterol-lowering agents, mainly fibrates, is discussed in the first model summarizing data from controlled clinical trials. The interaction with cyclosporin A is presented using the second model. A potential benefit of fluvastatin, as compared with other currently available HMG-CoA reductase inhibitors, which may be related to its relatively short plasma half-life and low systemic exposure, is discussed.",1996.0,0,0 2931,8905205,"A prospective clinical trial comparing the treatment of idiopathic membranous nephropathy and nephrotic syndrome with simvastatin and diet, versus diet alone.",B L Rayner; M J Byrne; R van Zyl Smit,"Of 17 patients with idiopathic membranous nephropathy (IMN) and nephrotic syndrome, 9 were allocated to treatment with simvastatin (an HMG CoA-reductase inhibitor) and low cholesterol diet, and 8 to diet alone. At entry, the treatment and control groups did not differ in mean serum creatinines, chromium-labelled EDTA clearances, urinary protein/creatinine ratios, serum albumins, and lipid profiles. The mean follow up period (+/- SEM) in the treated group was 19.3 (+/- 4.4) months compared with 16.6 (+/- 5.9) months in the control group. At the end of the trial the fall in chromium-labelled EDTA clearances was similar (-1.27 versus -1.28 mls/min/months/1.73 m2) in the treatment and control groups respectively. The mean (+/- SEM) total and LDL-cholesterol had gone from 10.5 (+/- 0.94) and 8.02 (+/- 1) mmol/l to 5.2 (+/- 0.49) and 3.47 (+/- 0.44) respectively in the treated patients. Additionally the mean (+/- SEM) albumin and urinary protein/creatinine ratio went from 25.6 (+/- 2.4) gm/l and 0.52 (+/- 0.09) gm/mmol to 45.5 (+/- 2.8) and 0.13 (+/- 0.04) respectively. There was little change in total and LDL-cholesterol; albumin and urinary protein/creatinine ratio in the control group. This study supports the observation that lowering serum cholesterol in the nephrotic syndrome reduces proteinuria and increases serum albumin levels. No difference in the rate of decline in renal function could be demonstrated.",1996.0,0,0 2932,8906896,Clinically significant drug interactions with cyclosporin. An update.,C Campana; M B Regazzi; I Buggia; M Molinaro,"Since its approval in 1983 for immunosuppressive therapy in patients undergoing organ and bone marrow transplants, cyclosporin has had a major impact on organ transplantation. It has significantly improved 1-year and 2-year graft survival rates, and decreased morbidity in kidney, liver, heart, heart-lung and pancreas transplantation. Several studies have supported the efficacy of cyclosporin in preventing graft-versus-host disease in bone marrow transplantation. Cyclosporin is also possibly effective in treating diseases of autoimmune origin and as an antineoplastic agent. The introduction of therapeutic drug monitoring of cyclosporin was extremely useful because of the wide inter- and intraindividual variability in the pharmacokinetics of cyclosporin after oral or intravenous administration. Optimal long term use of cyclosporin requires careful monitoring of the blood (or plasma) concentrations. Sustained and clinically significant drug-drug interactions can occur during long term therapy with cyclosporin. The coadministration of multiple drugs with cyclosporin could result in graft rejection, renal dysfunction or other undesirable effects. Any interaction that leads to modified cyclosporin concentrations is of potential clinical importance. Cyclosporin itself may have significant effects on the pharmacokinetics and/or pharmacodynamics of coadministered drugs, such as digoxin, HMG-CoA reductase inhibitors and antineoplastic drugs affected by multidrug resistance. Many drugs have been shown to affect the pharmacokinetics and/or pharmacodynamics of cyclosporin. Interactions between cyclosporin and danazol, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, metoclopramide, nicardipine, verapamil, carbamazepine, phenobarbital (phenobarbitone), phenytoin, rifampicin (rifampin) and cotrimoxazole (trimethoprim/sulfamethoxazole) are well documented in a large number of patients. Other interactions (such as those with aciclovir, estradiol and imipenem) are documented only in isolated case studies.",1996.0,0,0 2933,8909899,Interpretation of trials with drugs and devices; a double standard?,M L Simoons,,1996.0,0,0 2934,8913414,Prevention and regression of atherosclerosis: effects of HMG-CoA reductase inhibitors.,A Bjelajac; A K Goo; C W Weart,"To review the current literature on the effects of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors in secondary prevention and regression of atherosclerosis. A MEDLINE and journal search of recent studies evaluating the effects of lipid lowering with HMG-CoA reductase inhibitors on serum cholesterol as well as progression and regression of atherosclerotic coronary or carotid disease in patients with established atherosclerotic disease was conducted. Articles addressing the pathophysiology of atherosclerotic disease were identified by using the same sources. All available studies evaluating the use of HMG-CoA reductase inhibitors in the progression and regression of coronary and carotid atherosclerosis were reviewed. Lowering of total serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, as well as increasing high-density lipoprotein cholesterol can be achieved with HMG-CoA reductase inhibitors. Aggressive lipid lowering has been demonstrated to alter progression of established atherosclerotic disease and, in some patients, actually induce regression of the atheroma. An unexpected finding of several trials was the early and significant reduction in clinical cardiac events. Other mechanisms by which clinical event reduction may be explained include plaque stabilization and restoration of endothelium vasodilation. Aggressive lipid-lowering therapy using HMG-CoA reductase inhibitors appears to alter the natural progression and promote regression of atherosclerosis in selected patients with established coronary or carotid atherosclerosis. However, it is unlikely that regression of atherosclerosis alone is responsible for the marked reduction in clinical cardiac events seen in these trials.",1996.0,0,0 2935,8915817,Treatment of hypercholesterolemia with heparin-induced extracorporeal low-density lipoprotein precipitation (HELP).,R S Lees; N N Holmes; R W Stadler; S F Ibrahim; A M Lees,"Familial hypercholesterolemia (FH) can cause early disability and death from premature atherosclerotic cardiovascular disease. Patients homozygous for the disease have very high plasma cholesterol, extensive xanthomatosis, and die from atherosclerosis in childhood or early adulthood. Past attempts to improve the prognosis included removal of cholesterol from the circulation by ileal bypass or biliary diversion. Neither treatment was successful. Direct removal by plasmapheresis of low-density lipoprotein (LDL), the primary carrier of cholesterol in plasma, was first performed on an FH homozygous patient in 1966. The treatment was well tolerated and led to rapid diminution of xanthomas. Other experimental treatments included selective LDL apheresis with monoclonal or polyclonal antibody affinity columns. A method for selective LDL apheresis was developed in 1983 by Armstrong, Seidel, and colleagues based on heparin precipitation of LDL at low pH. This method, called HELP, removes all apolipoprotein B-containing lipoproteins including LDL and lipoprotein (a), as well as some fibrinogen. LDL apheresis by HELP is well tolerated; the incidence of side effects is low, and the treatment has been associated with regression of cardiovascular disease. LDL apheresis, rather than liver transplantation, is the treatment of choice for patients with severe, life-threatening hypercholesterolemia which does not respond to diet and drug therapy.",2000.0,0,0 2936,8916484,Atherosclerosis and restenosis: reflections on the Lovastatin Restenosis Trial and Scandinavian Simvastatin Survival Study.,W S Weintraub; J P Pederson,"Atherosclerosis is related to serum lipids, whereas restenosis after coronary angioplasty is probably not, reflecting different pathophysiologies. Nonetheless, treatment of lipid disorders is appropriate after angioplasty.",1996.0,0,0 2937,8916658,A comparative study of the therapeutic effect of probucol and pravastatin on xanthelasma.,M Fujita; K Shirai,"We examined and compared the effects of probucol and pravastatin on the regression of xanthelasma. Thirty-six cases treated by probucol and 18 cases by pravastatin were evaluated for 12 months. Thirteen of the 36 cases treated with probucol showed regression of xanthelasma. However, one of the 18 cases treated with pravastatin showed regression. These data were statistically significantly. The average total cholesterol value in both groups decreased during drug therapy. However, the average of HDL-cholesterol values in the probucol treatment group showed significant decreases, but those in the pravastatin treatment group did not. We discussed the mechanisms of the two drugs on the regression of xanthelasma and the mechanisms of development of xanthelasma.",1996.0,0,0 2938,8917325,Advances in treatment of cholesterol abnormalities. The role of HMG-CoA reductase inhibitors.,C E Rackley,"The introduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has provided an important new class of agents that reduce levels of total and low-density lipoprotein cholesterol more powerfully than any previously used drugs. Multiple clinical trials have shown a significant decrease in lipid values and cardiovascular events and a slowing of the progression of atherosclerosis in men and women of all ages. The Scandinavian Simvastatin Survival Study demonstrated a significant reduction in all-cause mortality as a result of reduced cardiovascular mortality. The HMG-CoA reductase inhibitors should be considered as first-line therapy for hypercholesterolemia in all patients with established atherosclerosis involving the coronary, carotid, or peripheral vessels.",1996.0,0,0 2939,8918276,West of Scotland Coronary Prevention Study: identification of high-risk groups and comparison with other cardiovascular intervention trials.,,"We assessed the potential benefit of treatment for low-risk and high-risk groups in the West of Scotland Coronary Prevention Study (WOSCOPS) population, and compared the benefits of primary and secondary prevention of coronary heart disease (CHD) by lipid lowering with the benefits of blood pressure reduction in the primary prevention of stroke. We did a subgroup analysis of placebo-treated men in the WOSCOPS population by age, vascular disease at trial entry, and other established risk factors. We also compared WOSCOPS findings with those of the Scandinavian Simvastatin Survival Study (4S) and the Medical Research Council (MRC) trial of treatment for mild to moderate hypertension in middle-aged men. The WOSCOPS population comprised 6595 men aged 45-64 years with no history of myocardial infarction (MI) and plasma total cholesterol concentrations of 6.5-8.0 mmol/L at initial screening. Participants were randomly allocated pravastatin (40 mg daily) or placebo, and followed up for an average of 4.9 years. Coronary event rates at 5 years in the WOSCOPS placebo group were higher than 10% (the recommended treatment threshold) in men with pre-existing vascular disease and in those 55 years or older without symptoms or signs of CHD but with at least one other risk factor. Event rates were low in men with hypercholesterolaemia but no other risk factor: 3.5% (95% CI 1.3-5.7) for men aged 45-54 years and 5.3% (2.7-8.0) for men aged 55-64 years. Three times more men had to be treated for 5 years to prevent one endpoint in WOSCOPS than in 4S. By contrast, two to four times fewer men with hyperlipidaemia were treated to save one coronary event in WOSCOPS than hypertensives to save one stroke in the MRC trial. These differences persisted after adjustment for the low-risk status of many of the patients with hypertension who took part in the MRC trial. There were a substantial number of men whose risk of a coronary event was more than 10% at 5 years in the WOSCOPS cohort. The absolute benefit of pravastatin treatment of hyperlipidaemia is less in the primary prevention of CHD than in secondary prevention, but is similar to that for primary prevention of stroke by treatment of mild to moderate hypertension in middle-aged men.",1996.0,0,1 2940,8918503,Low cholesterol and cancer.,H Kritz; C Zielinski; H Sinzinger,"The relation between plasma cholesterol (CH) concentration and mortality is complex. The plasma CH concentration correlates positively with mortality from coronary heart disease, but some studies have shown a negative relation with death from cancer. If these two relations reflect causal mechanisms that are reversible by changing the plasma CH concentration, the benefits of lipid reduction for heart disease might be offset by an increased mortality from cancer. Different aspects between lipid metabolism and cancer, as well as new insights into this interesting field, are discussed. The literature was searched using MedLine through 1966 and January 1996. There is no evidence from the data available at present that the association between low CH and a higher risk of cancer is causal. This issue should not affect the advice on health matters offered by doctors, especially to patients with other risk factors for cardiovascular disease. The possibility that hypercholesterolemia (HC) drugs can induce a reduction of tumor-cell growth makes them potentially useful as an adjuvant to chemotherapy and ultimately increases the probabilities in the prevention and treatment of cancer.",1996.0,0,0 2941,8920175,Age-related changes affecting atherosclerotic risk. Potential for pharmacological intervention.,L G Spagnoli; A Mauriello; A Orlandi; G Sangiorgi; E Bonanno,"The incidence of cardiovascular diseases that are related to the atherosclerotic process increases exponentially with age. Organ lesions, the clinical manifestation of atherosclerotic disease, are late events due to complications in the plaque (ulceration, thrombosis, calcification) which are the result of an increased vulnerability to disruption of a previously stable plaque. The higher incidence of age-related clinical events could be explained by a rising sensitivity of plaques to destabilising factors, both parietal and humoral. The increased probability that a plaque in an elderly patient will became vulnerable could be related to those destabilising factors that significantly increase with aging, such as advanced glycation end-products. For these reasons, it seems most important that the analysis of these age-related destabilising factors, rather than those factors that promote the development of early atherosclerotic plaques, should be undertaken. Taking the point of view of a pharmacological intervention, this should eventually lead to a more complete understanding of this process.",1996.0,0,0 2942,8926908,The effect of pravastatin in patients with primary hyperlipidaemia.,M Mafauzy; M Mokhtar; W B Wan Mohamad; M Musalmah,"Thirty-four (34) subjects with primary hyperlipidaemia were enrolled for this study. After low fat dietary therapy for 6 weeks, subjects' whose serum total cholesterol fell to below 6.2 mmol/l (11 subjects) were excluded from the study and those whose serum total cholesterol were 6.2 mmol/l or more (23 subjects) were started on pravastatin 10 mg nocte. After 8 weeks of treatment, there was a significant decrease in the mean total cholesterol and LDL-cholesterol. However 13 of the subjects still had serum total cholesterol 6.2 mmol/l or more and their pravastatin dose was increased to 20 mg nocte. After 12 weeks, there was a significant reduction in triglyceride, total cholesterol and LDL-cholesterol. There was also a significant increase in HDL-cholesterol. The triglyceride fell by a mean of 15.7%, total cholesterol by a mean of 18.1% and LDL-cholesterol by a mean of 26.3%. HDL-cholesterol on the other hand, increased by 19.4%. The subjects whose total cholesterol fell below 6.2 mmol/l at week 8 had significantly lower total cholesterol to begin with than those whose total cholesterol failed to do so and hence were commenced on 20 mg pravastatin. This suggests that the optimum dose of the drug is dependent on the initial level of total cholesterol. We conclude that pravastatin is effective as a lipid lowering agent.",1995.0,0,0 2943,8929256,Insoluble complex formation between LDL and arterial proteoglycans in relation to serum lipid levels and effects of lipid lowering drugs.,O Wiklund; G Bondjers; I Wright; G Camejo,"Lipoprotein deposition and increased intimal proteoglycans are characteristics of the atherosclerotic lesion in which low density lipoproteins (LDL) bind with high affinity to proteoglycans. The affinity of LDL to proteoglycans is dependent on its structural and compositional characteristics. This study investigated the relationship between serum lipid levels and LDL-proteoglycan reactivity. We also analyzed how lipid-lowering drugs affect this interaction. Patients with moderate hypercholesterolemia (n = 147) were randomized to pravastatin 40 mg o.d., gemfibrozil 600 mg b.i.d., gemfibrozil+pravastatin (same doses) or placebo. LDL reactivity with proteoglycans was analyzed by precipitation of serum with isolated human arterial proteoglycans. Reactivity was determined as amount of precipitated cholesterol or apolipoprotein (apo) B. Under the conditions used, 53% of the LDL cholesterol and 29% of serum apo B were precipitated. There were strong correlations between precipitated LDL and serum levels of cholesterol, LDL or apo B. No correlations were found with serum lipoprotein(a) (Lp(a)) levels. During pravastatin treatment, cholesterol was reduced by 26.5% and triglycerides by 9.8%. During gemfibrozil treatment corresponding figures were 16.8 and 40.2, and for the combined treatment, 27.5% and 34.2%. On all treatments, the reactivity of LDL with proteoglycan was reduced. The effects were significantly larger in the groups treated with gemfibrozil. This was correlated with the increase in high density lipoprotein (HDL) during gemfibrozil treatment. In hypercholesterolemia, the reactivity of LDL with proteoglycan is increased; treatment with lipid-lowering drugs lowers this reactivity, the effect being greatest for gemfibrozil. This might be due to conformational changes of LDL during treatment with gemfibrozil, unrelated to its lipid lowering effect. Since binding of LDL to proteoglycans is central in atherogenesis, this may be of importance for the role of gemfibrozil as an antiatherogenic drug.",1996.0,0,0 2944,8930429,"The lipid-lowering effects of atorvastatin, a new HMG-CoA reductase inhibitor: results of a randomized, double-masked study.",T M Heinonen; E Stein; S R Weiss; J M McKenney; M Davidson; L Shurzinske; D M Black,"This randomized, placebo-controlled, double-masked, parallel-group trial assessed the serum cholesterol-lowering effects of atorvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme. A reductase inhibitor, over 26 weeks in patients with primary hypercholesterolemia. Thirty-nine patients from four centers in the United States were originally randomized to one of two treatment groups and received either atorvastatin 10 mg (20 patients) or placebo (19 patients) once daily. Atorvastatin rapidly and significantly reduced serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B levels. LDL-C was reduced 35% with atorvastatin 10 mg compared with a 0% increase in LDL-C in the placebo group. Atorvastatin significantly reduced triglyceride levels, with improvements occurring over time. At 26 weeks, triglyceride levels were reduced by 21% with atorvastatin treatment compared with a 14% increase with placebo. The drug was well tolerated and no clinically significant laboratory abnormalities were detected.",1996.0,0,0 2945,8937448,"Action of lovastatin, simvastatin, and pravastatin on sterol synthesis and their antiproliferative effect in cultured myoblasts from human striated muscle.",A K van Vliet; P Nègre-Aminou; G C van Thiel; P A Bolhuis; L H Cohen,"Lovastatin, simvastatin, and pravastatin are fairly strong inhibitors of sterol synthesis in human myoblasts in culture. Lovastatin and simvastatin have IC50 values of 19 +/- 6 nM and 4.0 +/- 2.3 nM, respectively. Pravastatin is a weaker inhibitor of sterol synthesis (IC50 value of 110 +/- 38 nM). Through inhibition of mevalonate production, these compounds have a distinct inhibiting effect on cell proliferation. Because proliferation of myoblasts is important in the repair of damaged skeletal muscle, experiments were performed to investigate the effect of lovastatin, simvastatin, and pravastatin on cell proliferation and cell viability. The more potent inhibitors of sterol synthesis, lovastatin, and simvastatin, were able to inhibit the proliferation of these cells during 3 days of incubation with drug concentrations of 1 microM for lovastatin and 0.1 microM or 1 microM for simvastatin. DNA synthesis was decreased by more than 80% in the presence of 1 microM of lovastatin or simvastatin. In contrast, under these conditions, pravastatin had no influence on cell proliferation or DNA synthesis, which is probably related to the lack of inhibition of sterol synthesis by pravastatin on extended incubation. The three 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors did not disturb cell viability because mitochondrial dehydrogenase activity and ATP content remained proportional to the number of cells in the culture at any concentration used.",1996.0,0,0 2946,8937525,Macrophages and atherosclerotic plaque stability.,P Libby; Y J Geng; M Aikawa; U Schoenbeck; F Mach; S K Clinton; G K Sukhova; R T Lee,"Physical disruption of atheroma frequently causes coronary thrombosis. Ruptured plaques usually have thin fibrous caps overlying a large thrombogenic lipid core rich in lipid-laden macrophages. The biology of plaque monocyte-derived macrophages thus assumes critical importance in understanding plaque instability. Monocyte recruitment involves binding to leukocyte adhesion receptors on the endothelial surface such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Once adherent to the endothelial surface, monocytes enter the intima at sites of lesion predilection. This process probably requires directed migration of the mononuclear cells. A number of chemoattractant molecules, such as the monocyte chemoattractant molecule-1, may participate in signaling this entry of adherent monocytes into the artery wall. Once resident in the arterial intima, monocytes accumulate lipid, via increasingly well characterized receptor-mediated uptake, and transform into macrophage foam cells. These lesional macrophages also acquire other functional properties including production of the potent procoagulant, tissue factor, apolipoprotein E, and an increasing list of cytokines (protein mediators of information and immunity) that may participate importantly in autocrine and paracrine signaling among leukocytes and vascular endothelial and smooth muscle cells. Fatty streaks seldom cause clinical events but may evolve into complicated atheromatous plaques characterized by an accumulation of smooth muscle cells and extracellular matrix and formation of a central core containing extracellular lipid. Death of macrophages, including programmed cell death or apoptosis, probably promotes formation of this thrombogenic lipid pool whose size correlates with plaque instability. Lesion complication often culminates in rupture of the fibrous cap overlying this lipid core. The integrity of the fibrous cap, and thus its resistance to rupture, depends critically on the collagenous extracellular matrix of the plaque's fibrous cap. This aspect of plaque structure in turn depends upon the balance between synthesis and degradation of the macromolecules that comprise the extracellular matrix of the cap, principally interstitial forms of collagen derived from arterial smooth muscle cells. Collagen breakdown, however, appears to depend critically on macrophages. Plaque macrophages express a variety of matrix-degrading enzymes that can contribute to the weakening of the fibrous cap. In this way, macrophages can critically influence aspects of the biology of human atheroma related to lesion stability. We hypothesize that lipid-lowering reduces clinical events, as shown in recent trials, by stabilizing lesions in part by reversing some of the maladaptive functions of macrophages described above.",1996.0,0,0 2947,8946135,Advances in preventive cardiology.,R M Schieken,"Since the publication of the Report of the Expert Panel on Blood Cholesterol in Children in 1991, both multi-institutional and office-practice-based studies have attested to its diet recommendations' safety and efficacy in modestly lowering blood cholesterol. Normal growth was preserved. Investigators have found no aberrations of either macro- or micronutrients. Although the dietary changes recommended appear effective, the screening recommendations have been vigorously questioned, with adherents on both sides with opinions from never screen to universal screening. Conventional medical wisdom states that smoking is bad for smokers' health. The ill health effects have been extended to passive smoking. Previous studies have shown effects of maternal smoking on the birth-weight of the newborn. Now studies are emerging that show long-time effects of in utero smoke on coronary risk factors.",1996.0,0,0 2948,8946557,Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy.,J M Manson; C Freyssinges; M B Ducrocq; W P Stephenson,"Pregnancy outcomes in women with inadvertent exposure to lovastatin and simvastatin during pregnancy have been examined based on reports submitted to the manufacturer as part of worldwide postmarketing surveillance. There were 134 reports of exposure during pregnancy in which pregnancy outcome was known. Among prospectively followed pregnancies with known outcome, the proportion of normal outcomes was 85%, congenital anomalies 4.0%, spontaneous abortions 8.0%, fetal deaths/stillbirths 1.0%, and miscellaneous adverse outcomes 2.0%. While the number of prospective reports available for evaluation were only sufficient to rule out a three- to fourfold increase in the overall frequency of congenital anomalies, these proportions do not exceed what would be expected in the general population. Based on findings from this interim evaluation, there is no relationship between exposure to therapeutic doses of these agents during pregnancy and the occurrence of adverse pregnancy outcomes.",1996.0,0,0 2949,8952866,Effects of two different HMG-CoA reductase inhibitors on thromboxane production in type IIA hypercholesterolemia.,M Milani; C Cimminiello; M Lorena; G Arpaia; M Soncini; G Bonfardeci,"Many studies have found that familial hypercholesterolemia, a hyperlipoproteinemia associated with premature atherosclerosis, is characterized by enhanced platelet aggregation. This study was undertaken to measure the urinary excretion of the two main urinary thromboxane B2 (TXB2) metabolites (2, 3-dinor-TXB2 and 11-dehydro-TXB2) in 20 patients affected by familial hypercholesterolemia treated for one month with 40 mg/day of pravastatin (10 patients) in comparison to 10 normocholesterolemic subjects. After a run-in period, the type II A patients showed total cholesterol levels (296 +/- 32 mg/dL) significantly higher (P < 0.001) than those of control subjects (155 +/- 46 mg/dL). The urinary concentrations of 11-dehydro-TXB2 and 2,3-dinor-TXB2 also significantly differed (P < 0.001) between control group (1,463 +/- 1,440 and 386 +/- 447 pg/mg urinary creatinine) and treated patients (3,536 +/- 2,112 and 914 +/- 572 pg/mg urinary creatinine). At baseline there was a positive correlation between total cholesterol (TC) levels and urinary TXB2 metabolite concentrations (2,3-dinor-TXB2 r = 0.61, P < 0.02; 11-dehydro-TXB2, r = 48, P < 0.05), but not between low-density-lipoprotein cholesterol (LDL-C) and the urinary compounds. At the end of a four-week treatment. TC and LDL-C had decreased significantly from the baseline levels, by 27% and 30% in the fluvastatin group (P < 0.01) and by 23% and 31% in the pravastatin group (P < 0.01), with no significant difference between the two groups. After the two treatments with HMG-CoA reductase inhibitors, there was no statistically significant reduction of the urinary metabolite levels. In addition, the positive correlation seen at baseline between TC and TXB2 metabolites was no longer present. In accord with previous studies, we found a significant correlation between TC levels and TXB2 metabolites concentrations in type II A hypercholesterolemic patients. Although, short-term treatment with two statins reduced TC levels, it did not change the thromboxane metabolite excretion.",1996.0,0,0 2950,8960446,Secondary preventive potential of lipid-lowering drugs. The Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT).,U de Faire; C G Ericsson; L Grip; J Nilsson; B Svane; A Hamsten,"Current experience from coronary angiographic trials using different treatment regimens such as lifestyle changes, resins, nicotinic acid and statins, shows that progression of atheroma can be retarded, and that regression can sometimes be induced, by a marked lowering of LDL-cholesterol. Young post-myocardial infarction patients, however, usually exhibit a multiplicity of metabolic risk factors with dyslipidaemias, predominantly hypertriglyceridaemia, and disturbances of glucose-insulin homeostasis and of the haemostatic system. These factors, together coupled with coronary angiographic data showing that the degree of dyslipidaemia is related to the extent and degree of coronary atherosclerosis, and the fact that rapid progression of coronary atherosclerosis was foreseen in this group of patients, resulted in the initiation of the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) in 1985. BECAIT was a 5-year, double-blind, placebo-controlled study of bezafibrate (200 mg three times daily) and dietary intervention in dyslipidaemic male survivors of myocardial infarction below 45 years of age. The angiographic analysis included 81 patients (42 bezafibrate and 39 placebo) who underwent baseline and at least one post-treatment angiogram, at 2 and 5 years. Changes in mean minimum lumen diameter indicated that there was 0.13 mm less (95% Cl: 0.10; 0.15) disease progression in focal lesions in the bezafibrate group than in the placebo group (P = 0.049). Parallel, but non-statistically significant, treatment effects were observed for mean segment diameter and percent stenosis. Three patients treated with bezafibrate and 11 patients in the placebo group suffered coronary events during the course of the trial (P = 0.02 logrank test). The angiographic effects of bezafibrate were accompanied by statistically significant reductions in serum cholesterol and triglycerides. Furthermore, plasma fibrinogen levels were significantly reduced and HDL-cholesterol concentration increased but there was no net change in LDL-cholesterol. These findings show that bezafibrate slowed the progression of focal coronary atherosclerosis to a degree that is comparable to that achieved with the statins in angiographic trials such as MAAS and REGRESS. Bezafibrate also reduced the occurrence of coronary events in young post-infarction victims. Like BECAIT, analyses of data from the NHLBI type II study, CLAS, POSCH and MARS provide evidence for the role of triglyceride-rich lipoproteins in the progression of coronary artery disease. Retardation of progression of atherosclerosis and a reduction in coronary events is, therefore, possible without reducing LDL-cholesterol.",1996.0,0,0 2951,8962211,Comparison of pravastatin and lovastatin in renal transplant patients receiving cyclosporine.,V Kliem; C Wanner; T Eisenhauer; C J Olbricht; R Doll; M Boddaert; P O'Grady; M Krekler; B Mangold; U Christians,,1996.0,0,0 2952,8962554,Low density lipoprotein apheresis improves regional myocardial perfusion in patients with hypercholesterolemia and extensive coronary artery disease. LDL-Apheresis Atherosclerosis Regression Study (LAARS).,W R Aengevaeren; A A Kroon; A F Stalenhoef; G J Uijen; T van der Werf,"In a randomized study we evaluated the effect of biweekly low density lipoprotein (LDL) apheresis plus simvastatin versus medication alone on regional myocardial perfusion. In patients with severe hypercholesterolemia, diet and lipid-lowering drugs are often insufficient to achieve optimal LDL cholesterol values. Low density lipoprotein apheresis is a very effective lipid-lowering therapy. Assessment of regional myocardial perfusion enables evaluation of the functional state of the coronary circulation. We studied 42 patients with severe hypercholesterolemia and extensive coronary artery disease who were randomized to diet and simvastatin with or without biweekly LDL apheresis. Regional myocardial perfusion was assessed by digital subtraction angiography with videodensitometric calculation of hyperemic mean transit time (HMTT) of contrast medium at baseline and after 2 years of therapy. Low density lipoprotein cholesterol decreased by 63% (to 3.0 mmol/liter) in the LDL apheresis group and by 47% (to 4.1 mmol/liter) in the medication group. Paired HMTT measurements were assessed in 43 regions in the LDL apheresis group and 35 regions in the medication group. In the LDL apheresis group, regional HMTT decreased over 2 years from 3.35 +/- 1.18 (mean +/- SD) to 2.87 +/- 0.82 s (-14%, p = 0.001), whereas no change in the medication group was observed: 2.95 +/- 1.06 to 2.96 +/- 0.90 s (p = NS). In the patient-based comparison, the mean change in HMTT was -0.45 s (-14%, p = 0.01) in the LDL apheresis group and -0.05 s (-2%, p = NS) in the medication group, respectively. Only exercise-induced ischemia improved in the LDL apheresis group. Biweekly LDL apheresis plus simvastatin decreased time-averaged LDL cholesterol levels by an additional 31% (1.1 mmol/liter) compared with medication alone. After 2 years of therapy, regional myocardial perfusion improved in the LDL apheresis group and remained unchanged in the medication group. Thus, aggressive reduction of LDL cholesterol has a favorable effect on regional myocardial perfusion and alleviates ischemia.",1996.0,0,0 2953,8964646,Four years' treatment efficacy of patients with severe hyperlipidemia. Lipid lowering drugs versus LDL-apheresis.,R Schiel; R Bambauer; U A Müller,"A total of 47 patients suffering from heterozygous hyperlipidemia were treated with LDL-apheresis (24 patients, aged 49.5 +/- 11.5 years), diet and/or lipid-lowering drugs or with diet and lipid-lowering drugs only (23 patients, aged 48.0 +/- 11.9 years). After treatment periods of 44.4 +/- 14.3 (apheresis group) and 33.5 +/- 15.9 (drug group) months, respectively, the ensuing results revealed significant differences (p < 0.0001): total cholesterol decreased from 10.4 to 5.5 vs 9.9 to 8.7 mmol/l, LDL from 7.4 to 3.9 vs 6.6 to 5.2 mmol/l, triglycerides from 5.8 to 3.7 vs 4.8 to 4.1 mmol/l and the LDL/HDL-ratio decreased from 7.1 to 3.4 vs 6.7 to 5.8. In the apheresis group one patient died from myocardial infarction vs one non-fatal myocardial infarction and the manifestation of coronary heart disease in three cases in the drug group. There were no severe side-effects in either group. All patients in the apheresis group experienced an increased clinical performance. On the other hand physological well-being of these patients was lower than that of the drug group (scores 42.3 +/- 8.9 vs 50.2 +/- 9.9, p < 0.002). The present trial suggests that a continuing reduction in serum lipid concentrations may lower in a dose dependent manner the risk of development and progression of coronary heart disease. With respect to clinical and laboratory results, LDL-apheresis seems safe and appears to be the most effective therapy.",1995.0,0,0 2954,8967704,Effect of apheresis of low-density lipoprotein on peripheral vascular disease in hypercholesterolemic patients with coronary artery disease.,A A Kroon; W N van Asten; A F Stalenhoef,"Apheresis of low-density lipoprotein (LDL) is an effective lipid-lowering treatment in hypercholesterolemic patients who have coronary artery disease and are refractory to drugs. More aggressive lipid-lowering therapy may further slow the progression of atherosclerosis. To compare the effect of LDL apheresis and simvastatin therapy with the effect of simvastatin therapy alone on the progression of peripheral vascular disease. Open, randomized, single-center study. University hospital. 42 men with primary hypercholesterolemia (total cholesterol level > 8.0 mmol/L) and extensive coronary atherosclerosis. Biweekly apheresis of LDL plus simvastatin, 40 mg/d (n = 21), or simvastatin, 40 mg/d (n = 21), for 2 years. Lipid and lipoprotein levels, changes in hemodynamically significant stenoses in the aortotibial tract (measured by ankle:arm systolic blood pressure ratio combined with Doppler spectrum analysis of the femoral artery), and changes in the mean intima-media thickness of three carotid artery segments. Mean baseline LDL cholesterol levels decreased from 7.8 to 3.0 mmol/L in the apheresis and simvastatin group and from 7.9 to 4.1 mmol/L in the simvastatin-only group; mean lipoprotein(a) levels decreased from 57.0 to 44.5 mg/dL (change, -19%) in the former group and increased from 38.4 to 44.5 mg/dL (change, 15%) in the latter group. In the apheresis group, the number of patients with hemodynamically significant stenoses in the aortotibial tract decreased from 9 to 7; in the simvastatin-only group, the number increased from 6 to 13 (P = 0.002). Mean intima-media thickness decreased by a mean +/- SD of 0.05 +/- 0.34 mm in the apheresis group and increased by 0.06 +/- 0.38 mm in the simvastatin-only group (P < 0.001). According to multiple regression analysis, changes in apolipoprotein B, total cholesterol, and lipoprotein(a) levels accounted for changes in the aortotibial tract (R2 = 0.36); changes in lipoprotein(a) and apolipoprotein A1 levels accounted for changes in the intima-media thickness of the carotid artery (R2 = 0.49). Aggressive lipid lowering with simvastatin and LDL apheresis decreased the intima-media thickness of the carotid artery and prevented an increase in the number of hemodynamically significant stenoses in the lower limbs. Therapy with simvastatin alone did not prevent progression of carotid or aortotibial vascular disease.",1996.0,0,0 2955,8967711,Dose-response characteristics of cholesterol-lowering drug therapies: implications for treatment.,G Schectman; J Hiatt,"To develop an optimal treatment strategy that reduces low-density lipoprotein (LDL) cholesterol levels and improves adherence to therapy by reviewing clinical trials that define the dose-response characteristics for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), bile acid sequestrants, and niacin. Data were obtained from a MEDLINE search of the English-language literature published from 1975 through November 1995 and from an extensive bibliography review. Controlled, clinical trials were reviewed if they evaluated 1) the effectiveness and toxicity of one LDL cholesterol-lowering agent (statins, bile acid sequestrants, or niacin, at two or more doses) or 2) monotherapy with two LDL cholesterol-lowering agents at defined doses used alone and in combination. Studies that had fewer than 10 patients in a treatment group or that selected patients on the basis of previous response to therapy were not included. Trials were reviewed for overall methodology, inclusion and exclusion criteria, sources of bias, and outcomes. Dose-response relations for bile acid sequestrants and statins are nonlinear, and most of their LDL cholesterol-lowering effects can be obtained with lower doses. The few dose-response studies of niacin that have been done suggest that most of niacin's high-density lipoprotein cholesterol-increasing effect can also be achieved with relatively low doses, but higher doses are needed to substantially reduce LDL cholesterol levels. If bile acid sequestrants or niacin are added to statin therapy, the effect of combined therapy on LDL cholesterol levels is additive. The nonlinear dose-response relation of statins, bile acid sequestrants, and niacin and their additive LDL cholesterol-lowering effect when used together suggest a strategy for treating hypercholesterolemia that may optimize effectiveness while minimizing adverse effects and cost.",1996.0,0,0 2956,8968448,Effects of fluvastatin on hyperlipidemia after renal transplantation: influence of steroid therapy.,J L Austen; F A Shifrin; M R Bartucci; T C Knauss; J A Schulak; D E Hricik,"To assess the efficacy and safety of fluvastatin in hypercholesterolemic, cyclosporine-treated, renal transplant recipients, and to determine whether concomitant steroid therapy in such patients alters the lipid-lowering effects of fluvastatin. An open-label, prospective, parallel study was performed in 20 cyclosporine-treated renal transplant recipients with hypercholesterolemia defined by a low-density lipoprotein (LDL) concentration greater than 160 mg/dL or a total cholesterol/high-density lipoprotein (HDL) concentration ratio greater than 5.0. Lipid profiles were measured before and 1 month after treatment with fluvastatin 20 mg/d. Lipid profiles in a group of patients receiving concomitant therapy with prednisone (n = 12) were compared with those of patients who had not received steroids for at least 6 months (n = 8). The Renal Transplant Clinic at University Hospitals of Cleveland. The main outcome measures were serum concentrations of total cholesterol, LDL, HDL, and triglycerides. Treatment failure was defined by LDL concentrations persistently above 160 mg/dL after 1 month of fluvastatin therapy. Safety was assessed clinically and by serial measurements of liver enzymes and creatine phosphokinase. LDL concentrations decreased significantly in both the steroid-treated and steroid-free groups after 1 month of fluvastatin therapy. There was no significant change in HDL concentrations or serum triglycerides in either group. Treatment failure was more common in patients receiving steroids (4/12 patients) than in steroid-free patients (1/8 patients). After 1 month of therapy, LDL cholesterol was significantly lower in the steroid-free group (126 +/- 18 mg/dL) than in the steroid-treated group (147 +/- 23 mg/dL) (p < 0.05). There was no clinical or laboratory evidence of myonecrosis in either group. Low dosages of fluvastatin appear to be safe in cyclosporine-treated renal transplant recipients. Steroid-free patients exhibit a response to fluvastatin that is qualitatively similar to that of steroid-treated patients, consisting of a significant decrease in LDL concentrations and no change in HDL or serum triglyceride concentrations.",1996.0,0,0 2957,8970428,Effect of simvastatin on ejection fraction in cardiac transplant recipients.,G H Jenkins; L A Grieve; M H Yacoub; D R Singer,"In a prospective observational study, we looked at the effects of simvastatin on cardiac function, lipids, and blood pressure after cardiac transplantation. Our study suggests that simvastatin treatment is associated with improved ejection fraction in cardiac transplant recipients independent of effects attributable to the lipid profile.",1996.0,0,0 2958,8970497,Recent trends in the consumption of lipid-lowering drugs in Finland.,J Martikainen; T Klaukka; A Reunanen; S Peura; H Wahlroos,"The consumption of lipid-lowering drugs in Finland and in other Nordic countries increased almost steadily in 1988-1993. The exceptions were the year 1992 in Finland and 1993 in Iceland, when consumption was lower than in the previous year. In both cases the temporary decline in consumption was associated with a reduction in reimbursement for the costs of lipid-lowering drugs. In 1993, the consumption level was 2.7 defined daily doses/1000 inhabitants/day in Finland and ranged from 2.3 to 4.0 in other Nordic countries. According to the Finnish nationwide prescription register, 0.5% of men and 0.6% of women purchased lipid-lowering drugs in the period from January to September, 1994. The rate of use was highest among people of middle age. In the early 1990s, statins took the lead in the consumption of lipid-lowering drugs, accounting for 70% of prescriptions in 1993; the percentages of fibrates, resins, and nicotinic acid derivatives declined in the same period. In 1994 the prevalence of familial hypercholesterolemia (FH) according to strictly predetermined criteria was 0.8 per 1000 among Finns, and the proportion of FH patients among all users of lipid-lowering drugs was 11%. The use of lipid-lowering drugs is not particularly high in Finland and seems to be reasonably targeted.",1996.0,0,0 2959,8970607,Evaluation of fluvastatin in the treatment of hypercholesterolemia in renal transplant recipients taking cyclosporine.,R Goldberg; D Roth,"Occlusive atherosclerosis is a major cause of morbidity and mortality in renal transplant recipients. Hyperlipidemia associated with the transplanted state may be at least partially responsible for this complication and is therefore an important target of therapy. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are powerful cholesterol-lowering drugs, but their broad use in transplant recipients has been hindered by concerns about interactions with cyclosporine. Cyclosporine interferes with the elimination of these agents, increasing their plasma and tissue levels and predisposing the patient to rhabdomyolysis. Fluvastatin, the first entirely synthetic HMG-CoA reductase inhibitor, possesses a distinct pharmacologic profile, including a shorter half-life and virtually no active circulating metabolites. Therefore, it may interact differently with cyclosporine. The pharmacokinetics and safety of fluvastatin, 20 mg/day, were evaluated in 20 hypercholesterolemic renal transplant recipients also receiving cyclosporine, usually in combination with azathioprine and methylprednisolone, during the 14-week study. Fluvastatin area under the curve, maximum plasma concentration, and time to maximum plasma concentration were minimally increased in these patients, unlike findings reported for lovastatin, pravastatin, and simvastatin. This suggests that metabolism of fluvastatin may be less affected by cyclosporine than that of other reductase inhibitors. Fluvastatin was well tolerated, with no evidence of myopathy, rhabdomyolysis, or ophthalmologic abnormalities. These findings and the significant reductions in total cholesterol and low-density lipoprotein cholesterol levels and the ratio of low-density to high-density lipoproteins achieved in these patients support the broader use of fluvastatin to treat hypercholesterolemia in renal transplant recipients.",1996.0,0,0 2960,8974212,Decision rules for predicting future lipid values in screening for a cholesterol reduction clinical trial.,L A Moyé; B R Davis; F Sacks; T Cole; L Brown; C M Hawkins,"Recent large clinical trials have required screened patients to have serial measurements of an entry criteria variable, eliminating patients form further consideration if the average value is not in the eligibility range specified by the trial protocol. The increasing costs of large clinical trials required that they be executed efficiently. One way to improve efficiency would be to reduce the number of required screening measurements for a patient likely to be ineligible. A procedure is proposed that predicts the value of an average based on n measurements serially obtained on a patient during the screening phase when only m < n measurements are available. The employment of this procedure in a large clinical trial that uses low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglycerides as entry criteria during the screening process is described. As a second example, this procedure is applied to population screening for lipid levels above a treatment threshold. The National Cholesterol Education Program recommends that the average of two LDL cholesterol measurements be used to determine whether LDL cholesterol is above 130 mg/dl, the threshold for treating patients with coronary heart disease. However, data from a sample of patients from a postinfarction population suggest that, if a single LDL cholesterol is above 146 mg/dl, the probability is greater than 95% that the average of the two LDL cholesterol measurements will be above 130 mg/dl.",1996.0,0,0 2961,8974213,"The Lipoprotein and Coronary Atherosclerosis Study (LCAS): design, methods, and baseline data of a trial of fluvastatin in patients without severe hypercholesterolemia.",M S West; J A Herd; C M Ballantyne; H J Pownall; S Simpson; L Gould; A M Gotto,"Few direct clinical data are available regarding whether cholesterol-lowering therapy should be extended to patients with coronary heart disease (CHD) and normal or only slightly elevated plasma cholesterol concentrations. The one published angiographic trial designed to examine this question found no benefit. Additional prospective data will be provided by the Lipoprotein and Coronary Atherosclerosis Study (LCAS), a randomized, double-blind, placebo-controlled trial of fluvastatin therapy (20 mg twice daily) monitored by both quantitative coronary angiography (QCA) and, in a subset of patients, positron-emission tomography (PET). Eligible subjects in LCAS were men and women 35-75 years of age with low-density lipoprotein (LDL) cholesterol of 115-190 mg/dL on stable dietary therapy and with angiographic evidence by caliper measurement of at least one coronary atherosclerotic lesion causing 30-75% diameter stenosis. Among the 429 patients randomized (mean age 58.8, 81% male), mean baseline LDL cholesterol was only 145.6 mg/dL. Any patient with mean prerandomization LDL cholesterol of 160 mg/dL or higher also received open-label adjunctive cholestyramine. The primary endpoint is within-patient per-lesion change in minimum lumen diameter (MLD) as measured by QCA at baseline and 2.5-year follow-up. All evaluable lesions had MLD at least 0.8mm less than the reference lumen diameter at either baseline or follow-up and MLD at least 25% of the reference lumen diameter at baseline. Data obtained on myocardial perfusion changes (99 patients underwent initial PET), special lipid particles, and coagulation factors may help define which patients with CHD and relatively low LDL cholesterol will benefit from lipid-lowering treatment.",2001.0,0,0 2962,8979121,"Effect of HMG-CoA reductase inhibitors on red blood cell membrane lipids and haemorheological parameters, in patients affected by familial hypercholesterolemia.",M Martinez; A Vaya; R Marti; L Gil; I Lluch; R Carmena; J Aznar,Eighteen patients with familial hypercholesterolemia treated with lovastatin (40 mg/day) for three months were studied to find out whether the drug induces modifications in the lipid composition of the erythrocyte membrane and whether these induce changes in the rheological behaviour of the red blood cell. Our results show that the changes observed in plasma lipids correlate with a significant decrease in the cholesterol/phospholipid ratio of the red blood cell membrane. These changes in the lipid composition of the cell are statistically related to a decrease in the erythrocyte aggregability and an improvement in blood filterability probably due to an increase in the red blood cell deformability.,1996.0,0,0 2963,8983865,Lipid-lowering for prevention of coronary heart disease: what policy now?,I Ul Haq; L E Ramsay; D M Pickin; W W Yeo; P R Jackson; J N Payne,"1. Recent outcome trials suggest that lipid-lowering with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors is justifiable on risk-benefit grounds in subjects with serum cholesterol > 5.5 mmol/l who have coronary heart disease, other forms of atherosclerotic vascular disease, or who are free of vascular disease but have a risk of major coronary events > or = 1.5% per year. Choice of an appropriate treatment policy will require (i) knowledge of the proportion of the population who will need treatment for secondary prevention, and (ii) targeting of treatment for primary prevention at a specified absolute risk of coronary heart disease events. Selection of an appropriate coronary heart disease risk for primary prevention requires consideration of the number needed to be treated to prevent one coronary heart disease event, the proportion of the population requiring treatment, the cost-effectiveness of treatment and the total cost of treatment. 2. In a random stratified sample of subjects aged 35-69 years from the Health Survey for England 1993 we first examined the prevalence of subjects with cardiovascular disease and serum cholesterol > 5.5 mmol/l who may be candidates for secondary prevention. In those free of cardiovascular disease we then examined the prevalence of subjects with serum cholesterol > 5.5 mmol/l who had three different levels of coronary heart disease risk: coronary heart disease event rates of 4.5% per year, 3.0% per year and 1.5% per year. These subjects may be candidates for primary prevention depending on the treatment policy selected. 3. For secondary prevention, 4.8% (95% confidence interval 4.3-5.3) of the U.K. population aged 35-69 years might be candidates for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor treatment, comprising 2.4% (2.0 to 2.7) with a history of myocardial infarction, 1.9% (1.6 to 2.2) with angina and 0.5% (0.3-0.7) with a history of stroke--all with total cholesterol > 5.5 mmol/l. The prevalence of these diagnoses with total cholesterol > 5.5 mmol/l increased with age, from 1.5% at age 35-39 years to 16.2% at age 65-69 years in men, and from 0.2% at age 35-39 years to 10.0% at age 65-69 years in women. Approximately 13 people would need treatment for 5 years to prevent one coronary event, at a cost of 36,000 pounds per event prevented. The number needing treatment for secondary prevention would increase substantially if treatment was extended to patients above 70 years of age or to those with serum cholesterol < or = 5.5 mmol/l. 4. Primary prevention aimed at a coronary event risk of 4.5% per year would lead to treatment of only 0.3% (0.2-0.4) of those aged 35-69 years, and those treated would be predominantly older men with additional risk factors for coronary heart disease. The number needed to be treated and cost per coronary event prevented would be similar to those for secondary prevention. 5. Primary prevention targeted at subjects with a coronary event rate of 3.0% per year would entail treating 3.4% (3.0-3.9) of all those aged 35-69 years. At this level of risk, 20 people would need treatment for 5 years to prevent one coronary event, at a cost of 55,000 pounds per event prevented. 6. Primary prevention aimed at a coronary event rate of 1.5% per year would entail treating 19.6% (18.7-20.6) of all subjects aged 35-69 years, and about 80% of men aged 60-69 years for primary or secondary prevention. At this level of risk, 40 people would need treatment for 5 years to prevent one event, at a cost of 111,000 pounds per event saved. 7. Guidelines for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor treatment should take into account the considerable workload and financial resources needed to implement secondary prevention of coronary heart disease, the accepted first priority. For primary prevention they need to consider the number needed to be treated to prevent one event, the number of subjects needing treatment, the cost-effectiveness of treatment and",1996.0,0,0 2964,8985259,Simultaneous determination of plasma mevalonate and 7alpha-hydroxy-4-cholesten-3-one levels in hyperlipoproteinemia: convenient indices for estimating hepatic defects of cholesterol and bile acid syntheses and biliary cholesterol supersaturation.,J Shoda; J Miyamoto; M Kano; T Ikegami; Y Matsuzaki; N Tanaka; T Osuga; H Miyazaki,"The high prevalence of cholesterol gallstone disease in hypertriglyceridemic patients may be associated with frequent metabolic defects in cholesterol and bile acid syntheses and in the concomitant formation of bile supersaturated with cholesterol. This study had the two aims: 1) to assess whether the defects as well as the degree of biliary cholesterol supersaturation in patients with hyperlipoproteinemia (HLP) can be estimated by the simultaneous determination of plasma mevalonate (MVL) and 7alpha-hydroxy-4-cholesten-3-one (C4); and 2) to assess the possible application of an estimated cholesterol saturation index ([CSI]E) as a means of evaluating the clinical effects of simvastatin on biliary lipid composition. Biliary cholesterol supersaturation was observed in patients with both IIa and IV HLP types. Consistent with the high activity and steady-state messenger RNA level of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, plasma MVL was significantly higher in 86 patients with HLP (38 type IIa, 44.1 +/- 2.4 nmol/L and 48 type IV, 56.7 +/- 2.3; P < .01) than in 41 normolipidemic subjects (34.2 +/- 1.5), closely correlating with the molar percentage of cholesterol in bile (r = .61, P = .0001; n = 86). On the other hand, consistent with the high activity and messenger RNA level of cholesterol 7alpha-hydroxylase, plasma C4 was significantly higher in patients with HLP (type IIa, 28.8 +/- 2.3 nmol/L and type IV, 38.3 +/- 2.7; P < .01) than in normolipidemic subjects (17.4 +/- 1.5). Plasma C4 was closely correlated with plasma MVL (r = .40, P = .0001; n = 86), but was inversely correlated with the molar percentage of bile acids in bile (r = .49, P = .0001; n = 86). Assuming that cholesterol supersaturation in patients with HLP may be governed by both an enhanced cholesterol secretion (closely reflected by plasma MVL) and a decreased secretion of bile acids (closely reflected by plasma C4), the multivariate linear regression-analyses revealed that an index defined as estimated CSI ([CSI]E) (%) in patients with HLP was given by the following equation using plasma MVL and C4 (nmol/L): [CSI]E = 1[MVL] + 0.7[C4] + 44.4. Biliary cholesterol supersaturation in patients treated with simvastatin improved in a manner parallel to the time course of decreases in plasma MVL and C4. The [CSI]E before and at the end of treatment were correlated with biliary CSI. These results indicate that defects of hepatic cholesterogenesis, and bile acid synthesis, and the degree of biliary cholesterol supersaturation in patients with HLP can be estimated exactly by the simultaneous determination of plasma MVL and C4; furthermore [CSI]E may be adopted for clinical use as a convenient index of biliary CSI.",1997.0,0,0 2965,8989104,Effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.,J T Willerson,,1996.0,0,0 2966,8990341,HIV-1 protease inhibitors. A review for clinicians.,S G Deeks; M Smith; M Holodniy; J O Kahn,"The clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of HIV-specific protease inhibitors (PIs). The 4 PIs available are saquinavir mesylate, ritonavir, indinavir sulfate, and nelfinavir mesylate. Comparison studies have not been reported; therefore, an assessment of the available data to aid clinicians and patients in choosing appropriate treatment will be presented. A systematic review of peer-reviewed publications, abstracts from national and international conferences, and product registration information through September 1996. Criteria used to select studies include their relevance to PIs, having been published in the English language, and pertinence for clinicians. Data quality and validity included the venue of the publication and relevance to clinical care. Oral adminstration of ritonavir, indinavir, or nelfinavir generates sustainable drug serum levels to effectively inhibit the protease enzyme; however, saquinavir may not generate sustained levels necessary to inhibit the protease enzyme. Patients treated with ritonavir, indinavir, or nelfinavir experience similar reductions in viral load and increases in CD4+ lymphocytes; smaller effects occur among those treated with saquinavir. Two randomized placebo-controlled studies conducted among patients with severe immune system suppression and substantial zidovudine treatment experience demonstrated reduced HIV disease progression and reduced mortality with PI treatment. Genotypic resistance to PIs occurs; the clinical relevance of resistance is unclear. The costs of these agents including required monitoring impose new and substantial costs. The PIs have emerged as critical drugs for people with HIV infection. Optimal use involves combination with reverse transcriptase inhibitors. Resistance develops to each agent, and cross-resistance is likely. These agents must be used at full doses with attention to ensuring patient compliance. The expense of these agents may be offset by forestalling disease progression and death and returning people to productive life. Selecting the initial PI must be individualized, and factors to consider include proven activity, possible toxicities, dosing regimens, drug interactions, and costs.",1997.0,0,0 2967,8992351,The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts.,Post Coronary Artery Bypass Graft Trial Investigators,"Obstructive changes often occur in aortocoronary saphenous-vein bypass grafts because of atherosclerosis and thrombosis. We studied whether aggressive lowering of low-density lipoprotein (LDL) cholesterol levels or low-dose anticoagulation would delay the progression of atherosclerosis in grafts. We studied 1351 patients who had undergone bypass surgery 1 to 11 years before base line and who had an LDL cholesterol level between 130 and 175 mg per deciliter and at least one patent vein graft as seen on angiography. We used a two-by-two factorial design to assign patients to aggressive or moderate treatment to lower LDL cholesterol levels (with lovastatin and, if needed, cholestyramine) and to treatment with warfarin or placebo. Angiography was repeated an average of 4.3 years after base line. The primary angiographic outcome was the mean percentage per patient of grafts with a decrease of 0.6 mm or more in lumen diameter. As measured annually during the study period, the mean LDL cholesterol level of patients aggressive treatment ranged from 93 to 97 mg per deciliter; with moderate treatment, the range was from 132 to 136 mg per deciliter (P<0.001). The mean international normalized ratio was 1.4 in the warfarin group and 1.1 in the placebo group (P<0.001). The mean percentage of grafts with progression of atherosclerosis was 27 percent for patients whose LDL cholesterol level was lowered with aggressive treatment, and 39 percent for those who received moderate treatment (P<0.001). There was no significant difference in angiographic outcome between the warfarin and placebo groups. The rate of revascularization over four years was 29 percent lower in the group whose LDL cholesterol level was lowered aggressively than in the group receiving moderate treatment (6.5 percent vs. 9.2 percent, P= 0.03). Aggressive lowering of LDL cholesterol levels to below 100 mg per deciliter reduced the progression of atherosclerosis in grafts. Low-dose warfarin did not reduce the progression of atherosclerosis.",1997.0,1,1 2968,8993943,"Effects of simvastatin and ciprofibrate alone and in combination on lipid profile, plasma fibrinogen and low density lipoprotein particle structure and distribution in patients with familial combined hyperlipidaemia and coronary artery disease.",A G Kontopoulos; V G Athyros; A A Papageorgiou; H A Hatzikonstandinou; M C Mayroudi; H Boudoulas,"Hypolipidaemic agents do not usually normalize all of the multiple lipoprotein abnormalities in patients with familial combined hyperlipidaemia (FCHL). The effect of the simvastatin-ciprofibrate combination in comparison with each drug alone on the lipoprotein abnormality patterns was studied in patients with FCHL and coronary artery disease (CAD). Sixty patients (53 men and seven women), mean age 52 years (range 36-60 years), were studied. After a 4-week placebo period, patients were randomly assigned to three groups. The first group (n = 20) received simvastatin (20 mg daily), the second group (n = 20) ciprofibrate (100 mg daily) and the third group (n = 20) the combination of both drugs for a 12-week period. Parameters measured were as follows: plasma fibrinogen, total cholesterol, triglycerides, low density lipoprotein (LDL), very low density lipoprotein, intermediate density lipoprotein, and high density lipoprotein cholesterol, as well as LDL subfraction distribution and structure by density gradient ultracentrifugation. Apoproteins (apo) B and AI were assessed by immunoturbidometry. At baseline, apoB, LDL cholesterol and triglycerides were increased, whereas LDL particles were small and dense. ApoB was significantly reduced by all three interventions. Drug combination and ciprofibrate significantly reduced plasma fibrinogen (-24 and -25%, respectively; P < 0.001) and triglycerides (-51 and -49%, respectively; P < 0.001). Drug combination and simvastatin significantly reduced LDL cholesterol (-25 and -22%, respectively; P < 0.001) compared with ciprofibrate (-10%; P < 0.01). Ciprofibrate and drug combination increased LDL particle size (parameter K -0.24 versus -0.61 and -0.30 versus -0.62, respectively; P < 0.001), whereas simvastatin had no significant effect on LDL particle size. The cholesterol content of LDL particles was reduced with ciprofibrate and the drug combination only in the dense LDL particles (LDL3-5) and increased in the light (LDL1-2) subfractions, whereas simvastatin reduced the cholesterol content of all LDL subfractions except LDL2. Ciprofibrate and drug combination reduced the triglyceride content of all LDL subfractions. Combined treatment with simvastatin and ciprofibrate effectively reduced plasma fibrinogen, triglycerides, total and LDL cholesterol and increased LDL particle size in patients with FCHL and CAD. These effects might induce a clinical benefit for these patients.",1996.0,0,0 2969,8994481,Effect of pharmacologic lipid lowering on health-related quality of life in older persons: results from the Cholesterol Reduction in Seniors Program (CRISP) Pilot Study.,N C Santanello; B L Barber; W B Applegate; J Elam; C Curtis; D B Hunninghake; D J Gordon,"To determine the effect of lovastatin therapy on health-related quality of life in older persons. A prospective, randomized, double blind clinical trial. Four university medical center research clinics. There were 431 men and women, primarily 65 years of age or older, with low density lipoprotein levels greater than 159 mg/dL and less than 221 mg/dL. Exclusion criteria included a Mini-Mental state score less than 24 or presence of recent cardiovascular events or other serious chronic disease likely to shorten survival. All participants were administered the National Cholesterol Education Program step one diet and were then randomized to placebo, 20 mg lovastatin, or 40 mg lovastatin. Areas of health-related quality of life assessed in the Cholesterol Reduction in Seniors Program (CRISP) included: (1) physical functioning, (2) sleep behavior, (3) social support, (4) depression, (5) cognitive function, and (6) health perception. Three global change questions asked the patients to judge change in general health since starting the study diet or the study medication and change in ability to function or care for self. Although some patients were followed for a total of 12 months, all participants were followed for 6 months, and 6-month data have been used for the primary analysis in this paper. Patients treated with 20 mg of lovastatin had a 17% and 24% reduction in total cholesterol and LDL-cholesterol, respectively. Patients treated with the 40-mg lovastatin dose achieved reductions of 20% for total cholesterol and 28% for LDL-cholesterol. Complaints of possible adverse events were remarkably similar in the two active treatment groups and the placebo group. At 6 months of follow-up there were no statistically significant differences found in mean change scores from baseline between treatment groups on the health-related quality of life measures (physical functioning, sleep, social support, depression, cognitive function scales, health perception) or global questions. This study demonstrates that lovastatin was extremely well tolerated in an older cohort, both with regard to symptoms and to health-related quality of life.",1997.0,0,0 2970,8997473,"""Isolated"" low high-density lipoprotein cholesterol.",V M Wilt; J G Gums,"To present information on the function, structure, and importance of high-density lipoprotein cholesterol (HDL-C) and to evaluate the current literature regarding the controversy of managing patients with an ""isolated"" low HDL-C concentration. A MEDLINE search was performed (1966-June 1996) to identify English-language clinical and review articles pertaining to HDL-C. Some articles were identified through the bibliography of selected articles. STUDY SECTION: All articles were considered for possible inclusion in the review. Pertinent information, as judged by the authors, was selected for discussion. Important historical lipid studies, recent review articles, and clinical trials involving therapy for HDL-C were evaluated. The structure, function, and measurement of HDL-C and the state of an isolated low HDL-C are discussed for background. Lifestyle modification measures to increase HDL-C, medications to avoid, estrogen replacement, and lipid-altering agents used to raise an isolated low HDL-C are presented. An isolated low HDL-C concentration poses a risk for coronary heart disease. The management of this state is controversial. The first step in management is in agreement with experts and includes lifestyle modification (e.g., weight reduction, diet, smoking cessation, aerobic exercise). Estrogen replacement therapy and discontinuance of drugs that secondarily lower HDL-C are additional treatment options. The use of lipid-altering agents has been used in some patients. Nicotinic acid appears to be an effective agent for an isolated low HDL-C. A large clinical trial evaluating the effect of treating an isolated low HDL-C for primary and secondary prevention of coronary events is needed.",1997.0,0,0 2971,8998104,Glucagon therapy in the treatment of symptomatic bradycardia.,J N Love; J M Howell,"Symptomatic bradycardia is commonly seen in the emergency department. Effective drug therapy for this clinical scenario is limited. Although glucagon has been used in no clinical trial in this setting, its cardiac activity may prove useful, particularly in the setting of beta-adrenergic blockade. We report a case series comprising three patients taking maintenance beta-blocker therapy who presented to the ED with symptomatic bradycardia and hypotension and in whom glucagon therapy obviated the need for further treatment. Further study is warranted to evaluate and define the role of glucagon in the treatment of symptomatic bradycardia.",1997.0,0,0 2972,8999328,More on pravastatin and coronary disease.,S M Grundy,,1996.0,0,0 2973,9003110,Pravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic mediterranean population: the Carotid Atherosclerosis Italian Ultrasound Study.,M Mercuri; M G Bond; C R Sirtori; F Veglia; G Crepaldi; F S Feruglio; G Descovich; G Ricci; P Rubba; M Mancini; G Gallus; G Bianchi; G D'Alò; A Ventura,"The Carotid Atherosclerosis Italian Ultrasound Study (CAIUS) was performed to test the effects of lipid lowering on the progression of carotid intima-media thickness (IMT) in 305 asymptomatic patients from a Mediterranean country. Eligibility included hypercholesterolemia (baseline means: low-density lipoprotein [LDL] = 4.68 mmol/L, high-density lipoprotein [HDL] = 1.37 mmol/L), and at least one 1.3 < IMT < 3.5 mm in the carotid arteries. Patients (mean age 55 years, 53% male) were assigned to pravastatin (40 mg/day, n = 151) or placebo (n not equal to 154). Ultrasound imaging was used to quantify IMT at baseline, and semiannually thereafter for up to 3 years. The mean of the 12 maximum IMTs (MMaxIMT), was calculated for each patient visit, and used to determine each patient's longitudinal progression slope. The intention-to-treat group difference in the MMaxIMT progression was chosen a priori as the primary end point. Five serious cardiovascular events (1 fatal myocardial infarction), and 7 drop-outs for cancer were registered. In the pravastatin group, LDL decreased -0.22 after 3 months versus -0.01 in the placebo group, and remained substantially unchanged afterward (-0.23 versus +0.01 at 36 months, respectively). Progression of the MMaxIMT was 0.009 +/- 0.0027 versus -0.0043 +/- 0.0028 mm/year (mean +/- SE, P < 0.0007) in the placebo and pravastatin groups, respectively. IMT progression slopes diverged after 6 months of treatment. Pravastatin stops the progression of carotid IMT in asymptomatic, moderately hypercholesterolemic men and women. This finding extends the beneficial effects of cholesterol lowering to the primary prevention of atherosclerosis in a population with relatively low cardiovascular event rates, and suggests that this benefit is mediated by specific morphological effects on early stages of plaque development.",1996.0,0,0 2974,9006803,Simvastatin increases plasma NO2- and NO3- levels in patients with hypercholesterolemia.,Y Nakashima; Y Toyokawa; S Tanaka; K Yamashita; A Yashiro; H Tasaki; A Kuroiwa,"In this study, plasma NO2- and NO3- (NOx-) levels were studied after lowering cholesterol with simvastatin in 26 outpatients with hypercholesterolemia (male, 9; female, 17; mean age, 59 +/- 12 years; cholesterol level > 220 mg/dl). Simvastatin (5 mg) was orally administered once daily, and blood samples were collected before, and after 4 and 12 weeks of treatment. Total, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) cholesterol were lowered (total, 254 +/- 44 mg/dl to 209 +/- 34 mg/dl; VLDL, 48 mg/dl [5-126 mg/dl] to 34 mg/dl [10-67 mg/dl]; LDL, 171 +/- 41 mg/dl to 133 +/- 37 mg/dl), but high-density lipoprotein (HDL) cholesterol was elevated (33 +/- 9.5 mg/dl to 39 +/- 11 mg/dl) at 12 weeks after starting simvastatin. Although the effects of simvastatin on the lipid levels nearly reached their maximum levels at 4 weeks, NOx- was elevated in a linear fashion with simvastatin (before; 8 +/- 17 mumol/l, at 12 weeks; 57 +/- 32 mumol/l). The % changes in the NOx- correlated directly with those in HDL-cholesterol at 12 weeks (P < 0.002) but not with other lipoprotein cholesterol fractions. These results suggest that simvastatin lowers cholesterol levels and elevates HDL while increasing the plasma NOx- levels.",1996.0,0,0 2975,9008444,Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease.,T C Andrews; K Raby; J Barry; C L Naimi; E Allred; P Ganz; A P Selwyn,"Cholesterol lowering is associated with a reduction in cardiovascular morbidity and mortality. This study sought to determine whether cholesterol lowering also results in a reduction of myocardial ischemia during daily life. We enrolled 40 patients with proven coronary artery disease, total serum cholesterol between 191 and 327 mg/dL, and at least one episode of ST-segment depression on ambulatory ECG monitoring. Twenty patients were randomized to an American Heart Association Step 1 diet plus placebo (placebo group) and 20 to the same diet plus lovastatin (treatment group). Serum cholesterol and LDL cholesterol levels and ambulatory monitoring were repeated after 4 to 6 months of therapy. The two groups were comparable with respect to baseline characteristics, number of episodes of ST-segment depression, and baseline serum cholesterol levels. The treatment group had lower mean total and LDL cholesterol levels at study end and experienced a significant reduction in the number of episodes of ST-segment depression compared with the placebo group. ST-segment depression was completely resolved in 13 of 20 patients (65%) in the treatment group versus 2 of 20 (10%) in the placebo group. The treatment group exhibited a highly significant reduction in ischemia (P < .001). By logistic regression, treatment with diet and lovastatin was an independent predictor of ischemia resolution. Cholesterol lowering with lovastatin appears to be effective in eliminating myocardial ischemia during daily life in a significant proportion of patients.",1997.0,0,1 2976,9009414,The conservative treatment of xanthoma of the Achilles tendon in patients affected with type IIA hypercholesterolemia.,M Valeo; P Dalla Vedova; L Di Giorgio; A G Scarno; A Giuliante,Treatment of xanthoma of the Achilles tendon has up until the present been based on partial or total surgical resection of the affected tendon. Because of the different results of surgical treatment our study was aimed at using clinical and ultrasound data to reveal the effectiveness of hypocholesteremic medical therapy in 39 cases of tendinous xanthoma.,1996.0,0,0 2977,9010366,Lipid lowering in post-MI patients with normal cholesterol.,C Lawless; R Force,,1997.0,0,0 2978,9011785,Cost effectiveness of simvastatin treatment to lower cholesterol levels in patients with coronary heart disease. Scandinavian Simvastatin Survival Study Group.,M Johannesson; B Jönsson; J Kjekshus; A G Olsson; T R Pedersen; H Wedel,"The Scandinavian Simvastatin Survival Study (4S) showed that lowering cholesterol levels with simvastatin reduces mortality and morbidity in patients with angina pectoris or previous acute myocardial infarction. Before the widespread use of cholesterol-lowering drugs in such patients is recommended, its cost effectiveness should be demonstrated. We estimated the cost effectiveness of simvastatin treatment to lower cholesterol levels in relation to the age, sex, and cholesterol level before treatment of patients with coronary heart disease. We estimated the cost per year of life gained with simvastatin therapy. To model the increased life expectancy, hazard functions from 4S were used. The costs studied included those of the intervention and the direct and indirect costs associated with morbidity from coronary causes. We prepared separate estimates for men and women at various ages (from 35 to 70 years) and total cholesterol levels before treatment (213 to 309 mg per deciliter). In the analysis limited to direct costs, the cost of each year of life gained ranged from $3,800 for 70-year-old men with 309 mg of cholesterol per deciliter to $27,400 for 35-year-old women with 213 mg of cholesterol per deciliter. When we included indirect costs, the results ranged from a savings in the youngest patients to a cost of $13,300 per year of life gained in 70-year-old women with 213 mg of cholesterol per deciliter. In patients with coronary heart disease, simvastatin therapy is cost effective among both men and women at the ages and cholesterol levels studied.",1997.0,0,0 2979,9013093,Changes in biliary lipid output after interruption of pravastatin treatment in humans.,C G Hillebrant; M Eriksson; B Nyberg; K Einarsson,"The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (e.g. pravastatin) has gradually increased in the treatment of hypercholesterolaemia. By inhibiting HMG-CoA reductase (the rate-limiting enzyme in cholesterol synthesis) activity, cholesterol synthesis in the liver is reduced and the plasma level of cholesterol, especially low-density lipoprotein (LDL)-cholesterol, is substantially lowered. Simultaneously, inhibition of HMG CoA reductase activity is associated with increased synthesis and accumulation of larger amounts of HMG CoA reductase enzyme protein. The main purpose of this study was to determine if the cessation of pravastatin treatment causes a rapid increase in the synthesis and biliary secretion of cholesterol, a condition which might lead to a temporarily increased cholesterol saturation of bile. Nine patients undergoing surgery for stones in the common bile duct were fitted with T-tubes in the common bile duct peroperatively; the side arm of the T-tube was left open postoperatively, creating a biliary fistula. All patients were given 6 days' treatment with pravastatin (20 mg b.i.d.) following the operation. Bile was collected from the T-tube, in 12-h fractions during this period and for another 3 days after termination of the treatment. Plasma levels of lipoproteins and lathosterol--reflecting cholesterol synthesis--were determined on several occasions. After cessation of pravastatin treatment, the plasma levels of total cholesterol and LDL-cholesterol increased by 21% and 33% respectively. High-density lipoprotein (HDL)-cholesterol did not change. The plasma level of lathosterol was increased two- to fourfold. Outputs of bile acids and phospholipids were significantly increased (23% and 10% respectively) after termination of treatment, whereas the output of cholesterol was not significantly changed. Cholesterol saturation was reduced by 20%, from 175 +/- 37% to 140 +/- 19%, but this change was not significant. The results indicate that, with the present experimental model (biliary diversion), the synthesis and biliary secretion of bile acids seem to be largely dependent on the de novo synthesis of cholesterol in the liver, whereas the biliary output of cholesterol is not.",1996.0,0,0 2980,9024745,Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease.,M Bevilacqua; P Bettica; M Milani; T Vago; A Rogolino; V Righini; E Santoli; G Norbiato,"This randomized, double-blind, placebo-controlled study shows that 20-week fluvastatin treatment induces beneficial changes in the lipid panel and a shift in the fibrinolytic pathway toward activation through a decrease in tissue plasminogen activator antigen. Fluvastatin treatment causes no variation in lipoprotein(a) circulating levels.",1997.0,0,0 2981,9026840,[A comparison of bezafibrate and lovastatin treatment at the usual doses in post-heart transplant hyperlipemia].,J L Zambrana García; J López Miranda; M Anguita Sánchez; J Blanco Cerrada; F Vallés Belsúe; J Casares Mediavilla; I Muñoz Carvajal; J A Jiménez Perepérez; F Pérez Jiménez,"Coronary artery disease is a major limiting factor for long-term survival after heart transplantation. Hyperlipidemia is a probable risk factor for coronary artery disease in this kind of patient. Bezafibrate and lovastatin have proved to be effective in lowering total and low density lipoprotein cholesterol. The present study tested the safety and efficacy of both drugs on lipid levels in 21 patients with post-heart transplantation hyperlipidemia. Patients maintained the same diet for three months. Then, they were randomized to lovastatin (20 mg/day) or bezafibrate (400 mg/day) for 8 weeks, and then, crossovered to an additional 8 weeks of bezafibrate or lovastatin. Both drugs were effective in lowering total and low density lipoprotein cholesterol and apoprotein B concentrations, but the effect of lovastatin was significantly greater. Only bezafibrate produced a significant reduction in total triglycerides and a significant rise in high density lipoprotein cholesterol and apoprotein AI. The total cholesterol/high density lipoprotein cholesterol and low density lipoprotein cholesterol/high density lipoprotein cholesterol ratios were decreased under both treatments. Both drugs, bezafibrate and lovastatin appear to be safe, effective and well-tolerated therapies for hyperlipidemia in cardiac transplant recipients.",1996.0,0,0 2982,9028747,Pravastatin. A reappraisal of its pharmacological properties and clinical effectiveness in the management of coronary heart disease.,M Haria; D McTavish,"Pravastatin is an HMG-CoA reductase inhibitor which lowers plasma cholesterol levels by inhibiting de novo cholesterol synthesis. Pravastatin produces consistent dose-dependent reductions in both total and low density lipoprotein (LDL)-cholesterol levels in patients with primary hypercholesterolaemia. Favourable changes in other parameters such as total triglyceride and high density lipoprotein (HDL)-cholesterol levels are generally modest. Combination therapy with other antihyperlipidaemic agents such as cholestyramine further enhances the efficacy of pravastatin in patients with severe dyslipidaemias. Available data suggest that pravastatin is effective in elderly patients and in patients with hypercholesterolaemia secondary to diabetes mellitus or renal disease. The benefit of cholesterol-lowering in terms of patient outcomes is currently an area of considerable interest. Recently completed regression studies (PLAC I, PLAC II, KAPS and REGRESS) show that pravastatin slows progression of atherosclerosis and lowers the incidence of coronary events in patients with mild to moderately severe hypercholesterolaemia and known coronary heart disease. Large scale primary (WOSCOPS) and secondary (CARE) prevention studies, moreover, demonstrate that pravastatin has beneficial effects on coronary morbidity and mortality. In WOSCOPS, all-cause mortality was reduced by 22%. Pravastatin is generally well tolerated by most patients (including the elderly), as evidenced by data from studies of up to 5 years in duration. As with other HMG-CoA reductase inhibitors, myopathy occurs rarely (< 0.1% of patients treated with pravastatin): approximately 1 to 2% of patients may present with raised serum levels of hepatic transaminases. Thus, with its favourable effects on cardiovascular morbidity/mortality and total mortality, pravastatin should be considered a first-line agent in patients with elevated cholesterol levels, multiple risk factors or coronary heart disease who are at high risk of cardiovascular morbidity.",1997.0,0,0 2983,9034751,Endothelial function and the kidney. An emerging target for cardiovascular therapy.,T J Rabelink; H A Koomans,"Endothelial dysfunction is emerging as an important factor in the early development of acute and chronic renal disease. Drugs aimed specifically at rectifying this aberration are being developed, although other established agents such as calcium antagonists, angiotensin converting enzyme (ACE) inhibitors and HMG CoA reductase inhibitors also have beneficial effects in this setting. Calcium antagonists are particularly effective at ameliorating acute renal ischaemia associated with endothelial dysfunction. Combination therapy with a calcium antagonist and an ACE inhibitor might optimise the beneficial effects of calcium channel blockade on the sequelae of endothelial dysfunction in chronic renal failure.",1997.0,0,0 2984,9036802,Mechanisms determining course and outcome of diabetic patients who have had acute myocardial infarction.,D Aronson; E J Rayfield; J H Chesebro,"To review the pathogenic mechanism that lead to the poor prognosis of diabetic patients after myocardial infarction and to determine the efficacy of current interventions for myocardial infarction in these patients. Search of the MEDLINE database from 1985 to 1995, using the keywords diabetes, myocardial infarction, and cardiomyopathy, and a search of the reference citations of relevant articles. Experimental and clinical studies on myocardial infarction in diabetic patients and basic research studies relevant to this topic. The excess in-hospital mortality of diabetic patients results primarily from an increased incidence of congestive heart failure. Several combined mechanisms reduce the compensatory ability of the noninfarcted myocardium; such mechanisms include preexisting congestive heart failure caused by diabetic cardiomyopathy, severe coronary artery disease, decreased vasodilatory reserve of epicardial and resistance arteries, and possibly abnormal metabolism of myocardial substrate. Late mortality results from increased reinfarction rates caused by the diffuse nature of the atherosclerotic disease and hypercoagulable state. Platelet hyperactivity, reduced fibrinolytic capacity, increased concentrations of hemostatic proteins, and endothelial dysfunction promote thrombosis at the site of plaque rupture. Autonomic neuropathy predisposes patients to ventricular arrhythmias. Thrombolytic agents, aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors are effective in patients with diabetes. In the thrombolytic era, mortality rates of diabetic patients who have had acute myocardial infarction remain 1.5 to 2 times higher than those in nondiabetic patients. This increased mortality rate is caused by diverse mechanisms that affect myocardial function and blood supply and by the tendency toward thrombosis in diabetic patients. Current therapies for myocardial infarction are effective in these patients. Improved metabolic control may also decrease mortality rates.",1997.0,0,0 2985,9039919,Hyperlipidemia in solid organ transplantation.,J A Kobashigawa; B L Kasiske,,1997.0,0,0 2986,9039920,Treatment of hyperlipidemia in renal transplant recipients.,M Arnadottir; A L Berg,,1997.0,0,1 2987,9043838,The effect of simvastatin on progression of coronary artery disease. The Multicenter coronary Intervention Study (CIS).,H P Bestehorn; U F Rensing; H Roskamm; P Betz; L Benesch; K Schemeitat; G Blümchen; J Claus; P Mathes; L Kappenberger; H Wieland; A Neiss,"In several angiographic trials, HMG-CoA reductase inhibitors have shown a beneficial effect on the progression of coronary artery disease. Using 20 mg simvastatin, day-1, a treatment period of up to 4 years was necessary to show a significant reduction in coronary artery disease progression. The question remains however whether higher dosages of simvastatin would be more advantageous in respect to the magnitude of the effect and the required time interval to demonstrate treatment efficacy. In the Coronary Intervention Study (CIS), a multicentre randomized double-blind placebo-controlled study, the effects of lipid-lowering therapy with simvastatin on progression of coronary artery disease in 254 men with documented coronary artery disease and hypercholesterolaemia were investigated. Following a period of lipid-lowering diet, treatment with 40 mg simvastatin or placebo was maintained for an average of 2.3 years. Two primary angiographic endpoints were chosen: the global change score (visual evaluation according to the method of Blankenhorn) and the per patient mean change of minimum lumen diameter (evaluated by the CAAS I system). The mean simvastatin dose was 34.5 mg day-1. In the placebo group, the serum lipids remained unchanged; in comparison to the placebo group the simvastatin group showed a 35% LDL-cholesterol decrease. Coronary angiography was repeated in 205 patients (81%) and 203 film pairs (80%,) were evaluable by quantitative coronary angiography. In the simvastatin and placebo groups, the mean global change scores were +0.20 and +0.58 respectively, demonstrating a significantly slower progression of coronary artery disease in the treatment group (P = 0.02). The change in minimum lumen diameter assessed by computer-assisted quantitative evaluation with the CAAS I system was -0.02 mm in the simvastatin group and -0.10 mm in the placebo group (P = 0.002). In the simvastatin group, there was a significant correlation between the LDL cholesterol levels achieved therapeutically and the per patient mean loss of minimum lumen diameter (r = 0.29; P = 0.003). During the study period, there was no significant difference in the incidence of serious cardiac events (15 of 129 patients in the simvastatin group and 19 of 125 patients in the placebo group, ns). Treatment with 40 mg simvastatin day-1 reduces serum cholesterol and slows the progression of coronary artery disease significantly within a short period of treatment time. In the treatment group, retardation of progression is inversely correlated to the LDL-cholesterol levels achieved.",1997.0,1,1 2988,9043839,"Randomized placebo-controlled study of the effects of simvastatin on haemostatic variables, lipoproteins and free fatty acids. The Oxford Cholesterol Study Group.",K A Mitropoulos; J M Armitage; R Collins; T W Meade; B E Reeves; K R Wallendszus; S S Wilson; A Lawson; R Peto,"The Oxford Cholesterol Study is a randomized placebo-controlled trial designed primarily to assess the effects of simvastatin on blood cholesterol levels and side-effects in preparation for a large, long-term trial of the effects of cholesterol-lowering drug therapy on mortality. At present there is only limited evidence from randomized comparisons of the effects of HMG-CoA reductase inhibitors, such as simvastatin, on thrombogenic, as distinct from atherogenic, pathways in coronary heart disease. The present sub-study was carried out to assess the effects of simvastatin on a range of haemostatic variables, as well as on free fatty acids and on lipoprotein fractions not studied in detail previously. At an average of about 2 years after starting study treatment, non-fasting blood samples were obtained from a sequential sample of 162 participants who had been randomly allocated to receive 40 mg (54 patients) or 20 mg (57 patients) daily simvastatin or matching placebo treatment (51 patients). Only patients who reported taking their study treatment and who were not known to be diabetic or to be taking some other lipid lowering treatment were to be included. The principal comparisons were to be of those allocated simvastatin (i.e. 20 and 40 mg doses combined) vs those allocated placebo. Among patients allocated simvastatin, marginally significant lower factor VII antigen levels (12.10% +/- 6.08 of standard; 2P < 0.05) and non-significantly lower factor VII coagulant activity (8.24% +/- 4.99 of standard) and fibrinogen concentrations (0.10 +/- 0.08 g. l-1) were observed. In contrast, plasminogen activator inhibitor activity was significantly higher (2.62 +/- 1.03 IU; 2P < 0.01) among patients allocated simvastatin. No significant differences were seen in the other haemostatic factors studied (e.g. prothrombin fragment 1.2, factor XII and C1 inhibitor). Total free fatty acid concentration was marginally significantly reduced (2P = 0.02) with simvastatin, but none of the reductions in individual free fatty acids was significant. Lipoprotein fractions were only measured among patients allocated 40 mg daily simvastatin or placebo. Compared with placebo, simvastatin produced significant decreases not only in LDL cholesterol (1.74 +/- 0.15 mmol.1(-1): 2P < 0.0001) but also in VLDL cholesterol (0.28 +/- 0.08 mmol.1(-1); 2P < 0.001) and IDL cholesterol (0.17 +/- 0.03 mmol.1(-1); 2P < 0.0001). There were also lower triglyceride levels associated with LDL (0.07 +/- 0.01 mmol.1(-1); 2P < 0.0001), IDL (0.03 +/- 0.01 mmol.1(-1); 2P < 0.01) and VLDL (0.27 +/- 0.14; 2P = 0.05). The effects of simvastatin on haemostatic variables appear to be far less marked than its lipid effects. Given the associations of haemostatic factors with coronary heart disease incidence, larger randomized comparisons of the HMG-CoA reductase inhibitors (and of the newer fibrates which may produce greater effects) are needed to provide more reliable estimates of the extent to which they influence these variables.",1997.0,0,0 2989,9046759,Vascular health: the emerging appreciation of the endothelium.,J D Talley,,1997.0,0,0 2990,9049510,The low fat/low cholesterol diet is ineffective.,L A Corr; M F Oliver,,1997.0,0,0 2991,9050817,Endothelial dysfunction: clinical implications.,H Drexler,"The endothelium is involved in the control of vascular tone and homeostasis. Risk factors for arteriosclerosis, as well as other conditions have been shown to be associated with a dysfunctional endothelium. Clinically, endothelial function and dysfunction have been mostly evaluated by the assessment of endothelial dependent relaxation, for example in response to acetylcholine or increase inflow. The functional implications of endothelial dysfunction in cardiovascular disease are not well defined, but recent clinical trials have suggested that endothelial dysfunction may affect vascular tone and organ perfusion particularly during stress situations such as exercise. Moreover, endothelial dysfunction may represent an early event in the development of arteriosclerosis. Therefore, recent clinical studies have been performed to restore normal endothelial function in patients, using interventions such as L-arginine, lipid lowering drugs, vitamin C, other antioxidants, or exercise.",1997.0,0,0 2992,9051704,Cholesterol synthesis inhibitors do not reduce Lp(a) levels in normocholesterolemic patients.,F Pazzucconi; G Franceschini; G Gianfranceschi; G Campagnoli; C R Sirtori,"Experimental and clinical data suggest that activation of the LDL receptors by the use of HMG CoA reductase inhibitors, in the presence of normal plasma cholesterol levels, may result in a reduction of Lp(a) concentrations. This hypothesis has been tested in an open study on seven subjects with normal cholesterolemia but marked elevations of Lp(a) levels, three of whom received pravastatin and four simvastatin at standard therapeutic doses. While the two drugs caused the expected reduction of plasma total and LDL cholesterol levels, no significant changes in Lp(a) were noted. This study contradicts a prior clinical finding and suggests that HMG CoA reductase inhibitors are unlikely to reduce plasma Lp(a) levels even in the absence of hypercholesterolemia.",1996.0,0,0 2993,9054772,Perspectives on large-scale cardiovascular clinical trials for the new millennium. The Virtual Coordinating Center for Global Collaborative Cardiovascular Research (VIGOUR) Group.,E J Topol; R M Califf; F Van de Werf; M Simoons; J Hampton; K L Lee; H White; J Simes; P W Armstrong,,1997.0,0,0 2994,9054840,"Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month.",G O'Driscoll; D Green; R R Taylor,"Cholesterol-lowering therapy can improve cardiovascular morbidity and mortality in patients with atherosclerosis. Although the mechanisms responsible are unclear, these benefits precede macroscopic changes in the vasculature. Emerging evidence that improvement in endothelial function may occur requires substantiation; in particular, it is unclear how early any such improvement would be detectable after initiation of therapy. This randomized, double-blind, placebo-controlled crossover study evaluated the effect of simvastatin (20 mg daily for 4 weeks) on endothelium-dependent and endothelium-independent vasodilation and on the response to the inhibitor of nitric oxide synthesis, NG-monomethyl-L-arginine (L-NMMA), in the forearm vasculature of subjects with moderate elevation of total serum cholesterol (6.0 to 10.0 mmol/L) by use of strain-gauge plethysmography. Studies were repeated after 3 more months of open therapy. When the results are expressed as percentage changes in flow in the infused arm relative to the noninfused arm, the vasodilator response to acetylcholine was significantly increased after 4 weeks of treatment with simvastatin (P < .0005), and this improvement was further enhanced after 3 months (P < .005). Concurrently, simvastatin augmented the vasoconstrictor response to L-NMMA, an effect that was maintained at 3 months (P < .0005). The response to the endothelium-independent vasodilator sodium nitroprusside was unaltered. These observations indicate that within 1 month of treatment with simvastatin, both the stimulated and basal nitric oxide dilator functions of the endothelium are augmented, and the benefits of this HMG-coenzyme A reductase inhibitor persist with continued therapy.",1997.0,0,0 2995,9062827,Lipid-lowering effects of fluvastatin in renal transplant patients. A clinical observation.,S M Lal; N Gupta; O Georgiev; G Ross,"A Atherosclerosis-related cardiovascular disease remains an important cause of morbidity and mortality in renal transplant patients. We assessed the efficacy and safety of the newer synthetic HMG-CoA reductase inhibitor, fluvastatin, in 12 renal transplant patients who remained hypercholesterolemic, despite having been on the American Heart Association (AHA) Step I diet for 6 weeks. At 8 weeks, compared to the control phase, fluvastatin therapy, 20 mg/day, reduced the total cholesterol (TC) from 321 +/- 57 [+/-SD] to 301 +/- 123 mg/dl (p = 0.3); low-density lipoprotein cholesterol (LDL-C), from 209 +/- 56 to 176 +/- 81 mg/dl (p = 0.2); and the triglyceride (TG) levels from 343 +/- 119 to 277 +/- 117 mg/dl (p = 0.06); all these changes were statistically insignificant. However, the therapy significantly increased the high-density lipoprotein cholesterol (HDL-C) from 37 +/- 11 to 46 +/- 13 mg/dl (p = 0.006). During this short-term treatment period no adverse biochemical effects were noted with the therapy.",2001.0,0,0 2996,9068221,Lipid-lowering therapy for average lipid levels: the CARE trial.,D L Sprecher,,1997.0,0,0 2997,9069523,Statin therapy in a kindred with both apolipoprotein B and low density lipoprotein receptor gene defects.,F J Raal; G Pilcher; D C Rubinsztein; A Lingenhel; G Utermann,"We studied an extended family of similar genetic and environmental background to determine whether there is a difference in response to statin therapy in those subjects with heterozygous familial hypercholesterolaemia (FH Afrikaner-1 (FH1) or FH Afrikaner-2 (FH2)) compared to those with familial defective apo B-100 (FDB), or both FH plus FDB. Fasting lipid profiles and Lp(a) levels were done on 18 members of the family and then repeated following 6 weeks of therapy with simvastatin 20 mg daily. Statin therapy reduced LDL-cholesterol (LDL-C) by 31% in those with FH (n = 7); 29.8% in FDB (n = 5) and 25.4% in those with both FDB and FH (n = 5). There was no response to statin therapy in the single subject with both FH1, FH2, as well as FDB. Lp(a) levels did not change significantly either within or between any of the groups following statin therapy (FH from 6.5 (1.2-72.3) to 5.3 (1.2-52.3), FDB from 6.1 (4.70-71) to 8.2 (5.7 79) and FDB plus FH from 4.5 (2.6-17.4) to 3.1 (1.9-24) mg/dl). Statins are equally effective in lowering LDL-C in related subjects with heterozygous FH, FDB or both FDB plus FH. The ability of statins to lower LDL-C in FDB is probably due to increased hepatic uptake of lipoprotein precursors of LDL that can bind via apo E receptors. Lp(a) concentration is not reduced by drugs that stimulate LDL receptor activity implying that LDL receptors do not contribute greatly to normal clearance of Lp(a) in hypercholesterolaemic subjects with defects in receptor-mediated endocytosis of LDL.",1997.0,0,0 2998,9070199,Lipids and lipoproteins in women.,T O'Brien; T T Nguyen,"Coronary artery disease (CAD) is the most common cause of death in women in the United States. Dyslipidemia is a risk factor for CAD in both men and women. Low levels of high-density lipoprotein (HDL) cholesterol and hypertriglyceridemia, especially in association with a dense low-density lipoprotein (LDL) phenotype, may be of greater importance in women than in men. The relationship between CAD and dyslipidemia and the therapeutic approach to disorders of lipid metabolism in women have unique features because of the effects of exogenous and endogenous hormones on lipid pathways. Estrogen decreases LDL cholesterol and Lp(a) lipoprotein and increases triglyceride and HDL cholesterol levels. Progestogens decrease triglycerides, HDL cholesterol, and Lp(a), and they increase LDL cholesterol. Thus, oral contraceptives increase plasma triglycerides, whereas the effect of these agents on LDL cholesterol and HDL cholesterol levels is related to the androgenicity and dose of progestogen. Postmenopausal hormone replacement therapy increases triglycerides and decreases LDL cholesterol. The effect of hormone replacement therapy on HDL cholesterol is influenced by the addition of progestogen. Although no primary prevention studies have analyzed lipid lowering and CAD in women, secondary prevention studies have suggested that the response to drug treatment and the benefit of lipid lowering are similar in women and in men. Hormone replacement therapy should be considered in the treatment of hypercholesterolemia in postmenopausal women; however, individualization of treatment is important to avoid adverse effects.",1997.0,0,0 2999,9070554,Baseline risk factors and their association with outcome in the West of Scotland Coronary Prevention Study. The West of Scotland Coronary Prevention Study Group.,,"The West of Scotland Coronary Prevention Study recently demonstrated the benefits of pravastatin therapy in the prevention of coronary heart disease events in middle-aged hypercholesterolemic men without prior myocardial infarction. We present an analysis of the influence of baseline risk factors on coronary events and total mortality in the trial, and their interaction with therapy, using the Cox proportional hazards model. The multivariate predictors of fatal or nonfatal coronary events were treatment allocation (pravastatin or placebo), current smoking, diabetes mellitus, nitrate consumption, minor electrocardiographic abnormalities, angina pectoris, family history of premature coronary death, widowhood, blood pressure, and total cholesterol/high density lipoprotein cholesterol ratio. Independent of other risk factors, pravastatin reduced the risk of definite coronary heart disease death or nonfatal myocardial infarction by 32% (95% confidence interval 17 to 44, p = 0.0001), definite or suspected coronary heart disease death by 35% (3 to 56, p = 0.035), cardiovascular death by 33% (4 to 53, p = 0.027), coronary revascularization procedures by 38% (11 to 56, p = 0.009), and all-cause mortality by 24% (2 to 41, p = 0.037). The 5-year risk of fatal or nonfatal myocardial infarction, calculated using the predictors identified in the Cox analysis, ranged from <4.4% in the lowest quartile of risk to >9.6% in the highest quartile. The proportional benefit achieved by pravastatin was independent of other risk factors; hence, the absolute benefit of therapy was greatest in subjects with the highest baseline risk. Such subjects can be identified easily in the population and deserve high priority for treatment.",1997.0,0,0 3000,9072285,Lipid lowering: the case for identifying and treating the high-risk patient.,T A Pearson; H J Swan,"The rationale for the identification and aggressive treatment of lipid disorders in the patient with established vascular disease is thoroughly convincing. Elevated LDL cholesterol level is one of the few risk factors for which there is evidence of involvement in endothelial dysfunction, smooth-muscle proliferation, plaque destabilization, and thrombosis. Longitudinal studies have identified the role of elevated LDL cholesterol and low HDL cholesterol levels in the natural history of coronary artery disease. Clinical trials have successfully tested the feasibility of preventing coronary events using diet therapy or cholesterol-lowering drugs. These experiments have used a variety of end points, including myocardial infarction, cardiac death, total mortality rate, progression and regression of coronary artery stenoses, and progression of extracardiac atherosclerotic disease. The results are strikingly consistent. Economic analyses of the cost-benefit ratios also support these interventions in high-risk patients. These analyses also suggest that patients at high risk for coronary disease prior to its symptomatic presentation may be identified and treated to provide additional avenues for cost-effective primary prevention of this disease. The cardiologic community cannot ignore these results while embracing interventions such as angioplasty, coronary artery disease, antiarrhythmic therapy, and so forth. The scientific basis of cardiology demands the integration of techniques to control the atherosclerotic disease process itself, rather than merely the symptoms that it produces. Cardiology practices must reorganize to allow these proven interventions to become an integral part of comprehensive cardiologic care.",1996.0,0,0 3001,9072290,"Lessons from coronary atherosclerosis ""regression"" trials.",D Waters,"This article describes the background and methodology of the published studies assessing the effects of cholesterol-lowering therapy and of treatment of multiple risk factors on the progression of coronary atherosclerosis. The results are then presented, followed by a discussion of the lessons that can be learned from this large series of similar trials.",1996.0,0,0 3002,9076662,Simvastatin impairs mitogen-induced proliferation of malignant B-lymphocytes from humans--in vitro and in vivo studies.,S Vitols; B Angelin; G Juliusson,"Chronic lymphocytic leukemia (CLL) cells express lower low density lipoprotein (LDL) receptor activity and higher 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity than normal mononuclear blood cells indicating that CLL cells may depend on cholesterol synthesis for their proliferation. We studied the effects of competitive inhibitors of HMG-CoA reductase on malignant lymphocyte proliferation in vitro and in vivo. Tumor B-cells from 13 patients with CLL, hairy cell leukemia, or immunoblastic B-cell lymphoma were cultured for 4 d in the presence of B-cell mitogens and cholesterol synthesis inhibitors. Simvastatin and lovastatin suppressed, in a concentration-dependent manner, the mitogen-induced cellular thymidin uptake in medium with 10% human AB-serum or lipoprotein-deficient serum. Pravastatin was active only in medium with lipoprotein-deficient serum. Ten previously untreated patients with CLL received simvastatin orally, 40 mg daily for 12 wk. Mean reductions in total plasma and LDL cholesterol were 30% (range 9-46%) and 37% (range 16-63%), respectively. Cells from four patients showed moderate to minor increases in the degradation rate of 1251-LDL suggesting that the need for exogenous cholesterol had increased, three patients showed an increase in HMG-CoA reductase activity, and the cells from one patient showed both. There was no significant change in the clinical disease status during medication. However, four of the ten patients developed a therapy-demanding progressive disease during the subsequent year. Further clinical studies with cholesterol synthesis inhibitors in leukemia are warranted.",1997.0,0,0 3003,9077372,The additional effects of acipimox to simvastatin in the treatment of combined hyperlipidaemia.,N Hoogerbrugge; H Jansen; L De Heide; M C Zillikens; J W Deckers; J C Birkenhäger,"Nicotinic acid, an effective drug for treatment of combined hyperlipidaemia, is often not tolerated because of side-effects. Acipimox is a nicotinic acid like lipid lowering drug with less side-effects. We studied whether the addition of acipimox to simvastatin improves the lipid profile in patients with a combined hyperlipidaemia. Randomized double-blind placebo controlled crossover trial. Outpatient lipid clinic of a tertiary referral centre. Eighteen patients with combined hyperlipidaemia treated with diet and 20-40 mg simvastatin for at least 3 months. Acipimox in a daily dose of 3 x 250 mg for 12 weeks. Effects on the concentration of LDLc, TG, HDLc, Lp(a) and Apolipoprotein B, as well as on LDL-size and LDL-resistance to oxidative modification. Acipimox reduced Lp(a) levels by 8% (P < 0.05). A substantial but not statistically significant change in TG (-32%) and HDLc (+6%) levels was seen. All patients were found to have small dense LDL, with a size of 229 +/- 4 A. LDL size and the resistance to oxidation, reflected in the lag phase during in vitro oxidation, were not affected by the addition of acipimox. In a subgroup of 8 patients with the most severe hypertriglyceridaemia (baseline TG < 4 mmol L- [1]), acipimox induced a significant increase in HDLc (+15%, P < 0.01). The effects on TG (-41%), LDLc (-10%) and lag phase (+17%) were also more pronounced than in the group with a lower baseline TG, but non of these changes reached the level of significance. Adding acipimox to simvastatin reduced Lp(a) and substantially but not significantly lowered TG. However, in patients with the highest TG levels, HDLc was also significantly improved.",1997.0,0,0 3004,9078811,Effect of pravastatin in treatment of hypercholesterolemia in non-insulin-dependent diabetes patients.,S Soonthornpun; C Rattarasarn; R Leelawattana; A Thamprasit,"To evaluate the efficacy of pravastatin in treatment of hypercholesterolemia in non-insulin-dependent diabetes patients, a 6-month trial of once daily 10 mg-pravastatin was studied in 30 patients with fairly, well controlled non-insulin-dependent diabetes mellitus. For 27 patients who completed the study, serum total cholesterol and low-density lipoprotein cholesterol were significantly lower 16.7 +/- 2.3 and 20.2 +/- 3.3% from 286.7 +/- 5.9 and 198.6 +/- 7.2 mg/dl at before to 232.6 +/- 7.9 and 147.8 +/- 6.4 mg/dl at 4th week and 237.8 +/- 6.4 and 155.0 +/- 5.8 mg/dl at 24th week after treatment with pravastatin, respectively (P < 0.00001). Serum triglyceride level was decreased from 194.7 +/- 16.8 mg/dl to 175.0 +/- 16.8 mg/dl at 4th week and 176.6 +/- 14.1 mg/dl at 24th week and serum high-density lipoprotein cholesterol level was slightly increased from 45.4 +/- 2.8 mg/dl to 48.2 +/- 2.5 mg/dl at 4th week and 47.5 +/- 2.6 mg/dl at 24th week of pravastatin treatment, respectively (P > 0.05). There was no serious adverse effect except acute hepatitis in one patient who recovered spontaneously after drug withdrawal. Once daily 10 mg-pravastatin in effective in the treatment of hypercholesterolemia in patients with non-insulin-dependent diabetes mellitus.",1997.0,0,0 3005,9086443,"A comparison of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors simvastatin, lovastatin and pravastatin on leukaemic and normal bone marrow progenitors.",A Newman; R D Clutterbuck; R L Powles; D Catovsky; J L Millar,"Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and also selectively inhibits the growth of leukaemic progenitor cells. The antileukaemic action of simvastatin was compared in vitro with that of lovastatin and pravastatin, chemically related compounds which are also competitive inhibitors of HMG-CoA reductase. After 18 hours incubation with 2.5-20 microM of inhibitor, no effect was observed by any of the compounds on the subsequent clonogenic growth of normal bone marrow (BM) progenitor cells from 4 donors and BM cells from one patient in remission. However, simvastatin and lovastatin produced inhibition of acute myeloid leukaemia (AML) progenitor cell growth of between 25% and 100% in 5 populations tested (4 primary AMLs and the HL60 cell line). Pravastatin showed similar growth inhibitory effects to simvastatin and lovastatin in 2 out of 3 primary AMLs but was less active against one primary AML cell population and HL60 cells. These results indicate that, in addition to simvastatin, lovastatin and pravastatin are also selective inhibitors of leukaemic cell growth, however simvastatin was chosen for clinical trial in patients with leukaemia.",1997.0,0,0 3006,9088584,The effects of combined treatment with beta 1-selective receptor antagonists and lipid-lowering drugs on fat metabolism and measures of fatigue during moderate intensity exercise: a placebo-controlled study in healthy subjects.,C J Eagles; M J Kendall,"We examined the effects of different combinations of beta 1-selective adrenoceptor blockers and lipid-lowering drugs, on fat metabolism and fatigue during moderate intensity exercise in 14 healthy young volunteers. The study was a randomized crossover design, each subject completing 5, 90 min walks at 50% of predetermined maximal oxygen uptake (VO2 max), one following each 3 day treatment period with either: atenolol 100 mg and bezafibrate 400 mg, atenolol 100 mg and fluvastatin 40 mg, metoprolol CR 100 mg and bezafibrate 400 mg, metoprolol CR 100 mg and fluvastatin 40 mg, or placebo. Plasma free fatty acid (FFA) concentration during exercise was significantly reduced on all treatments, in comparison with placebo, P = 0.0001. Following 90 min of exercise FFA levels were as follows: placebo 573 mumol l-1 (105-1041), metoprolol CR + fluvastatin 277 mumol l-1 (0-647), metoprolol CR + bezafibrate 182 mumol l-1 (0-396), atenolol + fluvastatin 211 mumol l-1 (0-511), and atenolol + bezafibrate 123 mumol l-1 (0-352). Total fat oxidation during exercise was also reduced on all treatments in comparison with placebo: 38.1% (2-74), compared with 29.1% (0-61) on metoprolol CR + fluvastatin, P = 0.02, 26.2% (2-51) on metoprolol CR + bezafibrate, P = 0.002, 25.5% (3-48) on atenolol + fluvastatin, P = 0.009, and 22.8% (0-47) on atenolol + bezafibrate treatment, P = 0.0002. Plasma ammonia concentration was elevated on all treatments during exercise in comparison with placebo. After 90 min of exercise, plasma ammonia levels were as follows: placebo 37 mumol l-1 (0-84), metoprolol CR + fluvastatin 56 mumol l-1 (2-110), metoprolol CR + bezafibrate 79 mumol l-1 (0-167), atenolol + fluvastatin 90 mumol l-1 (10-170), and atenolol + bezafibrate 100 mumol l-1 26-174). In comparison with placebo, metoprolol CR + fluvastatin had the least adverse impact on measures of perceived exertion and the 'feeling scale' during exercise. Metoprolol CR + bezafibrate, atenolol + fluvastatin, and atenolol + bezafibrate treatments had greater adverse effects, particularly on perceived 'cardiorespiratory effort' and 'feeling scale' scores. In healthy volunteers, combinations of beta 1-selective blockers and lipid-lowering drugs were associated with significant reductions in fat metabolism, increased plasma ammonia levels, and raised the perception of effort during exercise, in comparison with placebo. Metoprolol CR + fluvastatin had the least effect, combinations metoprolol CR + bezafibrate and atenolol + fluvastatin had intermediate effects, and atenolol + bezafibrate had the most adverse effect.",1997.0,0,0 3007,9094885,Influence of lifestyle modification on atherosclerotic progression determined by ultrasonographic change in the common carotid intima-media thickness.,R A Markus; W J Mack; S P Azen; H N Hodis,"The Monitored Atherosclerosis Regression Study (MARS) was a randomized, double-blind, placebo-controlled angiographic trial of lipid-lowering therapy in subjects with coronary artery disease. Subjects were counseled to follow a low-fat, low-cholesterol diet. At every clinic visit, data were obtained on body weight, dietary intake, alcohol consumption, and tobacco use. Semiannual determinations of early preintrusive atherosclerosis were made with high-resolution B-mode ultrasonography of the carotid artery intima-media thickness (IMT). We evaluated the effects of lifestyle modification (diet, alcohol, smoking, and weight loss) on the rate of carotid artery IMT progression on the 94 subjects randomly assigned to the placebo group. Dietary cholesterol, insoluble fiber, body mass index, and smoking were significant predictors of the annual rate of carotid artery IMT progression (P < 0.05). For subjects experiencing IMT progression, increased intakes of monounsaturated fat relative to saturated fat and stearic acid (18:0) consumption were significant predictors of a reduction in the annual rate of carotid artery IMT progression; for subjects experiencing IMT regression, male sex was a significant predictor of a reduction in the annual rate of carotid artery IMT regression. Modifications reducing body mass index by 5 kg/m2, quitting a 10 cigarette/d smoking habit, and reducing dietary cholesterol intake by 100 mg/d on average would reduce the annual rate of carotid wall IMT progression by 0.13 mm/y, which is equivalent to the maximum rate of IMT progression observed in the MARS placebo group. Progression of early preintrusive atherosclerosis can be reduced and overall regression can occur with dietary and lifestyle modification.",1997.0,0,0 3008,9096917,Efficacy and safety of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin in hyperlipidemic patients treated with probucol.,S Sasaki; M Nakagawa; T Nakata; N Endo; K Miyao; K Kitamura; M Fukuyama; T Kitani; C Yamada,"The objective of this open trial was to investigate the efficacy and safety of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin in hypercholesterolemic patients already receiving probucol. All of the participants had hypercholesterolemia. i.e. serum total cholesterol > or = 220 mg/dl, despite administration of probucol, 500 mg/day, for more than 4 weeks. After this, fluvastatin, 30 mg/day, was added to probucol treatment for 12 weeks. Twenty-seven patients were recruited into this study; all were evaluated for safety, and 22 were evaluated for efficacy. The addition of fluvastatin to the probucol regimen produced a significant further reduction in serum total and low-density lipoprotein cholesterol concentrations (of 18 and 20%, respectively; p < 0.001); these effects were fully established within 4 weeks of treatment and were maintained throughout the treatment. Fluvastatin did not affect the serum high-density lipoprotein cholesterol concentration. Fluvastatin treatment decreased serum triglyceride concentrations slightly in all patients (not significant); in patients with hypertriglyceridemia, triglyceride levels were decreased significantly by 34% (p < 0.01; serum triglycerides > or = 150 mg/dl). In addition, fluvastatin significantly decreased serum apolipoprotein B, C-II, C-III and E levels, whereas serum apolipoprotein A-I and A-II levels were unaffected. One patient complained of slight abdominal discomfort during fluvastatin administration, but relationship to fluvastatin remains unclear. One patient had slight elevation of the serum alanine aminotransferase level, and another patient had an elevated gamma-glutamyl transferase level. The addition of fluvastatin to probucol treatment can be considered to be an effective and well tolerated treatment in hypercholesterolemic patients.",1997.0,0,0 3009,9096961,The Scandinavian Simvastatin Survival Study (4S) subgroup analysis of diabetic subjects: implications for the prevention of coronary heart disease.,S M Haffner,,1997.0,0,0 3010,9096989,Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S),K Pyŏrälä; T R Pedersen; J Kjekshus; O Faergeman; A G Olsson; G Thorgeirsson,"To assess in diabetic patients with coronary heart disease (CHD) the effect of cholesterol lowering with simvastatin on mortality and the risk of CHD and other atherosclerotic events. A post hoc subgroup analysis was carried out on data from 202 diabetic patients and 4,242 nondiabetic patients with previous myocardial infarction or angina pectoris, serum total cholesterol 5.5-8.0 mmol/l, and serum triglycerides < or = 2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S). Participants in the 4S were randomly assigned to double-blind treatment with simvastatin, 20 mg daily, with blinded dosage titration up to 40 mg daily, according to cholesterol response during the first 6-18 weeks, or placebo. Endpoints were 1) total mortality, 2) major CHD events (CHD death or nonfatal myocardial infarction), 3) other acute atherosclerotic events, 4) myocardial revascularization procedures. Over the 5.4-year median follow-up period, simvastatin treatment produced mean changes in serum lipids in diabetic patients similar to those observed in nondiabetic patients. The relative risks (RRs) of main endpoints in simvastatin-treated diabetic patients were as follows: total mortality 0.57 (95% CI, 0.30-1.08; P = 0.087), major CHD events 0.45 (95% CI, 0.27-0.74; P = 0.002), and any atherosclerotic event 0.63 (95% CI, 0.43-0.92; P = 0.018). The corresponding RRs in nondiabetic patients were the following: 0.71 (95% CI, 0.58-0.87; P = 0.001), 0.68 (95% CI, 0.60-0.77; P < 0.0001), and 0.74 (95% CI, 0.68-0.82; P < 0.0001). The results strongly suggest that cholesterol lowering with simvastatin improves the prognosis of diabetic patients with CHD. The absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with CHD because diabetic patients have a higher absolute risk of recurrent CHD events and other atherosclerotic events.",2000.0,0,0 3011,9099167,Cost-effectiveness of simvastatin in the secondary prevention of coronary artery disease in Canada.,M Rivière; S Wang; C Leclerc; C Fitzsimon; R Tretiak,"To determine the cost-effectiveness of simvastatin in the secondary prevention of coronary artery disease (CAD) in Canada. Cost-effectiveness model based on results from the Scandinavian Simvastatin Survival Study (45 study) and cost and resource utilization data from Canadian sources to simulate the economic impact of long-term simvastatin treatment (15 years). Subjects with mean age of 59.4 years at recruitment into 4S study. Overall death rate and incidence of 5 major nonfatal events associated with CAD: myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, stroke and transient ischemic attack. Direct medical costs associated with CAD were assessed from the perspective of provincial ministries of health (i.e., costs borne by the ministries); the impact of simvastatin treatment on these costs was determined. The 4S study, with a median follow-up of 5.4 years, showed significantly reduced mortality and morbidity among the patients given simvastatin compared with the control subjects. Three premises were designed to predict the consequences of simvastatin treatment of CAD in Canada over 15 years, 10 years beyond the end of the 4S study. The 2 most probable premises, which assumed that the clinical benefits of simvastatin would be cumulative for either the first 10 years or the full 15 years of the model, had incremental costs per year of life gained (cost-effectiveness ratio) of $9867 and $6108 respectively. This model suggests that simvastatin provides a cost-effective approach to the long-term prevention of secondary CAD in Canada.",1997.0,0,0 3012,9100140,,,,,0,0 3013,9101013,The use of HMG-CoA reductase inhibitors to prevent accelerated graft atherosclerosis in heart transplant patients.,M R Southworth; V F Mauro,"Initial trials hint that HMG-CoA reductase inhibitors may have a role in preventing or retarding the progression of AGAS. Whether the potential of HMG-CoA reductase inhibitors to prevent AGAS is due to their lipid-lowering effect, immunomodulating properties, or a combination of both is also not completely known at present. Further study is needed to fully identify their mode of preventing AGAS and, more important, to determine their usefulness and role in preventing AGAS, especially since concurrent HMG-CoA reductase inhibitor use with cyclosporine is not innocuous. Potential for a pharmacokinetic drug interaction, which results in an elevation of HMG-CoA reductase inhibitor concentrations, exists when these two agents are used together, thus increasing the potential for the HMG-CoA reductase inhibitor to cause musculoskeletal complications. When such combination therapy is used, the likelihood of this interaction can be reduced by prescribing the HMG-CoA reductase inhibitor conservatively--using the smallest effective dose and increasing the daily dosage slowly. Although the risk of musculoskeletal toxicity exists at any HMG-CoA reductase inhibitor dosage, most patients should be able to tolerate daily dosages of up to 20 mg of lovastatin, 10 mg of simvastatin, and 40 mg of pravastatin. Patients also need to be made aware of and monitored for musculoskeletal symptoms suggestive of myositis and/or myalgias. In addition, the avoidance of elevated cyclosporine concentrations and when practical, monitoring of HMG-CoA reductase inhibitor concentrations are recommended.",1997.0,0,0 3014,9104901,Effect of pravastatin (10 mg/day) on progression of coronary atherosclerosis in patients with serum total cholesterol levels from 160 to 220 mg/dl and angiographically documented coronary artery disease. Coronary Artery Regression Study (CARS) Group.,A Tamura; Y Mikuriya; M Nasu,"To evaluate the effect of pravastatin on progression of coronary atherosclerosis in normocholesterolemic patients with coronary artery disease (CAD), 90 patients with CAD and serum cholesterol levels of 160 to 220 mg/dl were randomized into a pravastatin (10 mg/day) group (n = 45) and control group (n = 45) in a 2-year study. The proportions of patients with progression (an increase of > or = 15% in percent stenosis) and regression (a decrease of > or = 15% in percent stenosis) of coronary atherosclerosis were compared between the 2 groups. Of 90 patients, 80 (89%) had a final angiogram: the pravastatin (n = 39) and control group (n = 41). Percent changes in total cholesterol, low-density lipoprotein cholesterol, and apoprotein B levels were significantly greater in the pravastatin group than in the control group (total cholesterol -11 +/- 12% vs 3 +/- 15%, p < 0.01; low-density lipoprotein cholesterol -18 +/- 16% vs 4 +/- 21%, p < 0.01; apoprotein B -5 +/- 20% vs 6 +/- 20%, p < 0.05). The proportion of patients with progression of coronary atherosclerosis was significantly smaller in the pravastatin group than in the control group (21% vs 49%, p < 0.05). The proportion of patients with disease regression did not differ in the 2 groups (3% vs 2%, p = NS). In conclusion, this study indicates that cholesterol-lowering therapy with pravastatin can prevent the progression of coronary atherosclerosis even in normocholesterolemic patients with established CAD.",1997.0,0,0 3015,9105566,"A comparative study of the efficacy of simvastatin and gemfibrozil in combined hyperlipoproteinemia: prediction of response by baseline lipids, apo E genotype, lipoprotein(a) and insulin.",P Nestel; L Simons; P Barter; P Clifton; D Colquhoun; I Hamilton-Craig; K Sikaris; D Sullivan,"Combined hyperlipoproteinemia (CHL) can be difficult to treat because of the heterogeneous nature of the lipoprotein abnormalities. We compared the relative efficacies of simvastatin and gemfibrozil and sought predictors of responsiveness in terms of the baseline lipids and other potential metabolic determinants (plasma insulin, Lp(a) and apo E genotype). Sixty-six subjects entered a cross-over, randomized trial involving 12 weeks on each drug. Efficacy was assessed after 6 and 12 weeks on each treatment. Simvastatin lowered total cholesterol 24%, triglycerides 12%, LDL cholesterol 33%, raised HDL cholesterol 13% and substantially reduced the cholesterol:triglyceride ratio in VLDL and IDL. Gemfibrozil lowered total cholesterol 5%, triglycerides 44%, raised HDL 26% and reduced VLDL and IDL lipids more than simvastatin did. LDL size increased with both treatments and HDL size increased with simvastatin. Responsiveness (25% fall in cholesterol or 40% fall in triglycerides) was shown by 31/61 subjects when taking simvastatin (cholesterol-lowering) and by 44/60 taking gemfibrozil (triglyceride-lowering). Responsiveness was greatest in those with apo E2 genotype with both drugs (P < 0.05). Unexpectedly, responders to simvastatin tended to have lower baseline total cholesterol but higher triglyceride levels than those whose cholesterol or triglyceride was lowered by gemfibrozil. Nevertheless, more hypercholesterolemic subjects responded to simvastatin and more hypertriglyceridemic subjects to gemfibrozil. Lp(a) (P = 0.04) and plasma insulin concentrations (P = 0.03) were negative predictors of percentage triglyceride-lowering with gemfibrozil. The difference between the two drugs in triglyceride-lowering lessened with rising insulin and falling HDL cholesterol. Thus, the responsiveness to the two major classes of lipid lowering drugs can be partly predicted from baseline lipids and related metabolic parameters.",1997.0,0,0 3016,9107233,Human leucocyte antigen (HLA) frequencies in rural Venda.,M J Coetzee; V R Gordeuk; A de Kock; H C Barnard; G Joubert; A F Stassen,,1997.0,0,0 3017,9110440,[Risk factors in elderly patients selected by primary care physicians for hypolipemic treatment].,A C Barretto; M Wajngarten; O C Gebara; J B do Serro Azul; H Pierri; A Nussbacher; L Pivotto; G Bellotti; F Pileggi,"To evaluate the influence of age on response to pravastatin treatment in patients treated by community physicians. According to age, 873 patients were divided in three groups: group A with ages ranging from 45 to 59 years (n = 55), group B with ages from 60 to 64 years (n = 182) and group C with ages from 65 to 70 years (n = 143). After four weeks only with diet orientation, patients received 10 mg/day of pravastatin for 12 weeks. There was a greater prevalence of risk factors in elderly patients: hypertension (45.7%, 54.4% and 57.1% in groups A, B and C respectively p = 0.0165), diabetes mellitus (9.3%, 17.6% and 25.8% respectively in groups A, B and C p < 0.0001), and previous heart disease (23.1%, 34.3% and 34.7% in groups A, B and C respectively p < 0.001). During the period of diet orientation there was a similar total cholesterol reduction in the three groups (about 10.5%), the reduction reached 30.0% with the introduction of pravastatin for 12 weeks. Low density cholesterol level decreased during the diet period in the three groups (about 10.5%), pravastatin prescription induced further reduction (about 31.7%). The high density cholesterol level (HDL) increased significantly with pravastatin treatment (12.7%). After pravastatin treatment the increase in HDL levels was more significantly among those patients with initial low levels of HDL (< 35 mg/dL) in the three groups. In patients selected by community physicians to receive lipid lowering therapy, increased age was associated with greater prevalence of risk factors and heart disease. Regardless of age, there was a good response to pravastatin treatment, however less than half of patients had received treatment prior to the protocol.",1996.0,0,0 3018,9114767,Contemporary cardiac rehabilitation services.,B A Franklin; L Hall; G C Timmis,"Major changes will be required in the components and delivery of cardiac rehabilitation services in the era of managed care. These include restructuring and amplifying the coronary risk reduction services that are currently provided, and offering group and home-based cardiac rehabilitation services to increase their availability.",1997.0,0,0 3019,9114914,Steady state serum concentrations of pravastatin and digoxin when given in combination.,J Triscari; B N Swanson; D A Willard; A I Cohen; A Devault; H Y Pan,"Pravastatin is an HMG CoA reductase inhibitor used in the treatment of hypercholesterolaemia. The steady state pharmacokinetics of pravastatin (20 mg) and digoxin (0.2 mg) were evaluated in 18 healthy male subjects following the administration of each drug alone or in combination for 9 days. Serum and urine were collected for up to 48 h after the ninth dose in this open, randomized 3-way crossover study. Digoxin concentrations were measured by radioimmunoassay, and pravastatin and its metabolites. SQ 31,906 and SQ 31,945 were measured by GC-MS. Digoxin and pravastatin pharmacokinetics were unchanged following combined administration. Combination therapy with pravastatin and digoxin is unlikely to expose patients to additional risk compared with pravastatin alone.",1993.0,0,0 3020,9115054,Rate of low-density lipoprotein cholesterol and apolipoprotein B changes on initiation and discontinuation of atorvastatin treatment.,R H Stern; R B Abel,"In a clinical trial, the changes in LDL cholesterol and in total apolipoprotein B with time were analyzed using a one-compartment model with constant input rate and first-order elimination rate constant after the initiation and discontinuation of treatment with atorvastatin. After initiation of treatment, input rate for total apoplipoprotein B (21 mg/dL/day) and elimination rate constants for both total apoplipoprotein B (0.36 days-1) and low-density lipoprotein (LDL) cholesterol (0.24 days-1) were similar to those reported for LDL-apolipoprotein B at steady state during treatment with other HMG-CoA reductase inhibitors. However, after discontinuation of treatment, very low elimination rate constants of 0.09 days-1 for LDL cholesterol and 0.07 days-1 for total apolipoprotein B are obtained. A likely explanation is that the model incorrectly assumes an immediate return to the pretreatment state, whereas transient stimulation of hepatic cholesterol synthesis on discontinuation of therapy with HMG-CoA reductase inhibitors is known to occur.",1997.0,0,0 3021,9117137,"Lipid-lowering trials in the primary and secondary prevention of coronary heart disease: new evidence, implications and outstanding issues.",G F Watts; V Burke,"Clinical, angiographic and ultrasonographic data from new trials of the primary and secondary prevention of atherosclerosis and coronary artery disease with lipid-lowering therapy are reviewed. In the West of Scotland Coronary Prevention Study pravastatin significantly decreased cardiovascular events in asymptomatic men with moderate hypercholesterolaemia without increasing noncardiovascular mortality. The favourable effects of pravastatin may also extent to carotid arteries. Preliminary data from the Cholesterol and Recurrent Events Study testify to the value of lowering cholesterol in patients with near normocholesterolaemia and established coronary artery disease. New angiographic and ultrasonographic studies concur with findings of previous trials and indicate that the benefits of statins extend to noncoronary vascular beds. Meta-regression analysis of angiographic trials shows that optimal treatment for regression of coronary artery disease should aim for an LDL-cholesterol of approximately 3.0 mmol/l. The value of regulating high plasma triglyceride and low HDL-cholesterol has been emphasized by a bezafibrate study. Angiographic trials also suggest that aggressive pharmacotherapy may match the beneficial effects of LDL apheresis in heterozygous familial hypercholesterolaemia. Post-hoc analyses from previous angiographic trials have provided new hypotheses for future studies. The implications of the new evidence presented is examined, as well as issues of cholesterol screening and the economics of treatment.",1996.0,0,0 3022,9117138,Economic issues in coronary heart disease prevention.,J P Reckless,"The effectiveness of cholesterol lowering is well established, but cost-effectiveness is an increasing issue because of financial pressures on healthcare services. New statin studies have prospectively demonstrated that secondary prevention of coronary heart disease is almost always cost-effective, as is primary prevention in individuals at higher risk who have one or more other additional risk factors.",1996.0,0,0 3023,9117139,What can we learn about dense low density lipoprotein and lipoprotein particles from clinical trials?,H R Superko,"The small LDL pattern B trait, and triglyceride rich lipoproteins, have now been established as major coronary heart disease risk factors and have been associated with its severity. The presence of these disorders identifies a patient subgroup which is at substantial coronary artery disease risk but also exhibits the best arteriographic response to treatment. Most lipid-lowering treatments have a differential effect in LDL subclass pattern A patients compared with those with pattern B that helps explain the differential arteriographic response seen in clinical trials.",1996.0,0,0 3024,9117143,"Statins: within-group comparisons, statin escape and combination therapy.",M J Tikkanen,"The successful use of statins in major coronary prevention trials has resulted in an explosive widening of their use. In most instances, statin therapy will result in adequate and sustained lowering of lipids. Comparing equal-weight doses, simvastatin is twice as effective as pravastatin and lovastatin in LDL-cholesterol lowering, and all three are more effective than fluvastatin according to recent comparative studies. Statin monotherapy is not always effective in severe hypercholesterolemia or in mixed (combined) hyperlipidemia with marked triglyceride elevations. All statins accepted for therapeutic use can be combined with resin or fibrate. Myopathy resulting from statin-fibrate combinations is less frequent than had been thought on the basis of early reports, and these combinations can be used in long-term therapy of mixed hyperlipidemia.",1996.0,0,0 3025,9118815,Choosing the right lipid-regulating agent. A guide to selection.,J A Farmer; A M Gotto,"If dietary therapy and other lifestyle changes do not adequately normalise blood lipid levels, lipid-regulating drugs, as single-drug or combination-drug therapy, may be prescribed to supplement lifestyle changes. Evaluation of the individual patient's health and risk status, determination of the dyslipidaemia, definition of treatment goals and a clear understanding of the mechanisms and effects of lipid-regulating agents are necessary for optimisation of treatment. Although all the available lipid-regulating agents lower low density lipoprotein (LDL) cholesterol, the agents with the greatest LDL cholesterol-lowering effect are the bile acid sequestrants, which up-regulate the LDL receptor by the decrease in intrahepatic cholesterol caused by the interruption of enterohepatic circulation of cholesterol-rich bile acids, and the HMG-CoA reductase inhibitors, which partially inhibit HMG-CoA reductase. The agents with the greatest triglyceride-lowering effect are nicotinic acid, which decreases the production of very low density lipoprotein (VLDL) cholesterol and reduces the availability of free fatty acids in the circulation, and the fibric acid derivatives, which increase lipoprotein lipase activity and may also decrease the release of free fatty acids. Although the safety profile of the available lipid-regulating drugs has been established, patients should be monitored for potential adverse effects and interactions with concomitantly administered agents. When used correctly, lipid-regulating drug therapy is highly effective in the treatment of a variety of dyslipidaemias.",2001.0,0,0 3026,9118820,Bezafibrate. An update of its pharmacology and use in the management of dyslipidaemia.,K L Goa; L B Barradell; G L Plosker,"The lipid-modifying profile of bezafibrate is characterised by marked decreases in elevated triglyceride levels, increases in high density lipoprotein (HDL) cholesterol levels and decreases in total and low density lipoprotein (LDL) cholesterol levels. Bezafibrate also reduces elevated levels of lipoprotein(a) [Lp(a)] and fibrinogen, which are independent cardiovascular risk factors. Bezafibrate is effective in most types of primary and secondary dyslipidaemia. It is of greatest benefit in conditions featuring hypertriglyceridaemia and/or HDL cholesterol deficiency. This is particularly true for patients with diabetes mellitus, notably those with non-insulin-dependent diabetes mellitus (NIDDM) who are also likely to have increased fibrinogen levels. In the limited comparisons available, there appear to be few consistent differences in lipid-modifying effects between bezafibrate and other fibrates. Compared with HMG-CoA reductase inhibitors, bezafibrate causes larger changes in triglyceride and, in general, HDL cholesterol levels, and has a lesser influence on LDL and total cholesterol levels. These differences are advantageous when bezafibrate and HMG-CoA reductase inhibitors are used as combined therapy in patients with severe dyslipidaemia unresponsive to either modality alone. The combination of bezafibrate plus an HMG-CoA reductase inhibitor in clinical trials has not led to the predicted increase in myalgia. Indeed, bezafibrate is generally free of serious unwanted effects: rhabdomyolysis is rare and has occurred mainly in patients with renal dysfunction given excessive dosages. Other patient groups in whom bezafibrate has improved serum lipid profiles are those with isolated HDL cholesterol deficiency, dyslipidaemia secondary to renal insufficiency, and following cardiac surgery or other procedures. However, data for these indications are not extensive. Evidence is now available to show a beneficial effect of bezafibrate on retarding atherosclerotic processes and in reducing risk of coronary heart disease. The 5-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) in young male survivors of myocardial infarction demonstrated a smaller decrease in luminal diameter and a reduction in coronary events with bezafibrate compared with placebo. The Bezafibrate Infarction Prevention (BIP) study is expected to provide mortality data which is currently lacking for bezafibrate. In conclusion, bezafibrate is a useful and well-tolerated lipid-modifying agent in the management of primary and secondary dyslipidaemia. It has particularly beneficial effects in patients with hypertriglyceridaemia and/or low HDL cholesterol levels, and reduces fibrinogen levels. Together with its ability to sustain or improve glycaemic control, these properties make it a logical choice for treating patients with diabetes mellitus and dyslipidaemia. Additionally, the drug may be of value as combination therapy in patients with severe dyslipidaemia. Importantly, there is evidence that the drug can slow the atherosclerotic process and reduce cardiovascular morbidity. The ongoing BIP secondary intervention study and other investigations will help clarify the effects of bezafibrate on cardiovascular mortality and morbidity.",1996.0,0,0 3027,9122535,[Long term treatment of moderate to severe hypercholesterolemia with low dose statin. Comparison of simvastatin and pravastatin].,W Spagnolli; C Ramponi; C Focher; A Dal Piaz; P Torboli; R Miori; G De Venuto,"Sixty-seven subjects with primary hypercholesterolemia were enrolled in an open study with ""low dosages"" of inhibitors of 3-hydroxy-3methylglutaril coenzyme A reductase. Patients were randomized in comparative and parallel study with simvastatin 10 mg (30 subjects) and pravastatin 20 mg (27 subjects) once in the evening for a treatment period of 12 months. At the end of the treatment the plasma concentrations of total and LDL cholesterol were reduced respectively by 21% (p < 0.001) and 29% (p < 0.001), plasma triglyceride concentration was reduced by 16%, high density lipoprotein (HDL) was increased by 2.9%. The efficacy of drugs was increasing during the study: at the third month 63% of subjects and at the twelfth month 89% of subjects showed a LDL < 160 mg/dL. In this study the drugs were well-tolerated, but 11 subjects showed a slight and transitory increase of CK. A treated group with simvastatin showed a similar decrease of the total cholesterol and LDL as that one treated with pravastatin. Pravastatin in comparison with simvastatin reduced significantly plasma triglycerides. There was no significant difference between the groups in the frequency of drug-related adverse effects. In conclusion ""low dosages"" of simvastatin and pravastatin in long term treatment were very efficacious in the reduction of total and LDL cholesterol. In our study, the decrease of total and LDL cholesterol was time-dependent, with the greatest reduction after sixth months. There were no significant differences between 10 mg of simvastatin and 20 mg of pravastatin on reduction of total and LDL cholesterol levels. Triglycerides decreased significantly only with pravastatin.",1996.0,0,0 3028,9125320,Comment on: effect of pravastatin sodium and simvastatin on plasma fibrinogen level and blood rheology in type II hyperlipoproteinemia.,D P Mikhailidis; E S Ganotakis; A F Winder,,1996.0,0,0 3029,9126664,Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia.,S Bertolini; G B Bon; L M Campbell; M Farnier; J Langan; G Mahla; P Pauciullo; C Sirtori; F Egros; R Fayyad; J W Nawrocki,"Plasma cholesterol and other lipoproteins play a significant role in the development of atherosclerosis and subsequent coronary heart disease (CHD). This 1 year study was designed to confirm the efficacy and safety of atorvastatin (Lipitor) compared to pravastatin, a marketed agent for low density lipoprotein cholesterol (LDL-C) reduction in hypercholesterolemic patients. Patients were recruited at 26 centers in six European countries. After a 6 week placebo baseline phase, patients were randomized to receive atorvastatin 10 mg or pravastatin 20 mg daily. The dose could be doubled at week 16, if LDL-C levels remained > or = 3.4 mmol/l (135 mg/dl). Atorvastatin significantly lowered LDL-C from baseline by 35% compared with 23% for pravastatin (P < 0.05). A total of 72% of atorvastatin patients attained the LDL-C target level of < 3.4 mmol/l, compared to 26% of pravastatin patients. Atorvastatin also significantly reduced TC, TG and apo B (P < 0.05). Safety was assessed by recording adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. Atorvastatin 10 and 20 mg once daily is superior to pravastatin 20 and 40 mg once daily in treating patients with hypercholesterolemia.",1997.0,1,1 3030,9127708,Homocyst(e)ine: an important risk factor for atherosclerotic vascular disease.,P B Duell; M R Malinow,"Homocysteine is an intermediate compound formed during metabolism of methionine. The results of many recent studies have indicated that elevated plasma levels of homocyst(e)ine are associated with increased risk of coronary atherosclerosis, cerebrovascular disease, peripheral vascular disease, and thrombosis. The plasma level of homocyst(e)ine is dependent on genetically regulated levels of essential enzymes and the intake of folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). Impaired renal function, increased age, and pharmacologic agents (e.g. nitrous oxide, methotrexate) can contribute to increased levels of homocyst(e)ine. Plausible mechanisms by which homocyst(e)ine might contribute to atherogenesis include promotion of platelet activation and enhanced coagulability, increased smooth muscle cell proliferation, cytotoxicity, induction of endothelial dysfunction, and stimulation of LDL oxidation. Levels of homocysteine can be reduced with pharmacologic doses of folic acid, pyridoxine, vitamin B12, or betaine, but further research is required to determine the efficacy of this intervention in reducing morbidity and mortality associated with atherosclerotic vascular disease.",1997.0,0,0 3031,9129860,A comparison of quantitative computerized and human panel coronary endpoint measures: implications for the design of angiographic trials.,W J Mack; S P Azen; M Dunn; H N Hodis,"The Monitored Atherosclerosis Regression Study was a double-blind, 2-year, placebo-controlled, randomized, serial angiographic trial which tested reduction of low density lipoprotein-cholesterol with monotherapy using lovastatin on the progression of coronary atherosclerosis. Angiographic outcome was evaluated both by a panel of human readers who visually inspected matched film pairs to arrive at a global change score and by automated computerized vessel edge finding and lesion measurement (quantitative coronary angiography, QCA). In this paper, we model the association between QCA measures of coronary artery lesion change and the panel-based global change score. QCA measures included: per-patient changes in percent diameter stenosis and minimum lumen diameter averaged over all lesions; per-patient changes in average diameter and percent involvement averaged over all segments; the numbers of progressing and regressing lesions and new total occlusions; and the development of any new lesions. We found that when evaluating coronary artery lesion change, panelists evaluate changes in percent diameter stenosis for both low grade (< 50% diameter stenosis at baseline) and high grade (> or = 50% diameter stenosis at baseline) lesions as well as new total occlusions and the number of progressing lesions. Although computerized quantification of the size of a lesion at baseline and as an endpoint may be a more precise measure than that by human panel interpretation, QCA fails to incorporate many other important aspects of coronary angiographic change visualized over the entire coronary artery tree by a panel of human interpreters. Thus, the global change score provides a ""multiple endpoint"" for coronary angiographic trials which does not suffer from the problems of statistical analysis and interpretation of multiple hypothesis tests which usually accompany true multiple endpoint measures. Choice of either or both endpoints in preparing angiographic trials depends on careful consideration of the desired information as well as the cost of carrying out the endpoint analysis.",1997.0,0,0 3032,9129869,Atorvastatin. A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias.,A P Lea; D McTavish,"Atorvastatin is a synthetic HMG-CoA reductase inhibitor which lowers plasma cholesterol levels by inhibiting endogenous cholesterol synthesis. It also reduces triglyceride levels through an as yet unproven mechanism. Dose-dependent reductions in total cholesterol, low density lipoprotein (LDL)-cholesterol and triglyceride levels have been observed with atorvastatin in patients with hypercholesterolaemia and in patients with hypertriglyceridaemia. In large trials involving patients with hypercholesterolaemia, atorvastatin produced greater reductions in total cholesterol, LDL-cholesterol, apolipoprotein B and triglyceride levels than lovastatin, pravastatin and simvastatin. In patients with primary hypercholesterolaemia, the combination of atorvastatin and colestipol tended to produce larger reductions in LDL-cholesterol levels and smaller reductions in triglyceride levels than atorvastatin monotherapy. Although atorvastatin induced smaller reductions in triglyceride levels and more modest increases in high density lipoprotein (HDL)-cholesterol levels than either fenofibrate or nicotinic acid in patients with combined hyperlipidaemia, it produced larger reductions in total cholesterol and LDL-cholesterol. As with other HMG-CoA reductase inhibitors, the most frequently reported adverse events associated with atorvastatin are gastrointestinal effects. In comparative trials, atorvastatin had a similar adverse event profile to that of other HMG-CoA reductase inhibitors. Clinical data with atorvastatin are limited at present. However, with its ability to markedly reduce LDL-cholesterol levels, atorvastatin is likely to join other members of its class as a first-line agent for the treatment of patients with hypercholesterolaemia, if changes in lipid levels with atorvastatin convert to reductions in CHD mortality and morbidity. Atorvastatin may be particularly suitable for patients with heterozygous or homozygous familial hypercholesterolaemia because of the marked reductions in LDL-cholesterol experienced with the drug. Additionally, because of its triglyceride-lowering properties, atorvastatin appears to have the potential to become an appropriate treatment for patients with combined hyperlipidaemia or hypertriglyceridaemia.",1997.0,0,0 3033,9130876,Recent developments in coronary heart disease prevention: the Scandinavian and west of Scotland studies.,M B Elam; W Cushman; W B Applegate; M Heimberg,,1997.0,0,0 3034,9133510,Intermediate-density lipoproteins and progression of carotid arterial wall intima-media thickness.,H N Hodis; W J Mack; M Dunn; C Liu; C Liu; R H Selzer; R M Krauss,"Although LDL cholesterol (LDL-C) is generally accepted to be a major risk factor for progression of atherosclerosis, the traditional measurement of LDL-C includes measurement of IDL. Little is known about the relationship between IDL and progression of atherosclerosis. Therefore, we investigated the association of plasma lipoprotein subclasses with progression of preintrusive carotid artery atherosclerosis in the Monitored Atherosclerosis Regression Study (MARS). MARS was a randomized, double-blind, placebo-controlled serial arterial imaging trial conducted in subjects 37 to 67 years old with angiographically defined coronary artery disease. Analytical ultracentrifugation was used to determine lipoprotein subclasses, including LDL (Sf 0 to 12), IDL (Sf 12 to 20), VLDL (Sf 20 to 400), and HDL (F1.20 0 to 9) in 188 subjects. Subjects were randomized to a cholesterol-lowering diet plus placebo or lovastatin 80 mg/d. The outcome measure, the annual progression rate of the distal common carotid artery far wall intima-media thickness determined by high resolution B-mode ultrasonography, was determined at baseline and every 6 months on trial. When the major apolipoprotein B-containing lipoproteins were measured independently, IDL (r=.21, P<.005) but not VLDL (r=-.09, P=.24) or LDL (r=.09, P=.26) was associated with the progression of carotid artery intimamedia thickness. These data provide further evidence for the role of triglyceride-rich lipoproteins in the progression of atherosclerosis and support the evidence that indicates that the risk of atherosclerosis attributable to LDL-C may in part be the result of lipoproteins in the IDL fraction (Sf 12 to 20) that is included within the traditional measurements of LDL-C.",1997.0,0,0 3035,9134232,"Suppression of neointimal thickening by a newly developed HMG-CoA reductase inhibitor, BAYw6228, and its inhibitory effect on vascular smooth muscle cell growth.",M Igarashi; Y Takeda; S Mori; N Ishibashi; E Komatsu; K Takahashi; T Fuse; M Yamamura; K Kubo; Y Sugiyama; Y Saito,"1. The aim of this study was to determine whether BAYw6228 (BAYw), a newly developed 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, could suppress an atherogenic process such as intimal thickening by a mechanism other than lowering the level of serum cholesterol. 2. First, we evaluated the in vitro effect of BAYw on the proliferation of vascular smooth muscle cells (SMC) from various species: Sprague-Dawley (SD) rats. New Zealand (NZ) white rabbits, intimal cells from Watanabe hereditary hyperlipidemic (WHHL) rabbit and SMC from the new-born human aorta. The increasing rate of total protein content of these cells was inhibited by the addition of BAYw in a dose-dependent fashion. In the presence of 2% foetal calf serum (FCS), the value of IC50 was 1.0 microM in SD rats, 2.1 microM in NZ white rabbits, and 0.3 microM in WHHL rabbits. With human SMC, the value was 0.02 microM in the presence of 10% FCS and 0.2 microM with a mixture of growth factors. 3. Based on these above in vitro findings, we next examined the in vivo effect of the agent to determine whether it could suppress rabbit intimal thickening induced by balloon catheterization. A balloon catheter was inserted from a peripheral branch of the left external carotid artery to the aorta to denude the endothelium of the left common carotid artery in Japanese white rabbits. After 12 days they were divided into control and BAYw groups. The former were subcutaneously injected with saline and the latter with BAYw 1 mg kg-1 day-1. Two days after the beginning of treatment, a second balloon injury was performed to the previously injured left common carotid artery in both groups. After another two weeks, the left common carotid artery was removed and variously stained. Although the total serum cholesterol in the BAYw group was significantly lower than in the control (P < 0.05), the difference was not enough to affect intimal thickening. In addition, the BAYw group had a smaller intima/media ratio than the control group, decreasing to 45% of control (P < 0.05). By anti-alpha smooth muscle actin antibody staining, these intimal thickening areas were entirely occupied by SMCs, and their amount was attenuated by BAYw. By anti-rabbit macrophage antibody (RAM 11) staining, the number of positive cells in the intimal thickening was markedly decreased in the BAYw group compared to control (P < 0.01). 4. These results indicate that BAYw has an inhibitory effect on intimal thickening by attenuating intimal SMC proliferation and infiltration of macrophages, suggesting that BAYw could be effective in the prevention of the progression of atherosclerotic plaque-like restenosis after angioplasty.",1997.0,0,0 3036,9137901,Efficacy of low-dose pravastatin in patients with mild hyperlipidemia associated with type II diabetes mellitus.,M Krempf; F Berthezène; J L Wemeau; S Moinade; I Desriac; E Amelineau; P Passa,"A 16 week, randomized, double-blind, parallel, placebo-controlled study was designed to determine the effects of low-dose pravastatin on cholesterol concentrations in patients with mild hypercholesterolemia and non-insulin-dependent diabetes mellitus (NIDDM). Following a 6-to 8-week dietary run-in period, a mean serum total cholesterol (TC) level > 5.2 mmol/L (200 mg/dL), but < 7.8 mmol/L (300 mg/dL) was required for entry. Metabolic control of diabetes was determined by a hemoglobin Alc (HbAlc) level less than twice the upper limit of normal on two occasions. Eighty six (86) patients recruited in 5 French diabetic clinics, were randomized in a ratio of 1:1 (pravastatin 10 mg or placebo), and 74 completed the study. There were 12 discontinuations: 5 (11.6%) in the pravastatin group and 7 (16.3%) in the placebo group. Drop-out was due to an adverse event in 1 patient (2.3%) in the pravastatin group and in 5 patients (11.6%) in the placebo group. Thirty five (35) placebo patients and 14 pravastatin patients had their dose of treatment doubled at week 8: the dose of treatment was to be doubled at week 8 in the event of non-response to treatment (TC at week 7 > 5.2 mmol/L and TC decrease < 15% from baseline). At week 16, pravastatin lowered TC from 6.4 to 5.6 mmol/L (-13.8%, p < 0.001 versus placebo), low-density lipoprotein cholesterol (LDL-C) from 4.3 to 3.4 mmol/L (-20.4%, p < 0.001 versus placebo) and slightly increased high-density lipoprotein cholesterol (HDL-C) from 1.18 to 1.25 mmol/L (+6.7%). Side effects were similar in both groups. Blood glucose control was not altered as assessed by serial HbAlc measurements which were unchanged during treatment. This study demonstrated that low-dose pravastatin is effective in lowering cholesterol levels in patients with hypercholesterolemia and NIDDM.",2000.0,0,0 3037,9140266,Triglycerides and coronary risk in women and the elderly.,J C LaRosa,"There seems little doubt that triglycerides are causally related to the progress of atherogenesis. Mechanisms for this effect include adverse quantitative and qualitative changes in circulating lipoproteins. In particular, the effects of lower high-density lipoprotein levels and the production by hypertriglyceridemia of small, dense low-density lipoproteins are of great significance. The role of triglyceride-rich remnant particles in atherogenesis is likely important. These remnants, which are lipoproteins rich in both cholesterol and triglycerides, can be shown to produce cholesteryl ester-laden macrophages in vitro and are probably atherogenic in vivo. Triglyceride levels are a significant risk factor for coronary artery disease in women, more so than in men. Triglyceride levels also increase in older patients and continue to be predictors of coronary risk in both men and women older than 65 years. It is unclear whether triglyceride intervention efforts should be directed at lowering triglyceride levels (such as is accomplished with niacin or fibric acid derivatives) or lowering low-density lipoprotein levels in patients with high triglyceride levels, assuming triglyceride levels are only a passive marker of atherosclerotic risk. Until more is known about the precise role of hypertriglyceridemia in atherogenesis in women and older patients, use of triglyceride-lowering drugs should be conservative and limited to those individuals with high triglyceride levels (> 4.5 mmol/L [> 400 mg/dL]) who do not respond to diet modifications and who are at risk of coronary disease either because of a history of vascular disease or the presence of other risk factors.",1997.0,0,0 3038,9141968,Quantitative relation of electrocardiographic and angiocardiographic measures of risk in patients with coronary atherosclerosis. Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT) Investigators.,K K Teo; J R Burton; J DeAlmeida; S Dolezsar; P A Montague; V Dzavik; W J Tymchak; D A Taylor; T J Montague,"To correlate angiocardiographic and electrocardiographic (ECG) measures of risk in coronary artery disease (CAD) patients. Baseline substudy of the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT), a 2 x 2 factorial, randomized, controlled trial of CAD regression. One hundred and twenty-three CAD patients, 113 males and 10 females; average age, 59 years. Bivariate correlations of multiple quantitative measures of epicardial coronary angiographic luminal narrowing (quantitative coronary angiography [QCA]) and body surface ECG maps of the sum of the decrease in the potential time integral of the ST segment (SST decrease) between rest and symptom-limited exercise and between rest and 1 and 5 mins postexercise recovery. The average number of epicardial coronary segments analyzed per patient was 12. The mean diameter averaged 2.78 mm; the minimal diameter, 2.01 mm. The mean percentage coronary stenosis averaged 29.6% and the most severe averaged 62.9%. sigma ST decrease averaged -5323 microV.s between rest and peak exercise and recovered slowly, averaging -5117 microV.s at 1 min postexercise and -4562 microV.s at 5 mins. No QCA measure correlated with any ECG variable (range of r, 0.002 to -0.179; not significant). Among CAD patients there are no close, or causal, relations between angiographic measures of anatomic epicardial coronary atherosclerosis and ECG functional measures of exercise-induced myocardial ischemia. These data suggest that demonstrated values of stress ECG and coronary angiography for the prediction of clinical risk in CAD patients are largely independent of each other.",1997.0,0,0 3039,9149652,Prevention of coronary heart disease through cholesterol reduction.,S M Grundy,"Growing evidence suggests that lowering serum cholesterol levels, particularly low-density lipoprotein levels, will reduce the risk for coronary heart disease. The benefit of cholesterol-lowering therapy has been documented by many clinical trials. Two secondary prevention trials, the Scandinavian Simvastatin Survival Study and the Cholesterol and Recurrent Events trial, demonstrated a striking reduction in recurrent coronary heart disease without an increase in noncardiovascular mortality; treatment with simvastatin reduced total mortality by 30 percent. A primary prevention trial, the West of Scotland Coronary Prevention Study, demonstrated similar results in high-risk patients without established coronary heart disease. More recent angiographic trials revealed that cholesterol-lowering therapy will reduce progression of atherosclerosis and, in some cases, will reverse existing lesions. Use of HMG-CoA reductase inhibitors also appears to be beneficial and safe. Evidence supports cholesterol-lowering therapy in high-risk patients, both with and without established atherosclerotic disease.",1997.0,0,0 3040,9150246,Inhibition of proliferation of human smooth muscle cells by various HMG-CoA reductase inhibitors; comparison with other human cell types.,P Nègre-Aminou; A K van Vliet; M van Erck; G C van Thiel; R E van Leeuwen; L H Cohen,"The effects of 6 HMG-CoA reductase inhibitors: pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin were analyzed in cultured human smooth muscle cells, fibroblasts, endothelial cells and myoblasts. In vascular smooth muscle cells, pravastatin was a much weaker inhibitor of cholesterol synthesis than the 5 other drugs which displayed equally strong inhibitory potency. The anti-proliferative effects of these 6 drugs were analyzed by measuring cell number and mitochondrial dehydrogenase activity (MTT assay) after 3 days of incubation. IC25 values for inhibition of proliferation were very similar among the 4 cell types and were in the following order of magnitude: pravastatin < lovastatin = simvastatin = atorvastatin = fluvastatin < cerivastatin. Only in the case of pravastatin was proliferation inhibited at lower concentration in smooth muscle cells than in the other cell types. Proliferation was also assessed by measuring DNA synthesis in these cells. A 3 day-incubation with 1 microM of pravastatin had no effect on this parameter in all 4 cell types. However, 1 microM of simvastatin or lovastatin caused either an inhibition (in smooth muscle cells and endothelial cells) or stimulation (in fibroblasts) of this process. The effects of simvastatin on cell number, mitochondrial dehydrogenase activity and DNA synthesis were counteracted by simultaneous mevalonate addition. Simvastatin treatment was also associated with a change in the post-translational modification of the ras protein in smooth muscle cells, probably by inhibition of its farnesylation. Moreover, simvastatin treatment blocked the PDGF and bFGF-induced DNA synthesis in synchronized smooth muscle cells, whereas it does not affect the fetal calf serum-induced DNA synthesis in synchronized fibroblasts, suggesting that simvastatin blocks various steps of the cell cycle and that this effect depends on the cell type and the growth signalling pathway activated.",1997.0,0,0 3041,9152263,Relative effectiveness of niacin and lovastatin for treatment of dyslipidemias in a health maintenance organization.,P J O'Connor; W A Rush; D L Trence,"We conducted an historical cohort study to evaluate the relative effectiveness of niacin and lovastatin in the treatment of dyslipidemias in patients enrolled in a health maintenance organization (HMO). To be eligible for this study, adults aged 18 years and older who were initially treated with either niacin or lovastatin between January 1, 1992, and December 31, 1993, were identified from pharmacy databases. Each potentially eligible member with a fasting lipid panel prior to initiation of drug therapy and with a second fasting lipid panel between 9 and 15 months after initiation of drug therapy was included in the study. A total of 244 patients treated with niacin and 160 patients treated with lovastatin had complete data and are subjects of this report. Patients initially treated with lovastatin had higher baseline mean cholesterol and low-density lipoprotein (LDL) levels as well as higher rates of diabetes mellitus and heart disease than did patients initially treated with niacin. Lovastatin use was associated with a mean 25.8% decrease in LDL cholesterol, while niacin use was associated with a mean 17.5% drop in LDL cholesterol (t = 3.19, P < .002). Niacin use was associated with a 16.3% improvement in high-density lipoprotein (HDL) cholesterol, while HDL-cholesterol levels in the lovastatin group improved 1.5% (t = 4.74, P < .001). Niacin use was associated with an 18.4% improvement in triglycerides, while lovastatin use was associated with an 8% improvement in triglyceride levels (t = 2.81, P = .005). Differences in LDL/HDL ratio from before treatment to follow-up were no different in the two groups of patients (t = -1.21, P = .22). A total of 46% of patients initially treated with either drug reached their treatment goals in accordance with those set by the National Cholesterol Education Program. Drug discontinuation rates were 73% for niacin and 52% for lovastatin at follow-up, which averaged 10.7 months in each group. These results suggest that both niacin and lovastatin are effective in treating dyslipidemic patients in this care system, and that physicians appropriately use lovastatin more often for patients with higher baseline LDL levels and more comorbidity. The data also strongly suggest that establishing an organized, population-based approach to systematically identify, treat, and monitor patients with dyslipidemias may be the single most important intervention HMOs should consider for improving control of dyslipidemias on a population basis.",1997.0,0,0 3042,9156156,Lipids and prevention in coronary care.,D J Betteridge,,1994.0,0,0 3043,9158202,Pharmacology of immunosuppressive medications used in renal diseases and transplantation.,A M de Mattos; A J Olyaei; W M Bennett,"As understanding of the molecular basis for the immune response has expanded rapidly, so have the possibilities for designing therapeutic interventions that are more effective, more specific, and safer than current treatment options. The promise of therapeutic advances in the future is based on the rapidly expanding insights into the pathogenesis of abnormal immunologic reactions. Nowhere is the understanding of molecular mechanisms, pathophysiology, and targeted therapy more relevant than in the field of renal transplantation, which makes up much of the clinical database for the use of immunosuppressive therapy for renal disease. Despite the recent advances in basic immunology, clinical validation of new agents and approaches is lacking for most drugs at present. This review will focus in the pharmacology of agents used in the therapy of immunologic renal disease and in renal transplantation. It should be recognized that clinical pharmacology and experience with newer agents is limited, and potential utility is based largely on experimental data.",1996.0,0,0 3044,9158261,Statins and coronary artery disease--it's the clinical endpoints that count.,G Jackson,,1997.0,0,0 3045,9158627,Race-ethnicity and determinants of carotid atherosclerosis in a multiethnic population. The Northern Manhattan Stroke Study.,R L Sacco; J K Roberts; B Boden-Albala; Q Gu; I F Lin; D E Kargman; L Berglund; W A Hauser; S Shea; M C Paik,"Risk factors for carotid atherosclerosis have been studied in white populations but infrequently in multiethnic cohorts. The aim of this study was to determine the importance of race-ethnicity and other factors associated with carotid atherosclerosis in a mixed population of Hispanics, blacks, and whites. As part of the Northern Manhattan Stroke Study, 526 stroke-free community residents (aged > or = 40 years; 41% men, 59% women; 46% Hispanic, 31% black, 23% white) were recruited through random-digit dialing and had vascular risk factor evaluations. Maximum internal carotid artery plaque thickness (MICPT) was measured with B-mode ultrasound. The frequency distribution of MICPT was examined in the three race-ethnic groups, and multivariate regression was performed to identify factors that were independently associated with MICPT. Mean MICPT in the entire sample was 1.5 +/- 1.4 mm, increased directly with age, and was greater in whites and blacks than Hispanics. Other independent determinants of MICPT included smoking, glucose, LDL cholesterol, and hypertension. After we controlled for these covariates, Hispanic (versus non-Hispanic) race-ethnicity was still an independent determinant of less carotid plaque. There was a significant interaction between race-ethnicity and LDL cholesterol, with a greater effect of increasing LDL cholesterol among Hispanics. Atherosclerotic risk factors were predictive of MICPT in this mixed-ethnic cohort. Hispanics had significantly less carotid plaque after adjustment for other known risk factors, but they also had a greater impact of increasing LDL cholesterol.",1997.0,0,0 3046,9158630,"Stroke, statins, and cholesterol. A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors.",G J Blauw; A M Lagaay; A H Smelt; R G Westendorp,"To estimate the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (""statins"") on stroke ris, we combined the data of the randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors published so far. The studies were identified using the Medline CD+ and Current Contents databases from January 1980 through May 1996, inclusive. All studies were evaluated on the use of a placebo control, monotherapy, and double blindness. When the type of stroke or the occurrence of clinical events or adverse effects were incompletely or not reported, the investigators were contacted personally. For each trial, the number of strokes in the treatment arm was compared with the number of strokes expected on all observations under the assumption that drug treatment had no effect. A total of 462 strokes among 20438 participants in 13 trials could be analyzed. A total of 181 strokes were observed in patients randomized to treatment with an HMG-CoA reductase inhibitor and 261 strokes in patients randomized to placebo. A lower than expected number of strokes was observed in the treatment groups of all but one trial (P = .001). Treatment with an HMG-CoA reductase inhibitor led to an overall risk reduction of 31% (odds ratio, 0.69; 95% confidence interval, 0.57 to 0.83). The combined data suggest that treatment with HMG-CoA reductase inhibitors prevents stroke in middle-aged persons. Because stroke is especially common in older age, these data reinforce the need for clinical trials to evaluate the effect of HMG-CoA reductase inhibitors in preventing stroke in the elderly.",1997.0,0,0 3047,9158824,Effect of simvastatin therapy on cell membrane cholesterol content and membrane function as assessed by polymorphonuclear cell NADPH oxidase activity.,A P Day; S Bellavia; O T Jones; D Stansbie,"Cell membrane cholesterol is an important determinant of membrane fluidity. Changes in fluidity have important consequences for membrane function. Treatment of hypercholesterolaemia could therefore affect membrane function by reducing cell membrane cholesterol levels. The aim of this study was to determine whether treatment with simvastatin affects membrane cholesterol and the activity of the polymorphonuclear cell membrane enzyme NADPH oxidase. Blood was obtained from 12 hypercholesterolaemic patients before, and 6 weeks after, treatment with simvastatin, and from 20 normolipidaemic subjects. Cell cholesterol was in the unesterified from indicating that it was membrane-associated. Pre-treatment mean cell cholesterol concentration in the hyperlipidaemics was higher (P < 0.05) than in the normolipidaemics [4.19 fmol/cell, 95% confidence interval (CI) 3.38-5.05 versus 3.10 fmol/cell, 95% CI 2.58-3.61]. There was a strong correlation between cell cholesterol content and NADPH oxidase lag phase (R(s) = 0.76, P < 0.01). Cell cholesterol fell to 3.52 fmol/cell (95% CI 2.77-4.28, P < 0.05) following treatment and there was a correlation (R(s) = 0.61, P < 0.05) between the reductions in cell cholesterol and lag phase.",1997.0,0,0 3048,9159603,The problem of compliance to cholesterol altering therapy.,W Insull,"This review's purpose is to describe for the practicing clinician the current knowledge about patient compliance to cholesterol-altering drugs and about procedures for compliance management applicable to clinical practice in the United States. Compliance is defined for four commonly measured major steps and, based on recent electronic monitoring data, for three quantitative categories of active medication-taking. The concepts and definition of compliance are undergoing evolutionary changes due to the measurement and availability of new dimensions through electronic monitoring of patient compliance. Substantial non-compliance to cholesterol-altering drugs has been reported in nine large clinical trials for primary and secondary prevention of coronary heart disease, in two HMOs, and, using electronic monitoring of compliance, in one clinical trial and a selected practice. The risks of treatment discontinuation increased continuously during treatment and totaled from 6 to 30% after 5 years. Patterns of day-to-day partial compliance are emerging. Procedures and knowledge for clinical management of compliance are described including methods of measuring compliance, risk factors for non-compliance, standards for compliance performance, epidemiology of compliance, procedures for managing compliance at the start of therapy and for addressing compliance problems during established treatment, simple office assessment of compliance by brief interview questions, compliance aids, prediction of compliance, and education and training of medical-care personnel in compliance management.",1997.0,0,0 3049,9160173,Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences.,H Lennernäs; G Fager,"Hypercholesterolaemia plays a crucial role in the development of atherosclerotic diseases in general and coronary heart disease in particular. The risk of progression of the atherosclerotic process to coronary heart disease increases progressively with increasing levels of total serum cholesterol or low density lipoprotein (LDL) cholesterol at both the individual and the population level. The statins are reversible inhibitors of the microsomal enzyme HMG-CoA reductase, which converts HMG-CoA to mevalonate. This is an early rate-limiting step in cholesterol biosynthesis. Inhibition of HMG-CoA reductase by statins decreases intracellular cholesterol biosynthesis, which then leads to transcriptionally upregulated production of microsomal HMG-CoA reductase and cell surface LDL receptors. Subsequently, additional cholesterol is provided to the cell by de novo synthesis and by receptor-mediated uptake of LDL-cholesterol from the blood. This resets intracellular cholesterol homeostasis in extrahepatic tissues, but has little effect on the overall cholesterol balance. There are no simple methods to investigate the concentration-dependent inhibition of HMG-CoA reductase in human pharmacodynamic studies. The main clinical variable is plasma LDL-cholesterol, which takes 4 to 6 weeks to show a reduction after the start of statin treatment. Consequently, a dose-effect rather than a concentration-effect relationship is more appropriate to use in describing the pharmacodynamics. Fluvastatin, lovastatin, pravastatin and simvastatin have similar pharmacodynamic properties; all can reduce LDL-cholesterol by 20 to 35%, a reduction which has been shown to achieve decreases of 30 to 35% in major cardiovascular outcomes. Simvastatin has this effect at doses of about half those of the other 3 statins. The liver is the target organ for the statins, since it is the major site of cholesterol biosynthesis, lipoprotein production and LDL catabolism. However, cholesterol biosynthesis in extrahepatic tissues is necessary for normal cell function. The adverse effects of HMG-reductase inhibitors during long term treatment may depend in part upon the degree to which they act in extrahepatic tissues. Therefore, pharmacokinetic factors such as hepatic extraction and systemic exposure to active compound(s) may be clinically important when comparing the statins. Different degrees of liver selectivity have been claimed for the HMG-CoA reductase inhibitors. However, the literature contains confusing data concerning the degree of liver versus tissue selectivity. Human pharmacokinetic data are poor and incomplete, especially for lovastatin and simvastatin, and it is clear that any conclusion on tissue selectivity is dependent upon the choice of experimental model. However, the drugs do differ in some important aspects concerning the degree of metabolism and the number of active and inactive metabolites. The rather extensive metabolism by different cytochrome P450 isoforms also makes it difficult to characterise these drugs regarding tissue selectivity unless all metabolites are well characterised. The effective elimination half-lives of the hydroxy acid forms of the 4 statins are 0.7 to 3.0 hours. Protein binding is similar (> 90%) for fluvastatin, lovastatin and simvastatin, but it is only 50% for pravastatin. The best characterised statins from a clinical pharmacokinetic standpoint are fluvastatin and pravastatin. The major difference between these 2 compounds is the higher liver extraction of fluvastatin during the absorption phase compared with pravastatin (67 versus 45%, respectively, in the same dose range). Estimates of liver extraction in humans for lovastatin and simvastatin are poorly reported, which makes a direct comparison difficult.",1997.0,0,0 3050,9162604,Treatment of dyslipoproteinaemia in diabetes mellitus.,J D Dean; P N Durrington,"Coronary heart disease (CHD) is the most common cause of premature death in diabetes. Hypercholesterolaemia occurs in diabetes with about the same frequency as in the general population, but it confers a greater risk of CHD in diabetes. Hypertriglyceridaemia and low serum high density lipoprotein (HDL) cholesterol levels are more common in diabetes, particularly non-insulin-dependent diabetes. Nephropathy increases the severity of dyslipoproteinaemia. There remains a reluctance to apply the results of cholesterol-lowering trials to diabetes. No trial has been specifically in diabetes, but this should not constrain the treatment of diabetic patients at clearly high CHD risk. It is suggested that fasting lipids should be measured in all diabetic patients aged less than 70 years with established CHD or whose non-fasting cholesterol is >6.00 mmol I(-1) or triglycerides >3.00 mmol I(-1). For those with raised lipids glycaemic control should be improved, if possible, and dietary therapy aimed at a decrease in fat intake, particularly saturated fat, and weight reduction in the obese. Lipid-lowering drugs are required in patients with CHD and serum cholesterol >5.5 mmol I(-1) with the aim of decreasing non-HDL to <4.00 mmol I(-1). In patients without CHD lipid-lowering drugs should be considered when serum cholesterol exceeds 6.5 mmol I(-1) and the risk of CHD is greater than 20 % over the next 10 years. There is no evidence that pursuing this policy beyond the age of 70 years is beneficial. Diabetic women with dyslipoproteinaemia should, however, be treated in the same way as men. The knowledge that hypertriglyceridaemia and low serum HDL cholesterol are present helps in the assessment of CHD risk and the choice of medication to decrease non-HDL cholesterol, but there is no evidence that their treatment in the absence of raised cholesterol is of benefit.",1996.0,0,0 3051,9162756,"Ro 48-8.071, a new 2,3-oxidosqualene:lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters, squirrel monkeys, and minipigs: comparison to simvastatin.",O H Morand; J D Aebi; H Dehmlow; Y H Ji; N Gains; H Lengsfeld; J Himber,"2,3-Oxidosqualene:lanosterol cyclase (OSC, E.C. 5.4.99.7) represents a unique target for a cholesterol lowering drug. Partial inhibition of OSC should reduce synthesis of lanosterol and subsequent sterols, and also stimulate the production of epoxysterols that repress HMG-CoA reductase expression, generating a synergistic, self-limited negative regulatory loop. Hence, the pharmacological properties of Ro 48-8.071, a new OSC inhibitor, were compared to that of an HMG-CoA reductase inhibitor, simvastatin. Ro 48-8.071 blocked human liver OSC and cholesterol synthesis in HepG2 cells in the nanomolar range; in cells it triggered the production of monooxidosqualene, dioxidosqualene, and epoxycholesterol. It was safe in hamsters, squirrel monkeys and Göttingen minipigs at pharmacologically active doses, lowering LDL approximately 60% in hamsters, and at least 30% in the two other species, being at least as efficacious as safe doses of simvastatin. The latter was hepatotoxic in hamsters at doses > 30 mumol/kg/day limiting its window of efficacy. Hepatic monooxidosqualene increased dose-dependently after treatment with Ro 48-8.071, up to approximately 20 micrograms/g wet liver or less than 1% of hepatic cholesterol, and it was inversely correlated with LDL levels. Ro 48-8.071 did not reduce coenzyme Q10 levels in liver and heart of hamsters, and importantly did not trigger an overexpression of hepatic HMG-CoA reductase, squalene synthase, and OSC itself. In strong contrast, simvastatin stimulated these enzymes dramatically, and reduced coenzyme Q10 levels in liver and heart. Altogether these findings clearly differentiate the OSC inhibitor Ro 48-8.071 from simvastatin, and support the view that OSC is a distinct key component in the regulation of the cholesterol synthesis pathway.",1997.0,0,0 3052,9164896,Efficacy of atorvastatin in primary hypercholesterolemia. Japan Cholesterol Lowering Atorvastatin Study (J-CLAS) Group.,,"A placebo-controlled, double-blind study on the efficacy of atorvastatin was conducted in several multicenters. Atorvastatin reduced total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B substantially in a dose-dependent manner without any serious adverse events.",1997.0,0,0 3053,9164913,Comparison of pravastatin with crystalline nicotinic acid monotherapy in treatment of combined hyperlipidemia.,J M Mostaza; I Schulz; G L Vega; S M Grundy,Pravastatin treatment of combined hyperlipidemia lowers low-density lipoprotein effectively; nicotinic acid lowers remnant cholesterol and raises high-density lipoprotein. A combination of these 2 drugs may be indicated for optimal treatment of lipoprotein abnormalities in combined hyperlipidemia.,1997.0,0,0 3054,9165562,Effect of pharmaceutical care on optimum colestipol treatment in elderly hypercholesterolemic veterans.,S L Konzem; D R Gray; M L Kashyap,"We conducted a prospective trial to determine whether a formal, integrated pharmaceutical care plan can enhance patient acceptance and compliance with colestipol therapy and improve outcomes. Forty patients with hypercholesterolemia were equally divided and assigned to either a usual care or pharmaceutical care group. In the pharmaceutical care group compared with the usual care group, after 52 weeks, colestipol therapy resulted in a greater reduction in total cholesterol (12.5% vs 7.3%), low-density lipoprotein cholesterol (LDL-C; 16% vs 9.4%), and LDL-C:high-density lipoprotein cholesterol (HDL-C) ratio (24.4% vs 12.2%, p < 0.05). The percentage of patients who achieved their LDL-C goal at week 52 was much greater in the pharmaceutical care group (29.4%) than in the usual care group (5.0%, p < 0.05). Co-management by a physician and a pharmacist of hypercholesterolemic veterans treated with colestipol can enhance patient acceptance of the drug, LDL-C reduction, and achievement of therapeutic goals.",1997.0,0,0 3055,9175401,The internist and the vessel wall.,T F Lüscher,"The essential problem of the vicious circle leading to end-stage cardiovascular disease is atherosclerosis. This paper focuses on the functional changes centred on the endothelium that accompany the development of atherosclerosis, examining in particular pathological alterations in the L-arginine/nitric oxide (NO) pathway. Changes in the NO system are associated with altered platelet and monocyte interactions with the vessel wall, abnormal vasoconstriction and altered vascular structure. Diabetes, hyperglycaemia, hypertension and hypercholesterolaemia are all involved in this process. Endothelin is a vasoconstrictor peptide produced by endothelial cells which is upregulated under these conditions. Normalising endothelial function could involve platelet inhibition, lipid-lowering agents to prevent foam cell formation and decrease the lipid load of the blood vessel wall, and agents to interfere with some of the mechanisms involved in vasoconstriction, proliferation and migration, including ACE-inhibitors and angiotensin receptor antagonists, and possibly new tools such as endothelin receptor antagonists.",1997.0,0,0 3056,9175404,Tomorrow's world: atherosclerosis in the year 2000.,J Shepherd,"Atherosclerosis is an increasing problem, largely due to lifestyle changes. Lipid accumulates in artery walls throughout life, and infiltration into the subintimal space of cholesterol and cholesterol esters and of inflammatory cells can lead to narrowing, clotting, thrombosis and death. Lipid-lowering agents, particularly statins [(3-hydroxy-3-methylglutarate coenzyme A (HMG-CoA) reductase inhibitors] represent one important approach to treatment. They work by blocking the conversion of 3-hydroxy-3-methylglutarate into mevalonate, a precursor of cholesterol. The West Of Scotland Coronary Prevention Study (WOSCOPS) was a large prospective randomised study comparing the effects of pravastatin versus that of placebo in 6595 middle-aged men. In the pravastatin group the rate of fatal or non-fatal myocardial infarction was reduced by one-third over 5 years, the rate of cardiovascular deaths by one-third, and overall deaths by 22% relative to the placebo group. Implications of the results are considered and the results of the US-CARE study are compared. Discussion of relative and absolute risk, and continuous and discrete risk factors leads to the formulation of rational cost/beneficial strategies for decreasing cardiovascular risk by targeting high-risk individuals with lipid-lowering drugs.",1997.0,0,0 3057,9180238,What targets should lipid-modulating therapy achieve to optimise the prevention of coronary heart disease?,G R Thompson,"Analysis of trials which have investigated the effects of lowering low density lipoprotein (LDL) levels on coronary heart disease (CHD), as determined by changes on quantitative coronary angiography and in the incidence of cardiovascular events, suggests that the percentage decrease in LDL cholesterol provides a better index of outcome than does its absolute level on treatment. Additional data suggest that it may be advantageous to employ therapy which not only lowers LDL cholesterol but also decreases serum triglyceride and/or increases HDL cholesterol. These conclusions have important implications for future guidelines on CHD prevention.",1997.0,0,0 3058,9180240,A brief review paper of the efficacy and safety of atorvastatin in early clinical trials.,R G Bakker-Arkema; J Best; R Fayyad; T M Heinonen; A D Marais; J W Nawrocki; D M Black,"Preclinical and clinical data on atorvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, indicate that it has superior activity in treating a variety of dyslipidemic disorders characterized by elevations in low-density lipoprotein cholesterol (LDL-C) and/or triglycerides. Results for patients randomized in early efficacy and safety studies were combined in one database and analyzed. This analysis included a total of 231 atorvastatin-treated patients (131 with hypercholesterolemia (HC), 63 with combined hyperlipidemia (CH), 36 with hypertriglyceridemia (HTG), and 1 with hyperchylomicronemia (Fredrickson Type V)). Patients were treated with a cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step 1 diet or a more rigorous diet) and either 2.5, 5, 10, 20, 40, or 80 mg/day of atorvastatin or placebo. Efficacy was based on percent change from baseline in total cholesterol, total triglycerides, LDL-C, very low-density lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apo B), and non-HDL-C/HDL-C. Safety was assessed in all randomized patients. Atorvastatin seemed to preferentially lower those lipid and lipoprotein component(s) most elevated within each dyslipidemic state: LDL-C in patients with HC, triglycerides and VLDL-C in patients with HTG, or all 3 in patients with CH. Atorvastatin was well-tolerated with a safety profile similar to other drugs in its class.",1997.0,0,0 3059,9182655,Long term effect of LDL apheresis on coronary heart disease.,M G Donner; W O Richter; P Schwandt,"LDL-apheresis is a treatment option for patients with coronary heart disease and severe hypercholesterolemia not adequately responding to drug treatment. 34 patients (21 men, 13 women), aged 47 +/- 9 years, with coronary heart disease and heterozygous familial hypercholesterolemia not adequately responsive to lipid lowering drugs received weekly (4 patients biweekly) LDL apheresis for 3.5 +/- 2.5 years, after 0.5 - 3.0 years simvastatin in the maximally tolerable dose was added. Baseline LDL cholesterol concentration under diet and lipid lowering drugs in the patients receiving immunoadsorption, dextran sulfate adsorption and HELP apheresis was 265.4 +/- 54.9, 230.8 +/- 75.8 and 253.7 +/- 55.7 mg/dl, respectively. The calculated mean LDL cholesterol concentration of the last 5 treatments of the observation period was 123.7 +/- 22.8, 126.8 +/- 26.7 and 138.8 +/- 19.7 mg/dl, respectively. The evaluation of coronary angiographies revealed a definite regression of coronary lesions in 3 patients (8.8%), in all other patients there was a stop in progression. 3 patients died of cardiac complications during the observation period. We conclude that aggressive lipid lowering with combined LDL-apheresis and drugs can stabilize coronary atherosclerosis in most patients with refractory hypercholesterolemia.",1997.0,0,0 3060,9183229,"A comparison of estrogen replacement, pravastatin, and combined treatment for the management of hypercholesterolemia in postmenopausal women.",M H Davidson; L M Testolin; K C Maki; S von Duvillard; K B Drennan,"To evaluate and compare the lipid-altering effects of conjugated estrogens and pravastatin, alone and in combination, in postmenopausal women with hypercholesterolemia. This was a double-blind, randomized, placebo-controlled clinical trial with 4 parallel groups. Participants (N = 76) were randomly assigned to receive conjugated estrogens, 0.625 mg/d; pravastatin sodium, 20 mg/d; conjugated estrogens plus pravastatin; or a placebo for 16 weeks. Primary end points were changes in serum lipid parameters. Among participants treated with conjugated estrogens, levels of non-high density lipoprotein cholesterol (non-HDL-C) (13.0%) and calculated low density lipoprotein cholesterol (LDL-C) (13.5%) decreased, while levels of HDL-C (22.5%) and triglycerides (4.2%) increased. Participants in the pravastatin group achieved reductions of 23.7% and 25.4% in non-HDL-C and calculated LDL-C levels, respectively. Levels of HDL-C increased slightly (3.7%) and triglycerides decreased by 12.1%. Among participants treated with a combination of conjugated estrogens plus pravastatin, the non-HDL-C (-25.2%) and calculated LDL-C (-28.7%) responses were similar to those of the pravastatin group, and the HDL-C response (21.2%) was similar to that observed in the conjugated estrogens group. Triglyceride levels remained similar to baseline (-0.9%) in the combined treatment group. Administration of conjugated estrogens resulted in potentially antiatherogenic changes in levels of non-HDL-C, HDL-C, and calculated LDL-C. The HDL-C response to combined treatment was similar to that observed in women taking conjugated estrogens alone, while the non-HDL-C and LDL-C responses to combined treatment were similar to those produced by pravastatin therapy alone. These findings support the position of the National Cholesterol Education Program that estrogen replacement, with a progestin where indicated, should be given consideration as a therapeutic option for the management of hypercholesterolemia in postmenopausal women.",1997.0,0,0 3061,9184704,Combination of low-dose niacin and pravastatin improves the lipid profile in diabetic patients without compromising glycemic control.,S F Gardner; M A Marx; L M White; M C Granberry; D R Skelton; V A Fonseca,"To determine the efficacy and tolerability of the addition of low-dose niacin (1.5 g/d) in a diabetic hypercholesterolemic population who were unable to attain desired lipid control with low-dose (20 mg) pravastatin monotherapy. This was a prospective, open-label study conducted over a 14-week period. Twenty-three diabetic patients with low-density lipoprotein (LDL) cholesterol concentrations of at least 150 mg/dL after dietary therapy were recruited from the outpatient diabetes clinic of a university teaching hospital. After 4 weeks of dietary stabilization and baseline determination of the lipid profile and glycemic control, patients received pravastatin 20 mg once daily for 4 weeks. Laboratory parameters were reassessed and niacin was added to the regimen in qualifying patients. Over 2 weeks, patients' regimens were titrated to a maximal dosage of 500 mg tid. Patients continued to receive the combination regimen for 4 weeks and were reassessed. Sixteen patients (14 non-insulin-dependent diabetes mellitus, 2 insulin-dependent diabetes mellitus) completed the study. Mean fasting blood sugar and fructosamine concentrations were unchanged throughout the study. Five patients required minor alterations (3 increased, 2 decreased) in their hypoglycemic regimens during the study. The addition of low-dose niacin to pravastatin therapy resulted in a significant lowering of LDL cholesterol compared with pravastatin monotherapy. Low-dose niacin is a promising addition to hydroxymethylglutaryl-coenzyme A reductase inhibitor therapy in the treatment of hypercholesterolemia in patients with diabetes mellitus.",1997.0,0,0 3062,9184709,The use of alternate-day lovastatin in hypercholesterolemic men.,V C Dennis; M L Britton; S M Sirmans; N A Letassy; D A Freeman,"To quantitate the therapeutic effects of alternate-day lovastatin on serum lipoprotein values in a small group of men with primary hypercholesterolemia. Retrospective review of medical, pharmacy, and laboratory records. A paired Student's t-test was performed on absolute changes in lipoprotein values with an a priori p value less than or equal to 0.05 being statistically significant. A lipid clinic within a tertiary care Department of Veterans Affairs Medical Center. Twenty men (mean age 62.5 +/- 8.3 y) with mean +/- SD baseline low-density lipoprotein cholesterol (LDL-C) concentration of 161.3 +/- 21.9 mg/dL and triglyceride concentrations below 400 mg/dL. All patients had been prescribed lovastatin 20 mg every other day. The mean absolute and percent changes in lipoprotein values from baseline for patients receiving lovastatin 20 mg every other day and the percentage of patients attaining a target mean LDL-C concentration as defined by the National Cholesterol Education Panel Adult Treatment Panel II guidelines. Mean +/- SD total cholesterol and LDL-C were significantly reduced by 32.4 +/- 17.8 (14.0% +/- 7.8%) and 34.1 +/- 14.6 mg/dL (21.5% +/- 9.7%), respectively. No significant changes were seen in high- density lipoprotein cholesterol or triglycerides. Four of 20 patients (20%) attained a goal LDL-C concentration. Lovastatin 20 mg every other day may effectively lower LDL-C in some elderly men, and target LDL-C concentrations may be obtained in some patients.",1997.0,0,0 3063,9184710,Implementation of pharmaceutical care services for patients with hyperlipidemias by independent community pharmacy practitioners.,M C Shibley; C B Pugh,"To implement and evaluate pharmaceutical care services for patients with hyperlipidemias in the community pharmacy setting, to evaluate the results of a pharmaceutical care training process for pharmacists by using an assessment quiz, and to measure patient outcomes resulting from provision of pharmaceutical care to patients with hyperlipidemia. A prospective study was conducted over a 1-year period. Patients served as their own controls. Two independent community pharmacies in Richmond, Virginia. Twenty-five adult patients with confirmed dyslipidemias completed the study. Study pharmacists assessed each patient and assisted in setting therapeutic goals; patients also completed a visit with a registered dietitian. Drug therapy recommendations were made to physicians by the pharmacist when appropriate. Follow-up was scheduled with the pharmacist to ensure positive outcomes and reduce adverse effects. Fasting lipoprotein profiles were measured initially and at 6 and 12 months. The SF-36 survey, the MacKeigan-Larson satisfaction survey, and a patient opinion survey were administered initially and at the conclusion of the study. Total cholesterol and low-density lipoprotein cholesterol values were significantly decreased at 12 months compared with either the baseline or 6-month values (p < 0.02). Significant improvement was found in several domains of the surveys; quality of life, patient satisfaction with pharmacy services, and patient opinions on the role of the pharmacist improved after the intervention. Pharmaceutical care may positively affect lipid values, quality of life, and patient satisfaction.",1997.0,0,0 3064,9185636,Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia. Atorvastatin Study Group I.,M Davidson; J McKenney; E Stein; H Schrott; R Bakker-Arkema; R Fayyad; D Black,"This double-blind study to evaluate long-term efficacy and safety of atorvastatin was performed in 31 community- and university-based research centers in the USA to directly compare a new 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (reductase inhibitor) to an accepted drug of this class in patients with moderate hypercholesterolemia. Participants remained on a cholesterol-lowering diet throughout the study. One thousand forty-nine patients were randomized to receive atorvastatin 10 mg, lovastatin 20 mg, or placebo. At 16 weeks the placebo group was randomized to either atorvastatin or lovastatin treatment. At 22 weeks, patients who had not met low-density lipoprotein (LDL) cholesterol target levels doubled the dose of reductase inhibitor. Efficacy evaluation was mean percent change from baseline in LDL cholesterol, triglycerides, total cholesterol, high-density-lipoprotein cholesterol, and apolipoprotein B (apoB). Safety profiles as determined by change from baseline in laboratory evaluations, ophthalmologic parameters, and reporting of adverse events were similar for the 2 reductase inhibitors. After 52 weeks, the atorvastatin group maintained a significantly greater reduction in LDL cholesterol (-37% vs -29%), triglyceride (-16% vs -8%), total cholesterol (-27% vs -21%), and apoB (-30% vs -22%) (p <0.05). More patients receiving atorvastatin achieved LDL cholesterol target levels than did lovastatin patients (78% vs 63%, respectively), particularly those with coronary heart disease (37% vs 11%, respectively). Atorvastatin is highly effective and well tolerated in patients with primary hypercholesterolemia with no increased risk of adverse events.",1997.0,1,1 3065,9185802,General internal medicine.,E B Larson; J V Sheffield,,1997.0,0,0 3066,9187418,Time course of serum lipids and apolipoproteins after acute myocardial infarction: modification by pravastatin.,H Kesteloot; G Claeys; N Blanckaert; E Lesaffre,Pravastatin was administered to patients suffering an acute myocardial infarction starting with a dose of 10 mg/day at day 3 and continuing with a dose of 20 mg/day up to a period of 3 months. The study was performed on the basis of a randomized placebo-controlled double-blind trial. At the dosage used pravastatin significantly lowered the total cholesterol and LDL-cholesterol levels and increased the HDL-cholesterol levels compared to placebo. A prospective clinical trial in order to examine the possible clinical relevance of these findings is recommended.,1997.0,0,0 3067,9187828,Nonpulmonary medical complications in the intermediate and long-term survivor.,J R Maurer; S Tewari,"This article deals with the nonpulmonary, non-infectious complications in intermediate and long-term survivors of lung transplantation. Although they are an infrequent cause of mortality, these disorders can cause significant morbidity in this population. Diseases associated with the gamut of medications used post-transplant are specifically discussed, as are diseases caused by the direct immunosuppressive action of some of these drugs. General care of transplant patients also entails attention to their underlying diseases, and to routine medical considerations common to all patients.",1997.0,0,0 3068,9191492,The promise and practice of cardiovascular risk reduction: a disease management perspective. Clinical Quality Improvement Network (CQIN) Investigators.,T Montague; P Montague; V Dzavik; K Teo,"Interpretive analysis of epidemiological, clinical trials and practice pattern data for cardiovascular risk reduction in the contemporary setting of unprecedented demographic changes. Literature review and audit results of the Clinical Quality Improvement Network (CQIN). Coronary artery disease (CAD) is the largest single cause of death in Canada. CAD is age-related and the population is rapidly ageing, a combination that threatens an epidemic of future CAD events. Epidemiological data demonstrate a direct relation of CAD risk and serum cholesterol levels and no threshold cholesterol level below which there is no CAD risk. The epidemiological data also suggest CAD risk can be reduced by lowering serum cholesterol and this hypothesis has now been incontrovertibly confirmed by repeated randomized clinical trials. Most recently, reduction of all-cause mortality with cholesterol-lowering therapy in high risk subjects has also been confirmed. Despite the overwhelming trials and epidemiological evidence, CQIN effectiveness analyses reveal far from optimal risk assessment and management practices among high risk patients. Serum cholesterol is directly related to CAD risk. Reduction of cholesterol reduces CAD, and all-cause, mortality in high risk patients. There is a large window of opportunity to improve lipid-lowering practices, and patient outcomes, for the most deadly diseases in our society.",1996.0,0,0 3069,9192327,Paradise regained: insights into coronary heart disease prevention from recent clinical trials and basic research.,B Lewis; G F Watts,"Many of the uncertainties regarding the place of lipid lowering in the prevention of coronary heart disease have recently been resolved. Some of the newer findings are reviewed, and the scope for a revised clinical approach examined. The results of trials of lipid lowering, based on clinical end-points and particularly on angiographic end-points, and their meta-analyses are discussed. The close relation between coronary-angiographic and clinical outcomes is reviewed in relation to recent advances in understanding of the underlying arterial pathology, and possible underlying mechanisms are proposed. The variables predictive of progression of coronary artery disease, including nutrient intake, are examined. The management of hyperlipidaemia requires that treatment and therapeutic goals are consonant with the patient's cardiovascular risk; for this purpose, clinical and biochemical assessment of risk may be enhanced by angiographic and non-invasive methods to detect potentially-infarctogenic atherosclerotic lesions.",1997.0,0,0 3070,9192484,Pathophysiology and treatment of lipid perturbation after cardiac transplantation.,C M Ballantyne; B el Masri; J D Morrisett; G Torre-Amione,"In this review we examine the complex interactions between lipoprotein metabolism, immunosuppressive drug therapy, and inflammation and the potential benefits of lipid-lowering drug therapy after heart transplantation. The newer formulations of cyclosporine, Neoral (Novartis Pharmaceuticals; Basle, Switzerland), and other newer agents such as tacrolimus may have advantages in regard to lipid metabolism as compared with traditional triple-drug immunosuppression. Lipoprotein levels may influence both the toxicity and efficacy of cyclosporine. Dyslipidemia may adversely influence inflammation and rejection in the allograft. Two recent clinical trials have shown that lipid-lowering therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor alone or in combination with low-density lipoprotein apheresis may confer significant benefits toward preventing transplant coronary artery disease.",1997.0,0,0 3071,9193431,"Genetic variant showing a positive interaction with beta-blocking agents with a beneficial influence on lipoprotein lipase activity, HDL cholesterol, and triglyceride levels in coronary artery disease patients. The Ser447-stop substitution in the lipoprotein lipase gene. REGRESS Study Group.",B E Groenemeijer; M D Hallman; P W Reymer; E Gagné; J A Kuivenhoven; T Bruin; H Jansen; K I Lie; A V Bruschke; E Boerwinkle; M R Hayden; J J Kastelein,"Lipoprotein lipase (LPL) is the rate-limiting enzyme in the lipolysis of triglyceride-rich lipoproteins, and the gene coding for LPL is therefore a candidate gene in atherogenesis. We previously demonstrated that two amino acid substitutions in LPL, the Asn291-Ser and the Asp9-Asn, are associated with elevated triglycerides and lower HDL cholesterol and are present with greater frequency in coronary artery disease (CAD) patients than in normolipidemic control subjects. Conversely, a third frequent mutation in this gene, the Ser447-Stop, is reported by some investigators to underlie higher HDL cholesterol levels and would represent a beneficial genetic variant in lipoprotein metabolism. We therefore sought conclusive evidence for these allegations by investigating the effects of the LPL Ser447-Stop mutation on LPL and hepatic lipase (HL) activity, HDL cholesterol, and triglycerides in a large group of CAD patients (n = 820) with normal to mildly elevated total and LDL cholesterol levels. Carriers of the Ser447-Stop allele (heterozygotes and homozygotes) had significantly higher postheparin LPL activity (P = .034), normal postheparin HL activity (P = .453), higher HDL cholesterol levels (P = .013), and lower triglyceride levels (P = .044) than noncarriers. The influence of the Ser447-Stop allele on LPL activity was pronounced in patients using beta-blockers (P = .042) and not significant in those not using them (P = .881), suggesting a gene-environment interaction between the Ser447-Stop mutation and beta-blockers. We conclude that the LPL Ser447-Stop mutation has a significant positive effect on LPL activity and HDL cholesterol and triglyceride levels and that certain subgroups of CAD patients carrying the Ser447-Stop mutation will have less adverse metabolic effects when placed on beta-blockers. The LPL Ser447-Stop mutation therefore should have a protective effect against the development of atherosclerosis and subsequent CAD.",1997.0,0,0 3072,9195116,Fosinopril. Clinical pharmacokinetics and clinical potential.,H Shionoiri; M Naruse; K Minamisawa; S Ueda; H Himeno; S Hiroto; I Takasaki,"Fosinopril is a phosphorus-containing ester prodrug of an angiotensin-converting enzyme (ACE) inhibitor. It is hydrolysed mainly in the gastrointestinal mucosa and liver to the active diacid, fosinoprilat, which has unique pharmacological properties. The majority of the active moieties of other ACE inhibitors are excreted in the urine. This means that an adjustment in either the dosage and/or the administration interval is needed in patients with moderate to severe renal dysfunction, in order to reduce drug accumulation and the possibility of an excessive decrease in blood pressure or other adverse effects. On the other hand, fosinoprilat is excreted both in urine and bile (as with temocaprilat, zofenoprilat and spiraprilat), and thus an adjustment of dosage and/or administration interval may be unnecessary in patients with moderate to severe renal dysfunction, as impaired renal function influences little of the pharmacokinetics of fosinoprilat. Furthermore, the available evidence suggests that the pharmacokinetic variables of fosinoprilat in patients receiving haemodialysis were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dose administration following dialysis may be unnecessary. The hypotensive effect of the combination of fosinopril and a diuretic is synergistic. Pharmacokinetic interactions with fosinopril are unlikely in patients receiving thiazide or loop diuretics. Fosinopril has beneficial effects for patients with hypertension and left ventricular hypertrophy because it produces an adequate reduction in blood pressure and reversal of left ventricular hypertrophy. There are a large number of studies of the pharmacokinetics of fosinopril. However studies of its pharmacokinetic drug interactions with other drugs are far fewer. Further investigations are needed in several clinical settings.",1997.0,0,0 3073,9195119,"General medicine update: NIDDM, prevention of CAD, & risks & benefits of hormone replacement therapy.",J V Sheffield,,1997.0,0,0 3074,9199267,Surface expression of low density lipoprotein receptor in EBV-transformed lymphocytes: characterization and use for studying familial hypercholesterolemia.,P Chan; C Jones; R Lafrenière; H G Parsons,"The objectives of the present study were to characterize the surface expression of low density lipoprotein receptor (LDL-R) in Epstein-Barr virus transformed lymphocytes (EBV-L) and to determine the applicability of the cellular system for the study of familial hypercholesterolemia. The EBV-L subsets and LDL-R expression were determined by immuno-cytofluorimetry. The LDL-R expression in EBV-L which consisted of mostly B cells was no different among antigenic subsets. EBV-L cultured in lipoprotein deficient serum demonstrated a 9.3-fold higher LDL-R expression than primary lymphocytes. Lovastatin caused an additional 1.9-and 1.4-fold increase in EBV-L and primary lymphocytes respectively. This difference in lovastatin response is statistically significant (paired t-test, P < 0.001). 54% of the high LDL-R expression in EBV-L was related to the changes in proliferation measured as stimulation index (SI). LDL and lovastatin modulated the LDL-R expression without affecting SI. FH subjects demonstrated 2% (homozygote, n = 1) and 44.6 +/- 12.3% (heterozygotes, n = 35) in LDL-R expression of controls (n = 30). This maintenance of the FH phenotype and the intrinsically high LDL-R expression in EBV-L make the cellular system suitable for the study of FH as well as the regulation of LDL-R.",1997.0,0,0 3075,9199281,Simvastatin reduces forearm vascular responsiveness to norepinephrine.,D Abbott; A Daher; P Manwaring; L G Howes,,1997.0,0,0 3076,9201001,Stain therapy and reduced incidence of stroke. Implications of cholesterol-lowering therapy for cerebrovascular disease.,A M Gotto,,2001.0,0,0 3077,9201004,Reductase inhibitor monotherapy and stroke prevention.,J R Crouse; R P Byington; H M Hoen; C D Furberg,"Epidemiologic evidence and meta-analyses of data from early clinical trials suggest that lowering the levels of cholesterol does not reduce the events of stroke. These analyses have not included more recent clinical trials using reductase inhibitors. To conduct a meta-analysis of the effect of reducing cholesterol levels on stroke in all reported clinical trials of primary (n = 4) and secondary (n = 8) prevention of coronary heart disease that used reductase inhibitor monotherapy and provided information on incident stroke. Analysis of combined data from primary and secondary prevention trials showed a highly statistically significant reduction of stroke associated with the use of reductase inhibitor monotherapy (27% reduction in stroke; P = .001). Analysis of secondary prevention trials alone disclosed a similar statistically significant effect (32% reduction in stroke; P = .001). A smaller nonsignificant reduction in stroke was noted in the primary prevention trials (15% reduction in stroke; P = .48). Reductase inhibitors now in use for lowering cholesterol levels are more potent and have fewer side effects than the cholesterol-lowering agents previously available. They appear to reduce stroke, most notably in patients with prevalent coronary artery disease, which may be partly due to the effects of lowering the levels of cholesterol on the progression and plaque stability of extracranial carotid atherosclerosis or the marked reduction of incident coronary heart disease associated with treatment.",2001.0,0,0 3078,9202359,Results of recent large cholesterol-lowering trials and implications for clinical management.,A M Gotto,"Three recent large clinical trials-the West of Scotland Coronary Prevention Study, the Scandinavian Simvastatin Survival Study, and the Cholesterol and Recurrent Events Trial-have all confirmed that cholesterol lowering with HMG-CoA reductase inhibitors is safe and effective therapy to prevent an initial or recurrent coronary event in patients at high risk for coronary heart disease. However, a number of questions related to the treatment of lipid disorders and risk reduction for coronary heart disease remain, including the cholesterol concentration at which treatment would best be initiated, the optimal cholesterol reduction or goal to be attained, and the mechanisms by which HMG-CoA reductase inhibitors reduce the risk for clinical events.",2001.0,0,0 3079,9202362,Intravascular ultrasound analysis of reduction in progression of coronary narrowing by treatment with pravastatin.,T Takagi; K Yoshida; T Akasaka; T Hozumi; S Morioka; J Yoshikawa,Serial intravascular ultrasound studies were performed to evaluate the effect of pravastatin on coronary atherosclerotic plaque. Administration of pravastatin reduced serum lipid levels and progression of coronary artery atherosclerotic plaque.,1997.0,0,0 3080,9205017,"A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia.",A Dart; G Jerums; G Nicholson; M d'Emden; I Hamilton-Craig; G Tallis; J Best; M West; D Sullivan; P Bracs; D Black,"We directly compared the safety and efficacy of atorvastatin and simvastatin in hypercholesterolemic patients. This 1-year, randomized, double-blind study was performed at 9 community- and university-based research hospitals in Australia. One-hundred seventy-seven patients between the ages of 18 and 80 years with baseline low-density-lipoprotein (LDL) cholesterol > or = 4.14 and < or = 7.76 mmol/L (160 and 300 mg/dl, respectively) and triglycerides < or = 4.52 mmol/L (400 mg/dl) received once-daily dosing with atorvastatin (Lipitor) 10 mg or simvastatin (Zocor) 10 mg. At week 16, the dose of medication was titrated to atorvastatin 20 mg or simvastatin 20 mg if patients did not meet LDL cholesterol target of < or = 3.36 mmol/L (130 mg/dl). Efficacy was reported as percent change from baseline in LDL cholesterol, total cholesterol, very low density lipoprotein cholesterol, total triglycerides, high-density lipoprotein cholesterol, apolipoproteins AI and B, and lipoprotein(a). Atorvastatin caused significantly greater reductions from baseline than did simvastatin for LDL cholesterol, total cholesterol, very low density lipoprotein cholesterol, triglycerides, and apolipoprotein B (p <0.05). No patient in either treatment group had clinically important elevations in creatine phosphokinase, alanine aminotransaminase, or aspartate aminotransaminase. No serious adverse events were considered associated with treatment. With atorvastatin 10 mg, 46% of the patients achieved LDL cholesterol target goal by week 16, whereas only 27% of the simvastatin patients achieved the target goal at the 10-mg dose. This cholesterol-lowering profile affords utility in many patient types.",1997.0,1,1 3081,9205026,Effect of fluvastatin on low-density lipoprotein peak particle diameter.,H R Superko; R M Krauss; C DiRicco,"The effect of fluvastatin on low-density lipoprotein (LDL) particle diameter was investigated in 42 hypercholesterolemic patients. Fluvastatin reduced LDL cholesterol significantly but had no effect on LDL particle diameter; it also had no differential effect on patients classified as LDL pattern A (large LDL), pattern B (small LDL), or I (intermediate LDL).",1997.0,0,0 3082,9205036,The rule of 5 and the rule of 7 in lipid-lowering by statin drugs.,W C Roberts,,1997.0,0,0 3083,9205850,Management of lipid disorders in the elderly.,D A Playford; G F Watts,"Cardiovascular disease has been inseparable from aging in developed societies and, as a result, it is the commonest cause of mortality in elderly populations. Atherosclerosis is associated with the progressive vascular accumulation of cholesterol-laden lipoproteins, and is linearly associated with the plasma level of low density lipoprotein (LDL) cholesterol. Clinical trials in patients aged < 65 years have conclusively shown that treatment of hypercholesterolaemia decreases the incidence of cardiovascular events and total mortality. However, few conclusive data are available regarding the treatment of hypercholesterolaemia in elderly patients. Extrapolation from clinical trials suggests that lipid lowering treatment in well selected elderly patients is effective in preventing cardiovascular events and is an efficient use of healthcare resources. In addition to cholesterol, high triglyceride and low high-density lipoprotein levels appear to be significant predictors of coronary artery disease in elderly patients. We do not advocate the indiscriminate screening of healthy elderly patients who have no other cardiovascular risk factors, because the marginal overall benefits are probably small and the costs of widespread screening and treatment high. On the other hand, chronological age itself cannot be considered a barrier to the screening and treatment of patients who have a good quality of life but have other cardiovascular risk factors and/or definite cardiovascular disease. Subgroup analysis of major clinical trials suggests that the aims of treatment should be to lower the LDL cholesterol level to 3.2 mmol/L (125 mg/dl), or the total cholesterol level to 5.2 mmol/L (200 mg/dl). Occasionally, multiple drug therapy is required to achieve this target, but statins (HMG-CoA reductase inhibitors) are the most commonly used first-line agents. With aggressive lowering of plasma lipid levels in this way, a reduction in clinical events is paralleled by regression of atheroma detectable by angiography, and an improvement in endothelial function. Global reduction of risk factors in elderly patients should always be undertaken, including dietary therapy, weight reduction in viscerally obese patients, postmenopausal estrogen replacement, smoking cessation, treatment of hypertension and control of diabetes mellitus. A secondary cause of dyslipidaemia should also be sought. The role of antioxidants is still not clear, but they are probably of little benefit in elderly patients. With the widespread use of effective, well tolerated treatments for lipid disorders in younger patients, significant improvements have already been attained in the morbidity and mortality associated with coronary artery disease. Since the current life expectancy at age 65 years is nearly 20 years in most Western countries, secondary prevention may increase the quality of life and the independent lifespan, even if eventual mortality is not delayed.",1997.0,0,0 3084,9207626,Platelet-dependent thrombin generation in patients with hyperlipidemia.,I Aoki; N Aoki; K Kawano; K Shimoyama; A Maki; M Homori; A Yanagisawa; M Yamamoto; Y Kawai; K Ishikawa,"We evaluated coagulability as determined by platelet-dependent thrombin generation in hypercholesterolemic patients before and after treatment with pravastatin and in hypertriglyceridemic patients to investigate the usefulness of coagulability as an index of atherosclerosis and to determine the importance of treating hyperlipidemia. An understanding of the interaction between platelets and the plasma coagulation system is important for clarifying the mechanism of the procoagulant process. We assessed coagulability in 58 patients with hypercholesterolemia (serum total cholesterol level > or = 220 mg/dl, age 56.5 +/- 1.5 years [mean +/- SEM]), 37 patients with hypertriglyceridemia (serum triglyceride level > or = 200 mg/dl, age 59.5 +/- 1.7 years), 13 patients with hypercholesterolemia plus hypertriglyceridemia (age 51.4 +/- 3.1 years) and 75 normal subjects (age 52.2 +/- 1.7 years). We also studied platelet-dependent thrombin generation in patients with hypercholesterolemia before and after treatment with pravastatin. Calcium chloride was added to 0.5 ml of platelet-rich plasma (150 x 10(9)/liter) to initiate coagulation. Ten microliters of the sample was transferred into 90 microliters of 3.8% sodium citrate at 10-min intervals for 30 min. A chromogenic substrate, S-2238, was added to each sample, and absorbance was measured spectrophotometrically at a wavelength of 405 nm to determine thrombin generation. Platelet-dependent thrombin generation was increased in patients with hypercholesterolemia and patients with hypercholesterolemia plus hypertriglyceridemia (p < 0.01) compared with patients with hypertriglyceridemia and control subjects. Treatment with pravastatin normalized thrombin generation. Hypercholesterolemia, but not hypertriglyceridemia, was associated with increased platelet-dependent thrombin generation. Pravastatin normalized the generation of thrombin.",1997.0,0,0 3085,9208077,Screening for and treatment of hypercholesterolaemia--a review.,K Hughes,"The screening for and treatment of hypercholesterolaemia is still a complex and controversial issue. As hypercholesterolaemia is a major risk factor for coronary heart disease (CHD), there was initially much enthusiasm for mass screening with intervention recommended for persons with serum cholesterol levels > or = 6.5 mmol/L. However, trials of treatment of hypercholesterolaemia using lipid lowering drugs showed overall benefit (i.e. reduced all-cause mortality) only for persons with pre-existing CHD (secondary prevention) or other major risk factors. For this and other reasons (e.g. cost effectiveness) screening for hypercholesterolaemia has been recommended for persons with CHD or major risk factors (family history of premature coronary heart disease, cigarette smoking, hypertension, and diabetes mellitus). Recent trials with statins have shown greater benefit than with other lipid lowering drugs, confirming the benefits of secondary prevention. In addition, one trial has shown overall benefit after 5 years for middle-aged hypercholesterolaemic males without a previous myocardial infarction, raising the possibility of mass screening. However, longer follow-up of a number of trials of primary prevention including on persons without risk factors together with a full assessment of the local situation with regards to hypercholesterolaemia is needed before mass screening can be recommended.",1997.0,0,0 3086,9208356,Short-term safety and efficacy of low-dose simvastatin in elderly patients with hypertensive hypercholesterolemia and fasting hyperinsulinemia.,P Chan; T Y Huang; B Tomlinson; C Lee; Y S Lee,"To evaluate the short-term safety and efficacy of low-dose (10 mg) simvastatin in hypercholesterolemic, hypertensive elderly Chinese patients receiving antihypertensive treatment, a randomized, double-blind, placebo-controlled, 3-month trial was conducted. The patients had a total plasma cholesterol level of at least 250 mg/dL and had been, for at least 3 months, consuming a standard lipid-lowering diet (American Heart Association Step 1 Diet). Elderly hypertensive patients (n = 76) were randomized to receive treatment with either placebo (n = 38) or simvastatin (n = 38). The dosage consisted of 10 mg simvastatin daily during the 3-month trial. During that period, in the simvastatin group, plasma levels of total cholesterol and low-density lipoprotein cholesterol decreased significantly (27% and 33%, respectively) compared with those levels in plasma in the placebo group. The plasma levels of high-density lipoprotein cholesterol increased (7%), whereas triglyceride levels slightly decreased (8%). There were no serious side effects, and simvastatin was generally well tolerated. Fasting hyperinsulinemia also improved (-21%) after 3 months of simvastatin therapy. Results of this study confirmed that a low dose (10 mg) of simvastatin daily is a safe and effective method of reducing plasma levels of total and low-density lipoprotein cholesterol in hypercholesterolemic, hypertensive elderly patients receiving concurrent antihypertensive drug therapy, and that it has the additional potential benefit of reducing plasma levels of insulin.",1997.0,0,0 3087,9215232,Rationale and design features of a clinical trial examining the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). SCAT Investigators.,K K Teo; J R Burton; C Buller; S Plante; S Yokoyama; T J Montague,"In the treatment of coronary atherosclerotic artery disease (CAD), the mechanisms by which lipid lowering, a proven therapy, produces beneficial clinical effects remain unclear. Moreover, although potential mechanisms of benefit are well known and increasingly applied clinically, there are no conclusive data from clinical trials studying primarily the antiischemic effects of angiotensin-converting enzyme (ACE) inhibition in patients with normal heart function. The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT) is designed to clarify some of these issues in CAD patients with normal or mildly elevated cholesterol. DESIGN AND OBJECTIVES: SCAT is a three- to five-year, multicentre, randomized, double-blind, placebo controlled, 2 x 2 factorial trial evaluating the effects of cholesterol lowering therapy by simvastatin and/or ACE inhibition by enalapril on anatomic coronary atherosclerosis progression assessed by quantitative coronary angiography in CAD patients with preserved left ventricular function and total cholesterol levels between 4.1 and 6.2 mmol/L. Of 460 patients (age 61 +/- 9 years; 409 males, 51 females) enrolled between June 1991 and July 1995, 230 were randomized to simvastatin and 230 to placebo, and 229 to enalapril and 231 to placebo. Average baseline total cholesterol level was 5.20 +/- 0.61 mmol/L, high density lipoprotein cholesterol was 0.99 +/- 0.25 mmol/L, low density lipoprotein cholesterol was 3.36 +/- 0.57 mmol/L and triglycerides were 1.82 +/- 0.75 mmol/L. The trial will be completed in June 1998. Insights gained from this long term angiographic trial will lead to a better understanding of the mechanisms of benefits of these two treatments, both alone and in combination. Of particular interest is that this trial will be able to examine a suspected beneficial interaction, if present, between these two treatments.",1997.0,0,0 3088,9217621,The efficacy of lovastatin in lowering cholesterol in African Americans with primary hypercholesterolemia.,R L Fong; H J Ward,"To evaluate the efficacy of lovastatin in African Americans (AA) diagnosed with primary hypercholesterolemia. Forty-seven AA patients from the King/Drew Medical Center in Los Angeles were recruited from the Hypertension, Family Practice, and General Medicine Clinics for a double-blinded, placebo-controlled trial. Forty-one patients completed the 10 week study. Eligibility for entrance into the study was determined by patient lipid profiles meeting the criteria for pharmacological intervention outlined by the National Cholesterol Education Program II guidelines. Patients were randomized into 2 groups: lovastatin 20 mg per day, or placebo. A registered dietitian counseled both groups on two visits during the study to ensure compliance with a low fat, low cholesterol diet. Lipid levels were compared at the first and last visit of the study. The lovastatin-treated group demonstrated significant reductions in mean total cholesterol (TC) (14.7%, 95% confidence interval [CI]-6.6 to -22.8, P < 0.01) and low-density lipoprotein (LDL) cholesterol (20.0%, 95% CI-7.9 to -32.1, P < 0.01) from baseline. Plasma triglyceride (TG) levels decreased by 10.5% (95% CI-2.4 to -18.6) and total cholesterol/high density lipoprotein (HDL) ratio fell below five in the lovastatin group, but neither reduction reached statistical significance. Placebo administration was not associated with any significant changes in TC, LDL, or TG. There were no significant differences between baseline and post-treatment hepatic transaminase levels in either group. The HMG-CoA (3-hydroxyl-3 methylglutary coenzyme A) reductase inhibitor lovastatin in a dose of 20 mg per day was effective in decreasing TC, LDL, and TG levels in an AA population. Considering that the AA population is at substantially increased risk for hypertension and cardiovascular morbidity, more aggressive and wider use of HMG-CoA reductase inhibitors should be employed in reducing elevated plasma cholesterol levels.",1997.0,0,0 3089,9217673,The secondary prevention of coronary artery disease.,C N Merz; A Rozanski; J S Forrester,"Randomized clinical trials demonstrate the efficacy of medical secondary prevention in coronary disease patients. The magnitude of risk reduction with exercise, diet, lipid modification, and smoking cessation is similar to other medical therapies for coronary disease such as aspirin, beta blockers, as well as coronary bypass surgery, (Table VI) In contrast to these therapies, however, secondary prevention stabilizes angiographic progression in about 50% of patients and induces regression in about 25% of patients. Both symptoms and perceived quality of life also are beneficially altered by secondary prevention programs, although possibly not by the magnitude reported for bypass surgery. These clinical trial results have led the American Heart Association, and the American College of Cardiology to strongly endorse secondary prevention. A reasonable projection based on these clinical trial data is that widespread use of these recommendations in the 12 million established coronary disease patients would significantly reduce coronary mortality and morbidity.",1997.0,0,0 3090,9220213,Effects of low-dose simvastatin therapy on serum lipid levels in patients with moderate hypercholesterolemia: a 12-month study. The Simvastatin Study Group.,T Itoh; M Matsumoto; H Hougaku; N Handa; Y Tsubakihara; Y Yamada; M Imaizumi; M Hoshi; Y Shimazu; M Hori; R Kawamori; N Ueda; H Fusamoto; T Kamada,"The aim of this study was to investigate the safety and long-term effects on serum lipid levels of low-dose simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in Japanese patients with moderate primary hypercholesterolemia. We assigned 201 patients (68 men and 133 women; mean +/- SD age, 61.3 +/- 10.2 years) with serum total cholesterol levels > or = 220 mg/dL to receive simvastatin 5 mg each evening; the treatment period was 1 year. Serum total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol levels decreased significantly in response to simvastatin therapy, and the changes were maintained throughout the treatment period. Mean total cholesterol decreased from 269.9 +/- 35.4 mg/dL to 215.2 +/- 34.5 mg/dL (20.3%), triglycerides decreased from 183.0 +/- 110.2 mg/dL to 155.5 +/- 88.5 mg/dL (15.0%), and LDL cholesterol decreased from 180.0 +/- 33.1 mg/dL to 130.1 +/- 35.1 mg/dL (27.7%). Total cholesterol, triglycerides, and LDL cholesterol tended to decline when the pretreatment values were higher; the critical values and the bidirectional changes of the serum lipid levels were 188.1, 109.5, and 91.6 mg/dL, respectively. Although the serum level of high-density lipoprotein cholesterol did not change significantly, it tended to increase more when the pretreatment values were lower; the ""critical value"" was 70 mg/dL. Nine patients experienced mild adverse events, but none discontinued simvastatin during the 12-month treatment period. We found that low-dose simvastatin therapy is effective in achieving long-term decreases in serum lipid levels and is well tolerated by patients with moderate hypercholesterolemia. Simvastatin therapy may result in normalization of serum lipid levels.",1997.0,0,0 3091,9220221,Cost-effectiveness of initial therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors to treat hypercholesterolemia in a primary care setting of a managed-care organization.,M E Spearman; K Summers; V Moore; R Jacqmin; G Smith; S Groshen,"From January 1994 through May 1995, Prudential HealthCare-North Texas prospectively studied 299 member patients diagnosed with hypercholesterolemia for whom pharmacotherapy with one of four 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, also known as statins, was prescribed. The purpose of this study was to measure the relative cost-effectiveness (CE) of these drugs in a real-world setting. This study provides information to assist decision makers in managed-care organizations (MCO) in making formulary selections. The study used a prospective, randomized, balanced cohort design, examining patients who had been prescribed initial therapy with a statin drug as monotherapy. Costs (direct medical and indirect costs) and effectiveness (percent reduction in low-density lipoprotein cholesterol levels) were based on approximately the first 6 months of initial therapy. Both the MCO and patient perspectives were considered. In the base case, mean CE ratios were significantly lower for fluvastatin compared with lovastatin, pravastatin, and simvastatin from both the managed-care perspective and the patient perspective. Sensitivity analysis did not alter the CE conclusions, even under conditions of varying cost structures. Although differences were found in the effectiveness of lovastatin, pravastatin, and simvastatin measured in this study versus efficacy measured for these drugs in controlled clinical trials, sensitivity analysis suggests that these differences alone do not determine the superior CE of fluvastatin. Finally, this study supports the idea that well-designed formularies should consider drug CE (based on safety, effectiveness, and cost) and that integration of the pharmacy benefit management with other medical management is essential. These results provide evidence that fluvastatin may represent a more cost-effective formulary choice among statin products used for initial monotherapy of hypercholesterolemia.",1997.0,0,0 3092,9222121,,,,,0,0 3093,9223386,Statins and fibrates in the management of diabetic dyslipidemia.,P Durrington,,1997.0,0,0 3094,9223394,Comparison of bezafibrate and simvastatin in the treatment of dyslipidaemia in patients with NIDDM.,T Jeck; W F Riesen; U Keller,"Fibrates and HMG CoA reductase inhibitors are commonly used in the treatment of diabetic dyslipidaemia. However, these two groups of drugs have not been compared in diabetic patients in a randomized controlled trial. Therefore, a multicentre study was performed in 73 subjects with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and combined hyperlipidaemia (serum cholesterol 6.2-10.0 mmol l(-1), serum triglycerides 2.3-10.0 mmol l(-1)), comparing the efficacy of 400 mg bezafibrate with 10 mg simvastatin in a double-blind fashion. Treatment with bezafibrate during 12 weeks reduced serum triglycerides significantly more than simvastatin (-41% vs -22%, p < 0.001) and increased HDL cholesterol more (bezafibrate: + 17% vs simvastatin: + 9%, p < 0.05). LDL cholesterol levels decreased by 14% (p < 0.001) during simvastatin and increased by 21% (p < 0.01) during bezafibrate. This increase in LDL cholesterol was positively correlated with fasting serum triglycerides (p < 0.001) and was associated with a reduction of the serum apolipoprotein B concentration, suggesting an increase in LDL particle size. Metabolic control of diabetes (fasting glycaemia; HbA1c) and insulin secretion (C-peptide levels) were unaffected by both treatments. The incidence of side-effects during treatment was similar for both drugs. Thus, 400 mg bezafibrate mainly increases HDL cholesterol and lowers serum triglycerides but at the expense of an increase in LDL cholesterol; 10 mg simvastatin lowers LDL cholesterin more effectively but has a smaller effect on HDL cholesterol and triglycerides.",1997.0,0,0 3095,9223762,Lipid-lowering therapy after coronary artery bypass surgery: the Post-CABG trial.,W J Stewart; B J Hoogwerf,"The Post Coronary Artery Bypass Graft trial is an important milestone that documents the benefits of treating hypercholesterolemia in patients with severe coronary atherosclerosis who have had bypass surgery. In the present article, we highlight the rationale, study design, and results of the Post-CABG study, which was recently published in the New England Journal of Medicine.",1997.0,0,0 3096,9226599,Cardiovascular disease and sleep-related erections.,R C Rosen; D N Weiner,"Sexual difficulties are highly prevalent in male patients with cardiovascular diseases, such as hypertension, atherosclerosis, and hypercholesterolemia. Recently, several studies have been conducted on the effects of cardiovascular diseases, as well as associated drug and nondrug treatments, on nocturnal penile tumescence (NPT) and other measures of sexual function. Although an overall trend has been observed toward decreased NPT in patients with chronic hypertension and other cardiovascular conditions, design and methodological difficulties have been noted in most studies, and results have been generally, inconclusive. Similarly, antihypertensive drugs such as beta-blockers and diuretics have been associated with diminished NPT in several studies, although methodological problems have again been noted. Furthermore, the mechanism of action of antihypertensive drugs on sleep-related erections has not been determined. Most recently, a positive effect of cholesterol-lowering drugs (pravastatin, lovastatin) on NPT has been observed in middle-aged males with chronic hypercholesterolemia. Additional studies of the effects of cardiovascular disease on NPT and other measures of sexual function are needed.",1997.0,0,0 3097,9227708,American Heart Association Prevention Conference. IV. Prevention and Rehabilitation of Stroke. Risk factors.,R L Sacco; E J Benjamin; J P Broderick; M Dyken; J D Easton; W M Feinberg; L B Goldstein; P B Gorelick; G Howard; S J Kittner; T A Manolio; J P Whisnant; P A Wolf,,1997.0,0,0 3098,9228438,"Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials.",P R Hebert; J M Gaziano; K S Chan; C H Hennekens,"To examine whether cholesterol lowering with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statin drugs) reduces the risks of stroke and total mortality. We conducted a computerized literature search from 1985 through 1995 to identify all published trials testing statin drugs. The Cholesterol and Recurrent Events (CARE) data were added after the report was published in October 1996. Our search was limited to English-language articles and included published overviews containing relevant individual trials. Criteria for inclusion of randomized trials in the overview were (1) statin drugs alone used to reduce lipid levels rather than multifactorial interventions including another type of cholesterol-lowering drug and (2) inclusion of data on deaths and/or strokes. Data were extracted by 2 researchers, and only minor discrepancies, which were easily resolved by discussion, occurred. Principal investigators of the trials and their funding agencies were also contacted to secure any relevant data not included in the published reports. A total of 16 individual trials including approximately 29 000 subjects treated and followed up an average of 3.3 years were included in the overview. The average reductions in total and low-density lipoprotein cholesterol achieved were large-22% and 30%, respectively. A total of 454 strokes (fatal plus nonfatal) and 1175 deaths occurred. Those assigned to statin drugs experienced significant reductions in risks of stroke of 29% (95% confidence interval [CI], 14%-41%) as well as total mortality of 22% (95% CI, 12%-31%), which was attributable to a significant reduction in cardiovascular disease (CVD) deaths of 28% (95% CI, 16%-37%). There was no evidence of any increased risk in non-CVD mortality (relative risk [RR], 0.93; 95% CI, 0.75-1.14). There was also no significant increase in risk of cancer (RR, 1.03; 95% CI, 0.90-1.17). This overview of all published randomized trials of statin drugs demonstrates large reductions in cholesterol and clear evidence of benefit on stroke and total mortality. There was, as expected, a large and significant decrease in CVD mortality, but there was no significant evidence for any increases in either non-CVD deaths or cancer incidence.",1997.0,0,0 3099,9229398,Benefits of hypercholesterolemia treatment.,M Soma; R Paoletti,,1997.0,0,0 3100,9229399,Simvastatin in the secondary prevention of coronary heart disease.,G Assmann,,1997.0,0,0 3101,9229400,The 4S study: a critical review.,G Crepaldi,,1997.0,0,0 3102,9229401,The 4S study: a critical review.,P Pauciullo,,1997.0,0,0 3103,9229402,Cholesterol-lowering drugs for primary prevention? The WOSCOP Study.,S Muntoni,,1997.0,0,0 3104,9229403,Cholesterol and coronary heart disease: new data from the WOSCOP Study.,A Poli,,1997.0,0,0 3105,9230143,"Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidemia and coronary artery disease.",B G Brown; J Bardsley; D Poulin; L A Hillger; A Dowdy; V M Maher; X Q Zhao; J J Albers; R H Knopp,"The efficacy, safety, and tolerability of a moderate dose, 3-drug lipid-lowering regimen were evaluated among 29 male patients with hyperlipidemia and coronary artery disease. In an initial 12-month phase, regular niacin, 500 mg qid, lovastatin, 20 mg bid, and colestipol, 10 g/bid, were given with dose adjustment for lipid targets and side effects. This was followed by 2 random sequence crossover phases (8 months each) alternating regular niacin with a polygel controlled-release formulation of niacin for use in this regimen. Lipid, lipoprotein, apoprotein, and clinical chemistry determinations were obtained at baseline, during the initial phase, at the 2 crossover phases, and at 6 weeks after therapy. A final questionnaire queried specific side effects and overall preferences. Low-/high-density lipoprotein (LDL/HDL) changed from means of 215/46 mg/dl at baseline, to 94/59 mg/dl after run-in, to 85/52 mg/dl after 8 months of controlled-release niacin, and to 98/56 mg/dl after 8 months of regular niacin (regular niacin vs controlled-release niacin, p <0.005/<0.05). The target of LDL < or = 100 mg/dl was achieved at 8 months by 83% of these patients with controlled-release niacin and by 52% with regular niacin (p <0.01). Compliance was 95% with controlled-release niacin versus 85% with regular niacin (p <0.001). The controlled-release niacin and regular niacin regimens did not differ in terms of uric acid, glucose, insulin, or asparate aminotransferase levels. Overall, 21% of patients called the 3 drugs ""very easy"" and 72% ""fairly easy"" to take. The controlled-release niacin-containing regimen was preferred by 21 patients and the regular niacin by 4. In conclusion, these regimens achieve striking lipid changes among hyperlipidemic patients. Controlled release is the preferred niacin preparation in terms of LDL reduction, compliance, patient preference, and achieving the National Cholesterol Education Program guideline of LDL < or = 100 mg/dl. The 2 niacin preparations did not differ in evidence of toxicity.",1997.0,0,0 3106,9237640,,,,,0,0 3107,9241092,The mechanism of the carbamazepine-valproate interaction in humans.,I Bernus; R G Dickinson; W D Hooper; M J Eadie,"The study investigated the mechanism of the interaction between valproate and carbamazepine which causes raised plasma carbamazepine-10,11-epoxide concentrations with unchanged plasma carbamazepine concentrations. This interaction has usually been attributed to valproate inhibiting epoxide hydrolase, the enzyme that catalyses the biotransformation of carbamazepine-10,11-epoxide to carbamazepine-10,11-trans-diol. Clearances of plasma carbamazepine, carbamazepine-epoxide and carbamazepine-diol to relevant carbamazepine metabolites present in urine were measured under steady-state conditions in 17 adults receiving carbamazepine as anticonvulsant monotherapy, and in 10 adults taking the drug together with valproate. Plasma carbamazepine-epoxide concentrations were higher, relative to carbamazepine dose, in the co-medicated patients. Plasma apparent clearances of carbamazepine, relative to drug dose, were similar whether or not valproate was taken. Formation clearances of carbamazepine-10,11-trans-diol conjugate, and probably of carbamazepine-10,11-trans-diol, were lower in subjects co-medicated with valproate, and a higher proportion of the carbamazepine dose was excreted in urine as carbamazepine-10,11-epoxide. Valproate appears to inhibit the glucuronidation of carbamazepine-10,11-trans-diol, and probably also inhibits the conversion of carbamazepine-10,11-epoxide to this trans-diol derivative, rather than simply inhibiting the latter reaction only.",1997.0,0,0 3108,9241100,Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets.,H Osamah; R Mira; S Sorina; K Shlomo; A Michael,"High plasma cholesterol concentration and increased platelet activity are two major risk factors for atherosclerosis. Lovastatin, the lipophilic drug was shown to inhibit platelet aggregation whereas pravastatin, the hydrophilic drug had no such effect. Analysis of the effect of fluvastatin which is both a lipophilic and hydrophilic drug, on platelet aggregation was the goal of the present study. Fluvastatin 40 mg daily was administered to 25 patients with hypercholesterolaemia for up to 24 weeks. Normal subjects acted as controls. The influence of fluvastatin on plasma lipids and on platelet aggregation and fluidity was studied. The direct effect of fluvastatin on platelets was compared with that of other statins. Fluvastatin therapy (40 mg day (-1) for a period of 4 weeks) in hypercholesterolaemic patients resulted in a 23% and 29% reduction in plasma levels of total cholesterol and LDL-cholesterol respectively. Platelet cholesterol/phospholipids molar ratio was reduced by 26% and platelet aggregation was significantly (P<0.02) reduced by 10% after 4 weeks of fluvastatin treatment. On continuing fluvastatin therapy for additional 20 weeks, no further decrement in plasma LDL cholesterol levels or in platelet cholesterol/phospholipid ratio were noted. However, platelet aggregation was further significantly (P<0.01) reduced by up to 15%. Incubation of platelets with increasing concentrations of fluvastatin or lovastatin, demonstrated a dose-dependent reduction in platelet aggregation, whereas pravastatin showed no effect. This inhibitory effect of fluvastatin or lovastatin on platelet aggregation (up to 34% or 22% respectively at a concentration of 1 microg statin ml (-1) was found both in platelet rich plasma and in washed platelet suspensions. Fluvastatin and lovastatin (but not pravastatin), seem to share similar platelet binding sites, as non labelled fluvastatin or lovastatin were able to displace [3H]-labeled-fluvastatin from its binding sites on platelets. Fluvastatin therapy reduces platelet aggregation via a dual effect which involves its in vivo hypocholesterolaemic action on platelet cholesterol content, and also a direct effect of the drug binding to the platelets. The antiatherogenicity of fluvastatin may be related, in addition to its plasma cholesterol lowering ability, to its inhibitory effect on platelet activation.",1997.0,0,0 3109,9241623,Effects of simvastatin and enalapril on serum lipoprotein concentrations and left ventricular mass in patients on dialysis. The Perfect Study Collaborative Group.,R Robson; J Collins; R Johnson; R Kitching; M Searle; R Walker; J Douglas; J Leary; G Whalley; N Sharpe; S MacMahon,"A randomised trial of simvastatin and enalapril in patients with chronic renal failure on dialysis: effects on serum lipoprotein concentrations and left ventricular mass. Left ventricular hypertrophy and abnormalities of lipoprotein metabolism are both possible contributors to the high risk of cardiovascular death in patients with chronic renal failure on dialysis. We investigated the effects of simvastatin on lipid and lipoprotein concentrations and the effects of enalapril on left ventricular mass in 107 patients receiving haemodialysis or continuous ambulatory peritoneal dialysis. Patients were randomised in a factorial design to receive simvastatin (10 mg daily) or placebo and enalapril (2.5-5 mg daily) or placebo. During follow-up, there was a significant excess of patients withdrawn from enalapril because of hypotension (2p = 0.002), and after 6 months only 55% of those assigned enalapril were still on treatment. From baseline to 6 months, there were no statistically significant differences in left ventricular mass or left ventricular dimensions between patients assigned enalapril and those assigned placebo. Among the patients assigned simvastatin, total cholesterol was reduced by 13% (2p = 0.001), LDL cholesterol was reduced by 17% (2p = 0.003) and apolipoprotein B was reduced by 12% (2p = 0.005) compared to patients assigned placebo. There were borderline significant (2p = 0.05 to 0.08) reductions in VLDL cholesterol, total triglyceride and VLDL triglycerides of 26%, 12% and 17% respectively. Large-scale trials are now required to determine whether reductions in lipid and lipoprotein concentrations confer a reduction in coronary heart disease morbidity and mortality in patients on dialysis.",2000.0,0,0 3110,9243155,Smoking cessation as a rigorous primary intervention for coronary events in middle-aged men. A commentary based on the WOSCOP findings. West of Scotland Coronary Prevention Study.,F E von Eyben,,1997.0,0,0 3111,9244193,Meeting highlights: 46th Annual Scientific Sessions of the American College of Cardiology.,J J Ferguson,,1997.0,0,0 3112,9244208,Functional evaluation of lipid-lowering therapy by pravastatin in the Regression Growth Evaluation Statin Study (REGRESS),W R Aengevaeren; G J Uijen; J W Jukema; A V Bruschke; T van der Werf,"Lipid-lowering therapy during 2 years in the Regression Growth Evaluation Statin Study (REGRESS) was associated with less progression of coronary atherosclerosis in the pravastatin group compared with the placebo group. The effect of lipid-lowering therapy on the functional state of the coronary circulation is less well known. The purpose of this study was to evaluate this effect. In a substudy of REGRESS, 69 patients were randomized to pravastatin or placebo. Thirty-seven of these patients were allocated to the medical management stratum. Quantitative coronary angiography, regional myocardial perfusion, exercise testing, and classification of angina pectoris were assessed at baseline and after 2 years of therapy. Regional myocardial perfusion was assessed by digital subtraction angiography after intracoronary papaverine with video-densitometric calculation of the hyperemic mean transit time (HMTT) of contrast. In the medical management stratum, regional myocardial perfusion was assessed in 31 regions in the pravastatin group and 25 regions in the placebo group. The change in HMTT in the pravastatin group was -0.18 seconds (-5%) and in the placebo group +0.52 seconds (+18%), a difference of 0.70 seconds (P=.004). The mean difference in change in classification of angina pectoris (scale, 1 to 4) between pravastatin and placebo was 0.7 (P=.03) in favor of the pravastatin-treated patients. The change in HMTT was correlated with the change in exercise time (r=-.65, P=.002). In patients with symptomatic coronary artery disease, treatment with the HMG-coenzyme A reductase inhibitor pravastatin during 2 years resulted in a preserved regional myocardial perfusion, whereas patients on placebo deteriorated. The classification of angina pectoris improved only in patients receiving pravastatin. In lipid-lowering therapy, the evaluation of myocardial perfusion by assessment of the HMTT reveals a combined measure of functional and structural changes in the coronary circulation.",1997.0,0,0 3113,9252790,Combined 3-methylglutaconic and 3-hydroxy-3-methylglutaric aciduria with endocardial fibroelastosis and dilatative cardiomyopathy in male and female siblings with partial deficiency of complex II/III in fibroblasts.,S Ruesch; S Krähenbühl; S Kleinle; S Liechti-Gallati; T Schaffner; B Wermuth; J Weber; U N Wiesmann,"We report on 2 children, brother and sister, who presented with cardiomyopathy and muscular hypotonia at the age of B months. They both excreted significant amounts of 3-hydroxy-3-methylglutaric acid (3-HMG) and 3-methylglutaconic acid (3-MGC) but no 3-methylglutaric acid (3-MG). Enzyme analysis in fibroblasts revealed normal activities of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase and of 3-methylglutaconyl hydratase and other enzymes of 3-HMG metabolism. Loading tests with leucine did not affect the excretion of 3-HMG and 3-MGC. The girl died as a result of her cardiomyopathy, while the boy recovered and was treated with cardiac supportive therapy. He showed a steady improvement during his clinical course with biochemical normalization of the urinary excretion of 3-HMG, concomitant with marked improvement in the hypertrophic cardiomyopathy. In cultured fibroblasts from both patients a reduced activity of complex II/III of the respiratory chain was measured which may be the cause of this new type of 3-HMG uria. Analysis of mitochondrial DNA heart muscle, liver and fibroblast culture of the patient did not reveal any major mitochondrial DNA rearrangements (deletion, duplication) or any point mutation that had been described in association with mitochondrial cardiomyopathy.",1996.0,0,0 3114,9253390,Efficiency optimization of the selection period in therapeutic trials.,C K Moons; G A van Es; T Stijnen; A A Bak; A Hofman; J J Jonker; J D Habbema; D E Grobbee,"To determine eligibility for a (randomized) clinical trial, measuring the inclusion and exclusion criteria can be extended over a period of time. During this period, known as the selection period, a patient is repeatedly examined at certain time intervals. This study describes an approach for optimizing the efficiency of the selection period. Efficiency is defined as the costs of randomizing one patient. The objective is to construct prediction models based on data obtained early in the selection period to predict subsequent exclusions. A prediction model increases the efficiency if after its application the costs per randomization are lower. The approach is illustrated using data from the selection period of the Rotterdam Cardiovascular Risk Intervention (ROCARI) trial which was composed of five consecutive patient visits. At each visit, data to determine eligibility was obtained. We found that logistic regression models based on data of the first and second visit could predict exclusions during the third visit. Application of the prediction models suggested that in this particular trial the costs per randomization would decrease by $52. As the initial costs per randomization were $1444, there would be a 3.6% (52/1444) savings in recruitment costs under the prediction models, accounting for a savings of more than $450,000. We conclude that the use of data obtained early in a selection period can predict subsequent exclusions, and therefore could increase the efficiency of such a period. The approach could be applied to data obtained in a pilot study as well as data obtained in the beginning of a prolonged intake period.",1997.0,0,0 3115,9253540,The menopause and lipid metabolism: strategies for cardiovascular disease prevention.,M R Soma; R Baetta; P Crosignani,"The menopause and its biology are as yet still incompletely understood. Very little is known about biological and molecular changes in cardiovascular target tissues and organs after menopause. Experimental and clinical evidence indicate that prevention of cardiovascular disease by estrogens is aimed both at the correction of risk factors and at the direct control of vessel structure and function. The effects of progestogens on these processes are still debated. Few other medical interventions have as great a potential for affecting morbidity and mortality as does hormone replacement therapy in postmenopausal women. Hormone replacement therapy has produced effects on health risk, some are reduced, some are raised, while some remain uncertain, suggesting that further testing through specific clinical trials are required before confident recommendations can be made about the full range of benefits and risks. Lipid lowering therapy may be an acceptable alternative for postmenopausal women at risk for cardiovascular disease.",1997.0,0,0 3116,9254045,Mevalonate-regulated mechanisms in cell growth control: role of dolichyl phosphate in expression of the insulin-like growth factor-1 receptor (IGF-1R) in comparison to Ras prenylation and expression of c-myc.,A Dricu; M Wang; M Hjertman; M Malec; H Blegen; J Wejde; M Carlberg; O Larsson,"One or more mevalonate derivatives of non-sterol type have been proposed to be of indispensable importance for cell growth. Conceivable mevalonate-dependent mechanisms involved in growth control are farnesylation of Ras proteins, regulation of c-myc expression, and N-linked glycosylation of the IGF-1 receptor. The latter mechanism might be rate-limited by dolichyl phosphate, which acts as a donor of oligosaccharides in glycoprotein synthesis in the endoplasmic reticulum. In order to study the significance for cell proliferation of the three aforementioned mevalonate-dependent processings, their inhibitory response due to mevalonate deprivation was explored and compared with the effect on DNA synthesis in the malignant melanoma cell line SK-MEL-2. We found that mevalonate depletion due to treatment with 3 microM lovastatin for 24 h, which efficiently growth-arrested the cells, hardly at all affected the expression of c-myc, and although Ras prenylation was inhibited by 50%, the most pronounced effect of lovastatin was seen on N-linked glycosylation of IGF-1 receptors, which was inhibited by more than 95%. The order and magnitude of the decreased IGF-1 receptor glycosylation, which was followed by a decreased expression of IGF-1 receptors at the cell membrane, correlated well with the inhibition of DNA synthesis. We investigated whether dolichol, and in particular dolichyl phosphate, through its participation in N-linked glycosylation, act as regulators of IGF-1 receptor expression. First, we could confirm that exogenous dolichol became phosphorylated and in this form took part in the glycosylation processing. Secondly, we showed that dolichyl phosphate, in a dose-dependent manner, could increase the number of IGF-1 receptors at the cell membrane, simultaneously as DNA synthesis was stimulated. Taken together, our results provide direct evidence for an important role of dolichyl phosphate as a regulator of cell growth through limiting N-linked glycosylation of the IGF-1 receptor.",1997.0,0,0 3117,9254075,Prolonged inhibition of cholesterol synthesis explains the efficacy of atorvastatin.,R P Naoumova; S Dunn; L Rallidis; O Abu-Muhana; C Neuwirth; N B Rendell; G W Taylor; G R Thompson,"HMG-CoA reductase inhibitors or statins are effective in both the primary and secondary prevention of coronary heart disease, the extent of benefit being proportional to the reduction in low density lipoprotein (LDL) cholesterol achieved. Atorvastatin, a newly licensed compound, reportedly lowers LDL with greater efficacy than other statins. The mechanism of this action was, therefore, explored in twenty patients with refractory familial hypercholesterolemia who received in a single-blind sequence simvastatin 40 mg/day, placebo and atorvastatin 10 mg/day each for 4 weeks. At the end of the placebo period the effects of single 40-mg doses of simvastatin and atorvastatin on plasma levels and urinary excretion of mevalonic acid, indices of HMG-CoA reductase activity, were compared. Administration of atorvastatin 10 mg daily for 1 month lowered LDL cholesterol by 32.5%, compared with placebo (P = 0.0001), which was 4.5% less than the decrease after simvastatin 40 mg daily (P = 0.33). The area under the plasma curve and urinary mevalonic acid/ creatinine ratio were both significantly less during the 24 h after a single dose of atorvastatin 40 mg than after a single dose of simvastatin 40 mg (P < 0.01). These findings suggest that the greater efficacy of atorvastatin compared with simvastatin is due to more prolonged inhibition of HMG-CoA reductase, presumably reflecting longer residence of atorvastatin or its active metabolites in the liver.",1997.0,0,0 3118,9257049,Effect of lipid-lowering therapy on the progression of renal disease in nondiabetic nephrotic patients.,N I Neverov; G A Kaysen; I E Tareyeva,,1997.0,0,0 3119,9257052,The effect of HMG-CoA reductase inhibitors on chronic allograft rejection.,S Katznelson,,1997.0,0,0 3120,9257071,An application of the Zucker-Wittes modified ratio estimate statistic in the Post Coronary Artery Bypass Graft (CABG) clinical trial.,P L Canner; B Thompson; G L Knatterud; N Geller; L Campeau; D Zucker,"In the Post Coronary Artery Bypass Graft (POST CABG) clinical trial, the primary outcome is substantial worsening (i.e., narrowing of the lumen diameter) of the vein grafts upon comparison of the baseline and follow-up angiograms. The patients had one to five non-occluded vein grafts at entry, so there may be from one to five primary outcome responses per patient. A modified ratio estimate (MRE) statistic, as described previously by Zucker and Wittes, may be used to analyze data of this kind. In the present paper we propose a more powerful MRE statistic when the event rates and/ or intraclass correlations vary according to number of grafts per patient. We also adapt this statistic to the factorial treatment design of the POST CABG clinical trial.",1997.0,0,0 3121,9257079,Diabetic nephropathy. Its relationship to hypertension and means of pharmacological intervention.,T Baba; S Neugebauer; T Watanabe,"Hypertension and diabetes mellitus are common chronic conditions which frequently coexist. Diabetic nephropathy is a major cause of elevated blood pressure in patients with insulin-dependent diabetes mellitus (IDDM). Diabetic nephropathy, arterial sclerosis, obesity and association of essential hypertension can be the causes of hypertension in patients with non-insulin-dependent diabetes mellitus (NIDDM). Ambulatory blood pressure monitoring has revealed that the nocturnal fall of blood pressure is blunted in patients with diabetic nephropathy. A blunted diurnal blood pressure variation is seen in microalbuminuric diabetic patients and even in some normoalbuminuric patients. Accumulating data suggest that normalisation of blood pressure in hypertensive IDDM patients is most important to minimise the loss of kidney function. Angiotensin converting enzyme (ACE) inhibitors have been reported to be effective in postponing the development of nephropathy and in slowing its progression. Whether only ACE inhibitors have such beneficial renal effects on diabetic nephropathy is under discussion. While many studies have suggested that insulin resistance and hyperinsulinaemia are related to an elevated blood pressure in hypertensive patients, there does not seem to be enough evidence to prove that insulin per se can raise blood pressure in humans. Neither an insulin infusion within a physiological range nor sustained hyperinsulinaemia and insulin resistance (e.g. patients with insulinoma, cystic ovary syndrome) have been associated with an elevated blood pressure. Insulin resistance in some hypertensive patients may be a consequence of a decreased blood flow due to an increased peripheral resistance. Preliminary evidence suggests that low birth weight or impaired fetal growth is related to hypertension and NIDDM. Familial clustering of diabetic nephropathy suggests the contribution of genetic susceptibility and/or environmental inheritance. The frequent association of nephropathy with hypertension has led to research on the genes related to hypertension (ACE, angiotensinogen). Nevertheless, to date no reliable and clinically useful genetic marker has been found. Attempts to correct the metabolic abnormalities derived from diabetes are a new topic in the treatment of diabetic nephropathy. The effects of HMG CoA reductase inhibitors (antihypercholesterolaemic drugs), aldose reductase inhibitors (inhibitors of the polyol pathway) and glycation inhibitors (inhibitors of formation of advanced glycosylation end-products) on diabetic nephropathy have been evaluated in animal studies and in some clinical trials. Thus far, results with HMG CoA reductase and aldose reductase inhibitors have been somewhat conflicting. The potential therapeutic role of glycation inhibition in the treatment of diabetes deserves further study.",1997.0,0,0 3122,9258416,"Effect of a new HMG-CoA reductase inhibitor, atorvastatin, on lipids, apolipoproteins and lipoprotein particles in patients with elevated serum cholesterol and triglyceride levels.",P Alaupovic; T Heinonen; L Shurzinske; D M Black,"The effects of atorvastatin (lipitor) on cholesterol-rich and triglyceride-rich lipoproteins were evaluated in this multicenter trial. Following a 6-week baseline period, 47 patients with elevated cholesterol and triglyceride levels were treated with atorvastatin 10 mg once daily (QD) for the initial 12 weeks (Period 1) increasing to 20 mg QD for the following 12 weeks (Period 2). At both the 10 and 20 mg doses, atorvastatin treatment resulted in significant reductions compared to pretreatment levels in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein (apo) B, apoB in LDL (LDL-apo B), apo B in VLDL (VLDL-apo B), lipoprotein (Lp)B, lipoprotein B-complex (LpBc), triglycerides (TG), low-density lipoprotein triglycerides (LDL-TG), very low-density lipoprotein triglyceride (VLDL-TG), high-density lipoprotein triglycerides (HDL-TG), and apo C-III. Atorvastatin 10 and 20 mg QD also resulted in significant increases in high-density lipoprotein cholesterol (HDL-C), apo AI, and LpAII:B:C:D:E. Due to its unique ability to normalize both cholesterol-rich and triglyceride-rich particles, atorvastatin is a promising candidate for monotherapy in a broad range of patients including those with varying degrees of hypercholesterolemia and hypertriglyceridemia.",1997.0,0,0 3123,9260485,"Effects of ketoconazole on plasma lipids and lipoprotein(a) in familial hypercholesterolaemia, compared with simvastatin.",A F Stalenhoef; P M Stuyt; J de Graaf,"Ketoconazole is an imidazole derivative that is active as a broad-spectrum antifungal agent. It is also an inhibitor of cholesterol production both in vivo and in vitro. We compared the effect of low-dose ketoconazole (200 mg/day) or simvastatin (20-40 mg/day) on lipids, lipoproteins and lipoprotein(a) [Lp(a)] in 10 patients with familial hypercholesterolaemia. Ketoconazole reduced serum total cholesterol and low-density lipoprotein (LDL)-cholesterol by 7.6 and 9.7%, respectively. Simvastatin was more effective, the respective changes being -34.4 and -40.6%. Serum triglycerides and high-density lipoprotein (HDL) were unchanged by ketoconazole therapy, whereas simvastatin decreased triglyceride levels by 33.8% and increased HDL-cholesterol levels by 8.7%. Median Lp(a) levels tended to increase during simvastatin and to decrease during ketoconazole therapy. However, due to the wide range of baseline concentrations of Lp(a), these changes were not significant. Ketoconazole has some hypocholesterolaemic potential, but the effect of simvastatin is much more pronounced. The increase in Lp(a) during simvastatin therapy has been reported earlier, whereas ketoconazole does not exhibit an effect on the level of Lp(a).",1997.0,0,0 3124,9263665,The explosion of morbidity and mortality trials in hypertension.,C E Nwachuku; J A Cutler,"The highlights of each generation of hypertension trials have been varied, but interrelated. The initial hypertension trials focused on middle-aged hypertensive individuals and later on the elderly, with emphasis on diastolic blood pressure and subsequently on systolic blood pressure. Past generations of trials elucidated whether and whom to treat. The current explosion of morbidity and mortality trials in hypertension largely seeks to learn what drugs should be used and to delineate what blood pressure goals should be targeted.",1997.0,0,0 3125,9264419,Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]).,J A Herd; C M Ballantyne; J A Farmer; J J Ferguson; P H Jones; M S West; K L Gould; A M Gotto,"Despite the potential for reduced morbidity and mortality, aggressive intervention against mild to moderate hypercholesterolemia in patients with coronary heart disease (CHD) remains controversial and infrequently practiced. Eligible patients in the 2.5-year Lipoprotein and Coronary Atherosclerosis Study were men and women aged 35 to 75 years with angiographic CHD and mean low-density lipoprotein (LDL) cholesterol of 115 to 190 mg/dl despite diet. Patients (n = 429; 19% women) were randomized to fluvastatin 20 mg twice daily or placebo. One fourth of patients were also assigned open-label adjunctive cholestyramine up to 12 g/day because prerandomization LDL cholesterol remained > or = 160 mg/dl. The primary end point, assessed by quantitative coronary angiography, was within-patient per-lesion change in minimum lumen diameter (MLD) of qualifying lesions. Across 2.5 years, mean LDL cholesterol was reduced by 23.9% in all fluvastatin patients (+/- cholestyramine) (146 to 111 mg/dl) and by 22.5% in the fluvastatin only subgroup (137 to 106 mg/dl). Primary end point analysis (340 patients) showed significantly less lesion progression in all fluvastatin versus all placebo patients, deltaMLD -0.028 versus -0.100 mm (p <0.01), and for fluvastatin alone versus placebo alone, deltaMLD -0.024 versus -0.094 mm (p <0.02). A consistent angiographic benefit with treatment was seen whether baseline LDL cholesterol was above or below 160 or 130 mg/dl. Beneficial trends with treatment were also consistently seen in clinical event rates but were not statistically significant. Thus, lipid lowering by fluvastatin in patients with mildly to moderately elevated LDL cholesterol significantly slowed CHD progression.",2001.0,1,1 3126,9264420,Design & rationale of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).,J R Downs; P A Beere; E Whitney; M Clearfield; S Weis; J Rochen; E A Stein; D R Shapiro; A Langendorfer; A M Gotto,"The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is a randomized, double-blind, placebo-controlled primary prevention trial. It is designed to test the hypothesis that in addition to a lipid-lowering diet, treatment with lovastatin is more effective than placebo in reducing acute major coronary events (i.e., sudden cardiac death, fatal and nonfatal myocardial infarction, and unstable angina) in a cohort with normal to mildly elevated total (180 to 264 mg/dl) and low-density lipoprotein (LDL) cholesterol (130 to 190 mg/dl) and low high-density lipoprotein (HDL) cholesterol (< or =45 mg/dl for men and < or =47 mg/dl for women). Two sites in Texas, Lackland Air Force Base in San Antonio and the University of North Texas Health Science Center in Fort Worth, will conduct the study. After at least 12 weeks of an American Heart Association Step 1 diet and 2 weeks placebo run-in, 6,605 men and women, ages 45 to 73 and 55 to 73 years, respectively, without clinical evidence of coronary heart disease, are randomized in equal numbers to either lovastatin (20 mg/day) or placebo. Study procedures maintain the blind, allowing titration of lovastatin from 20 to 40 mg/day to achieve an LDL cholesterol goal of < or = 110 mg/dl. All participants are followed until study completion, when 320 participants have had a primary end point or a minimum of 5 years after the last participant is randomized, whichever occurs last. All end points are adjudicated by an independent committee using prespecified criteria. Unique features of this trial are (1) the inclusion of unstable angina in the primary end point to reflect the increasing trend to treat coronary heart disease aggressively before a myocardial infarction has occurred, (2) aggressive pharmacologic intervention, with titration, to attain an LDL cholesterol goal less than the current National Cholesterol Education Panel guidelines for primary prevention, and (3) a cohort that includes women, the elderly, and those with mild to moderate hyperlipidemia and low HDL cholesterol. Compared with earlier studies, results will be applicable to a broader population and may help clarify the role of aggressive LDL cholesterol reduction measures in primary prevention. Treatment of this population is likely to realize the greatest cumulative long-term benefit in the prevention of acute major coronary events.",2001.0,0,0 3127,9264433,Effectiveness of atorvastatin for reducing low-density lipoprotein cholesterol to National Cholesterol Education Program treatment goals.,M H Davidson; J W Nawrocki; S R Weiss; S L Schwartz; P J Lupien; P H Jones; H E Haber; D M Black,"Atorvastatin is a highly efficacious hydroxymethylglutaryl-coenzyme A reductase inhibitor that has been shown to reduce low-density lipoprotein cholesterol by 40% to 60%. Monotherapy with atorvastatin (10 to 80 mg/day) is well-tolerated, convenient, and appears to be effective for achieving National Cholesterol Education Program treatment goals in most patients, regardless of risk status.",1997.0,0,0 3128,9264434,Changes in serum lipids when fluvastatin is substituted for lovastatin in the same doses.,J P Rindone; G Arriola; D Hiller; R Achacoso,"This study evaluated changes in serum lipids when fluvastatin was substituted for lovastatin using equivalent doses. Results showed that serum lipids, especially low-density lipoprotein cholesterol, significantly increase with this substitution.",1997.0,0,0 3129,9265282,[Cholesterol lowering therapy after myocardial infarction. Consequences of the CARE study].,J E Otterstad; E Hexeberg; I Holme; I Hjermann,"In the recently published CARE-study, 4,159 patients aged 21-75 years were included and randomised to treatment with pravastatin 40 mg once daily or placebo 3-20 months following a myocardial infarction. Inclusion criteria were a total cholesterol < 6.2 mmol/l and LDL-cholesterol 3.0-4.5 mmol/l. Mean follow-up time was five years. Average reduction of total cholesterol was 20% and of LDL-cholesterol 28% in the treatment group. The incidence of coronary death or non-fatal myocardial infarction was reduced by 24% (p = 0.003). The cholesterol levels in the CARE-study were similar to those in most western populations and lower than in the 4S study. This must be considered when evaluating the different results of the treatment in the two studies. It seems fair not only to offer statin treatment to patients complying with the 4S inclusion criteria, but also to patients with values as in the CARE population.",1997.0,0,0 3130,9268234,Crossover trial of simvastatin versus pravastatin in patients with primary hypercholesterolemia.,S Sasaki; S Sawada; T Nakata; H Itoh; K Takeda; M Nakagawa; K Kuriyama,"The effects of simvastatin and pravastatin administered alone at initial doses of 5 and 10 mg/day, respectively, on normalization of abnormal lipid metabolism in patients with hypercholesterolemia were evaluated by a crossover method. Patients whose serum levels of total cholesterol (TC) were > or = 220 mg/dl were randomly divided into two groups, and one of the groups (group S-P: 17 patients) was treated with simvastatin first and then with pravastatin whereas the other group (group P-S: 19 patients) was treated with pravastatin first and then with simvastatin. Simvastatin or pravastatin was replaced with the other drug after 8-week administration in each group. These drugs were administered for 8 weeks each. Simvastatin and pravastatin significantly reduced the following serum lipids as compared with the levels in the observation period: TC by 23.2 +/- 8.1% and 18.1 +/- 10.9%, triglyceride (TG) by 13.0 +/- 24.7% and 5.8 +/- 47.1%, and low-density lipoprotein cholesterol (LDL-C) by 31.3 +/- 10.1% and 23.1 +/- 14.3%, respectively. TC and LDL-C levels were significantly (p < 0.001) lower and decreased to significantly (p < 0.001) greater degrees after simvastatin treatment than after pravastatin treatment. TC was normalized in 77.8% of the patients (28 of 36) after simvastatin treatment and in 68.9% of the patients (23 of 36) after pravastatin treatment. LDL-C was normalized in 63.9% of the patients (23 of 36) after simvastatin treatment and in 44.4% of the patients (16 of 36) after pravastatin treatment. The percentage of patients whose LDL-C was normalized by simvastatin was significantly (p < 0.05) higher as compared with pravastatin. Results of this trial, which was conducted by a crossover method, show that the initial dose of simvastatin reduces serum cholesterol and LDL-C more potently than the initial dose of pravastatin in patients with hypercholesterolemia.",1997.0,1,1 3131,9270980,Short-term effects of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor on cholesterol and bile acid synthesis in humans.,T Yoshida; A Honda; J Shoda; M Abei; Y Matsuzaki; N Tanaka; H Miyazaki; T Osuga,"Competitive inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase improve hypercholesterolemia. However, reports about the effects of these agents on bile acid synthesis, the metabolic pathway of cholesterol, are conflicting. We studied the short-term effect on one of these agents, pravastatin, on bile acid synthesis. Six male volunteers were given 40 mg of pravastatin. Plasma mevalonate level (which reflects cholesterol synthesis) and 7 alpha-hydroxy-4-cholesten-3-one level (which reflects bile acid synthesis) were measured every 2 h for 8 h. These plasma levels were compared to those of the same volunteers without pravastatin. Plasma mevalonate level after 2 h was lower than control (3.0 +/- 1.1 ng/mL vs. 6.7 +/- 2.5, mean +/- SD; P < 0.05). This decrease continued for 8 h (2.5 +/- 0.8 vs. 5.2 +/- 1.5; P < 0.05). On the other hand, plasma 7 alpha-hydroxy-4-cholesten-3-one level did not change until after 6 h; then at 8 h it was lower than control (15.7 +/- 11.8 ng/mL vs. 24.7 +/- 16.9; P < 0.05). According to three-way layout analysis of variance, mevalonate level was influenced by both pravastatin treatment (P < 0.01) and time-course (P < 0.01). On the other hand, the 7 alpha-hydroxy-4-cholesten-3-one level was affected by both individual difference (P < 0.01) and time course (P < 0.01), but pravastatin treatment did not influence this compound. This indicates that bile acid synthesis was influenced by pravastatin, although cholesterol synthesis was inhibited. The short-term inhibition of cholesterol synthesis did not affect bile acid synthesis.",1997.0,0,0 3132,9271481,Estrogen and progestin compared with simvastatin for hypercholesterolemia in postmenopausal women.,G M Darling; J A Johns; P I McCloud; S R Davis,"Postmenopausal estrogen therapy has favorable effects on serum lipoproteins in women with normal serum lipid levels, but the effect of combined estrogen and progestin therapy on lipoproteins in women with hypercholesterolemia has not been determined, nor has it been directly compared with the effect of conventional lipid-lowering therapy. In a randomized crossover trial, we studied 58 postmenopausal women with fasting serum total cholesterol levels greater than 250 mg per deciliter. Each woman received simvastatin (10 mg daily) for eight weeks and postmenopausal hormone therapy (up to 1.25 mg of conjugated equine estrogens daily, along with 5 mg of medroxyprogesterone acetate daily) for eight weeks, with an eight-week washout period between the two treatment phases. At base line, the mean (+/-SD) cholesterol values were as follows: total cholesterol, 305+/-39 mg per deciliter; high-density lipoprotein (HDL) cholesterol, 62+/-19 mg per deciliter; and low-density lipoprotein (LDL) cholesterol, 217+/-39 mg per deciliter. For total cholesterol, the mean decrease with hormone therapy was 14 percent (95 percent confidence interval, 11 to 16 percent) and the mean decrease with simvastatin was 26 percent (95 percent confidence interval, 23 to 29 percent). For LDL cholesterol, the mean decrease was 24 percent (95 percent confidence interval, 20 to 28 percent) with hormone therapy and 36 percent (95 percent confidence interval, 32 to 40 percent) with simvastatin. The effect of simvastatin was significantly greater than that of hormone therapy (P<0.001). HDL cholesterol increased similarly with hormone therapy (mean increase, 7 percent; 95 percent confidence interval, 2 to 12 percent) and simvastatin (mean increase, 7 percent; 95 percent confidence interval, 4 to 10 percent). Triglyceride levels increased with hormone therapy (mean increase, 29 percent; 95 percent confidence interval, 15 to 42 percent) but decreased with simvastatin (mean decrease, 14 percent; 95 percent confidence interval, 8 to 20 percent). Lp(a) lipoprotein decreased with hormone therapy (mean decrease, 27 percent; 95 percent confidence interval, 20 to 34 percent), but not with simvastatin. In postmenopausal women with hypercholesterolemia, therapy with estrogen plus progestin has beneficial effects on lipoprotein levels. Hormone therapy may be an effective alternative to treatment with simvastatin, especially in women with normal triglyceride levels.",1997.0,0,0 3133,9271817,Fluvastatin and tissue factor pathway inhibitor in type IIA and IIB hyperlipidemia and in acute myocardial infarction.,M Lorena; S Perolini; F Casazza; M Milani; C Cimminiello,"Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor that regulates tissue factor-induced blood coagulation. In an open-label 8-week study, 20 hypercholesterolemic patients (10 type IIa and 10 type IIb) were enrolled and given fluvastatin 40 mg once daily at bedtime. At baseline (after a 4-week controlled diet) and at week 8, total cholesterol, total triglycerides and lipoprotein subfractions were assessed. TFPI antigen levels were measured at the same time by ELISA. We also measured TFPI concentrations in 10 control subjects and in 10 patients at the time of and ten days after acute myocardial infarction. In type IIa patients fluvastatin reduced total cholesterol levels by 26% and LDL-cholesterol by 30% (P < 0.001); in type IIb, fluvastatin significantly reduced total cholesterol levels by 24% (P < 0.001). In both dyslipidemic groups the baseline total TFPI levels were significantly higher than in the control group (P < 0.002). The therapeutic lipid-lowering effect was paralleled by a significantly reduction of total TFPI antigen concentrations from 132 +/- 23 to 71 +/- 37 ng/mL (P < 0.001) in type IIa and from 120 +/- 30 to 91 +/- 29 ng/mL (P < 0.05) in type IIb patients; in control subjects total TFPI levels were 81 +/- 22 ng/mL; however the lipoprotein-bound TFPI antigen subfractions did not differ significantly in the treated and control groups. In patients with recent myocardial infarction there was a significant reduction from day 0 to day 10 in total TFPI antigen levels, from 120 +/- 48 ng/mL to 80 +/- 16 ng/mL (P < 0.05). The reported reduction of TFPI antigen levels after fluvastatin treatment could be a sign of normalization of an up-regulated clotting system rather than an unfavourable reduction of a natural anticoagulant.",1997.0,0,0 3134,9272889,Evidence supporting cholesterol-lowering therapy for postmenopausal women with heart disease.,M R Goldstein,,1997.0,0,0 3135,9290755,Cholesterol reduction in cyclosporine-treated renal transplant patients: effect on platelet-derived growth factor levels and platelet activation.,O Rigatto; D Rush; Y Perry; S Walker; R Bose; P Bolli,,1997.0,0,0 3136,9293439,Potential role of lipids in the progression of glomerular diseases.,C J Olbricht,,1997.0,0,0 3137,9294990,Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia.,V G Athyros; A A Papageorgiou; H A Hatzikonstandinou; T P Didangelos; M V Carina; D F Kranitsas; A G Kontopoulos,"No monotherapy is able to tackle effectively all atherogenic features of familial combined hyperlipidemia: high low-density lipoprotein (LDL) cholesterol, triglycerides (TG), and plasma fibrinogen, as well as low high-density lipoprotein (HDL) cholesterol. The present study investigated the safety and efficacy of combined pravastotin or simvastatin with gemfibrozil or ciprofibrate treatment on total cholesterol, LDL, TG, plasma fibrinogen, and apoproteins B and A-I in patients with refractory familial combined hyperlipidemia, with or without coronary artery disease. From the initial 420 patients included in the study, 389 (294 men and 95 women, mean age 51 years [range 30 to 65]) completed the study. These patients were followed for a mean period of 29 months (1 year [n = 107], 2 years [n = 102], 3 years [n = 95], and 4 years [n = 85]). Patients given a hypolipidemic diet were randomly assigned to pravastatin + gemfibrozil (n = 135, 20 and 1,200 mg/day, respectively), simvastatin + gemfibrozil (n = 130, 20 and 1,200 mg), or simvastotin + ciprofibrate (n = 124, 20 and 100 mg). Lipid parameters, apoproteins B and A-I, and plasma fibrinogen were assessed every 3 months. Physical and laboratory investigations for adverse effects were performed every month for the first 3 months and every 3 months thereafter. No patient exhibited myopathy or rhabdomyolysis. Five patients (1.3%) were withdrawn from the study because of high transaminases (more than threefold the upper normal limit). Five nonfatal coronary artery disease events were recorded. All 3 combination treatments were more effective in normalizing lipid profile than any monotherapy in the past. Simvastatin + ciprofibrate was more effective than pravastatin + gemfibrozil in reducing LDL, TG, and plasma fibrinogen levels. Simvastatin + gemfibrozil increased HDL levels more than the other 2. The apoprotein B decrease was analogous to the LDL reduction by all combinations, whereas apoprotein A-I was increased more with simvastatin + gemfibrozil. The data suggest that the statin-fibrate combinations used in the study are safe and have a favorable effect on all major coronary artery disease risk factors in patients with refractory familial combined hyperlipidemia with or without coronary artery disease. Early detection of the rare drug-induced reversible hepatotoxicity calls for close monitoring of patients.",1997.0,0,1 3138,9296289,On the value of large multicenter drug intervention trials.,P Dernol; G E Hübner; T R Weihrauch,"Many large multicenter clinical drug trials are outcome trials with several thousand patients, therefore also called megatrials, numerous of which encompassing the cardiovascular field. Usually designed to test and compare the efficacy of a specific therapy with the major aim being improved outcome at hard end-points, specifically morbidity and mortality, they are representative of typical intervention trials. Considering also the risk of failure, examples of large multicenter therapy trials are examined as to their value to the patients, the society, the health care providers, and--finally--also the manufacturers of the respective drugs. The 'Syst-Eur Trial' (Systolic Hypertension in Europe) representing a very recent intervention trial to treat isolated high systolic blood pressure in elderly patients with treatment based on a calcium channel blocker, nitrendipine (CAS 39562-70-4, Bayotensin, Baypress), serves to indicate that besides the major end-point results, here total stroke rate, a number of important additional efficacy and safety results may be obtained with large trials, such as in this case favourable data on total mortality, myocardial infarctions, cancer, bleeding.",1997.0,0,0 3139,9296641,[Clinical trial with sodium fluvastatin in patients with hypercholesterolemia associated with mild and moderate essential arterial hypertension].,R Granero; G Linfa-Homes; C Isaacura-López; A Goyo; A Flores-Finizola; A Sira,"High serum cholesterol and LDL-cholesterol level and high blood pressure are risk factors for cardiovascular disease (CVD). CVD risk factors usually occur simultaneously, fact that enhance personal and population CVD risk. Data from interventional studies suggest that reducing CAD risk factors significantly lowered risk of CAD. Fluvastatin, a statine, has been used in hypercholesterolemic populations. We report on a clinical trial (random selection) of fluvastatin vs. placebo on hipercholesterolemic patients (total cholesterol > or = 240 mg/dl and/or low-density lipoprotein cholesterol (LDL-C) > or = 160 mg/dl) on treatment of mild to moderate high blood pressure. Forty Latin-American patients were randomized to placebo or 40 mg per day for 8 weeks of fluvastatin. Fluvastatin patients had a clinical and statistical significant reduction on total cholesterol (27.7%) and LDL-C (39.1%) Vs a non-significant reduction on the placebo group (6.9% total cholesterol and 9.1% LDL-C). One patient had elevated aspartate (AST) and alanine (ALT) aminotransferases (three times the local laboratory upper normal levels) associated with a chronic alcohol consumption, reverted 6 weeks after protocol completion. There was no important secondary effects; also there was no differences on this regard between placebo and verum group. Fluvastatin proved to be safe and well tolerated for this group of patients under a wide range of high blood pressure treatment.",1997.0,0,0 3140,9297070,[Economic aspects of drug therapy exemplified by pravastatin. A socioeconomic analysis of cholesterol synthase enzyme inhibition in coronary heart disease patients].,K Berger; G Klose; T D Szucs,"Decision makers in the field of health services are increasingly forced to identify and realise the grounds for spendings and savings. Therefore, preventive measures of cardiovascular diseases are becoming more and more scrutinized. The present analysis is answering the question: Is secondary preventive lipid-lowering therapy with a cholesterol-synthesis-enzyme-(CSE-)inhibitor in patients with manifest coronary heart disease cost-effective in comparison to other already proven medical interventions? The cost-effectiveness-analysis with the endpoint costs per life years saved had been chosen as a form of evaluation. The study is a retrospective analysis. The clinical data have been taken from the already published double blinded, randomised, placebo controlled PLAC-I- and -II-studies as well as from the PLAC-Meta-Analysis. The cost estimate (costs of myocardial infarction, stroke and cost therapy with pravastatin) were based on the perspective of the German statutory sick funds. With the reduced probability of a fatal myocardial infarction or a stroke in the group treated with pravastatin there are cost offsets of DM 2,400. This figure is opposed to an additional expenditure of about DM 6,900, -for the CSE-inhibitor. The calculation of the effectiveness resulted in an additional life expectancy of 0.28 years in the pravastatin cohorts in comparison with the group treated with placebo over an observation period of 3 years. The costs per life year saved are approximately DM 16,000,-. The preventive use of pravastatin in patients with coronary heart disease can be estimated as cost-effective as compared with other medical interventions.",2000.0,0,0 3141,9312763,[The effect of hypolipidemia treatment on the function of kidney transplanted from cadavers].,L Paczek; M Bill; J Wyzgał; Z Gaciong; L Gradowska; J Juskowa; M Durlik; M Lao,"The high prevalence of hypercholesterolemia (HCh) in kidney transplant recipients probably contributes to the high cardiovascular mortality of these patients. Additionally, HCh is a contributing factor to the progression of renal failure. We conducted a prospective, randomised study with low dose Lovastatin in 42 kidney transplant recipients during 32 weeks, focusing on side effect and kidney function 42 consecutive patients with kidney transplanted in our Institute, with stable renal function (creatinine level < 160 mmol/l) treated with ciclosporine, azathioprine, prednisone were enrolled for the study (regardless of the initial cholesterol level). Every second patient was given Lovastatin 20 mg/night. In the Lovastatin group total cholesterol (TC) and LDL concentration were significantly lower after 6 months of treatment (TC was reduced from 242.5 +/- 12.8 to 220 +/- 15.4 mg/dl, p < 0.05) in Lovastatin group whereas in control group it increased nonsignificantly. Similarly LDL in Lovastatin group decreased from 140.0 +/- 7.0 to 121.3 +/- 10.8 mg/dl, p < 0.02 whereas in control group it increased from 143.6 +/- 5.4 to 169.9 +/- 10.3 mg/dl, p < 0.01. HDL and trigliceride concentrations were unchanged. The Lovastatin treatment did not results in more adverse events than the placebo treatment. Notably, the tendency to increase creatinine level in Lovastatin group was observed from 1.59 +/- 0.17 to 1.74 +/- 0.22 in Lovastatin group versus 1.89 +/- 0.22 to 2.21 +/- 0.35 mg/dl (NS). Low dose Lovastatin treatment seems to be safe and efficient cholesterol-lowering procedure. However we did not observe beneficial effect on kidney graft function.",1997.0,0,0 3142,9313298,Therapy of blastomycosis.,R W Bradsher,"Blastomycosis is a rare but important fungal infection that is diagnosed primarily in the south-central and midwestern United States. Although some patients have subclinical infection and are not treated, the majority of patients with a clinical diagnosis of blastomycosis are treated with antifungal agents. Amphotericin B is curative but, because of toxicity, oral agents have been examined as therapy. Ketoconazole was shown to be effective for less than overwhelming blastomycosis, but adverse effects were relatively common. Itraconazole is a triazole agent that is more effective than ketoconazole, because it is often effective when ketoconazole fails or after relapse of infection following a response to ketoconazole. Fluconazole is not as effective therapy for blastomycosis based on the need for much higher doses than with itraconazole. In a patient with lifethreatening or central nervous system blastomycosis, amphotericin B should be given.",1997.0,0,0 3143,9314647,Topics in cardiovascular disease and diabetes.,Z T Bloomgarden,,1997.0,0,0 3144,9315428,Design of a cost-effectiveness study within a randomized trial: the LIPID Trial for Secondary Prevention of IHD. Long-term Intervention with Pravastatin in Ischemic Heart disease.,P P Glasziou; R J Simes; J Hall; C Donaldson,"The Long-term Intervention with Pravastatin in Ischemic Heart Disease (LIPID) trial is a double-blind, randomized, placebo-controlled trial evaluating the long-term effect of pravastatin on coronary mortality in patients with a previous myocardial infarction or unstable angina-ischemic heart disease (IHD). It is planned to run for at least five years with 9014 patients from 85 centers in Australia and New Zealand. The trial will monitor cause-specific mortality and major clinical events associated with each treatment. Running in parallel with the main study is a prospective economic analysis, the objectives of which are (1) to estimate the effectiveness of pravastatin compared with placebo in terms of survival, quality of life (QOL), and quality-adjusted life-years (QALY); (2) to estimate the resource usage associated with pravastatin compared with placebo-in particular, to study whether it alters resource usage through prevention of disease progression; and (3) to use this information for a cost-utility analysis with cost per quality-adjusted life-year as the unit of analysis. A novel aspect of the design is the use of a preliminary cost-effectiveness analysis, based on ""best-guess"" values, and a sensitivity analysis over plausible ranges to guide the choice of subsample size. Some data, such a mortality, days spent in hospital, major clinical events, and drug use, are being collected within the main LIPID trial. However, additional subsamples for the cost-effectiveness study will include information on quality of life, time off work, and resources used, such as time in hospital, procedures, and medications taken. The methods and sample sizes for these substudies have been a crucial issue in validity and feasibility.",1997.0,0,0 3145,9315523,Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial.,K Wenke; B Meiser; J Thiery; D Nagel; W von Scheidt; G Steinbeck; D Seidel; B Reichart,"Accelerated graft vessel disease (GVD) represents the most serious long-term complication of heart transplantation. A possible cause underlying this progressive coronary vascular disease is believed to be post-transplantation hypercholesterolemia. In a 4-year prospective randomized study with heart transplant recipients, the efficacy of primary antihypercholesterolemic therapy with simvastatin was compared with that of general dietary therapy. The aim of the treatment was to maintain post-transplantation LDL-cholesterol levels at <120 mg/dL. Seventy-two heart transplant recipients receiving standard triple immunosuppression were randomly assigned to an active-treatment group (low-cholesterol diet and simvastatin, n=35) or a control group (general dietary measures, n=37). In the course of 4 years after transplantation, the simvastatin group had significantly lower LDL-cholesterol concentrations than the control group (mean+/-SD, 115+/-14 versus 156+/-17 mg/dL,P=.002), a significantly better long-term survival (88.6% versus 70.3%,P=.05), and a lower incidence of GVD in the coronary angiographic findings (16.6% versus 42.3%,P=.045). The incidence of graft rejections did not differ between the two groups, although there was a tendency toward a lower number of serious rejections in the simvastatin group (2.8% versus 13.5%, P=.1). Intracoronary ultrasound performed after 4 years in a subgroup of 27 patients (simvastatin, 10; control, 17) showed less intimal thickening in patients with LDL-cholesterol levels of <110 mg/dL (170+/-84 versus 370+/-171 microm, P=.04) and a lower intimal index (13.8+/-7.1% versus 27.9+/-12.1%,P=.04). In comparison with dietary measures alone, the combination of a low-cholesterol diet and simvastatin after heart transplantation led to a significant reduction in cholesterol levels, a significantly higher long-term survival rate, and a lower incidence of GVD.",1997.0,0,0 3146,9315596,Separate and joint effects of marine oil and simvastatin in patients with combined hyperlipidemia.,M H Davidson; J R Macariola-Coad; A M McDonald; K C Maki; H A Hall,"Marine oil plus simvastatin is an effective therapy for improving serum triglycerides, non-high-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in patients with combined hyperlipidemia. Concurrent administration does not attenuate the individual effects of either marine oil or simvastatin on the serum lipid profile.",1997.0,0,0 3147,9315597,Pravastatin alone and in combination with low-dose cholestyramine in patients with primary hypercholesterolemia and coronary artery disease.,M K Ito; R Shabetai,"This randomized, open-label study compared the cost efficiency of low-dose pravastatin combined with low-dose cholestyramine with high-dose pravastatin monotherapy in 59 patients with moderate hypercholesterolemia and coronary disease. Both regimes were effective in improving lipid profiles in these patients; however, low-dose combination therapy enhanced achievement in therapeutic goals and cost efficiency.",1997.0,0,0 3148,9315598,Lipid-lowering therapy and long-term survival in heart transplantation.,D D Stapleton; M R Mehra; D Dumas; F W Smart; R V Milani; C J Lavie; H O Ventura,The influence of lipid-lowering therapy employing a historic cohort study design was assessed following heart transplantation. Lipid-lowering therapy appears to confer a survival benefit in cardiac transplant recipients who survive beyond the first year.,1997.0,0,0 3149,9316510,Effect of pravastatin on angiographic restenosis after coronary balloon angioplasty. The PREDICT Trial Investigators. Prevention of Restenosis by Elisor after Transluminal Coronary Angioplasty.,M E Bertrand; E P McFadden; J C Fruchart; E Van Belle; P Commeau; G Grollier; J P Bassand; J Machecourt; J Cassagnes; J M Mossard; A Vacheron; A Castaigne; N Danchin; J M Lablanche,"This study sought to determine whether pravastatin affects clinical or angiographic restenosis after coronary balloon angioplasty. Experimental data and preliminary clinical studies suggest that lipid-lowering drugs might have a beneficial effect on restenosis after coronary angioplasty. In a multicenter, randomized, double-blind trial, 695 patients were randomized to receive pravastatin (40 mg/day) or placebo for 6 months after successful balloon angioplasty. All patients received aspirin (100 mg/day). The primary angiographic end point was minimal lumen diameter (MLD) at follow-up, assessed by quantitative coronary angiography. A sample size of 313 patients per group was required to demonstrate a difference of 0.13 mm in MLD between groups (allowing for a two-tailed alpha error of 0.05 and a beta error of 0.20). To allow for incomplete angiographic follow-up (estimated lost to follow-up rate of 10%), 690 randomized patients were required. Secondary end points were angiographic restenosis rate (restenosis assessed as a categoric variable, > 50% stenosis) and clinical events (death, myocardial infarction, target vessel revascularization). At baseline, clinical, demographic, angiographic and lipid variables did not differ significantly between groups. In patients treated with pravastatin, there was a significant reduction in total and low density lipoprotein cholesterol and triglyceride levels and a significant increase in high density lipoprotein cholesterol levels. At follow-up the MLD (mean +/- SD) was 1.47 +/- 0.62 mm in the placebo group and 1.54 +/- 0.66 mm in the pravastatin group (p = 0.21). Similarly, late loss and net gain did not differ significantly between groups. The restenosis rate (recurrence > 50% stenosis) was 43.8% in the placebo group and 39.2% in the pravastatin group (p = 0.26). Clinical restenosis did not differ significantly between groups. Although pravastatin has documented efficacy in reducing clinical events and angiographic disease progression in patients with coronary atherosclerosis, this study shows that it has no effect on angiographic outcome at the target site 6 months after coronary angioplasty.",1997.0,1,1 3150,9323100,Cardiac allograft vasculopathy: a review.,M Weis; W von Scheidt,"Cardiac allograft vasculopathy (CAV) remains a troublesome long-term complication of heart transplantation. It is manifested by a unique and unusually accelerated form of coronary disease affecting both intramural and epicardial coronary arteries and veins.CAV is characterized by vascular injury induced by a variety of noxious stimuli, including the immune system response to the allograft, ischemia-reperfusion injury, viral infection, immunosuppressive drugs, and classic risk factors such as hyperlipidemia, insulin resistance, and hypertension. The obstructive vascular lesions are thought to progress through repetitive endothelial injury followed by repair response. The role of major histocompatibility complex donor-recipient differences in the pathogenesis of CAV has not yet been completely elucidated. Intracoronary ultrasound studies reveal a dual morphology with donor-transmitted or de novo focal, noncircumferential plaques in proximal segments and/or a diffuse, concentric pattern observed in distal segments. A lack of correlation between microvascular and epicardial vessel disease suggests discordant manifestations and progression of CAV. Apoptosis and loss of functional vascular remodeling have to be considered as important mediators of clinically relevant CAV. Strategies for blocking T-cell costimulation and expression of adhesion molecules may help prevent chronic rejection in clinical transplantation. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and antiproliferative drugs may slow progression of CAV by various effects. Methods to augment endogenous nitric oxide bioavailability as well as newer immunosuppressive regimens may be protective. Balloon angioplasty has a limited role in the treatment of focal lesions. Experiences with coronary stenting, coronary artery bypass grafting, and transmyocardial laser revascularization are limited. Retransplantation has a worse outcome than initial transplantation.",1997.0,0,0 3151,9327830,Pharmacological approaches for the prevention of restenosis after percutaneous coronary intervention.,J Lefkovits; E J Topol,"A large number of drug trials for prevention of restenosis have been conducted with many showing little or conflicting benefit. Antiplatelets such as aspirin, ticlopidine and thromboxane A2 receptor inhibitors have not shown a clear benefit. Similarly, antithrombotics, either acting indirectly such as heparin, or as direct thrombin inhibitors such as hirudin and hirulog, do not prevent restenosis. Trials with ACE inhibitors, HMG-CoA reductase inhibitors and fish-oil supplements have yielded inconclusive results. The antiproliferatives, angiopeptin, trapidil and tranilast have shown some benefit in small-scale studies. Other drug classes of potential benefit include the glycoprotein IIb/IIIa receptor antagonists, inhibitors of the early coagulation cascade, calcium channel blockers and nitric oxide donors. Drug research into restenosis prevention has been hampered by problems with the definition of restenosis and the applicability in humans of animal models. Although no single drug has conclusively proven effective yet, the promise of a number of agents, together with other nonpharmacological strategies will likely result in further reductions in the incidence of restenosis.",1997.0,0,0 3152,9337222,Coronary risk estimation and treatment of hypercholesterolemia.,A Simon; J L Megnien; J Levenson,"Evidence-based treatment of hypercholesterolemia currently recommended for rationalizing drug prescription requires justification of treatment by randomized trials, such as the West of Scotland Coronary Prevention Study (WOSCOPS) or the Scandinavian Simvastatin Survival Study (4S), and evaluation of its benefit from the estimation of the coronary risk of each patient. The latest European guidelines and Sheffield tables apply these principles and justify the decision to treat hypercholesterolemia if the Framingham coronary multivariate risk estimate is high enough, ie, >20% risk of coronary event at 10 years in the former and >1.5% risk of coronary death per year in the latter. Nevertheless, the practice of these two recent guidelines results in discrepancies in the decision to treat, because coronary morbidity was considered in one but mortality was considered in the other, and the risk required for treating may be extrapolated from different trials (4S or WOSCOPS). Although the principle of targeting lipid-lowering treatment to high-risk subjects is unquestioned, further studies are needed to demonstrate that the Framingham risk profile is useful in selecting persons who are likely to benefit and to determine the place of newer risk factors and that of early noninvasive detection of atheroma in the risk estimation-based treatment.",1997.0,0,0 3153,9339964,Micronised fenofibrate: a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia.,J C Adkins; D Faulds,"Micronised fenofibrate is a new formulation of the fibric acid derivative fenofibrate. It is indicated for the treatment of patients with type IIa, IIb, III or IV dyslipidaemia who have failed to respond to dietary control or other nonpharmacological interventions. Micronised fenofibrate has improved absorption characteristics compared with the standard preparation, allowing a lower daily dosage and once-daily administration. The lipid-modifying profile of micronised fenofibrate is characterised by a decrease in low density lipoprotein (LDL) and total cholesterol levels, a marked reduction in elevated plasma triglyceride levels and an increase in high density lipoprotein (HDL) cholesterol levels. Consistent with the standard formulation, which is administered as 300mg daily in divided doses, the micronised preparation has demonstrated efficacy in the treatment of type IIa, IIb and IV primary dyslipidaemias but at a lower daily dosage of 200mg once daily. Because of its significant triglyceride-lowering effect, micronised fenofibrate appears to be of greatest benefit in patients with hypertriglyceridaemia (with or without hypercholesterolaemia), including patients with type 2 (non-insulin-dependent) diabetes mellitus and dyslipidaemia. In the comparisons available, micronised fenofibrate 200mg once daily was of similar efficacy to or less effective than the HMG-CoA reductase inhibitors simvastatin 20mg daily and pravastatin 20mg daily at reducing LDL and total cholesterol levels. However micronised fenofibrate produced greater improvements in triglyceride and, generally, HDL cholesterol levels than both simvastatin and pravastatin. Data on the long term tolerability of micronised fenofibrate are limited. However, data from a large short term (3-month) study have indicated that gastrointestinal disorders are the most frequent adverse events associated with therapy. Elevations in serum transaminase and creatine phosphokinase levels have been reported rarely with micronised fenofibrate. In conclusion, available data suggest that the more convenient lower once-daily dosage of micronisedfeno fibrate retains the beneficial lipid-modifying effects of the standard formulation. Further studies are required to determine whether the lipid changes achieved with micronised fenofibrate result in a reduction in cardiovascular morbidity and mortality.",1997.0,0,0 3154,9342581,Increase or decrease of HDL-cholesterol concentrations during pravastatin treatment depending on the pre-treatment HDL cholesterol levels.,Y Narita; Y Kitazoe; Y Kurihara; Y Okuhara; K Takamatsu; N Saito; Y Doi,"The effect of pravastatin was evaluated using patient data accumulated in the data base of a hospital information system (HIS). We selected 130 patients treated with pravastatin 10 mg per day, for a minimum period of 4 weeks. In the t test analysis, the reduction rates of total cholesterol (TC) and low-density lipoprotein (LDL) levels for pravastatin administration were 18%, and 27%, respectively. These values were similar to previous reports. The high-density lipoprotein (HDL) level, however, did not change significantly, although previous reports have shown an elevation of HDL levels. In an attempt to explain the origin of this difference, we studied the pretreatment value dependence of the cholesterol change using regression analysis. We found that pravastatin raised the HDL level in those cases where pretreatment values were lower than 58 mg.dl-1 and reduced it for higher values. We also showed that the reductions of TC, LDL and triglyceride (TG) levels correlated positively with their pretreatment values.",1997.0,0,0 3155,9343498,Total cholesterol and risk of mortality in the oldest old.,A W Weverling-Rijnsburger; G J Blauw; A M Lagaay; D L Knook; A E Meinders; R G Westendorp,"The impact of total serum cholesterol as a risk factor for cardiovascular disease decreases with age, which casts doubt on the necessity for cholesterol-lowering therapy in the elderly. We assessed the influence of total cholesterol concentrations on specific and all-cause mortality in people aged 85 years and over. In 724 participants (median age 89 years), total cholesterol concentrations were measured and mortality risks calculated over 10 years of follow-up. Three categories of total cholesterol concentrations were defined: < 5.0 mmol/L, 5.0-6.4 mmol/L, and > or = 6.5 mmol/L. In a subgroup of 137 participants, total cholesterol was measured again after 5 years of follow-up. Mortality risks for the three categories of total cholesterol concentrations were estimated with a Cox proportional-hazards model, adjusted for age, sex, and cardiovascular risk factors. The primary causes of death were coded according to the International Classification of Diseases (ICD-9). During 10 years of follow-up from Dec 1, 1986, to Oct 1, 1996, a total of 642 participants died. Each 1 mmol/L increase in total cholesterol corresponded to a 15% decrease in mortality (risk ratio 0.85 [95% CI 0.79-0.91]). This risk estimate was similar in the subgroup of participants who had stable cholesterol concentrations over a 5-year period. The main cause of death was cardiovascular disease with a similar mortality risk in the three total cholesterol categories. Mortality from cancer and infection was significantly lower among the participants in the highest total cholesterol category than in the other categories, which largely explained the lower all-cause mortality in this category. In people older than 85 years, high total cholesterol concentrations are associated with longevity owing to lower mortality from cancer and infection. The effects of cholesterol-lowering therapy have yet to be assessed.",1997.0,0,0 3156,9348749,"Ways to make ""usual"" and ""successful"" aging synonymous. Preventive gerontology.",W R Hazzard,"Preventive gerontology is the study and practice of those elements of lifestyle, environment, and health care management that will provide the maximal longevity of highest quality for individuals and the population. As such, it focuses on a personalized hygiene agenda that varies in its emphasis according to a person's age, sex, and risk factor profile. It includes a matrix of strategies relating to diet, exercise, and the avoidance of substance abuse and adverse environmental exposure. Preventive gerontology carries differential emphases according to the life stage of a person, featuring long-term, low-cost, and low-risk lifestyle strategies in youth and middle age (generally to age 75) and more short-term, low-risk interventions in old age (> 75), especially secondary prevention, according to individualized estimates of risk, cost, and benefit. The aggregate effect of widespread application of this approach--especially insofar as it is coupled with a rising level of education and continued psychosocial development--will be progressive congruency between usual and successful aging. A by-product will also be an ever-advancing median age of the population and, inevitably, a growth in long-term health and social service needs. Responsible planning for this consequence of success in the 21st century will require a rededication of North Americans to care for those in need regardless of age.",1997.0,0,0 3157,9349402,The effect of membrane cholesterol content on ion transport processes in plasma membranes.,P Lijnen,,1998.0,0,0 3158,9349932,"Effects of fluvastatin therapy on lipids, antioxidants, oxidation of low density lipoproteins and trace metals.",W Leonhardt; T Kurktschiev; D Meissner; P Lattke; C Abletshauser; G Weidinger; W Jaross; M Hanefeld,"Oxidation of low density lipoproteins (LDL) is thought to be an important step in the development of atherosclerosis. Trace metals are involved in oxidative processes. It was of interest to determine whether lipid-lowering therapy with fluvastatin, a potent HMGCoA reductase inhibitor, affected LDL oxidation and trace metal levels. Twenty hypercholesterolemic patients were treated with fluvastatin (40 mg twice daily) or placebo for 8 weeks in a double-blind, randomized study. LDL composition, antioxidants and oxidizability as well as plasma zinc, copper, selenium and manganese concentrations were investigated. After fluvastatin treatment, total cholesterol was reduced by 24%, triglycerides fell by 26% and plasma Zn fell by 8%. Cu, Se and Mn changed insignificantly. LDL were separated by ultracentrifugation. LDL were reduced by 18%, LDL-C by 29% and LDL-TG by 19%. The concentrations of alpha-tocopherol and retinol in LDL changed insignificantly. LDL preparations were incubated with copper ions (204 mumol.1(-1) LDL-C/3.2 mumol.1(-1) Cu) and formation of conjugated dienes was monitored at 234 nm for 5 h. Treatment with fluvastatin caused a reduction of diene production by 16% and of diene production rate by 14%, effects being significantly different from placebo (P = 0.02). The change of the lagtime did not reach significance; however, it was positively correlated with the change in LDL alpha-tocopherol. In the placebo group, no significant effects were observed. Fluvastatin therapy had lipid-lowering and antioxidative effects.",1997.0,0,0 3159,9351079,Therapy of post-renal transplantation hyperlipidaemia: comparative study with simvastatin and fish oil.,R Castro; J Queirós; I Fonseca; J P Pimentel; A C Henriques; A M Sarmento; S Guimarães; M C Pereira,"Recipients of renal transplantation (RT) exhibit disturbances of serum lipids and apoproteins that may contribute to their cardiovascular morbidity and mortality. In our renal transplant department the hypercholesterolaemia prevalence at the first and fifth year of RT is 70.0% and 81.2%, respectively. Lipid-lowering therapy has been utilized in many Transplant Units. The aim of our study was to evaluate post-RT hyperlipidaemia control with simvastatin or fish oil. Forty-three RT patients (26 men and 17 women) with persistent hypercholesterolaemia and stable graft function which were resistant to a lipid-lowering diet (American Heart Association Step Two) were randomized into two groups and treated for 3 months with simvastatin (S) (10mg/day; n = 25) and fish oil (F) (6 g/day; n = 18). Total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), lipoprotein a (Lp(a)), apolipoprotein A1 (Apo A1), and apolipoprotein B (Apo B) were monitored and at the study baseline they were similar between the two groups. No side effects were detected after 3 months of therapy. In group S, the concentrations of TC (271 +/- 46 mg% vs 228 +/- 49 mg%; P < 0.001), TG (180 +/- 78 vs 134 +/- 45; P < 0.01), LDL-C (177 +/- 40 vs 144 +/- 43; P < 0.01) and Apo B (96 +/- 18 vs 82 +/- 16; P < 0.001) were significantly reduced, and Apo A1 concentration had increased (135 +/- 24 vs 149 +/- 30; P < 0.01). In group F, the concentrations of TC (266 +/- 25 vs 240 +/- 31; P < 0.001), TG (203 +/- 105 vs 156 +/- 72; P = 0.02) and HDL-C (63 +/- 15 vs 53 +/- 12; P < 0.01) were significantly reduced. We concluded that low-dose simvastatin and fish oil are both effective and safe in correcting post-RT hyperlipidaemia. Further prospective studies with larger follow-up are needed to clarify whether this therapy has an impact on cardiovascular morbidity and mortality in RT patients.",1997.0,0,0 3160,9353492,The use of statins: a case of misleading priorities?,N Freemantle; R Barbour; R Johnson; M Marchment; A Kennedy,,1997.0,0,0 3161,9354305,Lipoproteins and cardiovascular reactivity.,L G Howes; D Abbott; N E Straznicky,"The observation that relatively short periods of cholesterol lowering therapy can reduce the incidence of coronary artery disease events has prompted interest in the short term effects of lipoproteins on cardiovascular responsiveness. Numerous studies in animals and humans have demonstrated that oxidized LDL-cholesterol can impair endothelial dependent vasodilation in coronary arteries and peripheral resistance vessels. Reduction of plasma LDL-cholesterol levels in hypercholesterolaemic patients improves nitric oxide mediated vasodilator responses in the coronary and peripheral circulation. LDL-cholesterol also potentiates responses to vasoconstrictors such as noradrenaline and endothelin-1 in the absence of endothelium, possibly by enhancing calcium influx into vascular smooth muscle cells. Pharmacological reduction of plasma LDL-cholesterol levels has been shown to reduce blood pressure responses to intravenous infusions of pressor hormones and to stress. However, the relative contribution of changes in endothelial dependent vasodilation and vasoconstrictor or inotropic responses remains to be established. Short term changes in LDL-cholesterol produce changes in cardiovascular responsiveness that may influence the development of ischaemic events.",1997.0,0,0 3162,9359537,"Rationale, design, and baseline characteristics of a trial comparing aggressive lipid lowering with Atorvastatin Versus Revascularization Treatments (AVERT).",L S McCormick; D M Black; D Waters; W V Brown; B Pitt,"This study describes the design, methodologic features, and baseline characteristics of an open-label randomized trial to determine whether aggressive lipid-lowering therapy with atorvastatin is an alternative to angioplasty or other catheter-based revascularization procedures in patients with significant coronary artery disease. Three-hundred forty-one patients with low-density lipoprotein (LDL) cholesterol > or = 115 mg/dl and > or = 1 defined narrowing of a major coronary artery were randomized to atorvastatin or the indicated catheter-based revascularization and conventional care (including lipid-lowering therapy if prescribed). Ischemic events are tracked for 18 months. The primary efficacy parameter is the incidence of an ischemic event, defined as 1 of the following: cardiovascular death, cardiac arrest, nonfatal myocardial infarction, the need for coronary bypass grafting or angioplasty, cerebrovascular accident, and worsening angina verified by objective evidence requiring hospitalization (including unstable angina).",1997.0,0,0 3163,9362407,Modulation of lipoprotein(a) atherogenicity by high density lipoprotein cholesterol levels in middle-aged men with symptomatic coronary artery disease and normal to moderately elevated serum cholesterol. Regression Growth Evaluation Statin Study (REGRESS) Study Group.,C Cobbaert; J W Jukema; A H Zwinderman; A J Withagen; J Lindemans; A V Bruschke,"This study sought to examine whether lipoprotein(a) levels predict coronary artery lumen changes in patients with symptomatic coronary artery disease (CAD) and normal to moderate hypercholesterolemia. Recent conflicting reports have confirmed or refuted the association of lipoprotein(a) with clinical events or angiographically verified disease progression. The association between serum lipoprotein(a) and changes in coronary artery lumen was studied in 704 men entered into the Regression Growth Evaluation Statin Study (REGRESS), a double-blind, placebo-controlled, quantitative angiographic study that assessed the effect of 2 years of pravastatin treatment. The primary end points were changes in average mean segment diameter (MSD) and average minimal obstruction diameter (MOD). Pravastatin- and placebo-treated patients were classified as having progressing, regressing or stable CAD, and median lipoprotein(a) concentrations were compared. Bivariate and multivariate regression analyses were performed in the overall patient group and in high risk subgroups. Pravastatin treatment did not affect serum apolipoprotein(a) levels. Median in-trial (sampled at 24 months) apolipoprotein(a) levels for regressing, stable and progressing CAD were, respectively, 130, 162 and 251 U/liter in placebo-treated patients and 143, 224 and 306 U/liter in pravastatin-treated patients. Predictors of MSD and MOD changes were baseline MSD and MOD, in-trial apolipoprotein(a), in-trial high density lipoprotein (HDL) cholesterol and baseline use of long-acting nitrates. The multivariate models predicted 14% of MSD changes and 12% of MOD changes; apolipoprotein(a) predicted only 2.6% and 4.8%, respectively. However, in patients with in-trial HDL cholesterol levels <0.7 mmol/liter, apolipoprotein(a) predicted up to 37% of the arteriographic changes. Serum lipoprotein(a) levels predict coronary artery lumen changes in normal to moderately hypercholesterolemic white men with CAD; its atherogenicity is marked in the presence of concomitant hypoalphalipoproteinemia.",1997.0,0,0 3164,9365661,Fluvastatin in renal transplantation.,M Hadjigavriel; G Kyriakides,,1997.0,0,0 3165,9368582,Vascular effects of statins in stroke.,N Delanty; C J Vaughan,"Recent clinical trials and meta-analyses of beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated a reduction in ischemic stroke in patients with a history of coronary artery disease both with and without elevations of serum cholesterol. This review summarizes clinical trials of these compounds and their recent impact on stroke and explores the underlying vascular mechanisms of their actions. Use of statins in patients with vascular disease has been shown to lower the incidence of stroke by approximately 30%. Statins exhibit a number of antiatherosclerotic and antithrombotic properties that likely underlie the recently observed reductions in cerebrovascular disease. Statins reduce inflammatory, proliferative, and thrombogenic processes in plaque, making it less likely to rupture. Additionally, they reverse the endothelial dysfunction and platelet activation accompanying hypercholesterolemia and may reduce the tendency to thrombosis. Hypercholesterolemia has reemerged as a risk factor for ischemic stroke. Statins protect against thromboembolic stroke through multiple beneficial effects within the vascular milieu. Further data are awaited to support the growing importance of cholesterol as a risk factor for ischemic stroke and the benefits of statin therapy in patients with cerebrovascular disease.",1997.0,0,0 3166,9369038,,,,,0,0 3167,9374129,Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia.,A D Marais; R P Naoumova; J C Firth; C Penny; C K Neuwirth; G R Thompson,"Apheresis only partially controls raised low density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia, who usually respond poorly to lipid-lowering drugs. The efficacy and mechanism of action of a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, atorvastatin, was therefore investigated in seven homozygotes undergoing apheresis. One receptor-negative and six receptor-defective homozygotes undergoing plasma exchange or LDL apheresis every 2 weeks were studied during 2 months each on placebo and on atorvastatin 80 mg daily. Changes in plasma lipids and mevalonic acid, an index of cholesterol synthesis, were measured and the kinetics of the rebound of low density lipoprotein cholesterol and apolipoprotein B after apheresis were analyzed. All subjects had significant improvements on atorvastatin. Mean decreases in low density lipoprotein cholesterol were 31% greater both pre- and post-apheresis on atorvastatin compared with placebo, accompanied by a 63% decrease in mevalonic acid. Percentage changes in low density lipoprotein cholesterol and mevalonic acid were closely correlated (r = 0.89, P = 0.007). The mean production rates of low density lipoprotein cholesterol and apolipoprotein B were 21% and 25% lower, respectively, on atorvastatin than on placebo (P < 0.005 and <0.02) but changes in mean fractional clearance rates were not statistically significant. We conclude that atorvastatin enhances the efficacy of plasma exchange and low density lipoprotein apheresis in patients who lack low density lipoprotein receptors. This effect appears to be due to marked inhibition of cholesterol synthesis which results in a decreased rate of production of low density lipoprotein.",1997.0,0,0 3168,9377592,Pravastatin and lovastatin in cerebrospinal fluid.,J Triscari; J S Markowitz; M W McGovern,,1997.0,0,0 3169,9377621,Efficacy of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in the treatment of patients with hypercholesterolemia: a meta-analysis of clinical trials.,S X Kong; S Y Crawford; S K Gandhi; J D Seeger; G T Schumock; N P Lam; J Stubbings; M D Schoen,"Recent studies have documented the long-term impact of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on mortality and morbidity related to coronary heart disease, establishing the link between lowering cholesterol levels and reducing cardiac events. Our study was a comparative literature review and meta-analysis of the efficacy of four HMG-CoA reductase inhibitors-fluvastatin, lovastatin, pravastatin, and simvastatin-used in the treatment of patients with hypercholesterolemia. The data sources for our meta-analysis of the efficacy of these cholesterol-lowering agents were 52 randomized, double-masked clinical trials with at least 25 patients per treatment arm. The results showed all four agents to be effective in reducing blood cholesterol levels. We computed summary efficacy estimates for all published dose strengths for the four agents. Fluvastatin 20 mg/d reduced low-density lipoprotein cholesterol (LDL-C) levels by 21.0% and total cholesterol (total-C) levels by 16.4%; fluvastatin 40 mg/d reduced these levels by 23.1% and 17.7%, respectively. Lovastatin 20 mg/d reduced LDL-C levels by 24.9% and total-C levels by 17.7%; lovastatin 80 mg/d reduced these levels by 39.8% and 29.2%, respectively. Pravastatin 10 mg/d reduced LDL-C levels by 19.3% and total-C levels by 14.0%; pravastatin 80 mg/d reduced these levels by 37.7% and 28.7%, respectively. Simvastatin 2.5 mg/d reduced LDL-C levels by 22.9% and total-C levels by 15.7%; simvastatin 40 mg/d reduced these levels by 40.7% and 29.7%, respectively. The results of our meta-analysis can be used in conjunction with treatment objectives and comparative cost-effectiveness data for these agents to decide appropriate therapeutic alternatives for individual patients.",1997.0,0,0 3170,9377955,Lack of left ventricular dysfunction associated with sustained exposure to hyperlipidemia following lung transplantation.,S Kesten; L Mayne; M Scavuzzo; J Maurer,"Hyperlipidemia due to standard immunosuppressive agents occurs commonly following solid organ transplantation. A decision to treat hyperlipidemias would be based on the assumption that such disorders lead to accelerated atherogenesis and ultimately to cardiac dysfunction. We therefore sought to examine whether hyperlipidemias following lung transplantation were associated with a decline in left ventricular (LV) function. We retrospectively reviewed serial echocardiograms, radionucleotide angiograms (RNAs), and serum lipid levels following lung transplantation. Results of cardiac studies were defined as abnormal if a decline in LV grade occurred from the best result at any time postoperatively to the most recent study. A total of 184 patients with transplants between November 1983 and June 1995 were reviewed. Eighty patients were excluded owing to incomplete data. One patient was excluded because of severe perioperative myocardial dysfunction. Approximately 80% of patients had elevated cholesterol levels and 60% had elevated low-density lipoprotein levels. Triglyceride levels were raised in 34% of patients while only 4% had an abnormal serum high-density lipoprotein level. More than 80% of patients had no evidence of LV abnormalities in either RNA or echocardiographic studies (group 1). One patient had a change in echocardiographic LV function but no change in grade of RNA (group 2). Twenty patients had a decline in grade based on RNA but no change in the echocardiogram (group 3). There were no patients with changes in both RNA and echocardiogram (group 4). All changes in LV function were from grade I to II. The mean period of follow-up exceeded 30 months for patients in groups 1 to 3. Follow-up data at 3, 4, and 5 years were available on 47, 23, and 12 patients, respectively. There were no differences between the proportions of subjects with normal and abnormal serum lipid levels in each group. In the initial 5 years after lung transplantation, dyslipidemias affect the majority of patients but are not associated with evidence of deteriorating LV function.",1997.0,0,0 3171,9379151,"""Statin"" drugs, mortality, and stroke prevention.",M N Stiffman,,1998.0,0,0 3172,9381994,"Comparison of bezafibrate versus lovastatin for lowering plasma insulin, fibrinogen, and plasminogen activator inhibitor-1 concentrations in hyperlipemic heart transplant patients.",J L Zambrana; F Velasco; P Castro; M Concha; F Vallés; P Montilla; J A Jimenéz-Perepérez; J López-Miranda; F Pérez-Jiménez,"Accelerated coronary artery disease is the most serious obstacle to long-term survival in heart transplant recipients. Hyperlipemia, hyperinsulinism, and changes in endothelial cell hemostatic function have been implicated in cardiac allograft vascular disease. Both lovastatin and bezafibrate are safe, effective, and well tolerated therapies for hyperlipidemia. Our study compares the effect of these lipid-lowering drugs in 21 patients with post-heart transplantation hyperlipidemia on different risk factors related to insulin resistance syndrome. Patients were given the same diet for 3 months, then randomized to lovastatin or bezafibrate for a period of 8 weeks, and crossed over to an additional 8 weeks of either bezafibrate or lovastatin. Baseline parameters were also compared with those of a control group of healthy subjects and after both periods of pharmacologic treatment. Transplant patients had higher insulin (35 +/- 3 vs 24 +/- 3 microIU/L), fibrinogen (298 +/- 15 vs 261 +/- 14 mg/dl), and plasminogen activator inhibitor-1 (PAI-1) (17 +/- 2 vs 11.7 +/- 2 arbitrary units/ml) plasma levels than controls. Significant decreases in insulin (-37 +/- 3%), fibrinogen (-12 +/- 4%), and PAI-1 plasma levels (-18 +/- 12%) were only observed after bezafibrate treatment. In conclusion, bezafibrate decreases plasma insulin, fibrinogen, and PAI-1 in hyperlipidemic heart transplant recipients.",1997.0,0,0 3173,9382659,Secondary prevention for ischemic heart disease. Relative numbers needed to treat with different therapies.,D B Miller,"Secondary prevention of ischemic heart disease refers to the process of preventing further morbidity and reducing mortality rates in patients with clinical manifestations of the disease. Twenty-five large randomized, clinical trials addressing mortality rates and cardiovascular morbidity in patients with established ischemic heart disease are reviewed. Broadly defined, these were trials of aspirin and antiplatelet agents, anticoagulants, beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, lowering of cholesterol levels, exercise rehabilitation, and diet or vitamins. In trials using warfarin sodium, timolol maleate, propranolol hydrochloride, captopril, ramipril, and simvastatin and 2 diet studies, statistically significant improvements in total mortality rates were seen. Most other studies showed non-significant reductions in total mortality rates, with statistically significant reductions in 1 or more measures of cardiovascular morbidity. The methods necessary for the reader to calculate the number (of patients) needed to treat for other studies are also reviewed. The uses and limitations of the number needed to treat as a method to compare studies of different interventions in similar populations are discussed.",1997.0,0,0 3174,9388100,Treatment goals for low-density lipoprotein cholesterol in the secondary prevention of coronary heart disease: absolute levels or extent of lowering?,P Cullen; G Assmann,"The results of the Scandinavian Simvastatin Survival Study (4S) and the Cholesterol and Recurrent Events (CARE) study make abundantly clear the benefits of lowering low-density lipoprotein (LDL) cholesterol in patients with a history of coronary artery disease. Current guidelines in the United States and Germany recommend a treatment goal for LDL cholesterol of 100 mg/dl. However, the evidence for setting such a goal is not consistent among trials. It has even been argued that setting an absolute LDL goal may be unhelpful, per se, because the higher the patient's pretreatment LDL cholesterol, the more difficult achieving this goal becomes. It has also been recognized that measures to lower LDL cholesterol, and medications in particular, produce a relative rather than an absolute degree of reduction in circulating levels. For example, most statins produce a similar proportional decrease in LDL cholesterol irrespective of baseline LDL. Thus, if the baseline LDL is 180 mg/dl, the decrease in LDL with a particular statin dose may be 60 to 120 mg/dl, whereas if the baseline LDL is 120 mg/dl, the expected decrease in LDL with the same statin dose would be only 40 to 80 mg/dl (i.e., a 30% reduction in each case). These points have led some investigators to suggest that it may be more practicable to recommend the amount by which LDL should be lowered rather than by specifying an absolute level of LDL cholesterol which should be achieved. This report summarizes the proceedings of an international symposium held on this topic on October 4, 1996, in Berlin by the International Task Force for Prevention of Coronary Heart Disease and the Institute of Arteriosclerosis Research at the University of Münster.",1997.0,0,0 3175,9388128,,,,,0,0 3176,9395280,Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor.,H Bischoff; R Angerbauer; J Bender; E Bischoff; A Faggiotto; D Petzinna; J Pfitzner; M C Porter; D Schmidt; G Thomas,"The pyridine derivative cerivastatin is a new entirely synthetic and enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. As a sodium salt cerivastatin is present in the active, open ring form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.3 x 10(-9) M. The reference compound lovastatin was 100-fold less potent and exhibited a Ki value of 150 x 10(-9) M. Cerivastatin inhibited the cholesterol synthesis in the human hepatoma cell line HepG2 cells with a similar IC50 value of 1.0 x 10(-9) M. In vivo studies reflected its high in vitro activity. In both rats and dogs, cerivastatin inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate with an oral ED50 value of 0.002 mg/kg body weight, while lovastatin exhibited an oral ED50 value of 0.3 mg/kg in rats, showing again the ratio of 100 or more between cerivastatin and lovastatin. In the small intestine and testes, cerivastatin was at least 50-fold less active with oral ED50 values higher than 0.1 mg/kg, which is indicative for a high liver selectivity of cerivastatin. In cholestyramine-primed dogs cerivastatin dose-dependently lowered the serum cholesterol concentrations by up to 59% with 0.1 mg/kg after 20 days. Interestingly, the serum triglycerides were markedly reduced by 53 and 76% with 0.03 and 0.1 mg/kg, respectively. In normal chow fed dogs the low density lipoprotein (LDL) concentrations were reduced by up to 75% after 0.1 mg cerivastatin/kg. The ratio of HDL/LDL increased by 81% compared with a change of only 14% in the placebo treated control group. The antiatherogenic effect of cerivastatin was shown in rabbits fed a diet enriched with 0.2% cholesterol. After 9 weeks on diet 0.1 mg cerivastatin/kg decreased the accumulation of cholesterol ester in the arterial tissue by 73%. In summary, these data as compared to published data on other HMG-CoA reductase inhibitors demonstrate cerivastatin to be the most active compound in this class. Vastatins used in therapy are effective in mg doses, while cerivastatin offers a new low dose therapy in the microg range.",1997.0,0,0 3177,9395824,Cholesterol and atherosclerosis: a contemporary perspective.,M L Kashyap,"Monumental advances in the field of lipid metabolism and its relationship to atherosclerotic cardiovascular disease have been achieved during the last half century. Epidemiologic studies have defined lipid disorders as highly significant independent risk factors for coronary heart disease, along with diabetes mellitus, hypertension and smoking. Primary and secondary prevention studies including the Coronary Primary Prevention Trial, Helsinki Heart Study, and the Coronary Drug Project have shown that lowering the atherogenic low density lipoproteins (LDL) and very low density lipoproteins (VLDL) whilst raising the high density lipoproteins (HDL) significantly decreases the risk for coronary disease. Striking evidence that aggressive therapy (to sharply lower LDL and raise HDL with newer drugs) prevents progression and induces regression of coronary narrowing has been obtained in numerous recent studies using quantitative coronary arteriography. An interesting and unexpected lesson learned from these arteriographic studies was that a highly significant reduction within months in several studies in coronary events was out of proportion to improvements in luminal narrowing. Recently, three major clinical trials to assess the effects of cholesterol reduction by the newly discovered HMG CoA reductase inhibitors (statins) have been published. Pravastatin significantly reduced coronary events in hypercholesterolemic patients [mean LDL-Chol. = 5.0 mM/L (192 mg/dl)] without a history of myocardial infarction. In a secondary prevention study, simvastatin also reduced coronary complications in hypercholesterolemic patients [mean LDL-Chol. = 4.9 mM/L (190 mg/dl)] with pre-existing coronary disease. Very recently, pravastatin treatment significantly reduced coronary events and stroke in patients with a history of myocardial infarction and average cholesterol levels [mean LDL-Chol. = 3.6 mM/L (139 mg/dl)], representing the majority of patients with coronary disease. In all these studies, reduction in cardiovascular events was approximately one-third. In subgroup analyses, men, women, elderly, smokers and hypertensives benefited from cholesterol lowering. There was no significant increase in non-cardiovascular causes of death. In the United States of America, the National Cholesterol Education Program (NCEP) Adult Treatment Panel, representing major health organizations, developed national guidelines on the detection, evaluation and treatment of high blood cholesterol in adults. In a given patient, the Panel recognizes the importance of weighing all cardiovascular disease risk factors including age (men > 45 years, postmenopausal women), family history of premature coronary disease, smoking, hypertension, diabetes and HDL-Cholesterol (< 35 mg/dl) in determining how aggressive therapy should be. The patient with manifest coronary heart disease (CHD) is given a special position as such patients are at highest risk for recurrent events. Major goals of therapy are to lower the LDL-Cholesterol to 2.6 mM/L (< 100 mg/dl) in the CHD patient. In non-CHD patients with two or more risk factors, the LDL-Cholesterol goal is 3.4 mM/L (130 mg/dl). In those with fewer risk factors, the goal is 4.2 mM/L (160 mg/dl). These guidelines should be modified as appropriate for Singapore. Patients with elevated triglycerides usually have low HDL-Cholesterol levels and often represent a heterogeneous group who may have other concurrent abnormalities including the presence of small dense LDL, insulin resistance, hypertension, obesity, overt diabetes and combined hyperlipidemia. Such patients merit individualized treatment. The prevalence of this syndrome may be more common in Singapore and requires further investigation. Current therapeutic guidelines emphasize the need for weight loss and dietary restriction of total and especially saturated fat (< 7% to 10% total calories), cholesterol (< 200 to 300 mg/day), and exercise. (ABSTRACT TRUNCATED)",1997.0,0,0 3178,9399600,Atorvastatin calcium: an addition to HMG-CoA reductase inhibitors.,P H Chong; J D Seeger,"Atorvastatin calcium is an HMG-coenzyme A (CoA) reductase inhibitor that was approved by the Food and Drug Administration on December 17, 1996. Like other such agents, it inhibits the action of HMG-CoA reductase and thereby decreases endogenous cholesterol synthesis, leading to a decrease in circulating low-density lipoprotein cholesterol. In addition to its effect on lipoprotein profile, atorvastatin reduces triglycerides to a greater extent than other HMG-CoA reductase inhibitors. These actions occur in a dose-dependent fashion. The adverse effect profile is similar to that of other agents in this class. Indications for atorvastatin include primary hypercholesterolemia as well as other lipid disorders.",1997.0,0,0 3179,9402435,Optimizing cholesterol lowering therapy: contribution of the Post Coronary Artery Bypass Graft Trial.,L Campeau; G Knatterud; B Hunninghake; M Domanski,,1997.0,0,0 3180,9402441,,,,,0,0 3181,9402444,"Endothelial dysfunction and accelerated coronary artery disease in cardiac transplant recipients. Microcirculation Working Group, European Society of Cardiology.",G Vassalli; A Gallino,,1997.0,0,0 3182,9402445,Compliance and adverse event withdrawal: their impact on the West of Scotland Coronary Prevention Study.,,"To assess the additional benefit gained from high compliance in the West of Scotland Coronary Prevention Study and to examine cases where withdrawal from trial medication was due to an adverse event. The incidence of definite coronary heart disease or non-fatal myocardial infarction, cardiovascular mortality, definite or suspect coronary heart disease death or non-fatal myocardial infarction, the need for coronary revascularization procedures, all-cause mortality and incident cancers were measured in the entire cohort and compared with the high compliance group. The adverse events associated with withdrawal were coded by body system. In subjects with compliance > or = 75%, treatment with pravastatin resulted in a 38% risk reduction for definite coronary heart disease death or non-fatal myocardial infarction and for cardiovascular mortality, a 46% reduction in risk or coronary revascularization and a 32% risk reduction (P = 0.015) for all-cause mortality. The analysis of the effect of pravastatin in the subgroup of high compliers to randomized medication demonstrated a substantial increase in the estimated risk reductions in comparison with that achieved in the intention-to-treat analysis. This result has significant implications for the motivation of high compliance among patients and for the assessment of the cost-effectiveness of treatment.",1997.0,0,0 3183,9402446,Cholesterol lowering after participation in the Scandinavian Simvastatin Survival Study (4S) in Finland.,T E Strandberg; S Lehto; K Pyörälä; A Kesäniemi; H Oksa,"Patient compliance is crucial for the effectiveness of preventive medication. The aim of the study was to investigate changes in serum cholesterol levels and the use of cholesterol lowering drugs one year after the end of the Scandinavian Simvastatin Survival Study (4S), a randomized secondary prevention study of coronary heart disease with simvastatin and placebo. A questionnaire asking the current use of cholesterol lowering drugs, most recent serum cholesterol value and attitudes towards cholesterol lowering was sent to 785 surviving 4S participants in four 4S centres in Finland. The response rate was 94%. The current use of cholesterol lowering drugs and the reported mean serum cholesterol values were similar to the original simvastatin and placebo groups. In all, 74% (n = 546) reported that they had used cholesterol lowering drugs after the study, and 63% (n = 467) were currently using them, mostly simvastatin (96%) with an average dose of 14 (SD 5) mg.day-1. Cholesterol lowering was considered to be 'very important' by 53% and 'important' by 37% of the respondents. The most frequent reasons for discontinuation were 'drug costs' (38%) and 'normal cholesterol values' (30%). The reported mean serum cholesterol levels were 5.1 (SD 1.0) and 5.7 (SD 1.1) mmol-1 in the current cholesterol lowering drug users and non-users, respectively (P < 0.0001). The in-trial treatment goal of serum cholesterol (< or = 5.2 mmol-1) was not met in 38% of the users and in 68% of the non-users of cholesterol lowering drugs. One year post-trial the original simvastatin and placebo groups of the 4S had become similar with regard to the use of cholesterol lowering drugs and serum cholesterol levels. The adherence to medication, however, still remained relatively high, but there was a shift toward lower doses, and consequently toward higher post-trial serum cholesterol levels.",1997.0,0,0 3184,9403282,The pharmacokinetics of pravastatin in patients on chronic hemodialysis.,T W Gehr; D A Sica; P H Slugg; J L Hammett; R Raymond; N F Ford,"The single-dose and steady-state pharmacokinetics of the HMG CoA reductase inhibitor pravastatin and its two metabolites, SQ 31,906 and SQ 31,945, were evaluated in 12 hemodialysis patients. A single 20-mg i.v. dose was employed, followed by daily oral dosing of 20 mg over four hemodialysis intervals. No statistical differences in the pharmacokinetics of pravastatin or SQ 31,906 were evident when comparing the first and last days of oral dosing with pravastatin. The pharmacokinetic parameters of pravastatin and SQ 31,906 were similar to those of healthy volunteers. SQ 31,945, the inactive polar metabolite, did accumulate in dialysis patients, as evidenced by an accumulation index of 1.7 +/- 1.0. Although metabolic clearance is the predominant mode of elimination of pravastatin, hemodialysis clearances of pravastatin, SQ 31,906 and SQ 31,945 will contribute to total body clearance since dialytic clearance ranged from 40 to 80 ml.min-1. Pravastatin can be safely administered in the usual dosages to subjects with renal failure on hemodialysis and no change in dosing is necessary.",1997.0,0,0 3185,9403876,Atorvastatin: a new agent for hyperlipidemia.,D Kupecz,,1997.0,0,0 3186,9404223,Reproducibility of ultrasonographic measurements of different carotid and femoral artery segments in healthy subjects and in patients with increased intima-media thickness.,T J Smilde; H Wollersheim; H Van Langen; A F Stalenhoef,"1. The reproducibility of measurements of the arterial wall thickness in both the carotid and femoral artery was investigated by means of high-resolution B-mode ultrasonography. For this purpose, subjects with normal and increased intima-media thickness were selected. Images were stored on an optical disk and were analysed with a semi-automatic software program by two readers. Individuals were scanned twice by two independent observers. 2. Measurements were performed of the far and near wall of the common carotid artery and bulbous in 30 healthy subjects and 19 patients known to have an increased intima-media thickness. Far-wall measurements were made of the internal carotid artery on both sides and common femoral artery on the right side only. 3. In healthy subjects the mean within-observer coefficient of variation was 1.8% and 3.0% for the far wall in the common carotid artery on the right side and left side, respectively. For the near wall the mean coefficient of variation of the common carotid artery was 2.8% on the right and 3.4% on the left side. The mean coefficient of variation was less than 4% for both far and near wall in the bulbous and far wall in the internal carotid artery. Even in patients with increased intima-media thickness the mean coefficient of variation of each segment was less than 4.5%. In the control subjects the between-observer coefficient of variation of the common carotid artery was 2.8% and 5.1% for the far wall on the right and left side, respectively, and 3.4% and 4.2% for the near wall on the right and left side. In healthy subjects a mean difference of 0.002 mm within observers was found in the right far-wall common carotid artery, with limits of agreement of -0.048 to 0.052 mm. The coefficient of repeatability was 0.050 mm. For patients with increased intima-media thickness the mean difference in this segment was -0.006 mm (-0.094 to 0.082) with a coefficient of repeatability of 0.088 mm. For the near wall in the common carotid artery and far and near wall in the bulbous and internal carotid artery the mean differences were larger, but were all below 0.1 mm. The differences and limits of agreements increased between observers. In patients the between-observer mean difference of the far wall of the common carotid artery was -0.055 mm (-0.255 to 0.145). For the common femoral artery of normal control subjects the within- and between-observer mean differences were 0.005 mm (-0.119 to 0.129) and 0.015 mm (-0.081 to 0.111), respectively. 4. In conclusion, the reproducibility of intima-media thickness measurements in the common carotid artery is reliable, even in patients with increased artery wall thickness. Also in other segments prone to atherosclerosis, such as the bulbous, internal carotid artery and common femoral artery, a good reproducibility was found. To obtain good reproducibility it is highly recommended to use the same ultrasonographer to scan patients in follow-up studies.",1997.0,0,0 3187,9405913,,,,,0,0 3188,9408513,Oral angiotensin-converting-enzyme inhibitors.,C Verme-Gibboney,"The pharmacology, pharmacokinetics, clinical uses, adverse effects, drug interactions, dosage, cost, and therapeutic interchange of oral angiotension-converting-enzyme (ACE) inhibitors are reviewed. ACE inhibitors attenuate the formation of angiotension II and may lead to the accumulation of kinins. Although the hypotensive effects of many ACE inhibitors may persist for 24 hours, some patients require more than one dose per day to achieve adequate control. These agents accumulate in patients with renal or hepatic dysfunction, but it is unclear whether dosage adjustments are necessary. ACE inhibitors are effective against mild to moderate hypertension; for severe hypertension, additional anti-hypertensive agents may be necessary. Other conditions in which ACE inhibitors have shown efficacy include congestive heart failure, myocardial infarction, left ventricular dysfunction, left ventricular hypertrophy, chronic renal insufficiency, insulin sensitivity, and coronary artery disease. The most common adverse effect is a persistent nonproductive cough. Angioedema, fetal and neonatal morbidity and mortality, acute renal failure, and hyperkalemia may also occur. ACE inhibitors may interact with diuretics, lithium, nonsteroidal anti-inflammatory drugs, oral hypoglycemic agents, and some other drugs. ACE inhibitor therapy should be initiated with low doses that may then be slowly adjusted upward. Many of the agents have similar costs for lower and higher dosages. The only significant differences among the ACE inhibitors are the time of onset of hypotensive effects, time to peak effect, and duration of effect. Each formulary should include, at least, captopril and one intermediate-acting and one long-acting ACE inhibitor.",1997.0,0,0 3189,9408716,"Clinical trials with multiple outcomes: a statistical perspective on their design, analysis, and interpretation.",S J Pocock,"This article tackles both practical and statistical issues in the handling of multiple outcomes in clinical trials, with relevance to trial design, analysis, and reporting. Specific topics illustrated by examples include: the advantage of prespecifying priorities amongst outcomes and analyses, corrections for multiple significance testing and their limited value, problems with adverse event data, the use of a single global test of significance for clinically related outcomes, the use of a combined outcome for clinical event data, and the value of exploring interrelationships amongst outcomes. The problems in handling multiple outcomes are enhanced by trials being too small, dichotomous attitudes (is the trial ""positive"" or not?), obsession with p-values, and the manipulative instincts of human nature. While predeclarations of priorities in analysis and reporting of multiple outcomes are important in suppressing distortive claims, it would be unfortunate if too inflexible an approach suppressed unpredictable findings from being seriously considered.",1997.0,0,0 3190,9412771,Therapy and clinical trials.,P H Jones; K von Bergmann,,1997.0,0,0 3191,9412773,Therapy for lowering lipoprotein (a) levels.,B Angelin,"Elevated levels of lipoprotein (a), a complex between apolipoprotein (a) and LDL, indicate an increased risk of atherosclerosis and cardiovascular disease. The important genetic regulation of lipoprotein (a) is now relatively well understood, but the progress in finding ways of influencing plasma lipoprotein (a) has been disappointingly slow. Nicotinic acid, pharmacological doses of sex hormones and anabolic steroids, as well as LDL apheresis may provide sufficient lowering of lipoprotein (a) for the evaluation of clinical response. Presently, the most important aspect is to take an evaluated lipoprotein (a) level into consideration when deciding to institute particularly aggressive lipid lowering treatment in a given individual.",1997.0,0,0 3192,9412774,Treatment of lipid disorders in non-insulin-dependent diabetes mellitus.,H Gylling; T A Miettinen,"The basis for treatment of lipid disorders in patients with non-insulin-dependent diabetes mellitus is weight reduction by diet and exercise, and additional control of glycaemic condition with oral antidiabetics, alone or in combination with insulin. Hypercholesterolaemic, mildly hypertriglyceridaemic non-insulin-dependent diabetes mellitus patients respond to cholesterol malabsorption caused by dietary sitostanol ester margarine, while long-term statin treatment of respective coronary patients significantly lowers the recurrence of coronary events, in addition to improving the lipid disorder. However, no information is available concerning the preventive effect of long-term improvement of lipid disorders in non-insulin-dependent diabetes mellitus patients without coronary heart disease, or in patients with the 'classical' type of diabetic lipid disorder, that is, hypertriglyceridaemia with low HDL and normal-low LDL-cholesterol levels. In this group of patients, beneficial lipid effects can be obtained (although perhaps not normalization) with fibrates alone or, especially, in combination with current statins.",1997.0,0,0 3193,9412777,New lipid lowering drugs and new effects of old drugs.,C A Dujovne,"Old lipid acting drugs (fibrates, resins and niacin) continue to demonstrate morbidity and mortality benefits with variable efficacy and safety. Controlled trials have provided efficacy and safety data that support the use of statins as the first choice in the treatment and prevention of atherosclerosis. Knowledge of old and new mechanisms of action, optimal doses, pharmacokinetic behavior and drug interactions improve the safety and effectiveness of these hypolipidemic agents.",1997.0,0,0 3194,9412778,Improving health outcomes without increasing costs: maximizing the full potential of lipid reduction therapy in the primary and secondary prevention of coronary heart disease.,T A Jacobson,"To more efficiently reduce the risk of coronary heart disease with lipid lowering therapy, cost effectiveness analysis offers an important tool to best determine how to allocate inherently limited resources to improve the health of both individuals and society. Formal economic analysis of the most recent clinical trials with the 3-hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) suggest that secondary prevention of coronary heart disease is very cost effective compared to existing treatment and prevention strategies. Primary prevention is also cost effective but has a much wider range of cost effectiveness depending on an individual baseline risk. Cost effectiveness can be better maximized in primary prevention by treating patients at the highest absolute risk of coronary heart disease. The debate about lipid lowering therapy will now shift from that of efficacy and safety, to that of cost and cost effectiveness. Defining the optimal treatment thresholds for intervention in primary prevention will become a major focus of investigation.",1997.0,0,0 3195,9412944,"Pravastatin has no effect on bile lipid composition, nucleation time, and gallbladder motility in persons with normal levels of cholesterol.",B C Sharma; D K Agarwal; S S Baijal; V A Saraswat,"Pravastatin dissolves gallstones in patients with hypercholesterolemia by reducing the cholesterol saturation index (CSI) of bile. There are few reports on effect of pravastatin on bile lipids, CSI and nucleation time (NT) in patients with gallstones and normal plasma lipid levels, or on the effect of pravastatin on gallbladder motility. Therefore we studied the effect of pravastatin on bile lipids, CSI, NT, and gallbladder motility in persons with normal cholesterol levels. We included 10 patients (ages 32 +/- 8 years; 6 men) with symptomatic gallstones and normal plasma lipid profiles. Estimation of bile lipids, CSI, and NT in duodenal bile and gallbladder motility were done using standard methods. Subsequently each patient was given 40 mg pravastatin daily for 1 month. At completion of pravastatin therapy, bile lipids and gallbladder motility studies were repeated. After pravastatin therapy, we found no significant reduction in bile cholesterol (11.2 +/- 3.2 vs. 10.4 +/- 2.8 mmol/l), bile acids (114.6 +/- 7.4 vs. 133 +/- 16 mmol/l), phospholipids (23 +/- 3.5 vs. 24 +/- 6.2 mmol/l), CSI (1.28 +/- 0.4 vs. 1.22 +/- 0.3), and nucleation time (7 +/- 3 vs. 7 +/- 3 days). In addition, there was no significant change in gallbladder fasting volume (26 +/- 3 vs. 26.6 +/- 3 ml), residual volume (14.6 +/- 1.1 vs. 15.08 +/- 1.4 ml), ejection fraction (44% vs. 43%), and rate constant of gallbladder emptying (0.018/min vs. 0.022/min). One-month therapy with pravastatin does not alter bile lipids, CSI, NT, and gallbladder contractility in persons with normal levels of cholesterol.",1997.0,0,0 3196,9415344,Fenofibrate plus simvastatin therapy versus simvastatin plus cholestyramine therapy for familial hypercholesterolaemia.,A S Wierzbicki; P J Lumb; J Cheung; M A Crook,"Combination therapy is routinely used to achieve improved cholesterol reduction in familial hypercholesterolaemia. We compared the standard simvastatin plus bile-acid sequestrant (cholestyramine) therapy with simvastatin plus fenofibrate in 29 patients with severe familial hypercholesterolaemia. The fibrate regimen resulted in an 35.1 +/- 10.7% reduction in total cholesterol, a 40.6 +/- 20.5% in LDL cholesterol, 17.2 +/- 56.5% reduction in triglycerides and a 20.3 +/- 52.0% increase in HDL cholesterol. The cholestyramine regimen produced reductions of 29.3 +/- 13.2% in cholesterol, 37.1 +/- 21.9% in LDL cholesterol, and 12.5 +/- 48.9% in triglycerides, and a 5.0 +/- 25.4% rise in HDL cholesterol. The fibrate regimen was significantly more effective in reducing total cholesterol (p < 0.001) and LDL-cholesterol (p = 0.004), and also reduced triglycerides significantly (p = 0.05), compared to the cholestyramine regimen. There were significant improvements in the LDL:HDL cholesterol ratio (3.62 +/- 1.54 vs. 4.00 +/- 1.36; p = 0.05) and in the apolipoprotein B:A1 ratio (1.13 +/- 0.036 vs. 1.20 +/- 0.34; p = 0.05). Gastrointestinal side-effects occurred in 10 patients on cholestyramine therapy, and four patients on fibrate therapy had myalgia. There were no cases of rhabdomyolysis with either regime. No significant differences in liver biochemistry or creatine kinase were seen with either regimen.",1998.0,0,0 3197,9416875,Lowering cholesterol in patients with coronary heart disease: are we ready yet?,E Barrett-Connor,,1998.0,0,0 3198,9416884,Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S),T A Miettinen; K Pyörälä; A G Olsson; T A Musliner; T J Cook; O Faergeman; K Berg; T Pedersen; J Kjekshus,"The Scandinavian Simvastatin Survival Study (4S) demonstrated pronounced reductions in mortality and major coronary events in a cohort of patients with established coronary heart disease (CHD). The present study provides a detailed, post hoc assessment of the efficacy and safety of simvastatin therapy in the following subgroups of 4S patients: those > or = 65 years of age, those < 65 years of age, women, and men. The 4S cohort of 4444 CHD patients included 827 women and 1021 patients > or = 65 years of age. Total cholesterol at baseline was 5.5 to 8.0 mmol/L with triglycerides < or = 2.5 mmol/L. Patients were randomized to therapy with simvastatin 20 to 40 mg daily or placebo for a median follow-up period of 5.4 years. End points consisted of all-cause and CHD mortality, major coronary events (primarily CHD death and nonfatal myocardial infarction), other acute CHD and atherosclerotic events, hospitalizations for CHD and cardiovascular events, and coronary revascularization procedures. Mean changes in serum lipids were similar in the different subgroups. In patients > or = 65 years of age in the simvastatin group, relative risks (95% confidence intervals) for clinical events were as follows: all-cause mortality, 0.66 (0.48 to 0.90); CHD mortality, 0.57 (0.39 to 0.83); major coronary events, 0.66 (0.52 to 0.84); any atherosclerosis-related event, 0.67 (0.56 to 0.81); and revascularization procedures, 0.59 (0.41 to 0.84). In women, the corresponding figures were 1.16 (0.68 to 1.99); 0.86 (0.42 to 1.74), 0.66 (0.48 to 0.91), 0.71 (0.56 to 0.91), and 0.51 (0.30 to 0.86), respectively. Cholesterol lowering with simvastatin produced similar reductions in relative risk for major coronary events in women compared with men and in elderly (> or = 65 years of age) compared with younger patients. There were too few female deaths to assess the effects on mortality in women. Because mortality rates increased substantially with age, the absolute risk reduction for both all-cause and CHD mortality in simvastatin-treated subjects was approximately twice as great in the older patients.",1998.0,0,0 3199,9416886,Reduction of serum cholesterol in postmenopausal women with previous myocardial infarction and cholesterol malabsorption induced by dietary sitostanol ester margarine: women and dietary sitostanol.,H Gylling; R Radhakrishnan; T A Miettinen,"Reduction of serum cholesterol decreases mortality in primary and especially in secondary prevention. We investigated how effectively postmenopausal women with a previous myocardial infarction reduced their serum cholesterol with dietary means by using sitostanol ester rapeseed oil margarine, alone and in combination with statins, and to what extent cholesterol metabolism was affected. The first study group consisted of 22 randomly chosen women with angiographically documented coronary artery disease. Baseline studies on home diet were followed by double-blind, randomized, cross-over studies on margarine without and with sitostanol (3 g/d) ester for 7 weeks in random order. A second group of 10 women on simvastatin consumed sitostanol ester margarine for 12 weeks. Sitostanol ester margarine lowered serum total cholesterol by 13% (P<.05) and LDL cholesterol by 20% (P<.01). Sitostanol ester margarine reduced total cholesterol in all patients, LDL cholesterol <2.6 mmol/L (<100 mg/dL) in 32%, and <3.4 mmol/L (<133 mg/dL) in 73% versus none and 27% during the home diet (P<.01 for both). Combined with simvastatin, sitostanol still reduced total and LDL cholesterol by 11+/-3% and 16+/-5% (P<.01 for both). Sitostanol reduced absorption (-45%), increased fecal elimination (+45% as neutral sterols), and stimulated synthesis (+39%) of cholesterol. High cholestanol and plant sterol (high cholesterol absorption) and low baseline precursor sterol proportions (low cholesterol synthesis) predicted high decreases in serum cholesterol. Dietary use of sitostanol ester margarine normalizes LDL cholesterol in about one third of women with previous myocardial infarction, especially in those with high baseline absorption and low synthesis of cholesterol, and in combination with statins reduces the needed drug dose.",1998.0,0,0 3200,9416913,Cholesterol management in theory and practice.,A M Gotto,"The preponderance of evidence confirms the importance of aggressive lipid modification in patients at risk for coronary heart disease (CHD). However, data suggest that this information is underimplemented in the clinical setting, even in patients with existing CHD, in whom the greatest benefit of such treatment has been shown. The fact that many practitioners do not pursue a proven treatment strategy in patients who qualify must be redressed through education and reinforcement of existing recommendations. In the present review, the current clinical and mechanistic understanding of the benefit of aggressive lipid management is summarized, with a focus on the clinical implications of recent findings. These include growing public awareness of cholesterol as a modifiable CHD risk factor, recommendations for earlier and more aggressive intervention in patients with existing disease, and discussion of the cost-effectiveness of lipid-regulating therapy. Despite the secular trend of declining CHD morbidity and mortality rates in recent years, CHD remains the leading cause of death in both men and women in the United States. It is imperative to prevent any reduction in public focus on primary and secondary prevention.",2001.0,0,0 3201,9417765,"Update in Nephrology '97: Hypertension, Lipids, and Uremia Therapy. Symposium proceedings part 1. Brooklyn, New York, May 9, 1997.",,,1998.0,0,0 3202,9420339,The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group.,J A Kuivenhoven; J W Jukema; A H Zwinderman; P de Knijff; R McPherson; A V Bruschke; K I Lie; J J Kastelein,"The high-density lipoprotein (HDL) cholesterol concentration is inversely related to the risk of coronary artery disease. The cholesteryl ester transfer protein (CETP) has a central role in the metabolism of this lipoprotein and may therefore alter the susceptibility to atherosclerosis. The DNA of 807 men with angiographically documented coronary atherosclerosis was analyzed for the presence of a polymorphism in the gene coding for CETP. The presence of this DNA variation was referred to as B1, and its absence as B2. All patients participated in a cholesterol-lowering trial designed to induce the regression of coronary atherosclerosis and were randomly assigned to treatment with either pravastatin or placebo for two years. The B1 variant of the CETP gene was associated with both higher plasma CETP concentrations (mean [+/-SD], 2.29+/-0.62 microg per milliliter for the B1B1 genotype vs. 1.76+/-0.51 microg per milliliter for the B2B2 genotype) and lower HDL cholesterol concentrations (34+/-8 vs. 39+/-10 mg per deciliter). In addition, we observed a significant dose-dependent association between this marker and the progression of coronary atherosclerosis in the placebo group (decrease in mean luminal diameter: 0.14+/-0.21 mm for the B1B1 genotype, 0.10+/-0.20 mm for the B1B2 genotype, and 0.05+/-0.22 mm for the B2B2 genotype). This association was abolished by pravastatin. Pravastatin therapy slowed the progression of coronary atherosclerosis in B1B1 carriers but not in B2B2 carriers (representing 16 percent of the patients taking pravastatin). There is a significant relation between variation at the CETP gene locus and the progression of coronary atherosclerosis that is independent of plasma HDL cholesterol levels and the activities of lipolytic plasma enzymes. This common DNA variant appears to predict whether men with coronary artery disease will benefit from treatment with pravastatin to delay the progression of coronary atherosclerosis.",1998.0,0,0 3203,9421099,Itraconazole decreases renal clearance of digoxin.,K M Jalava; J Partanen; P J Neuvonen,"Itraconazole strongly interacts with some drugs metabolized by cytochrome P450 3A4, for example, felodipine and lovastatin, by inhibiting their metabolism. A concomitant use of itraconazole increases the serum concentrations of digoxin, although digoxin is excreted mainly unchanged in urine. To reveal the mechanism of the itraconazole-digoxin interaction, the effect of itraconazole on the serum concentrations and urinary excretion of digoxin was studied. Ten healthy volunteers in a double-blind, randomized, two-phase crossover study received either 200 mg itraconazole or placebo orally once a day for 5 days. On day 3, each volunteer ingested a single 0.5-mg oral dose of digoxin. The serum concentrations of digoxin and its excretion into urine as well as plasma concentrations of itraconazole were determined up to 72 hours after dosing. The mean area under the serum digoxin concentration-time curve, AUC(0-72), was approximately 50% higher (P < 0.001) during the itraconazole phase than during the placebo phase. In addition, the renal clearance of digoxin decreased about 20% (P < 0.01) by itraconazole. The increases in digoxin Cmax and T(1/2) by itraconazole were not statistically significant. The decreased renal clearance of digoxin during the itraconazole phase partially explains increased concentrations of digoxin during their concomitant use and may be caused by the inhibition of P-glycoprotein-mediated digoxin secretion in the renal tubular cells.",1998.0,0,0 3204,9424603,[When is lipid-lowering therapy appropriate for stroke?].,A Terént,"The results of the secondary preventive care cardiological studies, 4S and CARE, which showed treatment with statins to yield a 30 per cent reduction in the frequency of cardiovascular events, are not directly transposable to stroke care, mainly because the mean age of the patients studied was 15 years less than that of typical stroke populations. However, results obtained in both epidemiological and randomised clinical studies of patients with coronary heart disease suggest that cholesterol-lowering medication might prove to be an important feature of secondary preventive treatment following minor stroke or transient ischaemie attacks.",1998.0,0,0 3205,9428469,Current strategies for retarding progression of renal disease.,H S Mackenzie; B M Brenner,"Physiological insights gained in the 1980s into mechanisms of disease progression in experimental chronic nephropathies established the basis for therapeutic interventions to retard the progression of chronic renal disease in humans. In the 1990s, several large-scale clinical trials have confirmed the renoprotective effects of angiotensin-converting enzyme inhibitors in diabetic and nondiabetic nephropathies. Other studies have afforded strong support for the efficacy of dietary protein restriction in certain settings and underscored the importance of blood pressure control in proteinuric individuals. These interventions form the core of current strategies designed to preserve kidney function in patients with chronic renal disease.",1998.0,0,0 3206,9428949,Safe use of niacin.,A A Schuna,,1998.0,0,0 3207,9428952,ASHP Therapeutic Position Statement on the safe use of niacin in the management of dyslipidemias. American Society of Health-System Pharmacists.,,"ASHP supports the use of niacin as an effective therapy for the management of dyslipidemias in adults. Successful and safe therapy requires ongoing supervision and instruction by qualified health care providers to monitor the efficacy of therapy and minimize niacin's potential for adverse effects. Because many niacin products are available without a prescription, pharmacists are in a unique position to help ensure that patients make the best use of this medication.",1998.0,0,0 3208,9430375,Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia.,F J Raal; G J Pilcher; D R Illingworth; A S Pappu; E A Stein; P Laskarzewski; Y B Mitchel; M R Melino,"Patients with homozygous familial hypercholesterolaemia (HFH) have abnormalities in both low-density lipoprotein (LDL) receptor alleles, resulting in severe hypercholesterolaemia and premature coronary heart disease. Limited treatment options are available and the response to drug therapy has been poor. In the present paper, we have evaluated the efficacy and safety of simvastatin at doses beyond the current maximal dose of 40 mg/day in patients with HFH. After a 4 week placebo diet run-in period, 12 patients with well-characterized HFH were randomized to simvastatin 80 mg/day administered in three divided doses (n = 8; group 1) or 40 mg once daily (n = 4; group 2). After 9 weeks, the dose in group 1 was increased to 160 mg/day while the dose in group 2 was kept at 40 mg/day, but with the drug given in three divided doses and treatment continued for an additional 9 weeks. All 12 patients completed the study and there were no serious or unexpected adverse effects. LDL-cholesterol concentrations fell by 14% at the 40 mg/day dose, but were reduced further at the higher doses (25% at the 80 mg/day and by 31% at the 160 mg/day dosage, P < 0.0001). Excretion of urinary mevalonic acid, as an index of in vivo cholesterol biosynthesis, was reduced but did not correlate with reduction in LDL-cholesterol in the individual patients. The magnitude of response to therapy was not predicted by the LDL-receptor gene defect as patients with the same LDL-receptor mutations responded differently to the same dose of simvastatin therapy. The ability of expanded doses of simvastatin (80 or 160 mg/day) to reduce LDL-cholesterol levels in patients with HFH, even if receptor negative, suggests that at these doses, the drug reduces LDL production. Simvastatin therapy, at doses of 80 or 160 mg/day, should therefore be considered in all patients with HFH, either as an adjunct to apheresis, or as monotherapy for those patients who do not have access to apheresis or other such treatment modalities.",1998.0,0,0 3209,9431828,Effect of simvastatin on cyclosporine unbound fraction and apparent blood clearance in heart transplant recipients.,F Akhlaghi; A J McLachlan; A M Keogh; K F Brown,"To investigate the effects of lipid lowering therapy on the fraction unbound and dosage requirement of cyclosporine in heart transplant recipients. Cyclosporine fraction unbound (fu) was measured ex vivo in plasma obtained from heart transplant recipients (n=12) before and after lipid lowering treatment, using equilibrium dialysis. Cyclosporine trough concentration data were also collected from cardiac transplant recipients (n=32) who received simvastatin for the treatment of hyperlipidaemia. Cyclosporine daily dosage and total concentration (monoclonal FPIA method) were recorded for periods up to 6 months before and after simvastatin administration. The total number of dose rate-concentration observations was 172 before and 135 after simvastatin administration respectively. Using a population pharmacokinetic approach (implemented in P-PHARM software) the ratio of dose rate to trough concentration at steady state (DR/C[SS trough]), an estimation of apparent clearance, was determined. The posterior Bayesian estimate of DR/C(SS trough) was calculated for each patient before and after simvastatin administration. The mean fu increased by 29%, from 1.40 +/- 0.1% (mean +/- s.d.) to 1.82 +/- 0.22% after simvastatin administration (P < 0.01). Mean trough concentrations of cyclosporine in whole blood were 349 microg l-1 before and 242 microg l-1 after simvastatin administration (P < 0.0001). The mean cyclosporine daily dosage was 2.87 mg kg-1 and 2.33 mg kg-1 (NS), before and after simvastatin administration respectively. The average cyclosporine DR/C(SS trough) was significantly increased from 24.5 l h-1 before to 28.9 l h-1 after simvastatin administration (P < 0.05). Furthermore the median increase in cyclosporine DR/C(SS trough) was 18 l h-1 (-3.1 to 42.1 l h-1, interquartile range). Cyclosporine fraction unbound and clearance are increased following co-administration of lipid lowering agents, necessitating closer monitoring of cyclosporine total blood concentration when lipid lowering agents are administered concomitantly with cyclosporine.",1998.0,0,0 3210,9437275,The West of Scotland coronary prevention study: economic benefit analysis of primary prevention with pravastatin.,J Caro; W Klittich; A McGuire; I Ford; J Norrie; D Pettitt; J McMurray; J Shepherd,"To estimate the economic efficiency of using pravastatin to prevent the transition from health to cardiovascular disease in men with hypercholesterolaemia. Economic benefit analysis based on data from the West of Scotland coronary prevention study. Treatment specific hazards of developing cardiovascular disease according to various definitions were estimated. Scottish record linkage data provided disease specific survival. Cost estimates were based on extracontractual tariffs and event specific average lengths of stay calculated from the West of Scotland coronary prevention study. Men with hypercholesterolaemia similar to the subjects in the West of Scotland coronary prevention study. Cost consequences, the number of transitions from health to cardiovascular disease prevented, the number needed to start treatment, and cost per life year gained. If 10,000 of these men started taking pravastatin, 318 of them would not make the transition from health to cardiovascular disease (number needed to treat, 31.4), at a net discounted cost of 20m Pounds over 5 years. These benefits imply an undiscounted gain of 2,460 years of life, and thus 8121 Pounds per life year gained, or 20,375 Pounds per life year gained if benefits are discounted. Restriction to the 40% of men at highest risk reduces the number needed to treat to 22.5 (5601 Pounds per life year gained (undiscounted) and 13,995 Pounds per life year gained (discounted)). In subjects without evidence of prior myocardial infarction but who have hypercholesterolaemia, the use of pravastatin yields substantial health benefits at a cost that is not prohibitive overall and can be quite efficient in selected high risk subgroups.",1998.0,0,0 3211,9437409,Post-transplant hyperlipidaemia: low-dose lovastatin lowers atherogenic lipids without plasma accumulation of lovastatin.,L Gullestad; K P Nordal; K Forfang; H Ihlen; A Høstmark; K J Berg; H Cheng; M S Schwartz; O Geiran; S Simonsen,"The purpose of the present study was twofold. First, to determine the frequency of hyperlipidaemia after heart transplantation (Tx) in relation to values obtained before Tx. Secondly, to examine the effect of low-dose lovastatin on possible antiatherogenic mechanisms and test the hypothesis that the side-effects are dose-dependent. Retrospective study of the frequency of hyperlipidaemia disturbances in heart transplant patients. In addition, in a prospective study, the safety and efficacy of incremental low doses of lovastatin up to 20 mg day-1 were studied, with measurements of its plasma concentration in 24 cyclosporin A treated heart (n = 14) and kidney (n = 10) recipients with total cholesterol > 7.5 mmol L-1. Cholesterol increased markedly after heart transplantation from a pretransplant value of 5.3 (5.0,5.6) mmol L-1 to 6.7 (6.4,7.0) mmol L-1 after 1 year and then remained constant, but this increase was largely due to a 'normalization' since cholesterol decreased significantly during increasing heart failure before transplantation. Treatment with lovastatin decreased total cholesterol by 19% (P < 0.001), primarily by an effect on LDL cholesterol. HDL cholesterol increased by 15% (P < 0.05), whereas triglycerides remained unchanged. Lovastatin also caused a significant reduction in apolipoprotein B of 16%, and lipid peroxidation of 40%, whereas apolipoprotein A-I, fibrinogen, and glycerol were unchanged. Plasma concentration of lovastatin was significantly higher in transplant recipients compared with controls, but there was no accumulation during incremental dosing of lovastatin. The drug was well tolerated without significant symptoms or evidence of myopathy. Hyperlipidaemia is common after cardiac transplantation. Treatment with low dose lovastatin is well tolerated and has a favourable effect on atherogenic lipids.",1998.0,0,0 3212,9441587,"Effect of HMGcoA reductase inhibitors on stroke. A meta-analysis of randomized, controlled trials.",H C Bucher; L E Griffith; G H Guyatt,"Stroke is a leading cause of death in the industrialized world, and hypercholesterolemia may be a risk factor for stroke. To determine whether reducing cholesterol levels with HMGcoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors or other antilipidemic interventions reduces risk for nonfatal and fatal stroke. A systematic search in the MEDLINE and EMBASE databases of the English-language and non-English-language literature published from 1966 through October 1996. All randomized, controlled trials of any cholesterol-lowering intervention that reported data on nonfatal and fatal strokes, on death from coronary heart disease, and on overall mortality were included. Whether treatment effects differed according to the type of cholesterol-lowering intervention used was investigated. Trials were reviewed for methods, inclusion and exclusion criteria, and outcomes. 28 trials (for a total of 49,477 study participants in the intervention group and 56,636 participants in the control group) were included. The risk ratio for nonfatal and fatal stroke with HMGcoA reductase inhibitors was 0.76 (95% CI, 0.62 to 0.92; test of heterogeneity, P > 0.2). The risk ratios for nonfatal and fatal stroke with fibrates, resins, and dietary interventions were all close to 1.0, and the difference between the HMGcoA reductase inhibitor effect and the pooled estimate for all other interventions would, under the null hypothesis, be unlikely to occur by chance (P = 0.01). Trials with HMGcoA reductase inhibitors also showed reductions in rates of death from coronary heart disease and overall mortality. This meta-analysis of randomized, controlled trials suggests that in hyperlipidemic patients who have not previously had stroke, HMGcoA reductase inhibitors reduce the incidence of stroke.",1998.0,0,0 3213,9451475,Pravastatin in diabetes-associated hypercholesterolemia.,C Rustemeijer; J A Schouten; E N Janssens; P F Spooren; J J van Doormaal,"Patients with diabetes mellitus (DM), type 1 and type 2, have an increased risk of coronary heart disease as a result of accelerated atherosclerosis. Dyslipidemia, often found in these patients, plays an important role in this process. This study investigates the efficacy and safety of lipid-lowering therapy with pravastatin, a 3-HMG-Coenzym A reductase inhibitor in hypercholesterolemic type-1 and type-2 diabetic patients. Of 49 patients (22 type-1 DM and 27 type-2 DM), 24 patients were treated with pravastatin, 20 mg/day, and 25 patients with placebo. After 24 weeks, total cholesterol (TC) was decreased by 22.2%, low-density lipoprotein (LDL) cholesterol by 25.8% and triglycerides (TG) by 13.6%. Pravastatin treatment did not induce a significant change in high-density (HDL) cholesterol levels. No differences in effects of pravastatin treatment on serum lipids and lipoproteins were found with respect to the diabetes type. No serious side effects occurred and pravastatin treatment did not cause any deterioration in glycemia control. The data suggest that pravastatin is effective and safe in the treatment of dyslipidemia in both type-1 and type-2 diabetic patients.",1998.0,0,0 3214,9454018,[The 4S study is analysed. Cholesterol reduction is cost-efficient].,B Jönsson; M Johannesson; A G Olsson,,1998.0,0,0 3215,9456442,Measurement and management of hyperlipidemia for the primary prevention of coronary heart disease.,J Froom; P Froom; M Benjamin; B J Benjamin,"As part of the National Cholesterol Education Program (NCEP) two expert panel reports (1988, 1993) recommend serum cholesterol measurements in all adults aged 20 years and older and cholesterol-lowering treatment for those with abnormal levels. All major drug intervention trials for primary prevention of coronary heart disease were reviewed. Similarly, selected studies on risks of dyslipidemia and benefit of therapy for the elderly and for women without coronary heart disease were analyzed. These studies were evaluated to test the soundness of the NCEP panel's recommendations. Five major randomized drug intervention trials for primary prevention of coronary heart disease showed that cholestyramine, gemfibrozil, clofibrate, and pravastatin can reduce the rate of nonfatal myocardial infarctions in middle-aged men. All-cause and ischemic heart disease mortality were increased by clofibrate and unaffected by the other three drugs. Extrapolation of these findings to women and older and younger men is unwarranted because there is no evidence that either diet or drugs provide primary protection from coronary heart disease in these groups. It is uncertain whether dyslipidemia is a risk factor for coronary heart disease in the elderly. The annual cost of drugs for full implementation of the panel's recommendations ranges from $6 billion to $11.5 billion and an additional $13 billion will be required for initial screening, classifying, and monitoring serum cholesterol levels. Potential adverse consequences of a national program include possible risks from low cholesterol levels, drug side-effects, and disease labeling.",1998.0,0,0 3216,9456448,Reducing cardiovascular morbidity and mortality with the statins.,R W Force,,1998.0,0,0 3217,9456452,Benefits of cholesterol screening and therapy for primary prevention of cardiovascular disease: a new paradigm.,J H Stein; P E McBride,,1998.0,0,0 3218,9457149,Cardiovascular diseases in women.,J A Hsia,"Cardiovascular disease is the leading cause of death in women. Approaches to diagnosis and management of cardiovascular disease in women often differ from those in men. In some instances, these differences are justified by clinical trial and epidemiologic data.",1998.0,0,0 3219,9458414,ESC Population Studies Lecture 1996. Cardiovascular monitoring of a city over 30 years.,L Wilhelmsen,"This lecture on population studies was given in memory and honour of the late Professor Frederick Epstein. It relates to studies performed in Göteborg, Sweden. The main topics discussed in the presentation are: Coronary heart disease and stroke incidence according to the MONICA Project. Risk factors with special emphasis on relative and population attributable risk. Incidence and mortality of coronary heart disease in hospital and out of hospital. Quantitative aspects on treatment and prevention of myocardial infarction. The analysis was based upon a Myocardial Infarction Register which started in 1970, cross-sectional and prospective population studies primarily among men which started in 1963, cross-sectional studies among men and women based upon population studies (the MONICA Project) as well as studies of myocardial infarction. We have also been involved in many intervention trials in primary and secondary prevention regarding physical training, beta-blockers, thrombolytics, aspirin, anti-arrhythmics, ACE-inhibitors and lipid lowering drugs. In the Primary Prevention Study it was found during a 16 years' follow-up that the coronary heart disease risk was related to entry level of serum cholesterol both among those who had signs of coronary heart disease or angina pectoris, as well as among those with no such previous coronary heart disease events at entry. For each cholesterol level, the risk was about seven times higher among those who had had a myocardial infarction compared to those without any coronary heart disease event at entry. In those with angina the risk was about three to four times higher. An example shows how important it is to take the so-called 'regression dilution bias' into account, which results in steeper risk factor-incidence curves. The concept of 'population attributable risk' is also discussed. It is a general finding that the many with moderate elevations of risk factors contribute to most disease events. This is true for smoking, serum cholesterol, blood pressure etc. Results from various prospective studies have repeatedly demonstrated three main risk factors for coronary heart disease: cholesterol, high blood pressure and smoking, and they explain more than 90% of infarct cases in the middle-aged population. Other risk factors, including psychological, are, however, also of some importance and they are discussed briefly. The Göteborg population studies started in 1963. The data to 1990 show that among men there has been a decline in serum cholesterol and blood pressure, which has resulted in a decline in risk for coronary heart disease of 37%, well compatible with the registered decline of 30-40% in coronary heart disease incidence among men aged 45-54 years. Simultaneously, there has been a marked decline, especially among men, of 28-day fatality among hospitalized patients, but because most deaths occur outside hospital the decline in incidence has had greater importance for overall coronary heart disease mortality. Several studies have demonstrated the importance of stopping smoking, at least after myocardial infarction. Other interventions after a myocardial infarction are also important for the outcome, which has improved considerably over the last 20 years. In the general population in whom there is no sign of coronary heart disease, it is important to reduce risk factors among the many with moderate risk, by stopping smoking and changing diet.",1998.0,0,0 3220,9462596,Comparison of angiographic and clinical outcomes of coronary stenting of chronic total occlusions versus subtotal occlusions.,I Moussa; C Di Mario; J Moses; B Reimers; L Di Francesco; S Blengino; A Colombo,"The objective of this study was to assess the short- and long-term outcome of patients undergoing coronary stenting for chronic total occlusions compared with a control patient population with nonocclusive stenoses. A total of 789 consecutive patients (1,043 lesions) underwent coronary stenting using a high-pressure stent optimization technique. The study population was divided into total occlusion group (94 consecutive patients [95 lesions] with chronic total occlusions) and subtotal occlusion group (695 consecutive patients [948 lesions] with nonocclusive stenoses). There was no difference in post-procedure angiographic minimum lumen diameter (3.13 +/- 0.48 vs 3.15 +/- 0.57 mm, p = 0.72) and minimum intrastent cross-sectional area by intravascular ultrasound (7.31 +/- 2.06 vs 7.64 +/- 2.53 mm2, p = 0.26) between the total and subtotal groups, respectively. Subacute thrombosis occurred in 2 patients (2.1%) in the total group compared with 9 patients (1.3%) in the subtotal group (p = 0.63). Angiographic restenosis occurred in 27% vs 22% (p = 0.40) and repeat angioplasty in 15% vs 13% (p = 0.62) in the total and subtotal groups, respectively. Thus, coronary stenting of chronic total occlusions after successful recanalization could be performed with a high success rate. In addition, the incidence of stent thrombosis, angiographic restenosis, and the need for target lesion revascularization is comparable to that of an unselected cohort of patients with nonocclusive stenoses.",1998.0,0,0 3221,9462599,Prediction of death and neurologic outcome in the emergency department in out-of-hospital cardiac arrest survivors.,R J Thompson; P A McCullough; J K Kahn; W W O'Neill,"We reviewed the hospital records of 127 consecutive patients who were resuscitated from cardiac arrest in a retrospective cohort analysis. A cardiac arrest score utilizing time to return of spontaneous circulation, systolic blood pressure at the time of presentation, and initial neurologic exam were calculated. This score was analyzed with 39 other clinical variables for significance with regard to mortality or neurologic survival using multivariate analysis. Combining these variables into a cardiac arrest score (levels 0, 1, 2, 3, from least to most favorable) allowed prediction of neurologic outcomes and mortality from a single variable in an independent fashion (p < 0.0001). Logistic regression models found scores of 0, 1, 2, and 3 predicted in-hospital mortality rates of 90%, 71%, 42%, 18%, and neurologic recovery in 3%, 17%, 57%, and 89%, respectively. The cardiac arrest score was able to predict in-hospital mortality and neurologic outcomes in those who survived to emergency department arrival. This scoring scheme may aide in selection of patients for early aggressive measures, including triage coronary angiography and angioplasty.",1998.0,0,0 3222,9462602,Safety and efficacy of closed-loop arbutamine stress echocardiography for detection of coronary artery disease. International Arbutamine Study Group.,D S Bach; J L Cohen; P M Fioretti; L E Ginzton; J Sklar; M Zabalgoitia; L Crouse,"Closed-loop arbutamine stress echocardiography has been shown to be safe and effective for detecting coronary artery disease (CAD) using a standardized infusion protocol and centralized core laboratory analyses. However, the accuracy of arbutamine stress echocardiography using local test interpretation has not been previously tested in a large population. The present study reports the safety, sensitivity, and specificity of arbutamine stress echocardiography in a multicenter trial allowing user-defined, nonstandardized protocols and local test interpretation. In all, 1,070 patients underwent arbutamine stress testing at 81 sites. Heart rate increased from 73 +/- 13 to 124 +/- 15 beats/min, systolic blood pressure from 144 +/- 24 to 174 +/- 25 mm Hg, and pressure rate product x 10(3) from 10.5 +/- 2.8 to 19.6 +/- 3.9. Among 1,070 patients, there were only 2 (0.2%) significant adverse events related to arbutamine, both of which resolved completely with appropriate therapy. There were no incidents of ventricular fibrillation, sustained ventricular tachycardia, or death related to testing. Among 242 patients who underwent arbutamine stress echocardiography and diagnostic coronary angiography within 12 weeks, sensitivity and specificity for detection of CAD were 71% (95% confidence interval 64% to 77%) and 67% (95% confidence interval 52% to 80%), respectively. Closed-loop arbutamine stress echocardiography is a safe and effective method for evaluating CAD in clinical practice.",1998.0,0,0 3223,9462603,Vascular access site complications after percutaneous coronary intervention with abciximab in the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial.,J C Blankenship; A S Hellkamp; F V Aguirre; S L Demko; E J Topol; R M Califf,"Thrombolytic therapy or intense anticoagulation during percutaneous transluminal coronary revascularization (PTCR) increases the risk of vascular access site complications. This study evaluated the association of abciximab, a glycoprotein IIb/IIIa receptor blocker, with vascular access site complications after PTCR. Of 2,058 patients who underwent PTCR in the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial, major vascular access site bleeding (a drop in hematocrit > 15%), minor vascular access site bleeding (> 10% drop), or surgical repair of the access site occurred in 5%, 12%, and 1.4% of all patients, respectively. Minor and/or major bleeding or surgery occurred in 21.8% of abciximab patients, compared with 9.1% of placebo patients (p <0.001). Logistic regression analysis identified these predictors of minor and/or major bleeding and/or surgical repair, in descending order of importance: abciximab therapy, acute myocardial infarction at enrollment, high baseline hematocrit, time in catheterization laboratory, heavier weight, female gender, maximum in catherization laboratory activated clotting time, sheath size, and age (all p <0.05). Vascular access site complications increased median post-PTCR length of stay from 2 days (no bleeding) to 3 days (minor bleeding) and 6 days (major bleeding). Site-to-site variation in vascular access site complications varied sixfold. Analyses of subsequent studies of PTCR with abciximab will determine whether discontinuing heparin and removing sheaths early after PTCR reduces the risk of vascular access site complications.",1998.0,0,0 3224,9466141,A comparison of economic modelling and clinical trials in the economic evaluation of cholesterol-modifying pharmacotherapy.,S Morris,"There are various ways in which data for economic evaluations may be obtained, including via clinical trials and via economic modelling. There are numerous advantages and disadvantages associated with each method, although it is generally assumed that economic models lack the accuracy required for the calculation of meaningful cost-effectiveness data. In order to assess the predictive accuracy of economic modeling in the context of cholesterol-modifying pharmacotherapy it is possible to compare predicted coronary heart disease (CHD) incidence estimates obtained using CHD risk equations derived from the Framingham Heart Study (FHS) with actual CHD incidence rates achieved in a major clinical trial, the West of Scotland Coronary Prevention Study (WOSCOPS). FHS-derived CHD risk equations substantially underestimate the actual risks of nonfatal myocardial infarction obtained by WOSCOPS. However, in predicting risks of death from CHD, FHS-derived CHD risk equations estimate extremely accurately the incidence obtained by WOSCOPS. For example, from WOSCOPS the risk of an individual fulfilling the trial entry criteria incurring nonfatal myocardial infarction or CHD death in 4.9 years is 0.079 for placebo group and 0.055 for the intervention group. Therefore, the relative risk for the intervention group relative to placebo group is 0.696, implying a risk reduction of 30%. Comparable risks predicted using FHS-derived CHD risk equations are 0.116 for the placebo group and 0.088 for the intervention group. Consequent relative risks and risk reductions for the intervention relative to placebo are 0.757 and 24%, respectively. Using both model and trial estimates of CHD incidence in an economic evaluation of cholesterol-modifying pharmacotherapy, incremental costs per life year gained are 41,707 Pounds using WOSCOPS data and 36,480 Pounds using FHS-derived CHD risk equations.",2000.0,0,0 3225,9468077,Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S).,T R Pedersen; J Kjekshus; K Pyörälä; A G Olsson; T J Cook; T A Musliner; J A Tobert; T Haghfelt,"In patients participating in the Scandinavian Simvastatin Survival Study, cholesterol lowering with simvastatin reduced the incidence of carotid bruits and cerebrovascular events as well as new-onset or worsening of angina pectoris and intermittent claudication. These effects suggest that simvastatin may have a general antiatherosclerotic effect not limited to the coronary bed.",1998.0,0,0 3226,9472843,The extent and determinants of changes in CYP2D6 and CYP1A2 activities with therapeutic doses of sertraline.,V Ozdemir; C A Naranjo; N Herrmann; R W Shulman; E M Sellers; K Reed; W Kalow,"The extent of changes in CYP2D6 and CYP1A2 activities with higher therapeutic dosages (>50 mg/day) of sertraline is not well established in vivo. This study assessed the extent and determinants of changes in CYP2D6 and CYP1A2 isozyme activities after treatment with clinically relevant doses of sertraline. Patients and healthy volunteers aged 19 to 85 years (N = 21) were treated with sertraline for 5 to 55 days. The dosage of sertraline ranged from 25 to 150 mg/day (93.5+/-26.4 mg/day; mean +/- SD). All subjects had an extensive metabolizer phenotype for CYP2D6 and received a single oral dose of dextromethorphan (30 mg) and caffeine (100 mg) before and after sertraline treatment. The log O-demethylation ratio (ODMR) of dextromethorphan and the caffeine metabolic ratio (CMR) in overnight urine were used as in vivo indices of the CYP2D6 and CYP1A2 isozyme activities, respectively. Concurrent medications and lifestyle habits (e.g., smoking and diet) were monitored during the study. Baseline log ODMR (-2.33+/-0.45) but not CMR (5.1+/-1.9) (mean +/- SD) significantly changed after sertraline treatment (-2.19+/-0.62; 4.5+/-1.6, respectively) (p: ODMR = 0.04, CMR = 0.10). There was no significant effect of age, dose, duration of treatment, gender, sertraline and/or desmethylsertraline plasma concentration, subject type (patient or volunteer), and weight on the extent of changes in log ODMR or CMR (p > 0.05). In conclusion, sertraline treatment at a mean daily dosage of 94.0 mg did not significantly change CYP1A2 activity and resulted in a modest inhibition of CYP2D6 activity.",1998.0,0,0 3227,9472853,Lack of antidepressant-cyclosporine pharmacokinetic interactions.,J S Markowitz; H S Gill; N M Hunt; R R Monroe; C L DeVane,,2001.0,0,0 3228,9474468,Long-term patency (9 1/2 years) and atherosclerosis of a polytetrafluoroethylene (Gortex) coronary artery bypass graft.,S C Vlay; A Z Malik,"The patency of a polytetrafluoroethylene (Gortex) graft 9 1/2 years after coronary artery bypass graft surgery (CABG) is demonstrated. While this material is not commonly used as a conduit because of limited success in the past, this case demonstrates that, given the right circumstances, long-term patency is possible. Since available conduits for CABG are quite often limited, viable alternatives may be lifesaving and require further evaluation. In addition to mechanical considerations such as size, length, and material, anticoagulation and strict management of hyperlipidemia may be critical.",1998.0,0,0 3229,9474997,The effect of garlic on hypercholesterolemia in renal transplant patients.,J P Lash; L R Cardoso; P M Mesler; D A Walczak; R Pollak,,1998.0,0,0 3230,9475827,Update on the pharmacotherapy of obesity.,J Cerulli; B M Lomaestro; M Malone,"To review recent developments in the pharmacotherapy of obesity, including the agents currently approved for use in the management of obesity and those under development. A MEDLINE search from January 1990 to July 1997 was conducted to identify English literature available on the pharmacotherapy of obesity. The search was supplemented by a review of the bibliographies of identified literature. All controlled and uncontrolled trials were reviewed. When available, double-blind, placebo-controlled trials were used preferentially. Agents were reviewed with regard to mechanism of action, clinical trial data regarding efficacy, adverse effects, pharmacokinetics, drug interactions, and contraindications where information was available. Study design, selected population, results, and adverse effect information were included. The anorexiants currently available or under development for the management of obesity regulate food intake and satiety via the adrenergic and/or serotonergic pathways. Clinical trials have shown a 10-15% weight loss can typically be anticipated; however, little long-term safety and efficacy data are available. Adverse events tend to be mild and self-limiting, but serious adverse events can occur. Treatment options under development include thermogenic agents, digestive inhibitors, and analogs and antagonists of hormones that regulate food intake and satiety. Several mechanisms to control weight are currently under investigation for the management of obesity. Since obesity is a chronic condition, further studies should be conducted to evaluate the long-term safety and efficacy of these agents and the role of combination therapy using different modalities.",1998.0,0,0 3231,9476029,"Use of lipid-lowering drugs from 1990 to 1994: an international comparison among Australia, Finland, Italy (Emilia Romagna Region), Norway and Sweden.",N Magrini; T Einarson; A Vaccheri; P McManus; N Montanaro; U Bergman,"To compare the overall utilisation pattern of lipid-lowering drugs between 1990 and 1994 in Australia, Finland, Italy, Norway and Sweden as well as the pattern of use with respect to age and gender in Italy and Sweden. Data were retrieved from regulatory authorities in each country for the 5-year period and analysed according to the ATC/DDD methodology (Anatomical Therapeutic Chemical classification/Defined Daily Doses). Utilisation was calculated as the DDDs for 1000 inhabitants per day for all drugs of the ATC category B04 (serum lipid-reducing agents). Data from Sweden and Italy were also compared with respect to gender and age. In 1994, Australia demonstrated the highest degree of utilisation (11.9 DDD) and the Nordic Countries the lowest (Sweden 5.6; Norway 4.9; Finland 4.0). In all countries except Italy, a steady increase was observed; in Italy, utilisation of these drugs reached a maximum in 1992 (11.5 DDD), but then underwent a reduction which was caused by restrictions in the reimbursement status in 1993 (10.4) and 1994 (6.7). Administration of statins increased in all countries, becoming the most used group of the B04 class. In 1988, the number of different drugs listed by each national health service ranged from 4 (Norway) to 16 (Italy); in 1994 it ranged from 6 (Norway) to 9 (Sweden). Analysis with respect to gender showed the opposite pattern in Sweden (males 4.6 and females 3.3 in 1992; 6.2 and 4.5, respectively, in 1994) than in Italy (males 10.8 and females 17.8 in 1992; 6.4 and 9.2, respectively, in 1994). Exposure was highest in people aged 60-69 years in both countries, followed by age group 50-59 in Sweden and 70-79 in Italy. Large variations in the utilisation of lipid-lowering drugs exist between countries, with Australia and Italy much higher than others. Of the drugs in the ATC category B04, the use of statins predominates in all countries, but to varying degrees. The large difference in the degree of drug utilisation with respect to age and gender between Italy and Sweden suggests major deviations from evidence-based medicine.",1998.0,0,0 3232,9476046,Simvastatin reduces activation of normal platelets by LDL isolated from patients with familial hypercholesterolaemia and familial defective apolipoprotein B.,D A Tsakiris; U Keller; H Zulewski; A R Miserez; F Wolf; G A Marbet,,1998.0,0,0 3233,9483717,On the statistical modelling of coronary arteriographic data: dynamics of coronary atherosclerosis related to systemic and focal parameters. REGRESS Study Group. Regression Growth Evaluation Statin Study.,A H Zwinderman; J W Jukema; A J van Boven; J H Reiber,"Existing methods to analyse data from repeated arteriographic progression/regression studies are restrictive and do not fully explore the dynamics of coronary artherosclerosis. We present a new approach making a distinction between new occlusions, new lesions, and growth of existing lesions. Random effect models, based on the logistic, the Poisson, and the normal distribution are proposed with correlation depending on distance. The data from the Regression Growth Evaluation Statin Study (REGRESS) are used to validate the model. Lipid lowering treatment of pravastatin resulted in less growth of existing lesions and fewer new lesions than when placebo was given. Fewer new lesions were found in segments influenced by percutaneous transluminal coronary angioplasty (PTCA) than in segments not influenced by PTCA. Similarly, the growth of lesions influenced by PTCA was smaller than lesions not influenced by PTCA. More new occlusions were found in segments influenced by coronary arterial bypass grafting (CABG) than in segments not influenced by CABG, but 98 per cent of the new occlusions were located proximal to the bypass anastomosis. Similarly, existing lesions proximal to the bypass anastomosis showed larger growth (p < 0.001). We conclude that our new approach for analysing the arteriographic data from repeated coronary arteriographic studies appeared a fruitful way to analyse the dynamics of coronary atherosclerosis.",2000.0,0,0 3234,9484618,Recent advances in stroke therapy.,A Goldszmidt; R J Wityk,"Advances in stroke therapy have followed diverse paths over the past 2 years. Recent clinical trials have investigated the use of thrombolytic agents, anticoagulants, antiplatelet drugs and neuroprotective agents in acute stroke patients. The positive results of the National Institutes of Neurologic Disease and Stroke tissue plasminogen activator trial have increased interest in the field of acute stroke therapy and initiated significant changes in the management of stroke patients in the medical system. A new antiplatelet drug and a number of trials involving HMG Co-A reductase inhibitors are important advances in the secondary prevention of stroke.",1998.0,0,0 3235,9485553,"Development, validation, and interlaboratory comparison of an HMG-CoA reductase inhibition assay for quantitation of atorvastatin in plasma matrices.",Y Y Shum; N Huang; G Walter; A Black; C Sekerke; T Chang; L R Whitfield,"An HMG-CoA reductase inhibition assay was developed and validated for quantitation of atorvastatin in human, dog, rat, and mouse plasma. Atorvastatin was isolated from plasma by protein precipitation. Rat-liver microsomes were used to provide the reductase enzyme. The method was validated by assaying calibration standards and quality controls in triplicate on each of the 3 days. A customized computer program was used for data calculation. Quantitation of the assay ranged from 0.36 to 16 ng/ml of atorvastatin in different plasma matrices. Assay precision and accuracy, based on the coefficient of variation and percent relative error, respectively, of quality controls were 10.4% to 14.5% and within +/- 6.25% in human; 4.89% to 10.6% (+/- 8.13%) in dog; 2.68% to 8.62% (+/- 5.00%) in rat; and 3.68% to 8.96% (+/- 5.38%) in mouse plasma. The method has been applied to pharmacokinetic studies of atorvastatin in human and toxicokinetic studies in dog, rat, and mouse after atorvastatin administration. Atorvastatin equivalent concentrations in a set of plasma samples from subjects receiving single and multiple doses of atorvastatin were determined by validated HMG-CoA reductase inhibition assays at four different laboratories. Results were compared using linear regression and concordance correlation statistical procedures. Good agreements among these data indicated that results from different laboratories with the same validated method can be used interchangeably.",1998.0,0,0 3236,9487230,Coronary artery disease in women. A historical perspective.,J L Thomas; P A Braus,"Knowledge about the natural history of coronary heart disease in women was limited until recent years. Few studies included women, despite the fact that heart disease is the No. 1 cause of death in women older than 50 years and the cause of about 500,000 deaths annually. Over the past decade, knowledge has increased owing to a combination of greater participation of women in medical studies, improved medical technology, and political pressure. While much remains to be learned, researchers have found that coronary artery disease in women typically follows a different course than it does in men. Women's risk factors also differ from men's, in part owing to the key protective role played by estrogen. Increasing knowledge about women and heart disease can provide new tools for physicians caring for women at risk of heart disease.",1998.0,0,0 3237,9487235,Treating hyperlipidemia for the primary prevention of coronary disease. Are higher dosages of lovastatin cost-effective?,S Perreault; V H Hamilton; F Lavoie; S Grover,"To compare the average and marginal life-time cost-effectiveness of increasing dosages of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, such as lovastatin, for the primary prevention of coronary heart disease (CHD). We estimated the lifelong costs and benefits of the modification of lipid levels achieved with lovastatin based on published studies and a validated CHD prevention computer model. Patients were middle-aged men and women without CHD, with mean total serum cholesterol levels of 6.67, 7.84, and 9.90 mmol/L (258, 303, and 383 mg/dL), and high-density lipoprotein cholesterol levels of 1.19 mmol/L (46 mg/dL), as described in clinical trials. We estimated the cost per year of life saved for dosages of lovastatin ranging from 20 to 80 mg/d that reduced the total cholesterol level between 17% and 34%, and increased high-density lipoprotein cholesterol level between 4% and 13%. After discounting benefits and costs by 5% annually, the average cost-effectiveness of lovastatin, 20 mg/d, ranged from $11,040 to $52,463 for men and women. The marginal cost-effectiveness of 40 mg/d vs 20 mg/d remained in this range ($25,711 to $60,778) only for persons with baseline total cholesterol levels of 7.84 mmol/L (303 mg/dL) or higher. However, the marginal cost-effectiveness of lovastatin, 80 mg/d vs 40 mg/d, was prohibitively expensive ($99,233 to $716,433 per year of life saved) for men and women, irrespective of the baseline total cholesterol level. Assuming that $50,000 per year of life saved is an acceptable cost-effectiveness ratio, treatment with lovastatin at a dosage of 20 mg/d is cost-effective for middle-aged men and women with baseline total cholesterol levels of 6.67 mmol/L (258 mg/dL) or higher. At current drug prices, treatment with 40 mg/d is also cost-effective for total cholesterol levels of 7.84 mmol/L (303 mg/dL) or higher. However, treatment with 80 mg/d is not cost-effective for primary prevention of CHD.",1998.0,0,0 3238,9489067,Diagnosis and management of hyperlipidaemia.,A S Wierzbicki,Hyperlipidaemia is acknowledged as the major risk factor for coronary heart disease and atheroma progression. This review considers the strategies that should be followed to reduce overall cardiovascular risk in patients with hyperlipidaemia and deals with the identification and management of treating both polygenic and monogenic lipid disorders in the presence or absence of overt cardiovascular disease.,1998.0,0,0 3239,9490233,"Vessel size, antioxidants, and restenosis: never too small, not too little, but often too late.",E R Edelman,,1998.0,0,0 3240,9491945,The importance of lowering cholesterol in patients with coronary heart disease.,D Eisenberg,"Patients with prior manifestations of cardiovascular disease account for about 50% of all myocardial infarctions and 70% of deaths due to coronary disease. The benefits of lowering elevated cholesterol levels in patients with coronary disease are well documented. Recent clinical trials indicate that these benefits, in terms of reduced risk of cardiovascular morbidity and mortality, extend even to patients with ""average"" cholesterol levels and support the importance of reaching a target low-density lipoprotein cholesterol level of < or = 100 mg/dl. These findings argue in favor of attaining and maintaining optimal lipid targets for secondary (and primary) prevention of atherosclerotic vascular disease in patients at risk.",1998.0,0,0 3241,9497506,[Gemfibrozil reduces elevated lipoprotein (a) levels in hypercholesterolemic patients].,J A Ramires; A C Spósito; A P Mansur; M C Solimene; D Chamone; P L da Luz; F Pileggi,"To compare the effects of gemfibrozil and lovastatin in patients with hypercholesterolemia and increased lipoprotein(a) [Lp(a)] levels. Twenty-seven subjects with total cholesterol (TC) > 240 mg/dL, LDL-C > 160 mg/dL and Lp(a) > 25 mg/dL were studied. Patients were randomized to receive gemfibrozil 1200 mg/day, (n = 14, 54 +/- 7 years) or lovastatin 40-80 mg at night (n = 13, 55 +/- 9 years) for 12 weeks. Lipid profile and Lp(a) were determined at 4 and 12 weeks of treatment. Gemfibrozil reduced TC (-21%), LDL-C (-26%), triglycerides (TG)(-48%) and Lp(a) (-25%), increased HDL-C (+48%)(p < 0.001). Lovastatin reduced TC (-29%), LDL-C (-37%) and TG (-25%) (p < 0.001) however, it did not affect Lp(a). Besides reducing plasma LDL-C, TG and increasing HDL-C, gemfibrozil effectively lowers Lp(a) levels. Lovastatin did not affect Lp(a) levels.",1998.0,0,0 3242,9500689,Cholesterol metabolism and serum and biliary noncholesterol sterols in gallstone patients during simvastatin and ursodeoxycholic acid treatments.,T E Miettinen; T Kiviluoto; M Taavitsainen; M Vuoristo; T A Miettinen,"Effects of long-term high-dose ursodeoxycholic acid (UDCA) and simvastatin treatments on cholesterol metabolism and biliary lipid compositions were compared in patients with cholesterol gallstones. Absorption and synthesis of cholesterol, serum and biliary noncholesterol sterols and lipids were determined in 14 patients randomized to UDCA (23-25 mg/kg/d) or simvastatin (40 mg/d) for 1 year. Simvastatin reduced serum low-density lipoprotein cholesterol by 55%, and UDCA, by 9%. Cholesterol absorption was decreased (35%) by UDCA, but nonsignificantly increased by simvastatin (P < .05 for difference of changes caused by the two drugs). Whole-body synthesis and biliary output of cholesterol were both significantly decreased only by UDCA. In addition, UDCA inconsistently increased the proportions of serum and biliary precursor sterols of cholesterol, known to reflect cholesterol synthesis, but did not affect their biliary secretions. Simvastatin, however, dramatically reduced serum and also biliary cholesterol precursor sterol proportions and their biliary secretions and increased proportions of serum and biliary plant sterols and cholestanol, known to reflect cholesterol absorption, but had no effect on their biliary secretion. Only UDCA significantly decreased the molar percentage of cholesterol, the lithogenic index, and the cholesterol/phospholipid (CH/ PL) ratio in bile, whereas both treatments inconsistently decreased the vesicular CH/PL ratio (P < .07 in both groups). It is concluded that both drugs decreased serum cholesterol and inhibited cholesterol synthesis, but had a differing influence on precursor sterols and the absorption of cholesterol. UDCA had more beneficial effects than simvastatin on the antilithogenic properties of bile.",1998.0,0,0 3243,9503169,Fibrinogen and coronary heart disease--what does it mean?,M F Oliver,,1998.0,0,1 3244,9504445,Mortality rates in treated hypertensive men with additional risk factors are high but can be reduced: a randomized intervention study.,B Fagerberg; J Wikstrand; G Berglund; O Samuelsson; S Agewall,"The aim was to examine the feasibility and efficacy of a multifactorial risk factor intervention program in hypertensive patients at high cardiovascular risk. Treated hypertensive men, aged 50 to 72 years, with at least one of the following: serum cholesterol concentration > or = 6.5 mmol/L, diabetes mellitus, or smoking were randomized to multifactorial risk factor intervention (n = 253) or usual care (n = 255). The specific intervention was based on group meetings to encourage a lipid lowering diet and smoking cessation. Cholestyramine, nicotinic acid, fibrates, and later statins were used either as single drug therapy or in combination, following agreed guidelines in patients in whom the nonpharmacological intervention was judged to be insufficient. Usual care was given according to clinical practice. The median follow-up time was 6.6 years. Sixty-four patients (25.1%) died in the usual care group, compared with 41 patients (16.2%) in the intervention group (P = .016; 95% confidence interval, relative risk 0.42 to 0.92). The overall risk for fatal and nonfatal cardiovascular events was 29% lower in the intervention group than in the usual care group (P = .041). Relative to usual care, the intervention program lowered mean in-trial serum concentrations of total cholesterol (6.3%, P < .0001), LDL cholesterol (9.1%, P < .0001), and blood glucose (0.2 mmol/L, P < .05). Among smokers, at entry, cotinine-adjusted quit rates were 28% in the intervention group and 11% in the usual care group (P = .012) after 3 years. This study illustrates the very high cardiovascular risk in hypertensive patients 50 to 72 years of age with additional risk factors. The results indicate, however, that the gloomy prognosis may be improved by a dedicated risk factor intervention program.",1998.0,0,0 3245,9505147,Metformin increases circulating tumour necrosis factor-alpha levels in non-obese non-diabetic patients with coronary heart disease.,S M Carlsen; A Waage; V Grill; I Følling,"Metformin reduces insulin resistance and hyperinsulinaemia, as well as lipid levels and body weight. The mechanisms behind these effects are likely to involve intracellular insulin signalling. Recent evidence implicates tumour necrosis factor-alpha (TNF-alpha) as a modulatory factor on insulin resistance. The present investigation was undertaken to clarify whether metformin affects TNF-alpha and soluble TNF receptor levels. Sixty non-diabetic men with coronary heart disease were treated with diet and lifestyle advice and lovastatin 40 mg/day during a 4-week run-in period. During this period TNF-alpha and soluble TNF receptor p75 remained unchanged, whereas soluble TNF receptor p55 increased by 8% (P < 0.05). Twelve weeks of metformin treatment increased TNF-alpha by 33% (P < 0.05). This effect was restricted to non-obese patients in whom TNF-alpha increased by 68% (P < 0.01). Soluble TNF receptors p55 and p75 remained unchanged in the whole group, whereas soluble TNF receptor p55 increased by 11% (P < 0.05) in non-obese patients. Since metformin reduces insulin resistance both in obese and non-obese subjects but increases TNF-alpha levels only in the latter, it is concluded that the drug does not exert its effect on insulin resistance through regulation of circulating TNF-alpha levels.",1998.0,0,0 3246,9505908,Using cost-effectiveness for subsidy decisions.,P Glasziou,,1998.0,0,0 3247,9509055,Atorvastatin.,P J Hyatt,,1998.0,0,0 3248,9512650,Hepatic responses to inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase: a comparison of atorvastatin and simvastatin.,J D Bergstrom; R G Bostedor; D J Rew; W M Geissler; S D Wright; Y S Chao,"We have compared the cellular responses to simvastatin (Simva) and atorvastatin (Atorva), two potent HMG-CoA reductase inhibitors. The two drugs exhibited similar IC50's for inhibition of either rat or human reductase, and single oral dosing in rats showed the compounds to be nearly equipotent at inhibiting hepatic cholesterol synthesis. Treatment of rats with Simva or Atorva in the feed for four days yielded comparable inductions of hepatic reductase activity and reductase protein. For example, 0.05% Simva induced reductase activity 27.3 +/- 9.1 fold and 0.05% Atorva induced activity 26.9 +/- 4.7 fold. This adaptive response was also studied in HepG2 cells, a human hepatoblastoma line, cultured for 24 h in delipidated serum and then for an additional 24 h with Simva or Atorva. Over a broad range (10 nM-10 microM), both drugs caused similar inductions of reductase activity, reductase protein, and reductase mRNA. Under all conditions, the drugs induced similar changes in the ratio of mRNA/protein suggesting that Simva and Atorva have similar effects on both transcriptional and post-transcriptional regulatory machinery. Moreover, reductase in cells treated with Simva or Atorva for 22 h responded similarly to subsequent challenge with 25-hydroxycholesterol. Finally, we measured the ability of the two reductase inhibitors to reduce ApoB secretion by HepG2 cells. Simva and Atorva at 0.5 microM inhibited ApoB secretion nearly identically, 38% and 42% respectively. We conclude that these two drugs induce similar adaptive responses in cells and that their actions are qualitatively and mechanistically identical. Human studies have shown that plasma is cleared of Atorva much more slowly than it is of Simva. The large pharmacokinetic difference in man, rather than some difference in mechanism, is the most likely explanation for the finding that the equipotent dose ratio for cholesterol lowering in humans of Simva to Atorva is about 2/1.",1998.0,0,0 3249,9514453,Rationale and design of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction.,G G Schwartz; M F Oliver; M D Ezekowitz; P Ganz; D Waters; J P Kane; M Texter; M L Pressler; D Black; B R Chaitman; A G Olsson,"The goal of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is to determine whether early, rapid, and profound cholesterol lowering therapy with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave acute myocardial infarction. Within 1 to 4 days of hospitalization for one of these conditions, 2,100 patients will be randomly assigned to receive atorvastatin, 80 mg/day, or placebo in a double-blind design. Both groups receive dietary counseling. Over a 16-week follow-up period, the primary outcome measure is the time to occurrence of an ischemic event, defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. Secondary outcome measures are the time to occurrence and incidence of each of the primary outcome components, as well as nonfatal stroke, worsening angina, congestive heart failure requiring hospitalization, and need for coronary revascularization not anticipated before randomization. The sample size of 1,050 patients in each group is expected to provide 95% power to detect a 30% reduction in the primary outcome measure with a 5% level of significance. The results of the MIRACL study will determine the utility of profound cholesterol lowering as an early intervention in acute coronary syndromes.",1998.0,0,0 3250,9514454,"Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study)",P Jones; S Kafonek; I Laurora; D Hunninghake,"The objective of this multicenter, randomized, open-label, parallel-group, 8-week study was to evaluate the comparative dose efficacy of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor atorvastatin 10, 20, 40, and 80 mg compared with simvastatin 10, 20, and 40 mg, pravastatin 10, 20, and 40 mg, lovastatin 20, 40, and 80 mg, and fluvastatin 20 and 40 mg. Investigators enrolled 534 hypercholesterolemic patients (low-density lipoprotein [LDL] cholesterol > or = 160 mg/dl [4.2 mmol/L] and triglycerides < or = 400 mg/dl [4.5 mmol/L]). The efficacy end points were mean percent change in plasma LDL cholesterol (primary), total cholesterol, triglycerides, and high-density lipoprotein cholesterol concentrations from baseline to the end of treatment (week 8). Atorvastatin 10, 20, and 40 mg produced greater (p < or = 0.01) reductions in LDL cholesterol, -38%, -46%, and -51%, respectively, than the milligram equivalent doses of simvastatin, pravastatin, lovastatin, and fluvastatin. Atorvastatin 10 mg produced LDL cholesterol reductions comparable to or greater than (p < or = 0.02) simvastatin 10, 20, and 40 mg, pravastatin 10, 20, and 40 mg, lovastatin 20 and 40 mg, and fluvastatin 20 and 40 mg. Atorvastatin 10, 20, and 40 mg produced greater (p < or = 0.01) reductions in total cholesterol than the milligram equivalent doses of simvastatin, pravastatin, lovastatin, and fluvastatin. All reductase inhibitors studied had similar tolerability. There were no incidences of persistent elevations in serum transaminases or myositis.",1998.0,1,1 3251,9514463,Aggressive lipid lowering in postcoronary angioplasty patients with elevated cholesterol (the Lovastatin Restenosis Trial).,S J Boccuzzi; W S Weintraub; A S Kosinski; J B Roehm; J L Klein,"A substudy of the Lovastatin Restenosis Trial in patients with elevated cholesterol (>200 mg/dl) showed no evidence of an effect of aggressive lipid lowering on restenosis, confirming the results of the main trial.",1998.0,0,0 3252,9517370,Lipoprotein composition and oxidative modification during therapy with gemfibrozil and lovastatin in patients with combined hyperlipidaemia.,M Vázquez; D Zambón; Y Hernández; T Adzet; M Merlos; E Ros; J C Laguna,"To evaluate the resistance to oxidation of human lipoproteins after hypolipidaemic therapy. VLDL and LDL samples were obtained from patients with Familial Combined Hyperlipidaemia included in a randomized, double-blind, cross-over study, with 8 weeks of active treatment (gemfibrozil, 600 mg twice daily, or lovastatin, 40 mg daily) and a 4-week wash-out period. Oxidation related analytes after Cu-induced oxidation of VLDL and LDL have been investigated. Further, in order to relate possible changes in oxidative behaviour to lipoprotein composition, the proportion of the lipid species transported by lipoproteins (triglycerides, phospholipids, and cholesteryl esters), the molar composition of fatty acids for each lipoprotein lipid, and the content of antioxidant vitamins in plasma (vitamin C) and lipoproteins (vitamin E) have been studied. Both drugs reduced the plasma concentration of apo-B lipoproteins (-23% gemfibrozil, -26% lovastatin), but whereas lovastatin affected mainly LDL-cholesterol (-30%), gemfibrozil reduced triglycerides (-49%) and VLDL-cholesterol (-48%). Lovastatin treatment had no effect on the lipid and protein composition, the fatty acid profile, or the vitamin E content of either VLDL or LDL; likewise, lipoprotein oxidation markers (Cu-induced conjugated dienes, thiobarbituric acid reactive substances formation, and lysine residues) were similar before and after lovastatin treatment. Gemfibrozil therapy also had no effect on lipoprotein oxidation; nevertheless, it consistently: a) decreased the proportion of LDL-triglycerides (-32%), and b) increased the proportion (molar%) of 18:3 n-6 in VLDL triglycerides (+140%), phospholipids (+363%) and cholesteryl esters (+53%). Based on these results, lovastatin and gemfibrozil do not adversely affect lipoprotein oxidation in patients with mixed dyslipidaemia. In the case of gemfibrozil, this occurs in spite of an increased proportion of some polyunsaturated fatty acids in VLDL. In the context of a fixed dietary intake, such modifications suggest that the drug influences liver enzyme activities involved in fatty acid chain synthesis (elongases and desaturases).",1998.0,0,0 3253,9520115,Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study.,K Berg; G Dahlén; B Christophersen; T Cook; J Kjekshus; T Pedersen,"The Scandinavian Simvastatin Survival Study (4S) was a double-blind, randomized placebo-controlled multi-centre clinical trial of long-term Simvastatin therapy in patients with coronary heart disease who had total cholesterol levels between 5.5 and 8.0 mmol/l, comprising 4444 patients, equally distributed to a Simvastatin and a placebo group. Patients achieved a significant 30% relative reduction in overall mortality with Simvastatin therapy through a 42% relative reduction in coronary heart disease mortality. Lp(a) lipoprotein levels in Scandinavian coronary heart disease patients were strikingly higher than in healthy controls. Numbers of deaths in the Simvastatin group differed significantly between quartiles of Lp(a) lipoprotein levels, the reduction in deaths being most pronounced in the second (next to lowest) quartile. Subjects with major coronary events had significantly higher Lp(a) lipoprotein levels than subjects without such events, in all groups. The relationship between Lp(a) lipoprotein level and total mortality as well as between Lp(a) lipoprotein level and major coronary events was significantly different from zero, in logistic regression analyses. The findings show that Lp(a) lipoprotein predicts major coronary events as well as death in secondary prevention with Simvastatin. This prospective study provides independent confirmation that a high Lp(a) lipoprotein level is a significant coronary heart disease risk factor.",1998.0,0,0 3254,9521221,"An overview of the clinical safety profile of atorvastatin (lipitor), a new HMG-CoA reductase inhibitor.",D M Black; R G Bakker-Arkema; J W Nawrocki,"Statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) have been used for a decade to lower low-density lipoprotein (LDL) cholesterol levels and to improve cardiovascular disease and clinical outcomes. To evaluate the safety profile of atorvastatin (Lipitor). Data were pooled for 21 completed (2502 patients) and 23 ongoing (1769 patients) clinical trials of atorvastatin conducted in US and international community- and university-based research centers. In these trials, patients with lipid disorders received atorvastatin at dosages of 10 to 80 mg/d. The majority of patients had moderate to severe hypercholesterolemia and were treated from 4 weeks to more than 24 months. Transaminase and creatine phosphokinase levels and adverse events were recorded. Atorvastatin was well tolerated; fewer than 2% of the atorvastatin-treated patients withdrew due to drug-attributable adverse events. The overall adverse event profile for atorvastatin was similar to that observed with other statins. The most common adverse events with atorvastatin as well as with other statins tested were constipation, flatulence, dyspepsia, and abdominal pain. Approximately 5% of atorvastatin-treated patients had serious adverse events; only 2 of these events were possibly associated with treatment. Thirty patients (0.7%) had confirmed transaminase elevations greater than 3 times the upper limit of the normal range. Most elevations occurred within 16 weeks of beginning treatment. No patients had a conclusive characterization of drug-induced myopathy. The safety profile of atorvastatin was consistent with that of all statins tested and was similar to that seen in all compounds of this class.",1998.0,0,0 3255,9528716,Randomized trial of trovafloxacin and ofloxacin for single-dose therapy of gonorrhea. Trovafloxacin Gonorrhea Study Group.,R B Jones; J Schwebke; E M Thorpe; Z A Dalu; P Leone; R B Johnson,"To compare trovafloxacin, a new quinolone antibiotic with enhanced activity against Neisseria gonorrhoeae, with ofloxacin as single-dose oral therapy for uncomplicated gonococcal urethritis or cervicitis. In this multicenter, double-blind trial, 625 patients (270 men, 355 women) with uncomplicated gonococcal urethritis or cervicitis received one 100-mg tablet of trovafloxacin or two 200-mg capsules of ofloxacin as a single dose under direct supervision. Single-dose oral therapy with trovafloxacin was equivalent both bacteriologically and clinically to ofloxacin. Among evaluable patients, N gonorrhoeae was eradicated in 99% of trovafloxacin recipients and in 98% of ofloxacin recipients. Each treatment was well tolerated; vaginitis was the most frequently observed side effect (4% trovafloxacin, 7% ofloxacin). Based on the results presented here, trovafloxacin is a promising agent for single-dose therapy of uncomplicated gonorrhea.",2001.0,0,0 3256,9528717,Randomized trial of itraconazole oral solution for oropharyngeal candidiasis in HIV/AIDS patients.,J R Graybill; J Vazquez; R O Darouiche; R Morhart; D Greenspan; C Tuazon; L J Wheat; J Carey; I Leviton; R G Hewitt; R R MacGregor; W Valenti; M Restrepo; B L Moskovitz,"Oropharyngeal candidasis (thrush) is the most common opportunistic infection in individuals who are positive for the human immunodeficiency virus (HIV) and those who have progressed to AIDS. Itraconazole has a broad in vitro spectrum of activity, including a wide variety of Candida species. Our study determined the relative efficacy of a new oral solution formulation of itraconazole and fluconazole tablets in the treatment of oropharyngeal candidiasis. This was a prospective randomized, third-party-blind, multicenter trial conducted at 12 centers in the United States. One hundred seventy-nine HIV-positive patients with mycologically documented oropharyngeal candidiasis were treated with itraconazole oral solution 200 mg/ day for 7 or 14 days, or fluconazole tablets 100 mg/day for 14 days. Severity of disease was scored clinically before treatment and at clinical evaluations on days 3, 7, 14, 21, 35, and 42. Semi-quantitative cultures of mouth washings were also obtained on these days. Both 14-day and 7-day regimens of itraconazole oral solution were equivalent to fluconazole for most efficacy parameters. The clinical response rate was 97% after 14 days of itraconazole and 87% after 14 days of fluconazole. Itraconazole oral solution given for 7 days was also equivalent to fluconazole treatment for 14 days. Approximately one half of patients in all three groups relapsed by 1 month after completion of treatment. There were few adverse reactions to either drug. Itraconazole oral solution is well tolerated and offers an alternative at least as effective as fluconazole in the treatment of oropharyngeal candidiasis.",1998.0,0,0 3257,9528731,,,,,0,0 3258,9529261,Cholesterol reduction yields clinical benefit: impact of statin trials.,A L Gould; J E Rossouw; N C Santanello; J F Heyse; C D Furberg,"We determined the effect of incorporating the results of eight recently published trials of Hmg CoA reductase inhibitors (""statins"") on the conclusions from our previously published meta-analysis regarding the clinical benefit of cholesterol lowering. We used the same analytic approach as in our previous investigation, separating the specific effects of cholesterol lowering from the effects attributable to the different types of intervention studied. The reductions in coronary heart disease (CHD) and total mortality risk observed for the statins fell near the predictions from our earlier meta-analysis. Including the statin trial findings into the calculations led to a prediction that for every 10 percentage points of cholesterol lowering, CHD mortality risk would be reduced by 15% (P<.001), and total mortality risk would be reduced by 11% (P<.001), as opposed to the values of 13% and 10%, respectively, reported previously. Cholesterol lowering in general and by the statins in particular does not increase non-CHD mortality risk. Adding the results from the statin trials confirmed our original conclusion that lowering cholesterol is clinically beneficial. The relationships (slope) between cholesterol lowering and reduction in CHD and total mortality risk became stronger, and the standard error of the estimated slopes decreased by about half. Use of statins does not increase non-CHD mortality risk. The effect of the statins on CHD and total mortality risk can be explained by their lipid-lowering ability and appears to be directly proportional to the degree to which they lower lipids.",1998.0,0,0 3259,9530546,Cerivastatin.,K J McClellan; L R Wiseman; D McTavish,"Cerivastatin is a synthetic HMG-CoA reductase inhibitor with high liver selectivity, which lowers plasma cholesterol levels by inhibiting endogenous cholesterol synthesis. In vitro, the affinity of cerivastatin for HMG-CoA reductase was higher than that of lovastatin, simvastatin and pravastatin. This higher enzyme affinity was reflected in vivo, with a lower ED50 (dose causing 50% inhibition) for cerivastatin in rats and beagle dogs compared with lovastatin. Cerivastatin 0.2 mg/day significantly reduced low density lipoprotein (LDL)-cholesterol, total cholesterol and triglyceride levels, and increased high density lipoprotein (HDL)-cholesterol levels, in patients with type IIa hypercholesterolaemia. Available data indicate that cerivastatin has a tolerability profile similar to that of other HMG-CoA reductase inhibitors. No drug interactions were observed when cerivastatin was coadministered with digoxin, warfarin, cimetidine or the antacid magnesium/aluminium hydroxide.",1998.0,0,0 3260,9531695,[Cheyne-Stokes respiration in patients with congestive heart failure].,S Andreas; H Kreuzer,"Cheyne-Stokes respiration (CSR) during sleep is common in patients with severe congestive heart failure induces repetitive oxygen desaturation with arousals, and impairs sleep. This causes daytime symptoms and likely an increase in sympathetic activity. It has, therefore, been suggested that CSR is independently related to mortality. The major mechanisms behind CSR include reduced body stores of oxygen, a low apneic threshold for carbon dioxide, prolonged circulation time between the lung and the carotid body, and disturbance of respiratory control due to arousals. It is apparent that the main task in treating CSR is the therapy of congestive heart failure. Indeed, diuretics to treat pulmonary congestion as well as ACE-inhibitors reduce CSR. Recently, theophylline (an antagonist of the ventilatory depressant adenosine) was shown to reduce CSR and oxygen-desaturation. Continuous positive airway pressure did improve CSR but not sleep and may reduce cardiac output in a subgroup of patients with heart failure. Nocturnal oxygen reduces CSR and improves exercise tolerance as well as sleep. This and its apparent safety makes oxygen an appropriate treatment for nocturnal CSR. Whether successful treatment of nocturnal CSR has any impact on the natural course of heart failure needs to be determined in further studies.",1998.0,0,0 3261,9534058,[Prevention and therapy of vascular damage and endothelial dysfunction with hypocholesteremic agents].,R De Caterina; S Lenzi,"Several recent pieces of clinical evidence have demonstrated that reduction of cholesterol levels positively affects outcomes in both primary and secondary prevention of atherosclerotic vascular disease. The mechanism for the beneficial effects of cholesterol-lowering interventions has been attributed to decreased progression or actual regression of plaques as a consequence of reduced circulating LDL concentrations. Other mechanisms can be hypothesized, including a ""stabilizing"" effect on plaques, which would decrease chances of rupture, and an improvement of endothelial dysfunction, which would slow-down the progression of the disease. This review is aimed at offering an update on such mechanisms. The hypothesis of a direct action of cholesterol-lowering agents, in particular of statins, on endothelial functions, independently of LDL-lowering effects, will be discussed.",1998.0,0,0 3262,9534865,NO activity in familial combined hyperlipidemia: potential role of cholesterol remnants.,E Stroes; T de Bruin; H de Valk; W Erkelens; J D Banga; H van Rijn; H Koomans; T Rabelink,"Patients with familial combined hyperlipidemia (FCH) have an increased cardiovascular mortality despite only moderate elevations of LDL-cholesterol. Since endothelial NO release is intimately involved in the anti-atherosclerotic effects of the endothelium, we studied the effect of short-term lipid-lowering therapy on NO-mediated vasodilatation in patients with FCH. In view of only moderate LDL elevations, we evaluated whether alterations in other lipid fractions upon therapy correlated to changes in NO-mediated vasodilatation. NO activity was assessed by serotonin-induced, nitric oxide-mediated increase in forearm blood flow (FBF). Measurements were performed 2 weeks off and 4 weeks on lipid-lowering therapy in 12 FCH patients using forearm venous occlusion plethysmography. Control experiments were performed in 12 healthy subjects. Serotonin-induced vasodilatation was impaired in FCH patients (FBF (unit ml/100 ml forearm tissue/min) from 3.0 (0.3) to 4.8 (0.4)) compared to controls (FBF from 2.9 (0.3) to 6.5 (0.6); p < 0.05 vs. FCH). FBF response to serotonin improved significantly upon lipid-lowering therapy (from 3.0 (0.3) to 5.7 (0.5); p < 0.05 treated vs. untreated). The level of improvement in endothelial function was significantly correlated to the absolute reduction of intermediate density lipoproteins upon lipid-lowering therapy (r = -0.64; p < 0.05), whereas it did not correlate to changes in VLDL- or LDL-cholesterol, nor to Lp(a). Patients with familial combined hyperlipidemia have impaired NO-mediated vasodilatation, that responds rapidly to lipid lowering medication, and may be related to changes in intermediate density lipoproteins.",1998.0,0,0 3263,9538988,Management of dyslipidemia in adults with diabetes.,S M Haffner,"Subjects with diabetes have a greatly increased risk of CHD, which is only partially related to their elevated glucose. Other factors such as insulin resistance and dyslipidemia are likely to be important. The type of dyslipidemia that is most characteristic of type 2 diabetic subjects is elevated triglycerides and decreased HDL cholesterol levels, although all lipoproteins have compositional abnormalities. Surprisingly few good prospective studies of lipoprotein levels in relation to CHD have been done in diabetic subjects. Available studies suggest that low HDL cholesterol may be the most important risk factor for CHD in observational studies. In studies in which total cholesterol and triglyceride were done, cholesterol and triglycerides were risk factors for CHD, although triglycerides were often a stronger predictor. However, the strength of triglyceride as a risk factor for CHD may depend partially on its association with other variables (e.g., hypertension, plasminogen activator inhibitor 1 [PAI-1], etc.). In clinical trials in diabetic subjects, LDL reduction with statins has led to significant reductions in CHD incidence. In addition, overall mortality was reduced with statin therapy, although the results were not statistically significant. Gemfibrozil has led to reductions in CHD incidence in diabetic subjects, although the results were not statistically significant perhaps because of low sample size. Regarding lipoproteins and CHD risk in diabetic patients, the very positive results of statin trials point to LDL cholesterol being more important than previous realized. Apparently, having a borderline high LDL cholesterol (between 130 and 160 mg/dl) in a diabetic patient is equivalent to a much higher LDL cholesterol in terms of CHD risk for a nondiabetic subject. Therefore, the primary target of therapy in diabetic patients is lowering LDL cholesterol (or possibly, non-HDL cholesterol). Statins are the preferred pharmacological agent in this situation. Once LDL cholesterol levels have been lowered, attention can be given to treatment of residual hypertriglyceridemia and low HDL. The goal here is weight reduction and increased exercise. However, for selected patients, combining a fibric acid (or low-dose nicotinic acid) with a statin also can be considered. Reduction of LDL levels should take priority over reduction of triglycerides in combined hyperlipidemia because of the proven safety of the statin class of drugs as well as greater reduction in CHD incidence.",1998.0,0,0 3264,9544745,Influence of genotype at the low density lipoprotein (LDL) receptor gene locus on the clinical phenotype and response to lipid-lowering drug therapy in heterozygous familial hypercholesterolaemia. The Familial Hypercholesterolaemia Regression Study Group.,X M Sun; D D Patel; B L Knight; A K Soutar,"The relationship between molecular defect and clinical phenotype has been examined in 42 patients with heterozygous familial hypercholesterolaemia (FH) and premature coronary heart disease. The defined defects included mutations in the low density lipoprotein (LDL)-receptor gene (23/42) or the apolipoprotein B Arg3500Gln mutation (5/42). Mean LDL-cholesterol was higher, both before and during treatment with simvastatin and bile acid sequestrants, in patients predicted as having a 'severe' mutation than in those with a 'mild' mutation (8.72 +/- 2.02 mmol/l vs 6.63 +/- 1.8, P = 0.05 before and 4.51 +/- 0.90 mmol/l vs 3.19 +/- 0.58, P = 0.05 during treatment). Maximum inducible LDL-receptor activity in cultured lymphoblasts was inversely correlated with LDL-cholesterol before (r2 = 0.499, P = 0.002) and during (r2 = 0.478, P = 0.004) treatment in patients with a defined mutation in the LDL-receptor gene, but not in the 14 patients with no detectable molecular defect. LDL-cholesterol concentrations before and during treatment were significantly correlated in patients with a defined LDL-receptor gene mutation (r2 = 0.548, P = 0.0001), but not in those with no detectable genetic defect. All these correlations were weak, however and there were no differences in the response to treatment in terms of either relative reduction or absolute decrease in LDL-cholesterol concentration between patients with different LDL-receptor defects. We conclude that only part of the variable phenotype of heterozygous FH patients is explained by different LDL-receptor defects and that other factors determine the severity of their hypercholesterolaemia and the onset of coronary disease.",1998.0,0,0 3265,9545143,Statins in the prevention of coronary heart disease.,D R Williamson; C Pharand,"Although epidemiologic studies proved that a causal relationship exists between elevated serum cholesterol levels and coronary heart disease, it is only recently that cholesterol-lowering strategies have shown significant reductions in total mortality. In the last few years, three landmark coronary artery disease-reduction trials with HMG-coenzyme A reductase inhibitors (statins) showed significant reductions in coronary heart disease and mortality. Statins have beneficial effects on coronary heart disease and overall mortality in primary and secondary prevention, including in women and the elderly. Angiographic studies reveal the potential mechanisms through which statins exert their clinical benefits.",1998.0,0,0 3266,9546501,Statins for prevention of stroke.,C Rosendorff,,1998.0,0,0 3267,9546972,The pathophysiology of peripheral arterial disease: rational targets for drug intervention.,J P Cooke,"The most common cause of peripheral arterial disease (PAD) is atherosclerosis, which begins with an alteration in endothelial biology due to hypercholesterolemia, diabetes mellitus, hypertension, tobacco use, elevated levels of lipoprotein(a) or homocystinemia. With chronic and severe arterial disease, changes begin to occur in the microcirculation, including obstruction at the microvascular level and tissue injury. Based on insights into the vascular biology of PAD, new therapies have been developed and are at various stages of clinical trials. Future pharmacotherapy for PAD will include agents that have one or more of the following attributes; (1) reduce, or even reverse, the progression of atherosclerosis; (2) inhibit plaque rupture; (3) inhibit thrombosis by a novel mechanism; (4) induce angiogenesis; (5) reverse microvascular derangements; (6) affect blood rheology; and (7) enhance skeletal muscle's ability to use available nutrients.",1998.0,0,0 3268,9547437,The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease.,J Kjekshus; T R Pedersen; A G Olsson; O Faergeman; K Pyörälä,"Although treatment of myocardial overload effectively reduces death from progression of heart failure, it is not known whether the retardation of progressive coronary artery disease obtained with lipid lowering treatment will prevent the onset and consequences of heart failure in patients without previous symptoms of heart failure. In the Scandinavian Simvastatin Survival Study, 4444 patients with coronary heart disease without evidence of heart failure were randomized to placebo (n = 2223) or simvastatin 20-40 mg (n = 2221) and followed for more than 5 years. Among the patients who received placebo, 228 (10.3%) were diagnosed with heart failure during follow-up evaluation compared with 184 (8.3%) of patients who received simvastatin (P < .015). Mortality was 31.9% in the placebo group and 25.5% in the simvastatin group among patients who developed heart failure. These compare with 9.2 and 6.6%, respectively, among non-heart failure patients. There were 45 hospitalizations because of acute heart failure in the placebo group and 23 in the simvastatin group (NS). Patients who developed heart failure were more likely to have suffered a recurrent myocardial infarction and have a history of diabetes, peripheral artery disease, and hypertension than patients who did not develop congestive heart failure. Long-term prevention with simvastatin reduces the occurrence of heart failure in a cohort of patients with coronary heart disease without previous evidence of congestive heart failure.",1998.0,0,0 3269,9547438,,,,,0,0 3270,9549635,Renal dysfunction does not alter the pharmacokinetics or LDL-cholesterol reduction of atorvastatin.,R H Stern; B B Yang; M Horton; S Moore; R B Abel; S C Olson,"The objective of this study was to determine the effects of renal dysfunction on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Nineteen subjects with calculated creatinine clearances ranging from 13 mL/min to 143 mL/min were administered 10 mg atorvastatin daily for 2 weeks. Pharmacokinetic parameters and lipid responses were analyzed by regression on calculated creatinine clearance. Correlations between steady-state atorvastatin pharmacokinetic or pharmacodynamic parameters and creatinine clearance were weak and, in general, did not achieve statistical significance. Although the elimination rate constant, lambda z (0.579), was significantly correlated with creatinine clearance, neither maximum plasma concentration (Cmax, -0.361) nor oral clearance (Cl/F, 0.306) were; thus, steady-state exposure is not altered. Renal impairment has no significant effect on pharmacodynamics and pharmacokinetics of atorvastatin.",1998.0,0,0 3271,9551029,Comparison of efficacy and cost among lipid-lowering agents in patients with primary hypercholesterolemia.,A Lacour; F Derderian; J LeLorier,"To compare efficacy and cost of lipid-lowering agents in patients with primary hypercholesterolemia. A meta-analysis was conducted to determine estimates of efficacy for lipid-lowering agents. Efficacy was defined as the change in the ratio of total cholesterol:high density lipoprotein (HDL) induced by treatment. This ratio was selected because of its good predictive value for the risk of coronary disease. Lipid-lowering agents were grouped into three categories according to the decrease in the total cholesterol:HDL ratio. Acquisition prices for drugs were obtained from the Quebec provincial drug formulary. An analysis determined which drugs in each category 'purchased' the greatest decrease in ratio for the lowest cost. Clinical trial study centres. The population analyzed had a mean baseline total cholesterol:HDL ratio of 7.3, an average age of 50.5 years and mean proportion of men of 62.5%. Twelve lipid-lowering therapies at various doses were investigated. Drugs that were more recently introduced had the greatest effect on the total cholesterol:HDL ratio. A direct dose-effect relationship was not evident, although there was a trend in this direction. In each of the three categories, there was wide range of cost, suggesting that the same effect is available at a broad range of prices. The drugs with the greatest effect on the ratio at the lowest cost were fluvastatin 60 mg/day, fenofibrate (micronized) 200 mg/day and simvastatin 20 mg/day. These results can be useful for clinicians in the selection of agents that achieve a specified goal of therapy at the lowest cost.",1998.0,0,0 3272,9551706,Influence of erythromycin pre- and co-treatment on single-dose pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin.,W Mück; K Ochmann; G Rohde; S Unger; J Kuhlmann,"Cerivastatin is a novel, synthetic, highly potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that effectively reduces serum cholesterol levels at very low doses. It is exclusively cleared from humans via cytochrome P450-mediated biotransformation (demethylation M1; hydroxylation M23) and subsequent biliary/renal excretion of the metabolites. The influence of concomitant administration of erythromycin, a potent CYP3A4 inhibitor, on cerivastatin bioavailability and pharmacokinetics was investigated. Twelve healthy young male subjects received single oral doses of 300 microg cerivastatin alone or on the 4th day of a 4-day pre- and co-treatment with erythromycin 500 mg t.i.d. in a randomised, non-blind crossover study. Plasma and urine samples were analysed for cerivastatin and its major metabolites by validated specific high-performance liquid chromatography assays. Cerivastatin was safe and well tolerated. No clinically relevant treatment-emergent changes in laboratory parameters were observed. The pre- and co-treatment with erythromycin 500 mg t.i.d. had a modest influence on cerivastatin clearance, leading to a mean increase in the maximum plasma concentration (Cmax) of 13% and a slightly increased terminal half-life (approximately 10%), resulting in a mean elevation of the area under the curve (AUC) of 21%; time to peak (tmax) remained unchanged. While the mean AUC of the metabolite M1 following the combined dosing was decreased by 60% compared with mono-dosing, the mean AUC of M23 exhibited an increase of approximately 60%. The respective Cmax results paralleled these pronounced effects, whereas the influence on mean terminal half-lives was small (i.e. for M23, an approximate 20% increase) or not observable (i.e. for M1). Concomitant administration of erythromycin 500 mg t.i.d. affects, to a certain extent, the metabolism of cerivastatin, administered as a single oral dose of 300 microg, resulting in a slightly increased exposure of the parent drug and active metabolites which, however, does not need dose adjustment. In addition, the small increase in cerivastatin half-life does not predict an accumulation beyond steady state. The pharmacokinetic data for the major metabolites suggest that the M1 metabolic pathway is more sensitive to CYP3A4 inhibition than the parallel M23 pathway, supporting recent in vitro findings that further cytochrome P450 isozymes are differently involved in the metabolic pathways of cerivastatin.",1998.0,0,0 3273,9551707,Cimetidine does not alter atorvastatin pharmacokinetics or LDL-cholesterol reduction.,R H Stern; D M Gibson; L R Whitfield,"To determine the effects of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor. Twelve healthy subjects participated in a randomized two-way crossover study. Each subject received atorvastatin 10 mg every morning for 2 weeks and atorvastatin 10 mg every morning with cimetidine 300 mg four times a day for 2 weeks, separated by a 4-week washout period. Steady-state pharmacokinetic parameters (based on an enzyme inhibition assay) and lipid responses were compared. Pharmacokinetic parameters and lipid responses were similar following administration of atorvastatin alone and atorvastatin with cimetidine. Mean values for Cmax (the maximum concentration) were 5.11 ng eq.ml(-1) and 4.54 ng eq.ml(-1), for tmax (the time to reach maximum concentration) 2.2 h and 1.3 h, for AUC0-24 (area under the concentration-time curve from time 0 h to 24 h) 58.6 ng eq.h.ml(-1) and 58.5 ng eq.h.ml(-1), and for t1/2 (terminal half-life) 10.1 h and 17.0 h, respectively, following administration of atorvastatin alone and atorvastatin with cimetidine. Following treatment with atorvastatin alone and atorvastatin with cimetidine, mean values for the percentage change from baseline for total cholesterol were -29.5% and -29.9%, for low-density lipoprotein (LDL) cholesterol -41.0% and -42.6%, for high-density lipoprotein (HDL) cholesterol 6.3% and 5.8%, and for triglycerides -33.8% and -25.8%, respectively. The rate and extent of atorvastatin absorption and the effects of atorvastatin on LDL-cholesterol responses are not influenced by coadministration of cimetidine.",1998.0,0,0 3274,9552949,,,,,0,0 3275,9555684,Preventing coronary disease in women: brief observations from the clinical data.,A M Gotto,,2001.0,0,0 3276,9555782,Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Fibrate Consensus Group.,J C Fruchart; H B Brewer; E Leitersdorf,"The hypolipidemic action of fibrates has recently been shown to involve the activation of peroxisome proliferator activated receptors establishing a molecular mechanism for this class of drugs. Increasing clinical trial evidence supports the efficacy of fibrates in the treatment of dyslipoproteinemias, particularly in patients with hypertriglyceridemia and low high-density lipoproteins.",2001.0,0,0 3277,9555954,"Three-fold effect of lovastatin treatment on low density lipoprotein metabolism in subjects with hyperlipidemia: increase in receptor activity, decrease in apoB production, and decrease in particle affinity for the receptor. Results from a novel triple-tracer approach.",L Berglund; J L Witztum; N F Galeano; A S Khouw; H N Ginsberg; R Ramakrishnan,"To differentiate effects of lovastatin on low density lipoprotein (LDL) receptor activity from effects on LDL metabolic properties, LDL apolipoprotein B (apoB) turnover was studied in eight hyperlipidemic subjects during baseline and lovastatin treatment, in the latter case with LDL tracers isolated during both baseline (CLDL) and drug treatment (Rx-LDL) conditions. Lovastatin (40 mg/day) significantly lowered total plasma and LDL cholesterol levels (27% and 25%, respectively) as well as plasma triglyceride levels (30%). Using contemporaneous tracers (C-LDL before and Rx-LDL during treatment), lovastatin caused a modest increase in LDL fractional catabolic rate (FCR) (0.410+/-0.113 vs. 0.339+/-0.108 pools/day, P < 0.04 by paired t). The increase in LDL tracer FCR was higher when C-LDL tracer isolated during the untreated period was injected during lovastatin treatment (0.496+/-0.177 vs. 0.339+/-0.108 pools/day, P < 0.02). These in vivo studies in humans were confirmed by injecting LDL tracers from two patients into five guinea pigs. The C-LDL tracer was cleared consistently faster than the Rx-LDL tracer (0.082+/-0.018 vs. 0.057+/-0.015 pools/h, P< 0.001). The results demonstrate three important outcomes of lovastatin treatment in these subjects: LDL receptor activity increased by 49% (P < 0.02); LDL apoB production rate decreased by 17% (P < 0.03), and LDL particle in vivo affinity for the LDL receptor decreased by 15% (P < 0.01). The decrease in LDL particle affinity partially negated the expected effect of increased LDL receptors on LDL clearance. The present study provides an explanation for earlier observations by several investigators using contemporaneous tracers that treatment with HMG-CoA reductase inhibitors resulted in only modest increases in low density lipoprotein functional catabolic rate.",1998.0,0,0 3278,9566646,Effects of Simvastatin and omega-3 fatty acids on plasma lipoproteins and lipid peroxidation in patients with combined hyperlipidaemia.,A Nordøy; K H Bønaa; H Nilsen; R K Berge; J B Hansen; O C Ingebretsen,"Patients with combined hyperlipidemia are at increased risk for development of coronary heart disease. The purpose of this study was to evaluate the efficiency and the safety of treatment with Simvastatin and omega-3 fatty acids in patients with this lipid disorder. A double-blind placebo controlled, randomized study evaluating the effects of Simvastatin separately and in combination with omega-3 fatty acids in 41 healthy patients with defined hyperlipidemia. After a 16 weeks dietary run-in period the patients were treated in periods of 5 weeks. As expected Simvastatin (20 mg day[-1]) reduced serum total cholesterol, triacylglycerols, apolipoproteins B and E and increased HDL-cholesterol and apolipoprotein A1. Addition of omega-3 fatty acids (4 g day[-1]) further decreased serum triacylglycerols (P = 0.007), total cholesterol (P = 0.052) and apolipoprotein E (P = 0.035). No significant changes attributable to supplementation of polyunsaturated fatty acids on the content of lipid peroxides in plasma and in the various lipoprotein fractions were observed. The combined treatment of Simvastatin and omega-3 fatty acids seems to be an efficient and safe alternative for patients with combined hyperlipidemia.",1998.0,0,0 3279,9568741,"Relationship between bioavailability and hypocholesterolemic activity of YM17E, an inhibitor of ACAT, in cholesterol-fed rats.",T Uchida; K Aoyama; T Watanabe; S Higuchi,"The relationship between bioavailability and the serum cholesterol-lowering effect of YM17E, an ACAT inhibitor was investigated. Serum cholesterol levels in cholesterol-fed rats decreased after both oral and intravenous administration of YM17E. Marked inhibition of cholesterol absorption was observed after oral administration, but not after intravenous administration. YM17E and its five active metabolites were primarily distributed in the liver after intravenous administration, but in small intestine and liver after oral administration. Hepatic ACAT activity in cholesterol-fed rats was inhibited by intravenous administration. Cholesteryl ester input into plasma by Triton WR-1339 treatment to the rats was inhibited by intravenous administration of YM17E. Plasma clearance of 125I-LDL in cholesterol-fed rats increased after YM17E treatment suggesting a decrease in LDL production. These results indicate that the hypocholesterolemic effect of intravenous YM17E was due to hepatic ACAT inhibition, not an inhibition of intestinal cholesterol absorption. The contribution of ACAT inhibition in small intestine and liver on the pharmacological effect could be explained by plasma inhibitor concentration after oral or intravenous administration of YM17E. From these results, it is concluded that the change in bioavailability of ACAT inhibitors change the mechanism of hypocholesterolemic effects, shifting the relative contributions of small intestinal and hepatic ACAT inhibition.",1998.0,0,0 3280,9568752,Effects of atorvastatin monotherapy and simvastatin plus cholestyramine on arterial endothelial function in patients with severe primary hypercholesterolaemia.,L A Simons; D Sullivan; J Simons; D S Celermajer,"Endothelial dysfunction is an important early event in atherogenesis. Changes in arterial endothelial physiology were studied in patients with severe primary hypercholesterolaemia participating in an ongoing clinical trial evaluating atorvastatin and simvastatin. Endothelial function was assessed non-invasively using brachial ultrasound and the primary outcome measure was flow-mediated endothelium-dependent dilatation (FMD) in response to reactive hyperaemia. Patients were studied upon entry while still using simvastatin 40 mg daily and again after a 10-week washout (baseline). Over the next 30 weeks, 20 patients received atorvastatin titrated up to 80 mg daily and 12 patients received simvastatin titrated up to 40 mg daily (plus cholestyramine 4 g daily in 10/12), followed by a final ultrasound study. During simvastatin washout, total and low density lipoprotein (LDL) cholesterol rose by a median 23-29% and 30-34%, respectively. During atorvastatin therapy, total and LDL cholesterol fell by a median of 41 and 46%, respectively, triglycerides fell by 45%, and high density lipoprotein (HDL) cholesterol rose by 10%. During simvastatin plus cholestyramine therapy, the respective median changes were - 32, - 39, - 44 and + 11%. Patients at baseline showed evidence of impaired FMD and this improved significantly on either treatment, from a median + 2.2 to + 5.5% on atorvastatin and from + 1.8 to + 4.5% on simvastatin plus cholestyramine (P < 0.01 for both treatments). Typical response in healthy subjects would be from + 8 to + 9%. FMD at baseline was correlated with HDL cholesterol (r=0.49, P < 0.01). Change in FMD was inversely correlated with baseline FMD (r=-0.54, P < 0.001). Endothelial dysfunction in primary hypercholesterolaemia was improved by treatment with atorvastatin or simvastatin plus cholestyramine and this effect may result in the prevention of future coronary events.",1998.0,0,0 3281,9570187,Meeting highlights: highlights of the 70th Scientific Sessions of the American Heart Association.,J J Ferguson,,1998.0,0,0 3282,9571327,Treatment of hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM. A multicenter comparison study.,M J Tikkanen; M Laakso; M Ilmonen; E Helve; E Kaarsalo; E Kilkki; J Saltevo,"To compare the lipid-lowering efficacies of simvastatin and gemfibrozil in NIDDM patients with combined (mixed) hyperlipidemia (CHL) or isolated hypercholesterolemia (IHC). Patients with primary dyslipidemia and NIDDM were recruited for this double-blind, double-dummy comparison study from 10 Finnish centers. After a 4-week placebo run-in period, they were randomly assigned to simvastatin or gemfibrozil. The simvastatin group (n = 47) received 10 mg once nightly for 8 weeks, 20 mg for the next 8 weeks, and 40 mg for the third 8-week period. The gemfibrozil group (n = 49) received 600 mg twice daily throughout the 24 weeks. The lipid-lowering efficacies of both drugs were compared in all patients as well as separately in patients with CHL and IHC. In all patients, simvastatin reduced LDL and total cholesterol and the LDL-to-HDL cholesterol ratio more effectively, whereas gemfibrozil was more effective in elevating HDL cholesterol and decreasing triglyceride levels. The drug effects differed according to lipid phenotype at baseline. Simvastatin decreased LDL cholesterol levels by 30-40% in both phenotypes. Gemfibrozil caused a 15% reduction in LDL cholesterol in IHC but no change in CHL patients. Simvastatin produced 15-30% reductions in triglyceride levels in CHL but no change in IHC patients. Gemfibrozil caused reductions in triglycerides in CHL (50% and more) and in IHC (40%) patients, with 12-18% increases in HDL cholesterol in these groups. Simvastatin is useful in both CHL and IHC patients, whereas gemfibrozil can be used in patients with high triglyceride and low or normal LDL cholesterol levels.",1998.0,0,0 3283,9576422,Statin trials and goals of cholesterol-lowering therapy.,S M Grundy,,1998.0,0,0 3284,9576423,Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS).,,"The West of Scotland Coronary Prevention Study was a primary prevention trial that demonstrated the effectiveness of pravastatin (40 mg/d) in reducing morbidity and mortality from coronary heart disease (CHD) in moderately hypercholesterolemic men. The present analysis examines the extent to which differences in LDL and other plasma lipids both at baseline and on treatment influenced CHD risk reduction. Relationships between baseline lipid concentrations and incidence of all cardiovascular events and between on-treatment lipid concentrations and risk reduction in patients taking pravastatin were examined by use of Cox regression models and by division of the cohort into quintiles. Variation in plasma lipids at baseline did not influence the relative risk reduction generated by pravastatin therapy. Fall in LDL level in the pravastatin-treated group did not correlate with CHD risk reduction in multivariate regression. Furthermore, maximum benefit of an approximately 45% risk reduction was observed in the middle quintile of LDL reduction (mean 24% fall); further mean decrements in LDL (up to 39%) were not associated with a greater decrease in CHD risk. Comparison of event rates between placebo- and pravastatin-treated subjects with the same LDL cholesterol level provided evidence for an apparent treatment effect that was independent of LDL. We conclude that the treatment effect of 40 mg/d of pravastatin is proportionally the same regardless of baseline lipid phenotype. There is no CHD risk reduction unless LDL levels are reduced, but a fall in the range of 24% is sufficient to produce the full benefit in patients taking this dose of pravastatin. LDL reduction alone does not appear to account entirely for the benefits of pravastatin therapy.",1998.0,0,0 3285,9576424,Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol and Recurrent Events trial.,F M Sacks; L A Moyé; B R Davis; T G Cole; J L Rouleau; D T Nash; M A Pfeffer; E Braunwald,"Although LDL lowering has been shown to reduce recurrent coronary events in patients with coronary heart disease, little direct information is available on the extent of LDL lowering required to achieve this outcome. The Cholesterol and Recurrent Events (CARE) trial compared pravastatin and placebo in patients who had experienced myocardial infarction (MI) who had average concentrations of total cholesterol <240 mg/dL (baseline mean, 209 mg/dL) and LDL cholesterol (LDL) 115 to 174 mg/dL (mean, 139 mg/dL). Pravastatin reduced coronary death or recurrent MI by 24%. In multivariate analysis, the LDL concentration achieved during follow-up was a significant, although nonlinear, predictor of the coronary event rate (P=.007), whereas the extent of LDL reduction was not significant, whether expressed as an absolute amount (P=.97) or a percentage (P=.76). The coronary event rate declined as LDL decreased during follow-up from 174 to approximately 125 mg/dL, but no further decline was seen in the LDL range from 125 to 71 mg/dL. In multivariate analysis, triglyceride but not HDL concentrations during follow-up were weakly but significantly associated with the coronary event rate. The LDL concentrations achieved during treatment with pravastatin or placebo were associated with reduction in coronary events down to an LDL concentration of approximately 125 mg/dL. LDL concentrations <125 mg/dL during treatment were not associated with further benefit. Absolute or percentage reduction in LDL had little relationship to coronary events.",1998.0,0,0 3286,9576425,Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S),T R Pedersen; A G Olsson; O Faergeman; J Kjekshus; H Wedel; K Berg; L Wilhelmsen; T Haghfelt; G Thorgeirsson; K Pyörälä; T Miettinen; B Christophersen; J A Tobert; T A Musliner; T J Cook,"The Scandinavian Simvastatin Survival Study (4S) randomized 4444 patients with coronary heart disease (CHD) and serum cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with triglycerides < or =2.5 mmol/L (220 mg/dL) to simvastatin 20 to 40 mg or placebo once daily. Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction, P<.00001). Simvastatin produced substantial changes in several lipoprotein components, which we have attempted to relate to the beneficial effects observed. The Cox proportional hazards model was used to assess the relationship between lipid values (baseline, year 1, and percent change from baseline at year 1) and MCEs. The reduction in MCEs within the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total and LDL cholesterol, apolipoprotein B, and less so with HDL cholesterol, but there was no clear relationship with triglycerides. We estimate that each additional 1% reduction in LDL cholesterol reduces MCE risk by 1.7% (95% CI, 1.0% to 2.4%; P<.00001). These analyses suggest that the beneficial effect of simvastatin in individual patients in 4S was determined mainly by the magnitude of the change in LDL cholesterol, and they are consistent with current guidelines that emphasize aggressive reduction of this lipid in CHD patients.",1998.0,0,0 3287,9576433,,,,,0,0 3288,9585373,The role of myocardial revascularization preceding noncardiac surgery.,C S Rihal,"Of about 6.7 million Americans who have coronary artery disease, approximately 700,000 undergo various noncardiac operations annually in the United States. Perioperative cardiac complications remain the leading cause of morbidity and mortality not related to the primary operative procedure; the mechanisms of perioperative ischemia and infarction are unclear. Currently, clinicians, using a combination of clinical and laboratory findings, can estimate the risk of noncardiac surgical procedures with a high degree of precision, but much less is known about the preferred approach to patient management after noninvasive risk stratification. Coronary angiography and revascularization are frequently recommended for those determined by functional tests to be at moderate and high risk, but the risks of revascularization are often substantially higher among these patients. No randomized, controlled trials exist to guide patient management. Quantitative decision analysis based on published nonrandomized data suggests that coronary angiography with selective myocardial revascularization should be performed to reduce the risk of noncardiac surgery only if the risk of noncardiac surgery is greater than 5% and the risk of coronary angiography with selective revascularization is less than 3%. On the other hand, if independent indications exist for myocardial revascularization, it should generally be performed before the noncardiac operation.",1998.0,0,0 3289,9585392,Which drugs benefit diabetic patients for secondary prevention of myocardial infarction? DARTS/MEMO Collaboration.,T M MacDonald; R Butler; R W Newton; A D Morris,"Diabetic patients have increased mortality following myocardial infarction. We review the evidence for benefit in diabetic patients, of the major drug groups used as secondary prevention. Beta blockers: meta-analyses suggest a reduction in mortality of 35% with beta blockers. Diabetic patients should receive beta blockers post myocardial infarction. In many patients, the benefits of beta blockers will outweigh relative contraindications. Aspirin: meta-analyses of antiplatelet therapy in high-risk subjects have shown substantial benefits. Aspirin should be prescribed for secondary prevention. Lipid lowering with statins: subgroup analyses of the major secondary prevention trials show substantial benefits across a wide range of baseline cholesterol and LDL levels. These drugs should be prescribed as secondary prevention to patients with diabetes whose total cholesterol is > 4.0 mmol(-1). Angiotensin converting enzyme inhibitors (ACEIs): the few subgroup analyses that exist from ACEI trials suggest that diabetic and non-diabetic patients derive similar benefits. Diabetic subjects who have systolic dysfunction after myocardial infarction should receive ACEIs. Treatment combination: data exist to suggest that most of these drugs produce benefit independently. diabetic patients benefit from secondary prevention with drug treatment as much as, or more than, non-diabetic patients.",1998.0,0,0 3290,9589824,Conversion from fluvastatin to simvastatin therapy at a dose ratio of 8 to 1: effect on serum lipid levels and cost.,J P Rindone; G Arriola,"The objective of this study was to assess the effect on serum lipid levels of the substitution of simvastatin for fluvastatin at a dose ratio of 8:1 (fluvastatin to simvastatin). A secondary objective was to determine the number of patients at goal lipid levels before and after this substitution. The study included 60 outpatients with hyperlipidemia who had received a constant dose of fluvastatin for at least 6 weeks. After a baseline 12-hour lipid profile (total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein [LDL]) was obtained, patients were switched from fluvastatin to simvastatin at an 8:1 dose ratio. Patients were instructed to split the simvastatin tablets in half with a pill splitter and to take one half-tablet at bedtime. A repeat lipid profile and liver function testing were performed after 6 to 8 weeks of simvastatin therapy. Lipid components were compared before and during simvastatin therapy using a paired t test. Target LDL levels were based on guidelines issued by the National Cholesterol Education Program. Fifty-six patients completed the study. No change in lipid components was observed, except for a statistically significant decrease in LDL. The majority of patients had a decrease in LDL levels, rather than an increase, after the conversion to simvastatin. Six patients required a dose increase of simvastatin in response to increased LDL levels. Forty-one percent of patients achieved goal LDL levels with simvastatin, compared with 30% with fluvastatin. Four patients withdrew from the study, two because of troublesome side effects and two for failure to complete the protocol. The results show that simvastatin can be substituted for fluvastatin at a dose ratio of 8:1 without loss of lipid control in the majority of patients and that by using this ratio and splitting tablets, significant cost savings can be realized.",1998.0,0,0 3291,9590460,Effects of extensive and poor gastrointestinal metabolism on the pharmacodynamics of pravastatin.,M K Ito,"The enhanced nonenzymatic isomerization of pravastatin to SQ 31,906, a relatively inactive metabolite, has been demonstrated to occur on exposure to gastric acidity in humans. However, the effect of gastric metabolism on the pharmacodynamics of pravastatin has not been studied. In addition, it was hypothesized that some individuals may be more extensive gastric metabolizers than others. Sixteen men received 4 weeks of oral therapy with pravastatin 10 mg after a 6-week drug washout diet run-in period. Pharmacokinetic and pharmacodynamic parameters were determined after 8 hours of serum sampling on the final day of therapy. Patients with a metabolic ratio for area under the concentration-time curve (AUC0-8 of pravastatin/AUC0-8 of SQ 31,906) of less than 1.6 had a significantly lower reduction in total and low-density lipoprotein (LDL) cholesterol compared with those with a ratio > 1.6. An enteric formulation of pravastatin should increase the bioavailability of pravastatin and enhanced lipid-lowering efficacy.",1998.0,0,0 3292,9591525,Perspectives in the treatment of dyslipidemias in the prevention of coronary heart disease.,M C Borgia; F Medici,"In this review the indications for the available treatments for dyslipidemias in the prevention of coronary heart disease (CHD) are considered, and their efficacy according to the latest studies is analyzed. As data sources the authors used the main multicenter studies performed in the last twenty years to evaluate primary and secondary prevention of CHD by correcting dyslipidemias as well as the results of meta-analyses of these studies. All treatments considered were found effective in preventing CHD morbidity and mortality to some extent. In particular, the combination of diet with niacin or hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors seems to give the best results. These drugs induce a marked reduction of total and low-density lipoprotein (LDL) cholesterol and an increase of high-density lipoprotein (HDL) cholesterol concentrations. The use of diet, niacin, and HMG CoA reductase inhibitors reduces total as well as specific mortality. Treatment of dyslipidemia to prevent CHD depends on the pattern and severity of dyslipidemia, the presence of overt CHD, and the patient's response to diet. Pharmacologic treatment should be started only after dietary modifications have been tried and must be combined with diet. Drug side effects must also be considered, for they may affect patient compliance. High levels of total and LDL and low levels of HDL cholesterol are major risk factors for coronary atherosclerosis. Correcting lipid abnormalities can reduce the risk of development or progression of CHD. Diet and drugs are the main instruments available to normalize lipid levels. The choice of drug to combine with diet must be based on its specific effects on lipid metabolism, side effects, and efficacy in reducing CHD.",1998.0,0,0 3293,9593078,Direct effects of statins on the vascular wall.,A Corsini; F Pazzucconi; L Arnaboldi; P Pfister; R Fumagalli; R Paoletti; C R Sirtori,"The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on coronary events have generally been attributed to their hypocholesterolemic properties. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are necessary for cell proliferation and other important cell functions; thus effects other than cholesterol reduction may help to explain the antiatherosclerotic properties of statins. Recently we provided in vitro and in vivo evidence of decreased smooth-muscle cell (SMC) proliferation and migration by fluvastatin and simvastatin, but not by pravastatin, independent of plasma cholesterol reduction. The ability of fluvastatin to interfere with arterial SMC proliferation at therapeutic concentrations (0.1-1 microM) prompted us to investigate the pharmacologic activity of sera from 10 patients treated with fluvastatin, 40 mg once daily, on the proliferation of cultured human arterial myocytes. Pravastatin, 40 mg once daily, displays a lipid-lowering activity similar to that of fluvastatin without affecting SMC proliferation and was investigated as a control for assessing this non-lipid-related effect of fluvastatin. Fluvastatin and pravastatin, given for 6 days to patients with type IIa hypercholesterolemia, resulted in a similar decrease in low-density-lipoprotein (LDL) cholesterol. However, the addition of 15% whole-blood sera from patients treated with fluvastatin to the culture medium resulted in a 43% inhibition of cholesterol synthesis in SMCs (p < 0.01) that mirrored the pharmacokinetic profile of fluvastatin. When SMC proliferation was investigated, a significant inhibition of cell growth (-30%; p < 0.01) was detected with sera obtained 6 h after the last dose. No effect on SMC proliferation or cholesterol biosynthesis was observed when sera from patients treated with pravastatin were evaluated. These results suggest that statins exert a direct antiproliferative effect on the arterial wall, beyond their effects on plasma lipids, which could prevent significant cardiovascular disease.",1998.0,0,0 3294,9593550,Do calcium channel blockers and HMG-CoA reductase inhibitors attenuate allograft arteriopathy?,H A Valantine-von Kaeppler,"Recent epidemiologic studies of the risk factors for early and late phases of transplant coronary artery disease (TxCAD) have identified metabolic abnormalities such as hyperlipidemia and insulin resistance as important risk factors, independent of rejection. In randomized trials, calcium channel blockers and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were shown to decrease coronary artery intimal thickening and stenosis. Furthermore, HMG-CoA reductase inhibitors significantly decreased allograft loss during the first year after transplantation, resulting in a survival benefit, independent of TxCAD and cholesterol lowering. Prevention of acute allograft failure is consistent with known immunomodulatory actions of HMG-CoA reductase inhibitors, and the effects of calcium blockers in preventing TxCAD might have an immunologic basis by virtue of alterations of cyclosporine pharmacodynamics. Hence these two strategies for targeting antigen-independent mechanisms should lead to a significant reduction in the incidence of TxCAD, a goal that has until this time defied all the advances in immunosuppression during the past three decades of heart transplantation.",1998.0,0,0 3295,9595134,Immunosuppressive approaches to the prevention of graft vascular disease.,C R Gregory,,1998.0,0,0 3296,9595713,[Assessment of short-term effects of awareness programs and pravastatin therapy on subjects from private clinics at high risk for cardiovascular disease].,R D Santos; L O do Nascimento; R C Maranhão e Pesquisadores,"To evaluate short-term efficacy of awareness programs (AP) in reducing coronary heart disease risk factors (CHDRF). High risk hypercholesterolemic patients were divided in 2 groups during 16 weeks. Group A (n = 417, 54.3 +/- 10.0 years, 55% males) received verbal and written orientation on CHDRF control, and group B (n = 180, 54.4 +/- 10.9 years, 45% males) received only verbal orientation. All participants received pravastatin 10 mg q.d. for 12 weeks. The evolution of body weight, arterial pressure, lipid profile, Castelli's I and II indexes (TC/HDL and LDL/HDL), and Framingham scores were evaluated. At baseline, A had a lower HDL-C (40.0 +/- 11.0 vs 43.0 +/- 11.0 mg/dl, p = 0.013) and a higher index I (8.2 +/- 3.0 vs 7.6 +/- 2.3, p = 0.008) than B. After 16 weeks, A had greater change than B in TC (-28.0 vs -25.0, p < 0.05), LDL-C (-29.0 vs -27.6, p < 0.05), HDL-C levels (+13.7 vs +10.8, p < 0.05) and in the Castelli's Index (-39.0 vs -33.0; p < 0.05). In both groups pravastatin use potentialized the effects of diet on the lipid profile. The AP seemed to be more effective than verbal orientation alone in CHDRF reduction at short-term.",1998.0,0,0 3297,9600480,Persistence of use of lipid-lowering medications: a cross-national study.,J Avorn; J Monette; A Lacour; R L Bohn; M Monane; H Mogun; J LeLorier,"Although clinical trials have demonstrated the benefits of lipid-lowering therapy, little is known about how these drugs are prescribed or used in the general population. To estimate predictors of persistence with therapy for lipid-lowering drug regimens in typical populations of patients in the United States and Canada. A cohort study defining all prescriptions filled for lipid-lowering drugs during 1 year, as well as patients' demographic and clinical characteristics. New Jersey's Medicaid and Pharmacy Assistance for the Aged and Disabled programs and Quebec's provincial medical care program. All continuously enrolled patients older than 65 years who filled 1 or more prescriptions for lipid-lowering drugs (N = 5611 in the US programs, and N = 1676 drawn from a 10% sample in Quebec). Proportion of days during the study year for which patients had filled prescriptions for lipid-lowering drugs; predictors of good vs poor persistence with therapy. In both populations, patients failed to fill prescriptions for lipid-lowering drugs for about 40% of the study year. Persistence rates with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were significantly higher than those seen with cholestyramine (64.3% vs 36.6% of days with drug available, respectively). Patients with hypertension, diabetes, or coronary artery disease had significantly higher rates of persistence with lipid-lowering regimens. In New Jersey, multivariable analysis indicated that the poorest patients (those enrolled in Medicaid) had lower rates of drug use than less indigent patients (those enrolled in Pharmacy Assistance for the Aged and Disabled) after adjusting for possible confounders, despite virtually complete drug coverage in both programs. When rates of use were measured in the US population for the 5 years following the study year, only 52% of surviving patients who were initially prescribed lipid-lowering drugs were still filling prescriptions for this drug class. In all populations studied, patients who were prescribed lipid-lowering drug regimens remained without filled prescriptions for over a third of the study year on average. Rates of persistence varied substantially with choice of agent prescribed, comorbidity, and socioeconomic status, despite universal coverage of prescription drug costs. After 5 years, about half of the surviving original cohort in the United States had stopped using lipid-lowering therapy altogether.",2001.0,0,0 3298,9603532,Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group.,S MacMahon; N Sharpe; G Gamble; H Hart; J Scott; J Simes; H White,"Cholesterol lowering in patients with above-average cholesterol levels has been shown to reduce the progression of atherosclerosis and lower the risk of coronary heart disease events. However, there has been uncertainty about the effects of cholesterol lowering in patients with average or below-average cholesterol levels. In this study, 522 patients with a history of myocardial infarction or unstable angina and with baseline levels of total cholesterol between 4 and 7 mmol/L (mean, 5.7 mmol/L) were randomized to treatment with a low fat diet plus pravastatin (40 mg daily) or to a low fat diet plus placebo. Treatment with pravastatin reduced the levels of total cholesterol by 19%, LDL cholesterol by 27%, apolipoprotein B by 19%, and triglycerides by 13% (all 2P<.0001) and increased apolipoprotein A1 and HDL cholesterol levels by 4% (both 2P<.0005), in comparison with placebo. Carotid atherosclerosis was assessed from B-mode ultrasound measurements of the common carotid artery. After 4 years, mean carotid wall thickness had increased by 0.048 mm (SE=0.01) in the placebo group and declined by 0.014 mm in the pravastatin-treated group (SE=0.01) (2P for difference <.0001). The effect of treatment on wall thickness was similar in three groups classified by tertiles of total cholesterol at baseline, with mean levels of 4.8, 5.7, and 6.6 mmol/L, respectively (2P for interaction >.8). Treatment with pravastatin reduced the development of carotid atherosclerosis among patients with coronary heart disease and a wide range of pretreatment cholesterol levels. Treatment with this agent prevented any detectable increase in carotid wall thickening over 4 years of follow-up.",1998.0,0,0 3299,9603548,Functional evaluation of lipid-lowering therapy by pravastatin.,F C Schoebel; T W Jax; B E Strauer; M Leschke,,1998.0,0,0 3300,9603698,Behavioral issues in the efficacy versus effectiveness of pharmacologic agents in the prevention of cardiovascular disease.,T A Pearson; W Feinberg,"A number of pharmacologic interventions are now recommended for the prevention of cardiovascular disease, based on the results of randomized controlled trials. These include antihypertensive drugs, lipid-lowering agents, antiplatelet and anticoagulant drugs, estrogen replacement therapy, beta-blockers, and angiotensin converting enzyme (ACE) inhibitors. It is likely that additional pharmacologic interactions will soon be proven efficacious. Despite the strength of this evidence and the development of clinical guidelines incorporating their use, a surprisingly low proportion of patients are actively treated with these agents. There may be a variety of explanations for this, including barriers at the level of the patient, health care provider, and health care institution. Finally, a number of questions remain as to the optimal combination of interventions, both behavioral and pharmacologic, which will yield maximal reduction in risk. The description of factors which reduce the effectiveness of pharmacologic interventions below the efficacy demonstrated in randomized clinical trials should be a fertile area for epidemiologic and behavioral research.",1998.0,0,0 3301,9610529,C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction.,P M Ridker; R J Glynn; C H Hennekens,"C-reactive protein (CRP) is a sensitive marker of inflammation, and elevated levels have been associated with future risk of myocardial infarction (MI). However, whether measurement of CRP adds to the predictive value of total cholesterol (TC) and HDL cholesterol (HDL-C) in determining risk is uncertain. Among 14916 apparently healthy men participating in the Physicians' Health Study, baseline levels of CRP, TC, and HDL-C were measured among 245 study subjects who subsequently developed a first MI (cases) and among 372 subjects who remained free of cardiovascular disease during an average follow-up period of 9 years (controls). In univariate analyses, high baseline levels of CRP, TC, and TC:HDL-C ratio were each associated with significantly increased risks of future MI (all P values <0.001). In multivariate analyses, models incorporating CRP and lipid parameters provided a significantly better method to predict risk than did models using lipids alone (all likelihood ratio test P values <0.003). For example, relative risks of future MI among those with high levels of both CRP and TC (RR=5.0, P=0.0001) were greater than the product of the individual risks associated with isolated elevations of either CRP (RR=1.5) or TC (RR=2.3). In stratified analyses, baseline CRP level was predictive of risk for those with low as well as high levels of TC and the TC:HDL-C ratio. These findings were virtually identical in analyses limited to nonsmokers and after control for other cardiovascular risk factors. In prospective data from a large cohort of apparently healthy men, baseline CRP level added to the predictive value of lipid parameters in determining risk of first MI.",1998.0,0,0 3302,9612486,Evidence based strategies for secondary prevention of ischaemic heart disease: time to improve clinical practice.,C J Ellis; T O'Meeghan; A W Hamer; G D Gordon; H Patel,,1998.0,0,0 3303,9613910,Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.,J R Downs; M Clearfield; S Weis; E Whitney; D R Shapiro; P A Beere; A Langendorfer; E A Stein; W Kruyer; A M Gotto,"Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels. A randomized, double-blind, placebo-controlled trial. Outpatient clinics in Texas. A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51 st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile). Lovastatin (20-40 mg daily) or placebo in addition to a low-saturated fat, low-cholesterol diet. First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (1 83 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P =.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P = .003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.",2001.0,1,1 3304,9613915,Antiatherothrombotic properties of statins: implications for cardiovascular event reduction.,R S Rosenson; C C Tangney,"Clinical trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statin therapy have demonstrated that baseline or treated low-density lipoprotein (LDL) cholesterol levels are only weakly associated with net coronary angiographic change or cardiovascular events. The beneficial effects of statins on clinical events may involve nonlipid mechanisms that modify endothelial function, inflammatory responses, plaque stability, and thrombus formation. Experimental animal models suggest that statins may foster stability through a reduction in macrophages and cholesterol ester content and an increase in volume of collagen and smooth muscle cells. The thrombotic sequelae caused by plaque disruption is mitigated by statins through inhibition of platelet aggregation and maintenance of a favorable balance between prothrombotic and fibrinolytic mechanisms. These nonlipid properties of statins may help to explain the early and significant cardiovascular event reduction reported in several clinical trials of statin therapy.",2001.0,0,0 3305,9615912,Effects of short-term treatment with pravastatin on the hepatic synthesis of cholesterol and bile acids in gallstone patients.,C G Hillebrant; M Axelson; I Björkhem; F H Wang; B Nyberg; C Einarsson,"HMG-CoA reductase inhibitors are now the therapy of choice in the treatment of hypercholesterolaemia. The effects of long-term treatment with these substances on plasma lipoproteins, cholesterol metabolism and biliary secretion of lipids have been extensively studied in humans. Much less is known about the effects of short-term treatment. The aim of this study was to determine the time course of the effects of HMG-CoA reductase inhibitors on plasma lipoprotein levels as well as cholesterol and bile acid synthesis in gallstone patients. Thirty-six patients undergoing elective cholecystectomy were included in the study. Except for the gallstone disease, these patients were otherwise healthy. Four groups of subjects were treated with the HMG-CoA reductase inhibitor pravastatin (Pravachol), 20 mg twice daily for 12, 24, 48 and 72 h preoperatively. Plasma lipoproteins and plasma levels of lathosterol and 7 alpha-hydroxy-4-cholesten-3-one were determined before initiation of pravastatin treatment and on the morning of the day of the operation, lathosterol reflecting hepatic HMG-CoA reductase activity and 7 alpha-hydroxy-4-cholesten-3-one the activity of cholesterol 7 alpha-hydroxylase, the rate-determining enzyme in bile acid synthesis. All treatment groups displayed a significant decrease in total cholesterol and low-density lipoprotein (LDL)-cholesterol, by about 12% and 17% respectively. Lathosterol was reduced by about 50% in all treatment groups. Of great interest was the finding that 7 alpha-hydroxy-4-cholesten-3-one was unaffected in all treatment groups. The results show that short-term pravastatin treatment in gallstone patients rapidly inhibits cholesterol synthesis and lowers plasma LDL-cholesterol levels without effects on bile acid synthesis.",1998.0,0,0 3306,9620098,"Mibefradil, a pharmacologically distinct calcium antagonist.",M E Ernst; M W Kelly,"Mibefradil is the prototype of a new class of calcium antagonists that selectively block T-type voltage-gated plasma membrane calcium channels in vascular smooth muscle. The drug is structurally and pharmacologically different from traditional calcium antagonists. It does not have negative inotropism at therapeutic concentrations, and is not associated with reflex activation of neurohormonal and sympathetic systems. In clinical studies of hypertension, mibefradil 50 and 100 mg/day reduced trough sitting diastolic and systolic blood pressures in a dose-related manner. Dosages exceeding 100 mg/day generally did not result in significantly greater efficacy, but were associated with a higher frequency of adverse events. No first-dose hypotensive phenomenon was observed. Mibefradil has antiischemic properties resulting from dilation of coronary and peripheral vascular smooth muscle, and a slight reduction in heart rate. In clinical studies of chronic stable angina pectoris, dose-related increases in exercise duration, time to onset of angina, and time to 1-mm ST-segment depression during exercise tolerance tests occurred. Mibefradil reduced the number and duration of ischemic events recorded by 48-hour ambulatory electrocardiograph (ECG) monitoring, as well as number of anginal episodes and nitroglycerin consumption. Favorable hemodynamic and clinical profiles are reported, including high trough:peak ratios (> 80%), high oral bioavailability, and long elimination half-life (17-25 hrs) permitting once/day dosing. Dizziness, headache, leg edema, and lightheadedness are frequently reported, but overall the agent is well tolerated. First-degree atrioventricular block and sinus bradycardia are the most frequent ECG changes caused by the drug. In vitro studies indicate mibefradil inhibits cytochrome P450 1A2, 2D6, and 3A4, resulting in elevated plasma concentrations of drugs metabolized by those isoenzymes. Therefore, it is contraindicated in patients receiving terfenadine, astemizole, cisapride, lovastatin, or simvastatin.",1998.0,0,0 3307,9622140,Insulin-mediated venodilation is impaired in patients with high cholesterol.,B H Sung; M Ching; J Izzo; P Dandona; M F Wilson,"Recently we have reported that insulin attenuates norepinephrine (NE)-induced vasoconstriction via a cyclic GMP-NO synthase pathway. Because hypercholesterolemia has been associated with abnormal endothelial function, we investigated whether insulin-mediated vasodilation is impaired in hypercholesterolemia. To assess vasoreactivity, NE (12.5, 25, 50, and 100 ng/min), NE (100 ng/min) combined with insulin (8, 16, 24, and 32 microU/min), and NE (100 ng/min) combined with sodium nitroprusside (0.01, 0.1, 1, 10, and 100 ng/min) were infused into dorsal hand veins. Changes in venous diameter were measured by ultrasonography, using a 7.5-MHz transducer. Twenty-two healthy, normotensive hypercholesterolemic subjects (HC; mean total cholesterol 6.93 mmol/L, HDL 1.45 mmol/L, LDL 4.81 mmol/L) and 18 age-matched normal control subjects (NC; mean total cholesterol 4.81 mmol/L, HDL 1.16 mmol/L, LDL 3.18 mmol/L) were studied. All HC had normal glucose tolerance test results. Baseline vein diameters were similar between groups, and the vasoconstrictor response to NE was not significantly different between HC and NC. Insulin significantly attenuated NE-induced vasoconstriction in NC but not in HC (P<0.01). Both groups were able to venodilate with sodium nitroprusside. To investigate the effects of cholesterol reduction on vascular reactivity, venoreactivity studies were repeated in 12 HC after treatment with 20 to 40 mg/d lovastatin for 6 weeks. There were no significant venoreactivity changes with the treatment. Plasma LDL cholesterol concentration was inversely correlated to venodilator effect of insulin (r=-0.42, P<0.02). In conclusion, insulin-mediated vasodilation is impaired in patients with high cholesterol. Absence of normal insulin-mediated but not sodium nitroprusside-induced venodilation in hypercholesterolemia suggests that insulin-mediated vasodilation is endothelium dependent.",2001.0,0,0 3308,9626835,,,,,0,0 3309,9627154,Pharmacological treatment of diabetic patients with cardiovascular complications.,P T Sawicki; M Berger,"Cardiovascular complications are frequently present in insulin-dependent (IDDM) and non-insulin dependent diabetes mellitus (NIDDM) patients and confer a very poor prognosis. In this overview we critically analyse the current literature with regard to the benefits and also the possible harms of the available pharmacological treatment strategies in these patients. To date, insulin is the only hypoglycaemic agent which has been proven both effective and safe in NIDDM patients with cardiovascular complications. Also, several trials indicate that treatment with oral hypoglycaemic agents may confer a substantial risk in such patients. Conventional antihypertensive treatment, including betablockers and diuretics, has been convincingly shown to reduce mortality and morbidity in diabetic nephropathy and in NIDDM patients. However, this may not be the case with newer antihypertensive agents, such as angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers. Likewise, convincing evidence is lacking that these newer antihypertensive agents provide meaningful clinical benefit when compared to the conventional treatment regarding slower progression of diabetic nephropathy or their impact on lipid and glucose metabolism. Cholesterol lowering therapy with statins and aspirin treatment have also been repeatedly shown to improve the prognosis of diabetic patients with coronary heart disease.",1998.0,0,0 3310,9629123,Clopidogrel for reduction of atherosclerotic events.,,,1998.0,0,0 3311,9636530,Therapy of hyperlipidemia with lovastatin in kidney transplant patients on cyclosporine A immunosuppression: three-year experience.,A Kandus; D Kovac; D Cerne; M Koselj; S Kaplan-Pavlovcic; J Buturović; R Ponikvar; R Kveder; J Lindic; A F Bren,,1998.0,0,0 3312,9638964,Simvastatin compared to fluvastatin in the reduction of serum lipids and apolipoproteins in patients with ischaemic heart disease and moderate hypercholesterolaemia.,G Sigurdsson; S O Haraldsdottir; T H Melberg; M J Tikkanen; T E Miettinen; K J Kristianson,"Inhibitors of HMG-CoA reductase are widely used for the treatment of hypercholesterolaemia and have recently been shown in the Scandinavian Simvastatin Survival Study (4S), to reduce coronary mortality as well as total mortality in CH D patients. Although a couple of studies have already established the efficacy ratio between simvastatin and fluvastatin, one of the newest members of this class, we considered it to be important to verify the comparative efficacy in patients with coronary artery disease in the same type of patients that were included in 4S particularly since the previous studies include rather few patients with CHD, 17-28% only. Three Scandinavian lipid clinics participated in this randomized double-blind study and enrolled a total of 113 hypercholesterolaemic patients with a profile similar to the 4S patients, i.e. either a history of typical angina pectoris lasting at least three months or a myocardial infarction at least six months before the study and with moderate hypercholesterolaemia, total serum cholesterol between 5.5 and 8.0 mmol/l. After a diet run-in period lasting at least 8 weeks, followed by a two week placebo period, patients received treatment with active drug for a 16 week period, with measurement of lipids using the same technique and laboratory as was used in 4S. Patients were randomly assigned to simvastatin 20 mg or fluvastatin 20 mg. If after 6 weeks of double-blind treatment, the 4S total cholesterol target of < or = 5.2 mmol/l total serum cholesterol had not been reached, the dose was doubled at the next visit, i.e. at week 10 based upon blinded titration information from the central lipid laboratory like in the 4S study. A final assessment of serum lipids and lipoproteins was made at week 16. The mean percent reductions in LDL-cholesterol from baseline were 37% and 40% in the simvastatin group compared to 19% and 26% in the fluvastatin group, at weeks 10 and 16, respectively (p < 0.001). In the simvastatin group 18 percent of the patients needed an increase in the dose to 40 mg compared to 63 percent in the fluvastatin group (p < 0.001). At the 20 mg dosage, simvastatin produced a lowering of LDL-cholesterol approximately twice that of fluvastatin 20 mg and resulted in 82% of patients achieving the cholesterol target levels as defined in the 4S study, compared to 19% for fluvastatin. All other recorded lipid variables showed differences which favoured simvastatin over fluvastatin at comparable doses including serum triglyceride reductions where serum triglycerides at week 6 were borderline significantly different between the two groups. Patient tolerability of the two drugs was similar. At the recommended doses in patient with angina or a prior MI and mild to moderate hypercholesterolaemia simvastatin is considerably more effective than fluvastatin in lowering serum total cholesterol, LDL-cholesterol as well as other serum lipid risk factors. At an average titrated dose of 32 mg less than 50% of the fluvastatin patients reached the 4S cholesterol target of < 5.2 mmol/l compared to 89% of the simvastatin patients at an average dose of 23 mg daily and only 13% of the fluvastatin patients achieved an LDL-cholesterol reduction of at least 40% compared to 63% of the simvastatin patients.",1998.0,1,1 3313,9639958,Atorvastatin (Lipitor).,G Tucker,,1998.0,0,0 3314,9643764,Altering molecular mechanisms to prevent sudden arrhythmic death.,P D Henry; A Pacifico,"Trials of drug treatment for prevention of sudden arrhythmic death have been disappointing, perhaps because suppressive therapy with arrhythmic agents fails to address the mechanisms leading to electrophysiological failure. We propose that preventive treatment should pay more attention to molecular mechanisms responsible for the progression of cardiac disease to electrophysiological failure. Most sudden cardiac deaths occur in people with atherogenic dyslipidaemias. Our hypothesis is that the pathogenic molecular mechanisms of dyslipidaemias contribute directly to arrhythmogenesis. Proinflammatory-prothrombotic lipid-derived mediators that may play a part in arrhythmogenesis include phospholipids and leucotrienes acting through the platelet-activating-factor and peroxisome proliferator-activated-receptor pathways. There are drugs available to test the hypothesis of dyslipidaemias-specific prevention of electrophysiological failure.",1998.0,0,0 3315,9645507,"Cholesterol, endothelial function and cardiovascular disease.",I B Wilkinson; J R Cockcroft,"Hypercholesterolaemia is associated with endothelial dysfunction and increased risk of atheromatous disease. Although endothelial dysfunction has been demonstrated early in the course of the disease process, it remains difficult to establish a causal relationship. Despite this, endothelial function has been used as a surrogate marker in small trials to identify and assess the effectiveness of therapeutic interventions to reduce cardiovascular mortality, before large scale clinical trials are undertaken. Recently, arterial stiffness has emerged as an independent risk factor for cardiovascular disease and may provide a link between hypercholesterolaemia, endothelial dysfunction, hypertension and stroke.",1998.0,0,0 3316,9646098,T-lymphocytes and monocytes in atherogenesis.,G Schmitz; A S Herr; G Rothe,"Atherosclerosis is characterized as a chronic inflammatory-fibroproliferative disease of the vessel wall. The attachment of monocytes and T-lymphocytes to the injured endothelium followed by their migration into the intima is one of the first and most crucial steps in lesion development. The co-localization of CD4+ T-cells and macrophages in the lesion, the abundant expression of HLA Class II molecules and the co-stimulatory molecule CD40 and its ligand (CD40L) indicate a contribution of cell-mediated immunity to atherogenesis. Transgenic mouse models revealed that dependent on the model T- and B-cells may promote lesion progression, monocytes and macrophages are in contrast essential for the development of atherosclerotic lesions. Apart from the local process in the vessel wall, systemic signs of an inflammatory reaction are also associated with lesion development. Thus plasma levels of C-reactive protein and fibrinogen and the white blood cell count are positively correlated to the risk of cardiovascular disease. Recently, an inflammatory phenotype of circulating peripheral blood monocytes could be demonstrated as a specific cellular correlate to lipid and lipoprotein risk factors. Thus the pool size of LPS receptor (CD14)dim and Fc gamma IIIa receptor (CD16a)+ monocytes positively correlates to plasma cholesterol levels, to triglycerides levels and to the apolipoprotein E4 (apo E4) phenotype in contrast to a negative correlation to the high density lipoprotein (HDL) cholesterol concentration. This CD14dim CD16a+ monocytes are further characterized by a high expression of beta 1- and beta 2-integrins, suggesting a higher capacity for attachment at sites of inflammation. A proinflammatory cytokine pattern and an expansion of these cells in other inflammatory diseases are indicating that these cells promote the inflammatory process during atherogenesis. Surface expression of the activation antigen CD45RA on monocytes in correlation to plasma LDL cholesterol and Lp(a) levels further indicates an inflammatory reaction. Regarding the potential mechanisms of the phenotypic changes of peripheral blood monocytes, in a serum free in vitro differentiation model supplemented with M-CSF monocytes from probands which are homozygous for apo E4 showed a significantly higher increase of CD16a expression compared to apo E3/E3 cells indicating that a genetic polymorphism of a single apolipoprotein gene locus may affect monocyte differentiation. The further characterization of the cellular immunology of monocytes and T-lymphocytes in lesion development will provide new specific diagnostic and therapeutic targets in atherogenesis.",1998.0,0,0 3317,9646619,Vastatin trials: lessons from hypertension history.,A J Smit,,1998.0,0,0 3318,9646621,"Efficacy and safety of a new cholesterol synthesis inhibitor, atorvastatin, in comparison with simvastatin and pravastatin, in subjects with hypercholesterolemia.",B H Wolffenbuttel; G Mahla; D Muller; A Pentrup; D M Black,"High levels of total and LDL-cholesterol are associated with an increased risk of atherosclerotic vascular disease. Lowering of serum cholesterol levels by pharmacologic intervention with inhibitors of cholesterol synthesis, the so-called statins, reduces the incidence of cardiovascular events in subjects with and without atherosclerotic manifestations. In a 16-week, multicenter, randomized, open-label cross-over study we compared the efficacy and safety of the new compound atorvastatin for reducing LDL-cholesterol with simvastatin or pravastatin. Following a 4-week placebo-controlled baseline period patients with LDL-cholesterol between 4.1 and 6.2 mmol/l and serum triglycerides below 3.4 mmol/l were randomly assigned to treatment either with 5 or 20 mg atorvastatin, or with 10 mg simvastatin or 20 mg pravastatin once daily for 4 weeks. After a placebo-washout period of 4-6 weeks, patients switched to the alternate treatment. At the end of weeks 3 and 4 of each study phase the serum concentrations of lipid parameters and apolipoproteins as well as safety parameters were determined. A total of 78 subjects entered the study. Treatment with 5 mg atorvastatin reduced total and LDL-cholesterol by 21 and 27%, respectively, which was similar to 10 mg simvastatin (total cholesterol -20%, LDL-cholesterol -28%) and 20 mg pravastatin (-18 and -24%, respectively). The effects of this low dose of atorvastatin on triglyceride levels (-16%) was not different from that of simvastatin and pravastatin (-8 and -11%, respectively). Treatment with 20 mg atorvastatin caused significantly larger reductions in total cholesterol (-33%) and LDL-cholesterol (-44%), serum triglycerides (-23%), and apo B (-40%) compared to simvastatin and pravastatin. Atorvastatin was well-tolerated, and no serious or medically important adverse events were observed. We conclude that atorvastatin is a safe and very efficacious cholesterol-lowering agent, which also possesses significant triglyceride-lowering properties.",1998.0,1,1 3319,9648053,Effects of long-term pravastatin treatment on spermatogenesis and on adrenal and testicular steroidogenesis in male hypercholesterolemic patients.,G P Bernini; G Brogi; G F Argenio; A Moretti; A Salvetti,"To evaluate the influence of an hydrophilic statin, pravastatin, on adrenal and testicular steroidogenesis and spermatogenesis, eight male hypercholesterolemic patients were studied. All patients observed a hypocholesterolemic diet and received placebo for 4 weeks followed by pravastatin (20 mg/die) for 6 months. Before, during (4th-5th week) and at the end (23th-24th week) of active treatment, CRH (1 microgram i.v.), ACTH (Synacthen 250 micrograms i.v.) and human CG (HCG 3000 IU i.m.) tests were performed in addition to semen analysis. Pravastatin significantly reduced total cholesterol (20.3%), calculated LDL-cholesterol (24.6%) and apolipoprotein B (10.5%, increased apolipoprotein A1 (16.1%) and did not influence plasma HDL-cholesterol and triglycerides. Basal plasma cortisol, aldosterone, androstenedione, testosterone and oestradiol did not change under active treatment. Pravastatin administration affected neither adrenal hormone responses to CRH and ACTH or testicular response to HCG nor spermatogenesis in respect of motility, morphology and sperm count. In conclusion, long-term pravastatin treatment, at doses effective in improving lipid profile, did not influence testicular reproductive and endocrine function and did not interfere with basal and stimulated adrenal activity of male hypercholesterolemic patients.",1998.0,0,0 3320,9649013,A combination therapy with simvastatin and ursodeoxycholic acid is more effective for cholesterol gallstone dissolution than is ursodeoxycholic acid monotherapy.,S Tazuma; G Kajiyama; T Mizuno; G Yamashita; H Miura; T Kajihara; Y Hattori; H Miyake; T Nishioka; H Hyogo; Y Sunami; S Yasumiba; H Ochi; T Matsumoto; A Abe; K Adachi; F Omata; F Ueno; F Sugata; S Ohguri; H Shibata; S Kokubu,"Inhibitors of 3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase have been reported to decrease the cholesterol saturation index (CSI) in duodenal bile in humans and to prevent formation of cholesterol gallstones in animal studies. We performed a prospective study to evaluate the role of HMG-CoA reductase inhibitors as gallstone-dissolving agents. Fifty patients with radiolucent gallstones in a gallbladder opacifying at drip infusion cholecystography were treated with either 10 mg/day simvastatin plus 600 mg/day ursodeoxycholic acid (group 1, n=26) or 600 mg/day ursodeoxycholic acid alone (group 2, n=24) for 12 months. The ratio of solitary to multiple gallstone cases was 21:29. Plasma lipid levels were assessed and ultrasonographic examination of the gallbladder was performed at baseline and at 3-month intervals during treatment. Duodenal bile sampling was performed in five patients in each group at baseline and after 12 months of treatment. Plasma cholesterol decreased significantly in group 1 but not in group 2. In solitary gallstone cases, no significant difference in dissolution rates was observed between groups 1 (3 of 9, 33%) and 2 (4 of 12, 33%). In contrast, the dissolution rate in multiple gallstone cases was significantly higher in group 1 (12 of 17, 71%) than in group 2 (3 of 12, 25%) (p < 0.01). Bile cholesterol saturation index was significantly decreased (p < 0.01) but did not significantly differ between the two groups. These results suggest that combination therapy with simvastatin and ursodeoxycholic acid is more effective for cholesterol gallstone dissolution than ursodeoxycholic acid monotherapy in patients with multiple gallstones.",1998.0,0,0 3321,9651560,Compliance with and efficacy of treatment with pravastatin and cholestyramine: a randomized study on lipid-lowering in primary care.,M Eriksson; K Hådell; I Holme; G Walldius; T Kjellström,"Lipid-lowering drugs as 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors and cholestyramine are effective in reducing cardiovascular morbidity both in primary and secondary prevention. Patient compliance is an important determinant of the outcome of therapy. This study was designed to compare compliance with tolerance and lipid-lowering effectiveness of pravastatin and/or cholestyramine in primary care. Nine hundred and eighty nine women and 1047 men were randomized to treatment at 100 primary-care centres in Sweden. After dietary intervention, an eligible patient was randomly assigned to one of four programs of daily treatment: group Q, 16 g cholestyramine, group QP, 8 g cholestyramine and 20 mg pravastatin, group P20, 20 mg pravastatin or group P40, 40 mg pravastatin. In group Q, group QP, group P20 and group P40 the reductions in low density lipoprotein (LDL)-cholesterol were 26%, 36%, 27% and 32%. The dose actually taken was 91-95% of the prescribed for the pravastatin treatment groups and 77-88% for the cholestyramine groups. In the pravastatin and cholestyramine groups 76-78% and 44-53%, respectively, completed the trial. Only 8-27% of the patients reached a serum cholesterol target level of 5.2 mmol L-1. There was no difference in lipid-lowering effect between women and men. Pravastatin alone is efficacious and compliance is high, independent of dose. Combined treatment with cholestyramine and pravastatin had a better cholesterol lowering effect (although not statistically significant) than 40 mg pravastatin. Despite this, only 8-27% of the patients actually reached a serum cholesterol level of 5.2 mmol L-1. No unexpected serious adverse events were detected in any of the treatment groups. As predicted, the gastrointestinal disturbances were more common on cholestyramine treatment. These two factors suggest that an increase in the dosage of the HMG-CoA reductase inhibitor may be appropriate. Results from other studies indicate that there also might be other positive effects of statin treatment beyond cholesterol lowering.",1998.0,0,0 3322,9651568,The additional effects of acipimox to simvastatin in the treatment of combined hyperlipidaemia.,N Hoogerbrugge; H Jansen; L De Heide; M C Zillikens; J W Deckers; J C Birkenhäger,"Nicotinic acid, an effective drug for treatment of combined hyperlipidaemia, is often not tolerated because of side-effects. Acipimox is a nicotinic acid like lipid lowering drug with less side-effects. We studied whether the addition of acipimox to simvastatin improves the lipid profile in patients with a combined hyperlipidaemia. Randomized double-blind placebo controlled crossover trial. Outpatient lipid clinic of a tertiary referral centre. Eighteen patients with combined hyperlipidaemia treated with diet and 20-40 mg simvastatin for at least 3 months. Acipimox in a daily dose of 3 X 250 mg for 12 weeks. Effects on the concentration of LDLc, TG, HDLc, Lp(a) and Apolipoprotein B, as well as on LDL-size and LDL-resistance to oxidative modification. Acipimox reduced Lp(a) levels by 8% (P < 0.05). A substantial but not statistically significant change in TG (-32%) and HDLc (+6%) levels was seen. All patients were found to have small dense LDL, with a size of 229 +/- 4 A. LDL size and the resistance to oxidation, reflected in the lag phase during in vitro oxidation, were not affected by the addition of acipimox. In a subgroup of 8 patients with the most severe hypertriglyceridaemia (baseline TG > 4 mmol L- [1]), acipimox induced a significant increase in HDLc (+ 15%, P < 0.01). The effects on TG (-41%), LDLc (-10%) and lag phase (+17%) were also more pronounced than in the group with a lower baseline TG, but none of these changes reached the level of significance. Adding acipimox to simvastatin reduced Lp(a) and substantially but not significantly lowered TG. However, in patients with the highest TG levels. HDLc was also significantly improved.",1998.0,0,0 3323,9651906,Effect of a HMG-CoA reductase inhibitor combined with hormone replacement therapy on lipid metabolism in Japanese women with hypoestrogenic lipidemia: a multicenter double-blind controlled prospective study.,H Ohta; S Komukai; I Sugimoto; T Fuyuki; K Makita; K Takamatsu; F Horiguchi; S Nozawa,"Menopause is associated with a rise in serum lipid concentrations. We compared a regimen of pravastatin alone with pravastatin and hormone therapy in postmenopausal women with hyperlipidemia. We performed a double-blind, randomized, multicenter controlled study in postmenopausal women with hyperlipidemia. The women were randomly assigned to receive pravastatin alone (M group; n = 25) or pravastatin and hormone replacement therapy (HRT) (MC group; n = 32) for 12 weeks. Serum lipid and estrogen concentrations were measured at baseline and after 4 weeks and 12 weeks of treatment. The two groups were similar with respect to baseline demographic characteristics such as age, height, and body weight. As compared with baseline, the total cholesterol (TC) concentration was 15.0% lower at 4 weeks and 17.7% lower at 12 weeks in the M group and 15.1% lower at 4 weeks and 18.3% lower at 12 weeks in the MC group. The low-density-lipoprotein cholesterol (LDL-C) concentration decreased by 25.0% at both 4 weeks and 12 weeks in the M group and by 26.8% at 4 weeks and 30.0% at 12 weeks in the MC group. Serum TC and LDL-C concentrations were significantly lower in the MC group than in the M group after 4 weeks of treatment, but there was no significant difference between the groups in serum lipid concentrations after 12 weeks. Pravastatin combined with HRT was therefore suggested to lower serum lipid concentrations earlier than pravastatin alone. There were no significant differences between the treatment groups in serum high-density-lipoprotein cholesterol concentrations or triglyceride concentrations after the initiation of therapy. In the MC group, there was a significant positive correlation between the percentage change in serum lipid concentrations and that in estrogen concentrations, suggesting that the HRT-induced rise in estrone (E1) as well as that in estradiol (E2) contributed an improved serum lipid profile. TC and E2, and LDL-C and serum E1 had significant negative correlation at 12 weeks and 4 weeks, respectively. Pravastatin had no apparent effect on endogenous estrogen levels and was not associated with any side effects, which confirmed that pravastatin is safe, either alone or in combination with HRT. The combination of pravastatin and HRT in the management of hyperlipidemia in postmenopausal women is very useful therapeutically, because it additionally provides the broad benefits of HRT, without compromising the lipid lowering effects of either treatment.",1998.0,0,0 3324,9652566,Simvastatin reduces monocyte-tissue-factor expression type IIa hypercholesterolaemia.,D Ferro; S Basili; C Alessandri; B Mantovani; C Cordova; F Violi,,1998.0,0,0 3325,9653591,Application of a diabetes managed care program. The feasibility of using nurses and a computer system to provide effective care.,A L Peters; M B Davidson,"Treatment of patients with diabetes often falls short of recommended process and outcome guidelines. To improve the quality of the provided diabetes care, a program (the Comprehensive Diabetes Care Service [CDCS]) using a computerizing tracking and recall system in conjunction with nurses following protocols was implemented in a managed care setting. The impact of this program was studied and compared to the care provided to patients in another managed care setting. Patients followed in the CDCS who completed a diabetes education course were compared with patients followed in a group model health maintenance organization (GMH) who also completed a diabetes education course. CDCS patients received routine care in the program. GMH patients came to the CDCS yearly to have a diabetes evaluation. A chart review was also performed on their GMH outpatient records. Initial HbA1c levels were higher in the CDCS group than in the GMH group (median of 11.9 vs. 10.0%). In the CDCS patients, HbA1c levels not only fell significantly but were also significantly lower (P < 0.05) than in the GMH patients during the 2nd and 3rd year of follow-up care. There were no significant changes in HbA1c levels in the GMH patients. When CDCS patients were divided into compliant and noncompliant patients, the median HbA1c levels in compliant patients was 8.2%, compared with 11.5% in the noncompliant group. The CDCS patients who needed treatment for hypercholesterolemia were more likely to have a lowering of their cholesterol levels than the GMH patients. All process measures, such as yearly measurement of HbA1c levels, lipid levels, and foot and retinal exams, occurred much more frequently in the CDCS patients. The system developed and implemented for managing diabetes improved both outcome and process measures. The comparison group, followed at another managed care setting, received the care consistent with the average (suboptimal) quality of care provided to patients with diabetes in the U.S. Therefore, by using innovative systems of management, the treatment of patients with diabetes can be greatly improved.",1998.0,0,0 3326,9663363,"Effects of cerivastatin sodium, a new HMG-CoA reductase inhibitor, on biliary lipid metabolism in patients with hypercholesterolemia.",S Tazuma; G Yamashita; H Ochi; H Miura; T Kajihara; Y Hattori; H Miyake; T Nishioka; H Hyogo; Y Sunami; S Yasumiba; G Kajiyama,"The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has become common in the treatment of hypercholesterolemia. The present uncontrolled study was undertaken to determine the effect of cerivastatin sodium (BAY w 6228), a new HMG-CoA reductase inhibitor, on biliary lipid levels in patients with hypercholesterolemia. Twenty-one hypercholesterolemic patients (World Health Organization type IIa = 16 patients; type IIb = 5 patients) received placebo during a 4- to 6-week observation period, after which they received cerivastatin sodium 0.2 mg/d for 12 weeks. Fasting blood samples were drawn for the measurement of serum lipid levels early in the morning before the start of treatment and once a month for each of the 12 weeks of cerivastatin sodium treatment. Gallbladder bile samples were aspirated with a duodenal tube by cerulein stimulation to assess bile lithogenicity. Serum total cholesterol levels decreased markedly after 12 weeks. However, no significant difference was found in the molar percentage composition of biliary lipids (e.g., cholesterol, phospholipids, and total bile acids) or in individual biliary bile acids. Consequently, no significant change in bile cholesterol saturation index was found. The index values before and after 12 weeks of treatment were 0.81 +/- 0.38 and 0.80 +/- 0.47, respectively, whereas when patients were grouped by type of hypercholesterolemia, there was a tendency toward decreased lithogenicity in patients with type IIb but not type IIa hypercholesterolemia. We concluded that cerivastatin sodium was an effective cholesterol-lowering drug that did not appear to worsen biliary lipid metabolism and that may decrease lithogenicity in patients with type IIb hypercholesterolemia.",1998.0,0,0 3327,9663369,"A long-term comparative trial of cerivastatin sodium, a new HMG-CoA reductase inhibitor, in patients with primary hypercholesterolemia.",J Sasaki; K Arakawa; K Yamamoto; S Kobori; M Ageta; S Kono,"Cerivastatin sodium, a synthetic and pure enantiomeric 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, is considered effective in the treatment of mild-to-moderate primary hyper-cholesterolemia (total cholesterol < or = 220-259 mg/dL) at a daily dose of 0.15 mg. We compared the efficacy and tolerability of a dosage of 0.3 mg/d with those of a dosage of 0.15 mg/d in patients with severe primary hypercholesterolemia (serum total cholesterol > or = 260 mg/dL). After a minimum of 4 weeks' lead-in with placebo, 73 patients with severe primary hypercholesterolemia were randomly assigned to receive either 0.15 or 0.3 mg of cerivastatin sodium once daily after the evening meal for 12 weeks. In 58 patients, the same drug was continued at a flexible dosage for an additional 36 weeks or longer to assess the long-term efficacy and tolerability of cerivastatin sodium. During the 12-week treatment period, serum total cholesterol levels decreased significantly from baseline in both dosage groups, but the percentage reduction was significantly greater in the 0.3-mg group (range, 24.4% to 25.6%) than in the 0.15-mg group (range, 19.4% to 21.6%). The percentage reduction in levels of low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B and the percentage increase in levels of high-density lipoprotein cholesterol were significantly greater in the 0.3-mg group than in the 0.15-mg group. When the results for the 0.3- and 0.15-mg groups were combined, the percentage of change in serum lipid levels at 48 weeks remained as stable as at 12 weeks. No serious adverse reactions were observed. We concluded that the higher dose of cerivastatin sodium was more effective than the lower dose, with comparable tolerability, in the treatment of patients with severe primary hypercholesterolemia.",1998.0,0,0 3328,9663810,Comparison of the effects of moclobemide and selegiline on tyramine-evoked mydriasis in man.,P Bitsios; R W Langley; S Tavernor; K Pyykkö; M Scheinin; E Szabadi; C M Bradshaw,"To examine the feasibility of using the human iris in vivo for the assessment of the interaction between tyramine and monoamine oxidase (MAO) inhibitors. To examine the relative roles of the two forms of MAO in terminating the response to sympathomimetic amines in the iris, by comparing the effects of single oral doses of moclobemide, a selective MAO-A inhibitor, and selegiline, a selective MAO-B inhibitor, on mydriatic responses to tyramine. Twelve healthy male volunteers participated in three monthly sessions, each associated with ingestion of one capsule (moclobemide 450 mg, selegiline 10 mg, or placebo), according to a double-blind, balanced, cross-over design. Tyramine hydrochloride eye-drops (75 mM, 2 x 10 microl) were instilled three times in the left conjuctival sac at 40 min intervals. Pupil diameter was monitored with a binocular infrared television pupillometer before and for 4.5 h after ingestion of the capsule. The pupillary response to tyramine was expressed as the area under the pupil diameter x time curve (arbitrary units). A blood sample was taken before and 2 h after ingestion of the capsule, for the assay of platelet MAO-B activity, and plasma 3,4-dihydroxyphenylglycol (DHPG) concentration, an index of MAO-A activity. Platelet MAO activity was assayed radiochemically, using [14C]-phenylethylamine as substrate, and plasma DHPG by high performance liquid chromatography (h.p.l.c.). The results were analysed using analysis of variance with repeated measures, followed by Bonferroni's corrected t-test, using a significance criterion of P < 0.05. Both moclobemide and selegiline, compared with placebo, caused significant miosis in the right (untreated) eye. The changes in pupil diameter (mm +/- s.e. mean) from the pretreatment measurement were: placebo -0.09 +/- 0.07, moclobemide -0.52 +/- 0.09, selegiline -0.26 +/- 0.1. The mydriatic response to tyramine was potentiated by moclobemide, compared with the response recorded in the presence of placebo. The responses to tyramine (arbitrary units +/- s.e. mean) were: placebo 77.08 +/- 11.65, moclobemide 140.25 +/- 18.9, selegiline 72.75 +/- 12.35. Both moclobemide and selegiline significantly reduced platelet MAO activity, compared with placebo. The changes in platelet MAO activity (nmol h(-1) mg(-1) protein +/- s.e. mean) from the pretreatment level were: placebo 0.5 +/- 0.62, moclobemide -6.7 +/- 0.66, selegiline -17.7 +/- 0.87. Moclobemide significantly reduced plasma DHPG concentration, compared with placebo. The changes in plasma DHPG concentration (nmol l(-1) +/- s.e. mean) from the pretreatment level were: placebo -0.01 +/- 0.24, moclobemide -4.98 +/- 0.32, selegiline -0.51 +/- 0.26. The potentiation of tyramine-evoked mydriasis by moclobemide is likely to reflect the inhibition of MAO-A activity in the iris, consistent with the activity of this enzyme in sympathetic nerve terminals. The lack of effect of selegiline on tyramine-evoked mydriasis argues against a role of MAO-B in terminating the effects of sympathomimetic amines in the iris. The effects of the two drugs on platelet MAO activity and plasma DHPG concentration are in agreement with previous reports and consistent with the relative selectivity of moclobemide for MAO-A and of selegiline for MAO-B. The miosis caused by the two MAO inhibitors is likely to be due to a central sympatholytic action of the drugs.",1998.0,0,0 3329,9663814,Inter-ethnic comparisons of the pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin.,W Mück; S Unger; K Kawano; G Ahr,"During the world-wide clinical development of the HMG-CoA reductase inhibitor cerivastatin, pharmacokinetic data have been collected from studies performed in Europe, North America and Japan, covering different ethnic groups, mainly Caucasians and Japanese subjects, but also Black and Hispanics. The aim of the present investigation was to search for any inter-ethnic differences in cerivastatin pharmacokinetics. All concentration data were assessed by fully validated specific h.p.l.c. assays employing post-column photochemical derivatization with ultra-violet light and subsequent fluorescence detection. The comparability of analytical results was guaranteed by cross-validations between all analytical laboratories. The inter-ethnic comparison was based on retrospective analysis of the overall pharmacokinetic data pool (n = 340 complete profiles) in the key parameters AUC, Cmax, tmax and t1/2, assessed via non-compartmental methods. Based on the comparison of selected individual single- and multiple-dose escalation studies in healthy young males, performed when starting the clinical development, exposure and disposition of the parent compound and its cytochrome P450-mediated biotransformation products M-1 and M-23, and amounts of metabolites M-1, M-23 and M-24 excreted in urine were comparable for US Americans, mainly Caucasians, and Japanese. Retrospective analysis of the complete pharmacokinetic data pool revealed that there are no statistically significant differences in dose-normalized AUC- and Cmax-values. The respective ratios of weight-adjusted geometric least-squares (LS) means (95% confidence intervals) between Japanese and Caucasians were: for AUCdose-norm 0.96 (0.86-1.08) for single dose, and 1.04 (0.86-1.24) for multiple dose; for Cmax,dose-norm 0.93 (0.83-1.05) for single dose, and 1.01 (0.82-1.25) for multiple dose. Half-life was slightly, but statistically significantly shorter in Japanese than in Caucasian subjects following single dose: ratios (95% CI) were 0.68 (0.61-0.77) for single dose, and 1.00 (0.79-1.26) for multiple dose. Times to peak tended to be slightly greater in Japanese: differences of weight-adjusted LS means (95% CI) were 0.60 h (0.28 h-0.92 h) for single dose, and 1.15 h (0.48 h-1.81 h) for multiple dose. Black and Hispanics did not differ in their pharmacokinetic characteristics from Caucasians. Based on inter-study comparisons and a retrospective analysis of the complete PK data pool there is no evidence for any clinically relevant inter-ethnic differences in cerivastatin pharmacokinetics in Caucasians, Black and Japanese subjects after oral therapeutic doses.",1998.0,0,0 3330,9665425,Human cholesteryl ester transfer protein measured by enzyme-linked immunosorbent assay with two monoclonal antibodies against rabbit cholesteryl ester transfer protein: plasma cholesteryl ester transfer protein and lipoproteins among Japanese hypercholesterolemic patients.,K Sasai; K Okumura-Noji; T Hibino; R Ikeuchi; N Sakuma; T Fujinami; S Yokoyama,"Plasma cholesteryl ester transfer protein (CETP) concentrations were measured in Japanese subjects by an ELISA with two different monoclonal antibodies that were raised against rabbit CETP and cross-reacted against human CETP. Among 63 patients who consecutively underwent coronary angiography, the plasma CETP of 37 patients with luminal stenosis > or = 50% in their coronary arteries was not significantly different from that of the 26 patients with luminal stenosis < 50%. No other lipoprotein-related measurement except HDL-cholesterol differentiated the two groups. Among 40 hypercholesterolemic patients, no lipoprotein-related measurement other than LDL-cholesterol was found to positive correlate with the CETP. Before and after the treatment of 23 patients with simvastatin 5 mg a day for 4 weeks, plasma CETP markedly decreased in those whose pretreatment CETP was > or = 3 mg/L; no change was observed for those with lower pretreatment CETP. In the former group, negative correlation between CETP and HDL-cholesterol was demonstrated only in the posttreatment plasma.",1998.0,0,0 3331,9666222,Prevention of cardiovascular disease: the Scandinavian experience.,T R Pedersen,,1998.0,0,0 3332,9666952,High-dose atorvastatin therapy in severe heterozygous familial hypercholesterolaemia.,A S Wierzbicki; P J Lumb; Y K Semra; M A Crook,"Lipid targets can be difficult to attain in familial hypercholesterolaemia. To compare atorvastatin with simvastatin-fenofibrate and simvastatin-cholestyramine therapy, we studied 54 patients with familial hypercholesterolaemia over periods of 2-6 months on each therapeutic regimen. The atorvastatin regimen reduced total cholesterol by 41.2 +/- 11.2%, LDL by 45.6 +/- 15.5%, triglycerides by 33.8 +/- 24.8%, and increased HDL by 2.3 +/- 37.0%. Simvastatin-fenofibrate therapy achieved reductions of 33.9 +/- 8.5% in cholesterol, 42.0 +/- 12.2% in LDL, 34.7 +/- 38.3% for triglycerides, and a 25.4 +/- 55.1% increase in HDL. Simvastatin-cholestyramine gave a reduction of 31.3 +/- 11.8% in cholesterol, 36.0 +/- 14.4% in LDL, 13.7 +/- 36.3% in triglycerides, and a 1.1 +/- 30.3% rise in HDL. The atorvastatin regimen was marginally but not significantly better than simvastatin-fenofibrate in improving the LDL:HDL ratio, LDL:apoB and and apolipoprotein B:A1 ratios. Eleven patients (20.4%) had side-effects: two discontinued atorvastatin due to side-effects; two patients had rashes; six had myalgia and two had diarrhoea. Gastrointestinal side-effects were described in 16 (30.1%) patients on simvastatin-cholestyramine therapy and four cases of myalgia (11.2%) were seen with simvastatin-fenofibrate. In nine patients on atorvastatin (20.4%) a 30% or greater fall in HDL was observed, compared to five patients with resin therapy (9.2%) and two with fibrate therapy (5.5%). There were no significant differences in liver or muscle biochemistry between the regimens, but atorvastatin did raise transaminase and creatine kinase concentrations significantly compared to pre-treatment values (p = 0.001). Atorvastatin significantly improves the lipid profile in most patients compared with other regimens. It has a comparable incidence of side-effects to combination therapy regimens.",1998.0,0,0 3333,9669241,Results from late-breaking clinical trials sessions at ACC '98. American College of Cardiology.,E L Alderman,,1998.0,0,0 3334,9669262,Effect of pravastatin on cardiovascular events in women after myocardial infarction: the cholesterol and recurrent events (CARE) trial.,S J Lewis; F M Sacks; J S Mitchell; C East; S Glasser; S Kell; R Letterer; M Limacher; L A Moye; J L Rouleau; M A Pfeffer; E Braunwald,"We sought to determine the effect of pravastatin on recurrent cardiovascular events in women with average cholesterol levels after myocardial infarction (MI). Little information is available on the effectiveness of lipid lowering in secondary prevention of coronary heart disease (CHD) in women; in particular, those with CHD and average cholesterol levels. In the Cholesterol and Recurrent Events (CARE) trial, 576 postmenopausal women, between 3 and 20 months after MI, with a total cholesterol level <240 mg/dl and a low density lipoprotein cholesterol level 115 to 174 mg/dl, were randomized to receive pravastatin 40 mg/day or matching placebo for a median follow-up period of 5 years. The main outcome measures were combined coronary events (coronary death, nonfatal MI, percutaneous transluminal coronary angioplasty [PTCA] or coronary artery bypass graft surgery [CABG]), the primary trial end point (coronary death or nonfatal MI) and stroke. Women treated with pravastatin had a risk reduction of 43% for the primary end point (p = 0.035), 46% for combined coronary events (p = 0.001), 48% for PTCA (p = 0.025), 40% for CABG (p = 0.14) and 56% for stroke (p = 0.07). The 3,583 men in the CARE trial also showed a reduction in risk, but the magnitude tended to be less. Pravastatin improved plasma lipids similarly in men and women. There were no differences in risk of coronary events in the placebo group between men and women. Minor differences between men and women were present in baseline characteristics and treatment for MI, in general, conferring a higher risk status and a lower incidence of CABG in the women. Pravastatin led to significant early reduction of a wide range of cardiovascular events in post-MI women with average cholesterol levels.",1998.0,0,0 3335,9671003,Variations of autonomic tone preceding onset of atrial fibrillation after coronary artery bypass grafting.,C Dimmer; R Tavernier; N Gjorgov; G Van Nooten; D L Clement; L Jordaens,"Assessment of autonomic tone preceding the onset of atrial fibrillation (AF) after coronary artery bypass grafting (CABG) with heart rate variability was examined in 64 patients scheduled for elective CABG (days 2 to 5). Ninety-six-hour Holter tapes were analyzed in each patient and all events labeled by an experienced technician. The hour preceding AF was divided into 4 quarters (heart rate variability calculated per quarter) and compared with similar time episodes from the group without AF. Twenty-six of 64 patients (40%) had a total of 35 episodes. Only increased age (68+/-5 vs 62+/-9 years) and lower ejection fraction (66+/-16% vs 73+/-8%) were associated with an increased risk for AF. Before onset, a greater number of atrial premature complexes was observed. The standard deviation of all RR intervals (SDNN) showed an increase in the group with AF in the last 15 minutes (significant vs controls and within the AF group). The low-frequency/high-frequency ratio was significantly lower in patients in the first 30 minutes, followed by an increase mainly because the high-frequency spectrum became less important. Thus, initiation of postoperative AF is influenced by autonomic tone variations. A shift in the autonomic balance with a loss of vagal tone and a moderate increase in sympathetic tone are observed before the onset of AF compared with those in controls.",1998.0,0,0 3336,9671004,Coronary revascularization in the treatment of moderate and severe postischemic left ventricular dysfunction.,F Fath-Ordoubadi; D Pagano; N V Marinho; B E Keogh; R S Bonser; P G Camici,"Chronic postischemic left ventricular (LV) dysfunction can improve following coronary revascularization (hibernating myocardium). However, it is not clear whether the severity of LV dysfunction determines functional outcome after revascularization and the accuracy of tests to predict myocardial viability. We studied 47 patients with coronary artery disease and chronic LV dysfunction. Before coronary bypass, patients underwent (18F)2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) during euglycemic hyperinsulinemic clamp to assess viability. Global and regional LV function were assessed before and 4 to 6 months after surgery. Patients were arbitrarily divided into 2 groups with moderate and severe LV dysfunction. Group 1 (n = 26) had an ejection fraction (EF) of < or = 30% and group 2 (n = 21) > 30%. After bypass, the EF (22+/-6% vs 31+/-10%; p <0.0001) and global wall motion score (WMS) (2.05+/-0.39 vs 1.56+/-0.34; p <0.001) improved in group 1, whereas the EF (43+/-9% vs 43+/-12%; p = NS) was unchanged in group 2, although WMS tended to improve (1.42+/-0.38 vs 1.32+/-0.39; p = 0.09). The proportion of dysfunctional segments (72% vs 32%; p <0.0001) and FDG uptake in these segments (0.44+/-0.15 vs 0.34+/-0.15 micromol/g/min, p <0.0001) were greater in group 1 than in group 2. The baseline EF influenced the predictive accuracy of PET, with highest positive predictive accuracy in group 2 and highest negative predictive accuracy in group 1. Thus, coronary revascularization has the potential for greatest benefit in patients with the most severe dysfunction, but with evidence of viability, and the entity of LV dysfunction affects the predictive accuracy of viability studies.",1998.0,0,0 3337,9671005,Impact of stents on clinical outcomes in percutaneous left main coronary artery revascularization.,R Kornowski; M Klutstein; L F Satler; A D Pichard; K M Kent; A Abizaid; G S Mintz; M K Hong; J J Popma; R Mehran; M B Leon,"Despite effective treatment of left main coronary artery (LMCA) disease by coronary bypass, there is still need for treatment of the LMCA due to progression of disease or bypass graft failure. We compared the in-hospital and follow-up (1-year) outcomes of patients with LMCA stenosis treated with stents (n = 88), with a matched group of patients undergoing LMCA non-stent procedures (n = 36). Ninety-seven percent of patients in each group underwent previous coronary bypass. Procedural success (angiographic success without major in-hospital complications) tended to be higher in stent patients than in their non-stent counterparts (98% vs 92%, p = 0.12), and overall procedural complications were higher for the non-stent group (5.4% vs 0%, p = 0.03). The incidence of non-Q-wave myocardial infarction was higher in patients with the LMCA treated with stents than in non-stent patients (13% vs 2.7%, p = 0.09). There was no difference in death or Q-wave myocardial infarction between the 2 groups during follow-up. Overall target lesion revascularization at 1 year was 15% after LMCA stenting, and 18% in non-stent patients (p = 0.71). Also, any cardiac event-free survival (including death, Q-wave myocardial infarction, coronary bypass, or angioplasty) was similar for both groups (78% for stents vs 76% for non-stents, p = 0.85). We conclude that in patients undergoing LMCA interventions, stents reduce major hospital complications, but may not significantly reduce repeat revascularization or major cardiac events at 1 year compared with non-stent LMCA procedures.",1998.0,0,0 3338,9671014,Effects of caregiver specialty on cost and clinical outcomes following hospitalization for heart failure.,K J Harjai; L M Boulos; F W Smart; T Turgut; M A Krousel-Wood; D D Stapleton; M R Mehra; J P Murgo; H O Ventura,"In 614 consecutive hospitalizations with the primary discharge diagnosis of diagnosis-related group (DRG) 127 (heart failure and shock), we sought to assess the effect of caregiver specialty (generalist, n = 217; cardiologist, n = 397) on hospital costs, length of stay, and in-hospital mortality. Patients treated by cardiologists were younger (68 vs 71 years) and less likely to have hypertension (52% vs 61%), but were more likely to be men (61% vs 44%), require an intensive care stay (13% vs 5%), have coronary artery disease (49% vs 23%), have a left ventricular ejection fraction <40% (74% vs 49%), and have lower systolic (132 vs 146 mm Hg) and diastolic (76 vs 81 mm Hg) blood pressures on admission. Predictors of acute disease severity were similarly distributed between the 2 groups. No difference was found between patients treated by cardiologists versus those treated by generalists with respect to crude or adjusted hospital cost, length of stay, and in-hospital mortality. However, in subsets of patients who required intensive care during hospitalization (n = 64), as well as those who did not (n = 550), care by cardiologists was associated with a lower adjusted hospital cost. Any potential cost savings that could have accrued from care by cardiologists was, however, negated by the higher proportion of patients treated by cardiologists who required intensive care during hospitalization. We conclude that when differences in clinical variables are adjusted, care by cardiologists versus generalists is associated with similar or lower hospital cost for patients with DRG 127. Our findings challenge the notion that in-patient care provided by specialists is more expensive than that provided by generalists.",1998.0,0,0 3339,9671018,,,,,0,0 3340,9673599,Venous thromboembolism and cancer.,R W Sander; C A Flynn,,1998.0,0,0 3341,9673745,Comparison of atorvastatin alone versus simvastatin +/- cholestyramine in the management of severe primary hypercholesterolaemia (the six cities study).,L A Simons,"Atorvastatin is a new member of the class of drugs which inhibit the enzyme Hydroxy-Methylglutaryl Co-A reductase, the rate limiting step in cholesterol biosynthesis. To compare the effects of atorvastatin alone versus simvastatin +/- low dose resin (i.e. versus standard care) on low density lipoprotein (LDL) cholesterol in severe primary hypercholesterolaemia. An open, multi-centre, randomised study in patients previously stabilised on a cholesterol-lowering diet and simvastatin 40 mg daily, having LDL cholesterol > or = 5.0 mmol/L and triglycerides < 4.0 mmol/L. After five weeks washout, 92 were randomised to receive atorvastatin 10 mg and 44 to receive simvastatin 10 mg. The dose was doubled every six weeks if LDL cholesterol remained > or = 3.5 mmol/L. In accordance with manufacturers' recommendations, maximum dosage was atorvastatin 80 mg daily or simvastatin 40 mg daily (+cholestyramine 4 g daily in 84% of cases). Treatment was continued over 30 weeks. Lipids, lipoproteins, haematological and biochemical safety parameters were measured at regular intervals. Adverse events were monitored. Baseline LDL cholesterol was approximately 9 +/- 2 mmol/L (SD). After 30 weeks treatment serum cholesterol reduction was 42 +/- 10% on atorvastatin versus 32 +/- 13% on simvastatin +/- resin (p < 0.001), LDL cholesterol reduction 49 +/- 12% versus 38 +/- 14% (p < 0.001), and triglyceride reduction 33 +/- 20% versus 25 +/- 22% (p < 0.02). High density lipoprotein cholesterol increased by 7-10% on both treatments. The proportion of subjects achieving goal LDL cholesterol < 3.5 mmol/L was two to three times greater in those on atorvastatin compared with those on simvastatin +/- resin at each titration point. Six patients on simvastatin and one on atorvastatin were withdrawn. The drugs were generally well tolerated and the pattern of adverse events was similar with either treatment. Atorvastatin up to 80 mg daily appears to be an effective new treatment for the management of primary hypercholesterolaemia. It shows greater efficacy than simvastatin up to 40 mg daily +/- resin and has a similar safety profile.",1998.0,0,0 3342,9676722,"Ostensible day-night difference of QT prolongation during long-term treatment with antiarrhythmic drugs: reappraisal of the law of ""regression to the mean"".",Y Murakawa; T Yamashita; K Ajiki; K Sezaki; M Omata,"This study was designed to test whether the law of regression to the mean explains the diurnal variation in the modulation of electrocardiographic variables during the treatment with antiarrhythmic agents. In part 1, in 34 subjects, ambulatory ECG monitorings were repeated twice, and the corrected QT interval (QTc) at a heart rate of 60 beats/min was calculated separately for the daytime and night. The individual diurnal QTc variation (day-night difference) of the first recording (4.4 +/- 3.3%) was significantly correlated with that of the second recording (5.0 +/- 3.1%; r = 0.61; p < 0.0001), and naturally, the second measurement tended to be lower than the first value in those with relatively greater baseline diurnal QTc variation and vice versa (p < 0.005). In part 2, 30 subjects undertook ambulatory ECG recordings before and during treatment with class Ia antiarrhythmic drugs. Mean QTc changes in the daytime and in the night with the drugs were comparable (18 +/- 17 ms and 19 +/- 15 ms). However, the day-night difference of postdrug QTc changes in each subject was inversely correlated with baseline diurnal QTc variation (r = -0.64; p < 0.0001). These observations in part 2 were comparable with those in part 1, and individual day-night difference in QT prolongation with antiarrhythmic drugs seemed to be a chance occurrence. It was suggested that the law of regression to the mean is appreciably reflected in the ostensible intraday variation of pharmacologic modulation of electrocardiographic variables.",1998.0,0,0 3343,9678767,HMG-CoA reductase inhibitor therapy and stroke risk reduction: an analysis of clinical trials data.,J R Crouse; R P Byington; C D Furberg,"Although associations of cholesterol and coronary heart disease (CHD) are well accepted, the association between cholesterol and stroke has been a subject of some confusion. Epidemiologic evidence suggests no association between plasma concentrations of cholesterol and stroke, and earlier clinical trials were also negative. Two early meta-analyses of clinical trials designed to evaluate the effects of cholesterol lowering on CHD concluded that cholesterol lowering had no effect. More recently newer, more potent and better tolerated agents (HMG-CoA reductase inhibitors, reductase inhibitors) have become available and have been tested for their efficacy in reducing cholesterol and CHD in both primary prevention and secondary prevention trials. Meta-analyses of these trials, in contrast to the earlier trials, reveal a powerful statistically significant effect to reduce stroke as well as CHD in secondary prevention (30%); the direction of the effect is the same in trials of primary prevention or trials that randomized patients with and without CHD (mixed primary and secondary prevention trials) where the risk reductions for stroke, although not reaching statistical significance are 11 and 30%, respectively. An important difference in the newer analysis is the availability of several trials of secondary prevention in which low density lipoprotein cholesterol was lowered 25-30% and in which CHD event reduction was similarly reduced by 30%. Mechanisms for stroke reduction likely involve retardation of plaque progression in the intracranial and extracranial carotid arteries, plaque stabilization, and, in addition, stroke may be reduced partly as a consequence of CHD reduction.",2001.0,0,0 3344,9678976,Reports from the Canadian Coordinating Office for Health Technology Assessment (CCOHTA). HMG-CoA reductase inhibitors: a review of published clinical trials and pharmacoeconomic evaluations.,,,1998.0,0,0 3345,9683056,Lipids in hypertensive patients.,S M Cobbe,"Hypertension and hyperlipidemia are common and powerful risk factors for cardiovascular disease. Although they may coexist in the same individual by chance, the syndrome of insulin resistance is the common mechanism in many individuals, in whom there is a specific lipoprotein profile of small, dense, low-density lipoprotein particles, reduced plasma high-density lipoprotein cholesterol levels, and increased plasma triglycerides. This lipoprotein profile may be exacerbated by diuretics or beta-blockers. Initial management of the insulin resistance syndrome is by weight loss and dietary measures. Optimum antihypertensive and lipid-lowering drug strategy remains to be established.",1998.0,0,0 3346,9684746,Ubiquinone supplementation during lovastatin treatment: effect on LDL oxidation ex vivo.,A Palomäki; K Malminiemi; T Solakivi; O Malminiemi,"A randomized, double-masked, placebo-controlled cross-over trial was carried out to evaluate whether ubiquinone supplementation (180 mg daily) corrects impaired defence against initiation of oxidation of low density lipoprotein (LDL) related to effective (60 mg daily) lovastatin treatment. Nineteen men with coronary heart disease and hypercholesterolemia received lovastatin with or without ubiquinone during 6-week periods after wash-out. The depletion times for LDL ubiquinol and reduced alpha-tocopherol were determined during oxidation induced by 2,2-azobis(2,4-dimethylvaleronitrile) (AMVN). Copper-mediated oxidation of LDL isolated by rapid density-gradient ultracentrifugation was used to measure the lag time to the propagation phase of conjugated diene formation. Compared to mere lovastatin therapy, ubiquinone supplementation lead to a 4.4-fold concentration of LDL ubiquinol (P < 0.0001). In spite of the 49% lengthening in depletion time (P < 0.0001) of LDL ubiquinol, the lag time in copper-mediated oxidation increased only by 5% (P = 0.02). Ubiquinone loading had no statistically significant effect on LDL alpha-tocopherol redox kinetics during high radical flux ex vivo. The faster depletion of LDL ubiquinol and shortened lag time in conjugated diene formation during high-dose lovastatin therapy may, at least partially, be restored with ubiquinone supplementation. However, the observed improvement in LDL antioxidative capacity was scarce, and the clinical relevance of ubiquinone supplementation during statin therapy remains open.",1998.0,0,0 3347,9685274,Number needed to screen: development of a statistic for disease screening.,C M Rembold,"To develop the number needed to screen, a new statistic to overcome inappropriate national strategies for disease screening. Number needed to screen is defined as the number of people that need to be screened for a given duration to prevent one death or adverse event. Number needed to screen was calculated from clinical trials that directly measured the effect of a screening strategy. From clinical trials that measured treatment benefit, the number needed to screen was estimated as the number needed to treat from the trial divided by the prevalence of heretofore unrecognised or untreated disease. Directly calculated values were then compared with estimate number needed to screen values. Standard literature review. For prevention of total mortality the most effective screening test was a lipid profile. The estimated number needed to screen for dyslipidaemia (low density lipoprotein cholesterol concentration >4.14 mmol/1) was 418 if detection was followed by pravastatin treatment for 5 years. This indicates that one death in 5 years could be prevented by screening 418 people. The estimated number needed to screen for hypertension was between 274 and 1307 for 5 years (for 10 mm Hg and 6 mm Hg diastolic blood pressure reduction respectively) if detection was followed by treatment based on a diuretic. Screening with haemoccult testing and mammography significantly decreased cancer specific, but not total, mortality. The number needed to screen for haemoccult screening to prevent a death from colon cancer was 1374 for 5 years, and the number needed to screen for mammography to prevent a death from breast cancer was 2451 for 5 years for women aged 50-59. These data allow the clinician to prioritise screening strategies. Of the screening strategies evaluated, screening for, and treatment of, dyslipidaemia and hypertension seem to produce the largest clinical benefit.",1998.0,0,0 3348,9690949,,,,,0,0 3349,9690952,Risk factors for mortality in users of ibopamine.,J Feenstra; B A in't Veld; P D van der Linden; D E Grobbee; B H Stricker,"In September 1995, the indication for the oral dopamine agonist ibopamine was restricted in the Netherlands and in several other European countries to patients with NYHA-class II heart failure as a result of an interim analysis of the PRIME-II trial. This trial demonstrated an increased risk of mortality in patients with NYHA-class III/IV heart failure on ibopamine. In September 1995, we initiated an assessment of the effects of ibopamine under everyday circumstances in a cohort of users of ibopamine in all NYHA-classes. In a nationwide retrospective cohort study all 2147 community pharmacies and drug dispensing general practitioners received a request to list all patients to whom they had dispensed ibopamine in the preceding years. All responding drug dispensing outlets (DDO) received a questionnaire on cardiovascular risk factors and mortality for the general practitioner of a random sample of these patients. DDO were also requested to send an anonymised printout of the complete medication record. On the end-date of follow-up, February 15th 1996, mortality rates were compared across categories of ibopamine use, adjusted for potential confounders. To assess medication use, drug exposure was compared in a 3 months' period before date of death in the deceased, and before a random date in those patients who were still alive. In patients with NYHA-class III/IV heart failure, multivariate analysis indicated that current use of ibopamine was significantly associated with mortality (RR 1.37;95% CI: 1.15-1.64). In patients with NYHA-class I/II heart failure, however, multivariate analysis showed a 2.03 (95% CI: 1.10-3.72) risk of mortality in current users of ibopamine. Apart from current use of ibopamine, male gender and increased serum creatinine were also independent risk factors for mortality in all NYHA-classes. No statistically significant association was found between mortality and current use of amiodarone or use of amiodarone at baseline. The increased risk of mortality in patients with NYHA-class III and IV heart failure on ibopamine seems to confirm the main finding of the recently published PRIME-II trial. However, our results indicate that also patients with NYHA-class I/II heart failure may be at an increased risk of mortality when using ibopamine. Additional research on the effects of ibopamine in these patients is warranted and the use of ibopamine in NYHA-class II heart failure patients may have to be reconsidered.",1998.0,0,0 3350,9692657,A comparison of fluvastatin 40 mg every other day versus 20 mg every day in patients with hypercholesterolemia.,J P Rindone; D Hiller; G Arriola,"To assess the efficacy of fluvastatin administered every other day versus an equivalent dose given daily in patients with hypercholesterolemia. Randomized, nonblinded, crossover study. Veterans Affairs Medical Center. Twenty-three patients with low-density lipoprotein (LDL) levels above 160 mg/dl despite diet therapy Patients received fluvastatin 40 mg every other day or 20 mg/day, all doses taken at bedtime. Each treatment arm was 6 weeks in duration. A lipid profile was determined at baseline and after each regimen. Both regimens significantly lowered total cholesterol and LDL versus baseline. The LDL levels were lowered by 24% and 21% by fluvastatin 20 mg/day and 40 mg every other day, respectively. There was no statistically significant difference in lipid components between regimens. Fluvastatin 40 mg every other day is effective in lowering total cholesterol and LDL in patients with hypercholesterolemia.",1998.0,0,0 3351,9693942,Use of cholesterol precursors to assess changes in cholesterol synthesis under non-steady-state conditions.,M Pfohl; R P Naoumova; K D Kim; G R Thompson,"Quantification of plasma levels of an early and late intermediate on the cholesterol pathway, mevalonic acid (MVA) and lathosterol respectively, provides a useful method of estimating cholesterol synthesis in humans. The aim of this study was to assess further their roles as indices of cholesterol synthesis under non-steady-state conditions. The short-term effects of pharmacological inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase on both variables were determined in four normolipidaemic subjects during and after treatment with simvastatin 20 mg daily. Plasma MVA was measured using gas chromatography-mass spectrometry, and lathosterol using gas chromatography. A single dose of 20 mg of simvastatin decreased plasma MVA after 2 h and decreased the lathosterol-cholesterol (L/C) ratio after 4 h. Treatment with simvastatin 20 mg daily for 9 days decreased both variables by approximately 50%, the nadir of plasma MVA occurring on the second day and of the L/C ratio on the fifth day, and resulted in a 39% reduction in low-density lipoprotein (LDL)-cholesterol. After discontinuing simvastatin, there were rebounds in plasma MVA and the L/C ratio to above basal levels but not in LDL cholesterol or apolipoprotein B (apoB), the latter continuing to decrease for a further 2 days. These results suggest that simvastatin rapidly down-regulates cholesterol synthesis, which is then up-regulated when the drug is withdrawn.",1998.0,0,0 3352,9697820,"Increased bioavailability of nitric oxide after lipid-lowering therapy in hypercholesterolemic patients: a randomized, placebo-controlled, double-blind study.",S John; M Schlaich; M Langenfeld; H Weihprecht; G Schmitz; G Weidinger; R E Schmieder,"Impaired endothelium-dependent vasodilation is an early sign of atherosclerosis in hypercholesterolemic patients. We hypothesized that lipid-lowering therapy can improve endothelial function and that this effect is mainly mediated by increased bioavailability of nitric oxide (NO). In a randomized, double-blind, placebo-controlled trial, we studied 29 patients (age, 50+/-12 years) with hypercholesterolemia (LDL cholesterol > or = 160 mg/dL) randomly assigned to receive either fluvastatin (40 mg twice daily; 17 patients) or placebo (12 patients). Forearm blood flow was measured by plethysmography before and after 24 weeks of treatment. Endothelium-dependent vasodilation was assessed by intra-arterial infusion of acetylcholine (ACh; 3, 12, 24, and 48 microg/min) and basal NO synthesis rate by intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA; 1, 2, and 4 micromol/min). Simultaneous intra-arterial infusion of L-NMMA (4 micromol/min) and ACh (12, 24, and 48 microg/min) was used to test whether any increase in endothelium-dependent vasodilation after lipid-lowering therapy could be blocked by this NO synthase inhibitor. Endothelium-dependent vasodilation improved significantly after 24 weeks of lipid-lowering therapy compared with before therapy (ACh 24 microg/min: 240+/-34% before versus 347+/-50% after therapy; P< or =0.01) and placebo (changes between after and before therapy with ACh 24 microg/min: 108+/-39% for fluvastatin versus -26+/-32% for placebo; P< or =0.05). This improvement in endothelium-dependent vasodilation could be blocked by simultaneous administration of L-NMMA (ACh 24 microg/min plus L-NMMA 4 micromol/min: 170+/-69% before versus 219+/-47% after treatment; P=NS). Lipid-lowering therapy with fluvastatin can improve disturbed endothelial function in hypercholesterolemic patients compared with placebo. This improvement is mediated by increased bioavailability of NO.",1998.0,0,0 3353,9699886,Worldwide distribution of blood lipids and lipoproteins in childhood and adolescence: a review study.,C Brotons; A Ribera; R M Perich; D Abrodos; P Magaña; S Pablo; D Terradas; F Fernández; G Permanyer,"Review and pooled analysis of the relevant worldwide literature was investigated from 1975 to 1996. Eighteen surveys out of 54 were suitable for analysis according to the selection criteria. This represents a total of 60494 observations from 26 countries all over the world. Data suggests differences as great as 76 mg/dl when comparing northern European countries to black African children. The overall curve of cholesterol with age observed in the pooled population indicates a pre-adolescent peak and then a slightly inverse change is observed for both boys and girls, from 3 to 12 years old being almost coincident absolute values. Beyond age 12, values for boys continue to slightly decrease to age 16, while for girls values tend to increase through this age-range. The curve in the late teens (16-18 years) tends to reach pre-teen levels for both sexes, although girls have consistently higher absolute values than boys. There is a great variation in the specific age-sex and race levels of cholesterol among different populations or even in the same populations over a period of time. However, an apparently universal pattern of an early rise, a fall, and a subsequent rise in mean values of total cholesterol by age from the preadolescence to late teens is observed. More data are needed on total cholesterol and lipid fractions between late school age and mid-adulthood.",1998.0,0,0 3354,9699902,LPS-induced cytokine production and expression of LPS-receptors by peripheral blood mononuclear cells of patients with familial hypercholesterolemia and the effect of HMG-CoA reductase inhibitors.,N de Bont; M G Netea; C Rovers; T Smilde; P N Demacker; J W van der Meer; A F Stalenhoef,"Inflammatory processes play an important role in atherogenesis, and proinflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, and tumour necrosis factor alpha (TNFalpha) are thought to be mediators in this phenomenon. We have previously established that peritoneal macrophages of LDL-receptor knock-out mice, which are hypercholesterolemic and are prone to atherosclerosis, have an increased LPS-induced cytokine production capacity, ex vivo. The aim of the present study was to investigate whether the process leading to atherosclerosis in patients with familial hypercholesterolemia (FH) is associated with increased cytokine production capacity of peripheral blood mononuclear cells (PBMC) and/or increased expression of adhesion molecules on monocytes and lymphocytes. Furthermore, we assessed the effect of cholesterol lowering on the production capacity of PBMC, as these drugs are beneficial with regard to cardiovascular diseases. LPS-induced IL-1beta and TNFalpha production by PBMCs of 21 heterozygous FH patients appeared to be similar to the production by PBMCs of 21 healthy volunteers. In addition, expression of the LPS-receptors CD14 and beta2-integrins in nine patients and controls did not differ either. In a second series of experiments, HMG-CoA synthesis inhibitors were ineffective to change the LPS-induced production by PBMC of IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1ra), IL-6, and TNFalpha. In conclusion, cytokine production capacity of blood cells or the expression of LPS-receptors on circulating PBMC do not deviate in subjects with FH and also do not change as a result of treatment with cholesterol synthesis inhibitors.",1998.0,0,0 3355,9702933,Cardiovascular risk in hypertension: implications of the Sheffield Table for lipid-lowering strategy.,S Hasnain; J Webster; J S McLay,"To determine the actual use of 'statin' therapy for primary and secondary prevention and the potential effect of using the Sheffield Table for primary prevention of coronary heart disease upon 'statin' use in a consultant-run Hypertension and Cardiovascular Risk Clinic. Prospective audit of the current use of cholesterol-lowering therapy and the effect of implementing the criteria used in the Sheffield Table and the Scandinavian Simvastatin Study for cholesterol lowering in 'at risk' patients upon statin use in a consultant-led cardiovascular risk clinic. The Aberdeen Hypertension Clinic. A total of 1500 patients were reviewed of which 416 (27.7%) had experienced at least one clinical manifestation of atherosclerotic cardiovascular disease (CVD) and 392 (94%) of these had a total cholesterol measured of whom 298 (76%) had a total cholesterol >5.5 mmol/l. Only 11.2% of eligible patients were actually receiving lipid-lowering treatment for secondary prevention. A total of 1084 patients with no prior cardiovascular disease were identified, 97 (8.9%) were excluded because of age. Using the Sheffield Table, 92 (9.4%) of these patients were eligible for statin therapy and only six of the 92 patients were actually receiving treatment. The results of this study reveal that even in a consultant-led cardiovascular prevention clinic there is a significant discrepancy between optimal evidence-based management and the actual delivery of clinical care. Seventy-two per cent and 9.3% of patients attending the clinic were eligible for statin treatment for secondary and primary prevention, respectively. However, only 11.2% of patients suitable for secondary prevention and 6.5% of patients suitable for primary prevention were actually receiving appropriate lipid-lowering therapy. Considering the proven benefit of this form of medical intervention the results of this study are of real importance to practising clinicians and patients alike.",1998.0,0,0 3356,9704163,"Medical, surgical, and interventional treatment for carotid artery disease.",S Chaturvedi,"Internal carotid artery atherosclerosis is a major cause of ischemic stroke. Medical, surgical, and interventional options are available for stroke prevention in patients with carotid artery stenosis. Optimal management of the patient depends to a great degree on whether the individual is symptomatic or asymptomatic. Coexisting medical morbidities also greatly influence treatment decisions regarding carotid endarterectomy. This review highlights the current status of antiplatelet therapy and warfarin for stroke prevention in patients with carotid stenosis. The appropriate role of carotid endarterectomy for symptomatic and asymptomatic patients is also discussed. Finally, the current status of carotid angioplasty and stenting is outlined.",1998.0,0,0 3357,9706127,Vascular disease and lipids in diabetes.,A J Garber,"Atherosclerosis kills more patients with diabetes than all other causes combined. Aggressive reversal and treatment of dyslipidemias is the only proven prevention for coronary events in the patient with type 2 diabetes. Glycemic control with diet, oral hypoglycemic agents, and insulin, when necessary, is often only partially effective in normalizing lipid values in type 2 diabetes. Intensive treatment with lipid-regulating agents, particularly HMG-CoA reductase inhibitors, is often necessary to normalize diabetes-associated dyslipidemias. HMG-CoA reductase inhibitors are also the only agents thus far shown in prospective multicenter trials to reduce the risk of coronary events in diabetic patients.",1998.0,0,0 3358,9708659,,,,,0,0 3359,9710685,Effects of vitamin E and HMG-CoA reductase inhibition on cholesteryl ester transfer protein and lecithin-cholesterol acyltransferase in hypercholesterolemia.,C Napoli; M Leccese; G Palumbo; F de Nigris; P Chiariello; P Zuliani; P Somma; M Di Loreto; C De Matteis; F Cacciatore; P Abete; A Liguori; M Chiariello; F P D'Armiento,"The enzyme lecithin-cholesterol acyl transferase (LCAT) esterifies free cholesterol on high-density lipoprotein (HDL) and the cholesteryl ester transfer protein (CETP) transfers cholesteryl ester to very-low-density lipoprotein (VLDL) and low-density lipoproteins (LDL). Using statins, contradictory findings have been made regarding CETP activity in normolipidemic individuals and in those with familial dysbetalipoproteinemia. In contrast, LCAT activity appears to be unaffected by simvastatin. Antioxidants have also been proposed for the use of anti-atherosclerotic treatment, because the oxidation of LDL may have a key role in the pathophysiology of atherogenesis. To investigate, in hypercholesterolemic patients, whether a combination of pravastatin with the antioxidant, vitamin E, has greater effects on the activity of CETP and of LCAT than does pravastatin alone. This placebo-diet-controlled multicenter trial included 220 hypercholesterolemic patients who were assigned randomly to groups to receive: diet and 20-40 mg pravastatin (n = 52), diet and alpha-tocopherol (n = 60), or diet associated with placebo (n = 52). Plasma LCAT activity was determined using excess exogenous substrate, containing [3H]cholesterol. Plasma CETP activity was measured in the supernatant fraction after precipitation of endogenous apo B-containing lipoproteins with phosphotungstate-Mg2+. The exchange of cholesteryl esters between [14C]cholesteryl ester-labeled LDL and unlabeled HDL was measured during a 16-h incubation, while LCAT was inhibited. The addition of pravastatin to the diet induced a significant decrease in plasma CETP activity (P < 0.05); this effect was less evident in the group cotreated with vitamin E. For the first time, it was shown that CETP concentrations increased significantly after vitamin E alone (P < 0.05). No significant differences in the plasma activity of LCAT were observed among the groups. Pravastatin reduced CETP activity, but not that of LCAT. Addition of vitamin E prevented the decrease in CETP activity and had no effect on LCAT activity. The mechanism responsible for these effects is unknown, but could involve the prevention of radical-induced damage to CETP by vitamin E.",1998.0,0,0 3360,9712327,A tale of two trials: The West of Scotland Coronary Prevention Study and the Texas Coronary Atherosclerosis Prevention Study.,J Shepherd,Few areas in medicine offer such an impressive portfolio of evidence of clinical benefit as does the implementation of statins in the avoidance of coronary heart disease. The West of Scotland Coronary Prevention Study and the Air Force Coronary Atherosclerosis Prevention Study together have triggered a fundamental reappraisal of the use of these agents in preventing the first heart attack. The scientific evidence in support of cholesterol lowering therapy is incontrovertible. Some questions still remain by they relate more to how treatment should be applied rather than whether it is advisable. There is no longer any controversy about the merits of lipid lowering and no justification for inertia.,1998.0,0,0 3361,9713078,[Comparison of hypercholesterolemic men and women at high risk for atherosclerosis. Study of risk factors and response to pravastatin treatment].,R D Santos; R C Maranhão,"To compare the prevalence of risk factors, and the response to pravastatin treatment between men and women. We evaluated 486 men and 386 women, of these 230 men and 187 women received 10 mg of pravastatin for three months. There were differences between women and men in respectively: arterial hypertension (45.5% vs 40.8%; p = 0.0012), left ventricular hypertrophy (33.0% vs 22.0%; p = 0.0041), sedentarism (94.8% vs 87.8%; p = 0.0005), smoking (43.0% vs 61.8%; p < 0.0001), Framingham scores (20.0 +/- 7.1 vs 16.0 +/- 7.6 p < 0.0001), HDL-C (43.0 +/- 11.0 vs 38.0 +/- 9.0 mg/dL; p 0.001), triglycerides-TG (216.0 +/- 115.0 vs 271.0 +/- 172.0 mg/dL; p < 0.001) and Castelli's indexes (CI) I and II (7.7 +/- 2.6 vs 8.6 +/- 3.2; p = 0.002 and 5.0 +/- 1.5 vs 5.5 +/- 2.0; p = 0.015). In men under pravastatin treatment there was a greater reduction in TG (32.0 vs 21.0% p < 0.05) and CI I (-41.0% vs -37.0%; p < 0.05) and II (-40.0% vs -38.0%; p < 0.05). Men and women differed in risk factors prevalence and response to treatment with pravastatin.",1998.0,0,0 3362,9717348,[Therapeutic compliance in dyslipidemias. A trial of the efficacy of health education].,E Márquez Contreras; J J Casado Martínez; M López de Andrés; E Corés Prieto; J M López Zamorano; J P Moreno García; J L Martín de Pablos; J Marín Fernández,"To analyse the efficacy of health education (HE) through group session with postal back-up in furthering compliance with therapy for Lipaemia. Controlled clinical trial, with random distribution. Primary care. 110 patients with Hypercholesterolaemia, with new diagnoses or not in treatment, in which medical treatment with statins was indicated as a start or change in medication. They were distributed in two groups at random, with observation four months after being included in the study and appointments after one, two and four months. 1. Control group (CG): 55 patients who received HE from their family doctor. 2. Intervention group (IG): 55 patients whose HE was monitored: a) a group HE session and b) back-up by letter sent to their homes. Patients whose consumption was between 80 and 110% of the amount prescribed were defined as compliant. The pill count was recorded. The percentages of compliant patients and mean compliance (chi squared, Student's t) were analysed. 108 individuals, 41 men and 67 women, completed the trial. There was no difference between the two groups as to age, sex, evolution time, number of diseases and dosage of medicines consumed. 71.3% were compliant (CI, 62.8-79.8%), CG = 61.8% and IG 81.1% (p < 0.05). The mean percentage of compliance was 86.1 +/- 14.3 overall, with CG = 83.8 +/- 14 and IG 88.5 +/- 14 (p = NS). The HE intervention with a group session and postal back-up is an effective way of improving therapeutic compliance in cases of hypercholesterolaemia.",1998.0,0,0 3363,9721772,Effect of estrogen and simvastatin on low-density lipoprotein subclasses in hypercholesterolemic postmenopausal women.,A Wakatsuki; N Ikenoue; C Izumiya; Y Okatani; Y Sagara,"To identify the effects of estrogen and simvastatin, individually and in combination, on the levels of low-density lipoprotein (LDL) subclasses in postmenopausal women with type IIa hypercholesterolemia. Fifty-five postmenopausal women with type IIa hypercholesterolemia were assigned randomly to 0.625 mg of conjugated equine estrogen (n = 20), 5 mg of simvastatin (n = 18), or both (n = 17) daily for 3 months. Cholesterol, triglyceride, and apolipoprotein B levels in the plasma and in the LDL1 (density 1.019-1.045 g/mL) and LDL2 (density 1.045-1.063 g/mL) fractions were measured before and after treatment. Estrogen treatment significantly reduced LDL1 cholesterol and LDL1 apolipoprotein B levels by 18.4% and 20.8%, respectively; simvastatin treatment by 21.9% and 29.2%, respectively; and combination therapy by 38.5% and 34.4%, respectively. In contrast to estrogen or simvastatin treatment, the combination therapy also significantly lowered the levels of LDL2 cholesterol by 19.5% and LDL2 apolipoprotein B by 30.5%. Posttreatment levels of total cholesterol, LDL1 cholesterol, and LDL1 apolipoprotein B were significantly lower after combination treatment than after estrogen treatment. Estrogen treatment, but not combination therapy, significantly increased total plasma triglyceride levels (103.1+/-26.0 mg/dL to 138.8+/-75.6 mg/dL, P < .01). Significantly more patients receiving combination therapy than those receiving estrogen had total and LDL cholesterol concentrations reduced to target levels. Combination therapy with estrogen and simvastatin favorably affected lipid metabolism by reducing large and small LDL particles and prevented the estrogen-induced increase in plasma triglyceride levels.",1998.0,0,0 3364,9722499,Recent natural products based drug development: a pharmaceutical industry perspective.,Y Z Shu,,1998.0,0,0 3365,9722787,Lovastatin to prevent acute coronary events with average cholesterol levels.,L L MacFarlane; P J Carek,,1998.0,0,0 3366,9723378,Conversion to tacrolimus to ameliorate cyclosporine toxicity in kidney recipients.,L Burrows; R Knight; Y Genyk; B Schwartz; V Moran; R Anand,,1998.0,0,0 3367,9723390,Treatment of hypercholesterolemia with fluvastatin in kidney transplant patients.,J L Melchor; C Gracida,,1998.0,0,0 3368,9723640,,,,,0,0 3369,9723817,Grapefruit juice-drug interactions.,D G Bailey; J Malcolm; O Arnold; J D Spence,"The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.",1998.0,0,1 3370,9725547,"Influence of age on the safety, tolerability, and pharmacokinetics of the novel HMG-CoA reductase inhibitor cerivastatin in healthy male volunteers.",A Mazzu; J Lettieri; L Kaiser; W Mullican; A H Heller,"The safety, tolerability, and pharmacokinetics of cerivastatin, a novel, synthetic, potent, and highly selective HMG-CoA reductase inhibitor, were studied in 48 young and elderly male volunteers in a randomized, double-blind, placebo-controlled study. Eight men ranging from 18 to 38 years of age (young) and 15 men ranging from 65 to 78 years of age (elderly) received 0.1-mg cerivastatin tablets daily for 7 days. The remaining subjects (8 young and 17 elderly) received matching placebo tablets. Cerivastatin was well tolerated in elderly and young subjects. Adverse events were mild and occurred less frequently in the participants receiving cerivastatin than in those receiving placebo. In those participants given cerivastatin, the incidence of adverse events was similar for both age groups (4 of 8 young subjects and 8 of 15 elderly subjects). Transient and mild elevations in creatine kinase and transaminase levels were evenly distributed across the cerivastatin and placebo groups. Pharmacokinetic parameters, including area under the concentration curve (AUC), peak plasma concentration (Cmax), time to Cmax (tmax), and elimination half-life (t1/2), were similar between the two age groups. The mean elimination t1/2 for both groups was approximately 4 hours. These results indicate that cerivastatin is well tolerated in elderly male volunteers at a dosage of 0.1 mg/day. Further, the pharmacokinetics of cerivastatin are not altered as a consequence of age. Dose adjustment is therefore not required in elderly men.",1998.0,0,0 3371,9725552,Atorvastatin does not produce a clinically significant effect on the pharmacokinetics of terfenadine.,R H Stern; J A Smithers; S C Olson,"The effect of atorvastatin, a CYP3A4 substrate, on the pharmacokinetics of terfenadine and its carboxylic acid metabolite, fexofenadine, were evaluated. Single 120-mg doses of terfenadine were given 2 weeks apart to healthy volunteers with 80-mg daily doses of atorvastatin administered from 7 days before through 2 days after the second terfenadine dose. Concentrations of terfenadine and fexofenadine were measured for 72 hours after each terfenadine dose. Administration of terfenadine alone or in combination with atorvastatin produced no alterations in the QTc interval. For terfenadine, atorvastatin coadministration produced an 8% decrease in maximum concentration (Cmax), a 35% increase in area under the concentration-time curve extrapolated to infinity (AUC0-infinity), and a 2% decrease in elimination half-life (t1/2). For fexofenadine, atorvastatin coadministration produced a 16% decrease in Cmax, a 2% decrease in AUC0-infinity and a 51 % increase in t1/2. None of these changes achieved statistical significance. Coadministration of atorvastatin with terfenadine does not result in a clinically significant drug interaction. Because 80 mg is the highest atorvastatin dose used clinically, drug interactions mediated by CYP3A4 inhibition are unlikely in clinical practice.",1998.0,0,0 3372,9727666,"A decade of clinical trial developments in postmyocardial infarction, congestive heart failure, and sustained ventricular tachyarrhythmia patients: from CAST to AVID and beyond. Cardiac Arrhythmic Suppression Trial. Antiarrhythmic Versus Implantable Defibrillators.",G V Naccarelli; D L Wolbrette; J T Dell'Orfano; H M Patel; J C Luck,"Multiple trials using antiarrhythmic drugs, pharmacologic therapy, and implantable cardioverter defibrillators have been performed in an attempt to improve survival in patients: (1) postmyocardial infarction; (2) with congestive heart failure, with and without nonsustained ventricular tachycardia; and (3) with sustained ventricular tachycardia and those who have survived an out-of-hospital cardiac arrest. This article reviews some of the key findings and limitations of completed and ongoing trials. We also make recommendations for the current treatment of such patients based on the results of these trials.",1998.0,0,0 3373,9729143,Lovastatin for X-linked adrenoleukodystrophy.,I Singh; M Khan; L Key; S Pai,,1998.0,0,0 3374,9732899,Underutilization of lipid-lowering drugs in older persons with prior myocardial infarction and a serum low-density lipoprotein cholesterol > 125 mg/dl.,W S Aronow,A prospective study of 500 consecutive persons (aged 60 years with Q-wave myocardial infarction admitted to a long-term health care facility) investigated the prevalence of the use of a lipid-lowering drug at the time of admission in persons with a fasting serum low-density lipoprotein (LDL) cholesterol >125 mg/dl measured the day after admission. The prevalence of a lipid-lowering drug in persons with myocardial infarction and an LDL cholesterol >125 mg/dl was 7% (11 of 153 persons) in persons 60 to 80 years of age and 3% (6 of 182 persons) in persons 81 to 100 years of age.,1998.0,0,0 3375,9732913,Twenty-four more days.,M R Goldstein,,1998.0,0,0 3376,9738605,Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study.,R N Lemaitre; C D Furberg; A B Newman; S B Hulley; D J Gordon; J S Gottdiener; R H McDonald; B M Psaty,"To describe recent temporal patterns of cholesterol-lowering medication use and the characteristics that may have influenced the initiation of cholesterol-lowering therapy among those aged 65 years or older. A cohort of 5201 adults 65 years or older were examined annually between June 1989 and May 1996. We added 687 African American adults to the cohort in 1992-1993. We measured blood lipid levels at baseline and for the original cohort in the third year of follow-up. We assessed the use of cholesterol-lowering drugs at each visit. The prevalence of cholesterol-lowering drug use in 1989-1990 was 4.5% among the men and 5.9% among the women; these figures increased over the next 6 years to 8.1% and 10.0%, respectively, in 1995-1996. There was a 4-fold increase in the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors during the 6 years of follow-up, from 1.9% of all participants in 1989-1990 to 7.5% in 1995-1996. The use of bile acid sequestrants, nicotinic acid, and probucol declined from initial levels of less than 1% each. Among the participants who were untreated in 1989-1990, but eligible for cholesterol-lowering therapy after a trial of dietary therapy according to the 1993 guidelines of the National Cholesterol Education Panel, less than 20% initiated drug therapy in the 6 years of follow-up, even among subjects with a history of coronary heart disease. Among participants untreated at baseline but eligible for either cholesterol-lowering therapy or dietary therapy, initiation of cholesterol-lowering drug therapy was directly associated with total cholesterol levels, hypertension, and a history of coronary heart disease, and was inversely related to age, high-density lipoprotein cholesterol levels, and difficulties with activities of daily living. Other characteristics that form the basis of the 1993 National Cholesterol Education Panel guidelines-diabetes, smoking, family history of premature coronary heart disease, and total number of risk factors-were not associated with the initiation of cholesterol-lowering drug therapy. Given the clinical trial evidence for benefit, those aged 65 to 75 years and with prior coronary heart disease appeared undertreated with cholesterol-lowering drug therapy.",2001.0,0,0 3377,9738634,Withdrawal of Posicor from market.,R SoRelle,,1998.0,0,0 3378,9738637,"Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators.",P M Ridker; N Rifai; M A Pfeffer; F M Sacks; L A Moye; S Goldman; G C Flaker; E Braunwald,"We studied whether inflammation after myocardial infarction (MI) is a risk factor for recurrent coronary events and whether randomized treatment with pravastatin reduces that risk. A nested case-control design was used to compare C-reactive protein (CRP) and serum amyloid A (SAA) levels in prerandomization blood samples from 391 participants in the Cholesterol and Recurrent Events (CARE) trial who subsequently developed recurrent nonfatal MI or a fatal coronary event (cases) and from an equal number of age- and sex-matched participants who remained free of these events during follow-up (control subjects). Overall, CRP and SAA were higher among cases than control subjects (for CRP P=0.05; for SAA P=0.006) such that those with levels in the highest quintile had a relative risk (RR) of recurrent events 75% higher than those with levels in the lowest quintile (for CRP RR= 1.77, P=0.02; for SAA RR= 1.74, P=0.02). The study group with the highest risk was that with consistent evidence of inflammation (elevation of both CRP and SAA) who were randomly assigned to placebo (RR=2.81, P=0.007); this risk estimate was greater than the product of the individual risks associated with inflammation or placebo assignment alone. In stratified analyses, the association between inflammation and risk was significant among those randomized to placebo (RR=2.11, P=0.048) but was attenuated and nonsignificant among those randomized to pravastatin (RR=1.29, P=0.5). Evidence of inflammation after MI is associated with increased risk of recurrent coronary events. Therapy with pravastatin may decrease this risk, an observation consistent with a nonlipid effect of this agent.",1998.0,0,0 3379,9739497,Therapy and clinical trials.,R Cramb,,1998.0,0,0 3380,9741509,"Treating patients with documented atherosclerosis to National Cholesterol Education Program-recommended low-density-lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin and simvastatin.",A S Brown; R G Bakker-Arkema; L Yellen; R W Henley; R Guthrie; C F Campbell; M Koren; W Woo; R McLain; D M Black,"This study compared the efficacy and safety of atorvastatin, fluvastatin, lovastatin, and simvastatin in patients with documented atherosclerosis treated to U.S. National Cholesterol Education Program (NCEP) recommended low-density-lipoprotein (LDL) cholesterol concentration (< or = 100 mg/dl [2.59 mmol/liter]). For patients with advanced atherosclerosis, NCEP recommends lipid-lowering drug therapy if LDL cholesterol remains > or = 130 mg/dl (3.36 mmol/liter). A total of 318 men or women with documented atherosclerosis and LDL cholesterol > or = 130 mg/dl (3.36 mmol/liter) and < or = 250 mg/dl (6.5 mmol/liter), and triglycerides < or = 400 mg/dl (4.5 mmol/liter) participated in this 54-week, multicenter, open-label, randomized, parallel-group, active-controlled, treat-to-target study. Patients were titrated at 12-week intervals until the LDL cholesterol goal was reached. Number of patients reaching target LDL cholesterol levels and dose to reach target were evaluated. At the starting doses, atorvastatin 10 mg produced significantly greater decreases (p < 0.05) in plasma LDL cholesterol than the other treatments. Subsequently, the percentage of patients reaching goal at the starting dose was 32% for atorvastatin, 1% for fluvastatin, 10% for lovastatin and 22% for simvastatin. Atorvastatin-treated patients required a lower median dose than other treatments. Median doses at week 54 with the last available visit carried forward were atorvastatin 20 mg/day, fluvastatin 40 mg/day + colestipol 20 g/day, lovastatin 80 mg/day, simvastatin 40 mg/day. A significantly greater number (p < 0.05) of patients with confirmed atherosclerosis treated with atorvastatin reached the target LDL cholesterol concentration at the starting dose than patients treated with fluvastatin or lovastatin, and significantly fewer (p < 0.05) patients treated with atorvastatin required combination therapy with colestipol to achieve target LDL cholesterol concentrations than all other statins tested.",2001.0,1,1 3381,9757381,,,,,0,0 3382,9758309,The role of troglitazone in treating the insulin resistance syndrome.,M C Granberry; E F Schneider; V A Fonseca,"Insulin resistance is characterized by impaired responsiveness to endogenous or exogenous insulin and often results in the insulin resistance syndrome, a clustering of cardiovascular risk factors that includes abdominal obesity, hypertension, dyslipidemia, glucose intolerance, and hyperinsulinemia. Although the mechanism responsible for insulin resistance has not been completely defined, it is likely due to defective insulin receptor signaling and results in decreased use of glucose. Troglitazone, the first in a new class of drugs, directly decreases insulin resistance by improving insulin-mediated glucose disposal and reduces plasma insulin concentrations. Glycemic control achieved with troglitazone monotherapy is equivalent to that with sulfonylurea and metformin, and when combined with these agents offers additional plasma glucose reduction. Studies are necessary to determine the effect of thiazolidinediones on morbidity and mortality of patients with type 2 diabetes and insulin resistance.",1998.0,0,0 3383,9759748,Atorvastatin and gemfibrozil for protease-inhibitor-related lipid abnormalities.,K Henry; H Melroe; J Huebesch; J Hermundson; J Simpson,,1998.0,0,0 3384,9761083,Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia.,J R Guyton; A C Goldberg; R A Kreisberg; D L Sprecher; H R Superko; C M O'Connor,"We performed a multicenter, open-label study to determine the long-term safety and efficacy of a new extended-release once-a-night niacin preparation, Niaspan, in the treatment of hypercholesterolemia. Niaspan, 0.5 to 3.0 g once a night at bedtime, was used alone or in combination with a statin (inhibitor of hydroxymethylglutaryl coenzyme A reductase), a bile acid sequestrant, or both. Patients included 269 hypercholesterolemic male and female adults enrolled in a 96-week study, and 230 additional adults for whom short-term safety data were available. The dosages of Niaspan attained by 269 patients were 1,000 mg (95% of patients), 1,500 mg (86%), and 2,000 mg (65%). After 48 weeks of treatment, Niaspan alone (median dose 2,000 mg) reduced low-density lipaprotein (LDL) cholesterol (18%), apolipoprotein B (15%), total cholesterol (11%), triglycerides (24%), and lipoprotein(a) (36%), and increased high-density lipoprotein (HDL) cholesterol (29%). Niaspan plus a statin lowered LDL cholesterol (32%), apolipoprotein B (26%), total cholesterol (23%), triglycerides (30%), and lipoprotein(a) (19%), and increased HDL cholesterol (26%). Reversible elevations of aspartate aminotransferase or alanine aminotransferase more than twice the normal range occurred in 2.6% of patients. One patient discontinued Niaspan because of transaminase elevations. Intolerance to flushing, leading to discontinuation of Niaspan, occurred in 4.8% of patients. The overall rate of discontinuance due to flushing in this study combined with 2 previous randomized trials was 7.3%. In the long-term treatment of hypercholesterolemia, Niaspan produced favorable changes in LDL and HDL cholesterol, triglycerides, and lipoprotein(a). Adverse hepatic effects were minor and occurred at rates similar to those reported for statin therapy.",1998.0,0,0 3385,9762380,Update on drug interactions with azole antifungal agents.,B M Lomaestro; M A Piatek,"To review and update the incidence, mechanism, and clinical relevance of drug interactions with itraconazole, ketoconazole, and fluconazole. Literature was identified by MEDLINE search (from January 1990 to May 1997) using the name of each antifungal and the term ""interaction"" as MeSH headings. Abstracts were identified by literature citation and by review of Interscience Conference on Antimicrobial Agents and Chemotherapy from 1995 to 1996. Randomized, controlled, double-blind studies were emphasized; however, uncontrolled studies and case reports were also included. In vitro data were selected from literature review and citations. Data were evaluated with respect to study design, clinical relevance, magnitude of interaction, and recommendations provided. The incidence of fungal infections and consequent azole antifungal usage continues to increase. By virtue of their antifungal mechanism (i.e., inhibition of cytochrome P450 fungal enzyme systems), azoles have been investigated and implicated in several drug interactions. The magnitude of interactions can vary from trivial to potentially fatal, and also vary with specific azole and interactant. The azole antifungal agents represent a commonly used class of agents with a broad range of potential interactions. Recent data have increased our understanding of drug--drug interactions with azoles. Pharmacists are in a unique position to identify these interactions and to intervene to decrease their morbidity and improve patient care.",1998.0,0,0 3386,9763118,Vasomotor tone and the role of nitric oxide.,C E Fields; R G Makhoul,"Vasomotor tone is the end result of a complex set of interactions that control relaxation and contraction of blood vessels. The critical role of nitric oxide (NO) in modulating vasomotor tone has become increasingly apparent over the last 15 years. A phenomenal amount of resources have been invested in the study of this simple molecule, and the volume of scientific literature that has resulted is astounding. In this review, we discuss the pertinent physiology and biochemistry of NO as it relates to the control of vasomotor tone. Methods of measuring NO in basic science and clinical settings are outlined, and the derangements of endothelial NO production and release (endothelial dysfunction) in pathophysiologic and disease states are discussed. Finally, potential therapies aimed at preserving endothelial function and augmenting NO production also are reviewed.",1998.0,0,0 3387,9764046,Arterial or venous conduits for redo coronary artery bypass grafting?,D P Taggart,,1998.0,0,0 3388,9766701,The search for novel antiarrhythmic strategies. Sicilian Gambit.,,"The past fifty years of antiarrhythmic drug development have seen limited success in prolonging life and reducing morbidity. It is likely that arrhythmias are in most instances final common pathways through which changes in the cardiac substrate and in trigger mechanisms are expressed. We propose that the development and administration of therapies for the arrhythmias themselves, while offering a panacea for a disease entity that has evolved and is being overtly manifested, is also an admission of failure to identify and prevent evolution of the substrate and triggers such that arrhythmias can occur. We suggest that while strategies for treatment and prevention of recurrence of arrhythmias still warrant exploration, greater hope for the future lies in identifying means for earlier diagnosis of the arrhythmogenic substrate and triggers, and in developing therapies that are ""upstream"" to the arrhythmia and prevent their initial expression. Means to achieve this end are suggested, using specific arrhythmias as examples. Similarly, to increase the likelihood that clinical studies of new therapies can be successfully concluded and interpreted, we suggest new approaches to patient selection, risk stratification, trial endpoints, outcome events and trial methodologies.",1998.0,0,0 3389,9767373,,,,,0,0 3390,9773745,"American Diabetes Association Annual Meeting, 1998: cardiac disease and related topics.",Z T Bloomgarden,,1998.0,0,0 3391,9777289,Familial defective apolipoprotein B-100.,P S Hansen,"Abnormal interaction between low density lipoprotein receptors (LDLR) and their ligands, apolipoprotein E and B, causes decreased catabolism of lipoproteins which carry these apolipoproteins (VLDL, IDL and/or LDL) and thereby increased plasma concentrations of these. In familial hypercholesterolemia (FH), abnormal interaction is due to mutations in the LDLR gene, and in type III hyperlipidemia due to mutations in the apo E gene. A few mutations in the apolipoprotein B (apo B) gene have been described, of which the apo B-3,500Arg-Gln seems by far the most frequent, that causes defective binding to normal LDLR. The metabolic disorder associated with these mutations has been named familial defective apolipoprotein B-100 (FDB). The frequency of the apo B-3,500Arg-Gln mutation is particularly high in Central Europe (Switzerland) with lower frequencies south of the Alpes, in Russia and in Scandinavia. We found an incidence of 1/1250 of the mutation in Denmark (III), employing a DNA based assay optimized to allow detection of the mutation in very small amounts of DNA (I). Since other mutations in the receptor binding domain of the apo B-100 have been described, we developed another DNA based assay, employing DGGE technique, to screen for other mutations in the region of amino acid 3,456 to 3,553 (II). However, no other mutations but the apo B-3,500Arg-Gln have so far been detected in Danish hypercholesterolemic patients. In a study of 5 Danish families with FDB (46 heterozygous FDB patients and 57 unaffected relatives) we found that FDB patients had significantly increased mean cholesterol and LDL cholesterol concentrations, but with a wide range of variation and with approximately 30% having cholesterol concentrations below the 95th percentile for the general population (IV). This was confirmed in a compilation of data on 205 FDB patients from the Netherlands, Germany and Denmark (V). In this study we also compared the biochemical and clinical features of FDB with those of 101 Danish FH patients in whome FDB had been ruled out. Our data support, that the LDL cholesterol elevation is less pronounced in FDB than in FH and that the age-specific prevalence of atherosclerotic cardiovascular disease (CVD) is lower in FDB than in FH. In the compiled study of 205 FDB heterozygotes (V), we found that age, gender and genetic variation in the LDLR gene explained a considerable part of the between-individual variation in total and LDL cholesterol. We conducted a prospective study of the lipid lowering effect of pravastatin and gemfibrozil in 30 Danish FDB patients (VI). Together with other, retrospective, studies, we conclude that the cholesterol lowering effect of HMG-coA-reductase inhibitors, anion binding resins and nicotinic acid is fully comparable to that observed when treating FH patients and type IIa hypercholesterolemic patients, without clinical signs of FH.",1998.0,0,0 3392,9778197,Maximizing the cost-effectiveness of lipid-lowering therapy.,T A Jacobson; J R Schein; A Williamson; C M Ballantyne,"Cardiovascular disease, including coronary heart disease, is the leading cause of death both in men and in women in the United States. The purpose of this review is to describe the effectiveness of lipid-lowering therapy in reducing cardiovascular morbidity and mortality, which has recently been extended to patients with mild to moderate hypercholesterolemia, and the cost of providing therapy, which would be prohibitive if all persons with hypercholesterolemia received treatment. Cost-effectiveness analysis provides a rational means of allocating limited health care resources by allowing the comparison of the costs of lipid-lowering therapy, in particular, therapy with beta-hydroxy-beta-methylglutaryl-CoA (coenzyme A) reductase inhibitors (statins), with the costs of atherosclerosis that could be prevented by lowering cholesterol. To extend the benefits of treatment to the large number of persons not receiving therapy, we need to implement more cost-effective treatment by improving risk assessment, increasing treatment effectiveness, and reducing the cost of therapy.",1998.0,0,0 3393,9783644,Present status of HMG reductase inhibitors in treatment of dyslipidemia.,R B Kalmansohn; R W Kalmansohn; D L Schiff,"HMG reductase inhibitors have significant desirable effects on patients with dyslipidemia. Multiple factors are involved in these desirable effects. Other factors that might play a role in the risk of coronary artery disease are fibrinogen concentration, homocysteine, Lp (a), small dense LDL, insulin resistance, and infection with chlamydia. High-dose reductase inhibitors may be indicated in select patients. The ideal end point may be 150 mg/dL for adults.",1998.0,0,0 3394,9784451,From trial data to practical knowledge: qualitative study of how general practitioners have accessed and used evidence about statin drugs in their management of hypercholesterolaemia.,K Fairhurst; G Huby,"To explore how general practitioners have accessed and evaluated evidence from trials on the use of statin lipid lowering drugs and incorporated this evidence into their practice. To draw out the practical implications of this study for strategies to integrate clinical evidence into general medical practice. Qualitative analysis of semistructured interviews. General practices in Lothian. 24 general practitioners selected to obtain a heterogeneous sample. Respondents were generally aware of the evidence relating to the use of statins in secondary prevention of coronary heart disease, but they were less clear about the evidence in primary prevention. The benefits of statins in secondary prevention were clearer to them and the social and economic issues less complex than was the case for use in primary prevention. Respondents rarely said they appraised the methods and content of trials, rather they judged the trustworthiness of the source of trial evidence and interpreted it within the context of the economic and social factors which impinge on their practice. Moreover, trial data become relevant for routine practice only when underpinned by a consensus on these issues. Strategies to promote incorporation of evidence from clinical trials into everyday practice are likely to be effective if they tap into and build on the process of local consensus building. Strategies such as teaching critical appraisal skills and guideline development may have little effect if they are separated from this process.",1998.0,0,0 3395,9784452,Time trend analysis and variations in prescribing lipid lowering drugs in general practice.,C Baxter; R Jones; L Corr,,1998.0,0,0 3396,9787748,Hyperlipidemia and diabetes mellitus.,T O'Brien; T T Nguyen; B R Zimmerman,"The increased risk of coronary artery disease in subjects with diabetes mellitus can be partially explained by the lipoprotein abnormalities associated with diabetes mellitus. Hypertriglyceridemia and low levels of high-density lipoprotein are the most common lipid abnormalities. In type 1 diabetes mellitus, these abnormalities can usually be reversed with glycemic control. In contrast, in type 2 diabetes mellitus, although lipid values improve, abnormalities commonly persist even after optimal glycemic control has been achieved. Screening for dyslipidemia is recommended in subjects with diabetes mellitus. A goal of low-density lipoprotein cholesterol of less than 130 mg/dL and triglycerides lower than 200 mg/dL should be sought. Several secondary prevention trials, which included subjects with diabetes, have demonstrated the effectiveness of lowering low-density lipoprotein cholesterol in preventing death from coronary artery disease. The benefit of lowering triglycerides is less clear. Initial approaches to lowering the levels of lipids in subjects with diabetes mellitus should include glycemic control, diet, weight loss, and exercise. When goals are not met, the most common drugs used are hydroxymethylglutaryl coenzyme A reductase inhibitors or fibrates.",1998.0,0,0 3397,9790411,Aggressive lipid therapy in the statin era.,J A Farmer,"Aggressive cholesterol lowering with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor (statin) therapy has contributed to the substantial decrease in coronary heart disease (CHD) morbidity and mortality in recent years, as documented in a number of controlled clinical trials in both primary- and secondary-prevention patients. Although benefit was first established in patients with severe hypercholesterolemia, more recent trials have extended the benefit to patients with mildly to moderately elevated cholesterol. In addition to improvements on the lipid profile, statins appear to confer nonlipid benefits, such as improved endothelial function, modification of plaque cellularity, and plaque stabilization.",1998.0,0,0 3398,9790412,"Treatment strategies for management of serum lipids: lessons learned from lipid metabolism, recent clinical trials, and experience with the HMG CoA reductase inhibitors.",M Rubenfire; A T Coletti; L Mosca,"The Adult Treatment Panel (ATP) guidelines, published initially in 1988 and revised in 1993, are based on sentinel observations and early clinical trials in support of treating and preventing coronary artery disease by cholesterol lowering. With the conclusion of several large long-term trials using HMG CoA reductase inhibitors for primary and secondary coronary prevention, the ATP II recommendations, which remain remarkably accurate, can be supplemented with more evidence-based strategies. Increasing evidence suggests that thoughtful lipid management for coronary prevention should include a more complete assessment of lipoproteins with an emphasis on apolipoproteins, triglycerides, and very low-density (VLDL) remnant particles, LDL particle size, and lipoprotein(a). This review summarizes clinically relevant lipid metabolism with an emphasis on the concept of atherogenic plasma lipids, discusses the clinical benefits and specific uses of each of the lipid-lowering drug classes, and provides an analysis of recent cholesterol-lowering primary and secondary coronary prevention trials from which a new treatment strategy can be derived.",1998.0,0,0 3399,9790415,Defining specific goals of therapy in treating dyslipidemia in the patient with low high-density lipoprotein cholesterol.,L M Belalcazar; C M Ballantyne,"Because patients with low high-density lipoprotein (HDL) cholesterol (HDL-C) are at high risk for clinical coronary artery disease (CAD) events, these patients require aggressive treatment with lifestyle modifications-increased exercise, smoking cessation, and weight loss in overweight patients-and available pharmacological agents. Drugs that raise HDL-C include nicotinic acid, fibric acid derivatives, estrogens, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), alpha-blockers, and alcohol. However, all agents that increase HDL-C may not have the same clinical benefit, just as, as shown in genetic studies in humans and mice, genetic causes of high HDL-C do not always protect against CAD, nor do genetic causes of low HDL-C always increase risk for CAD. Better understanding of the complexities of HDL metabolism and the mechanisms by which HDL protects against CAD is needed to enable the development of new therapeutic strategies--novel drugs or gene delivery systems--to increase HDL-C and reduce CAD events. The statins are the agents with the greatest evidence for slowing progression of CAD and reducing clinical events in patients with low HDL-C, but additional research is needed to determine the potential benefits of additional interventions that increase HDL-C, including combination therapy, which may provide greater improvements in the entire lipid profile.",1998.0,0,0 3400,9792257,"Usual care dietary practice, achievement and implications for medication in the management of hypercholesterolaemia. Data from the U.K. Lipid Clinics Programme.",P F Butowski; A F Winder,"To evaluate long-term responses to cholesterol-lowering diets in usual care and their associations with responses to lipid medication. Analysis of paired data from the U.K. Lipid Clinics Programme computerized database for lipid responses, and associations of weight loss with later response to medication, plus analysis of a questionnaire on clinic dietary practice. Cholesterol, predominantly as low density lipoprotein was reduced in 60% of 2508 patients entered, and maintained long-term. Moderate 5-7% average responses incorporated reductions of at least 0.6 mmol x (-1) in 40% of patients, consistent with a 25% fall in the risk of cardiac events if maintained for 2 years. Responses to medication were greater for up to 2194 patients who previously lost weight on diet, an effect not apparent for 291 patients on statins alone. Physicians worked with dieticians in most clinics, and with individually tailored diets but with incomplete appreciation of the differences between available dietary protocols. Usual care dietary advice can be effective in lipid management, weight loss is important and associates with greater responses to lipid medication although statin monotherapy may not be affected. However, average responses are modest and physicians are not well informed of the dietary principles involved.",1998.0,0,0 3401,9793596,Atorvastatin in the treatment of primary hypercholesterolemia and mixed dyslipidemias.,H S Yee; N T Fong,"To review the efficacy and safety of atorvastatin in the treatment of dyslipidemias. A MEDLINE search (January 1960-April 1998), Current Contents search, additional references listed in articles, and unpublished data obtained from the manufacturer were used to identify data from scientific literature. Studies evaluating atorvastatin (i.e., abstracts, clinical trials, proceedings, data on file with the manufacturer) were considered for inclusion. English-language literature was reviewed to evaluate the pharmacology, pharmacokinetics, therapeutic use, and adverse effects of atorvastatin. Additional relevant citations were used in the introductory material and discussion. Open and controlled animal and human clinical studies published in the English-language literature were reviewed and evaluated. Clinical trials selected for inclusion were limited to those in human subjects and included data from animals if human data were not available. Atorvastatin is a recent hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor for the treatment of primary hypercholesterolemia, mixed dyslipidemias, and homozygous familial hypercholesterolemia. In patients who have not met the low-density lipoprotein cholesterol (LDL-C) goal as recommended by the National Cholesterol Education Program Adult Treatment Panel II guidelines, atorvastatin 10-80 mg/d may be used as monotherapy or as an adjunct to other lipid-lowering agents and dietary modifications. In placebo-controlled clinical trials, atorvastatin 10-80 mg/d lowered LDL-C by 35-61% and triglyceride (TG) concentrations by 14-45%. In comparative trials, atorvastatin 10-80 mg/d showed a greater reduction of serum total cholesterol (TC), LDL-C, TG concentrations, and apolipoprotein B-100 (apo B) compared with pravastatin, simvastatin, or lovastatin. In comparison, currently available HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin) lower LDL-C concentrations by approximately 20-40% and TG concentrations by approximately 10-30%. In pooled placebo-controlled clinical trials of up to a duration of 52 weeks, atorvastatin in dosages up to 80 mg/d appeared to be well tolerated. The most common adverse effect of atorvastatin was gastrointestinal upset. The incidence of elevated serum hepatic transaminases may be greater at higher dosages of atorvastatin. The risk of myopathy and/or rhabdomyolysis is increased when an HMG-CoA reductase inhibitor is taken concomitantly with cyclosporine, gemfibrozil, niacin, erythromycin, or azole antifungals. Atorvastatin appears to reduce TC, LDL-C, TG concentrations, and apo B to a greater extent than do currently available HMG-CoA reductase inhibitors. Atorvastatin may be preferred in patients requiring greater than a 30% reduction in LDL-C or in patients with both elevated LDL-C and TG concentrations, which may obviate the need for combination lipid-lowering therapy. Adverse effects of atorvastatin appear to be similar to those of other HMG-CoA reductase inhibitors and should be routinely monitored. Long-term safety data (> 1 y) on atorvastatin compared with other HMG-CoA reductase inhibitors are still needed. Cost-effectiveness studies comparing atorvastatin with other HMG-CoA reductase inhibitors remain a subject for further investigation. Published clinical studies evaluating the impact of atorvastatin on cardiovascular morbidity and mortality are still needed. Additionally, clinical studies evaluating the impact of lipid-lowering therapy in a larger number of women, the elderly (> 70 y), and patients with diabetes for treatment of primary and secondary prevention of coronary heart disease are needed.",1998.0,0,0 3402,9801932,Effect of HMG-CoA reductase inhibitors on plasma polyunsaturated fatty acid concentrations in patients with hyperlipidemia.,N Nakamura; T Hamazaki; H Jokaji; S Minami; M Kobayashi,"We investigated the effect of 12 months' HMG-CoA reductase inhibitor treatment on plasma polyunsaturated fatty acid concentrations in 19 patients with hyperlipidemia. Arachidonic acid concentrations were significantly increased following treatment (from 110.1 +/- 20.4 mg/l to 129.2 +/- 31.6 mg/l, P < 0.05). The ratio of eicosapentaenoic acid to arachidonic acid was significantly decreased at the end of 12 months' treatment (from 0.702 +/- 0.370 to 0.541 +/- 0.204, P < 0.05). These results suggest that HMG-CoA reductase inhibitors may increase the synthesis of metabolites from arachidonic acid in patients with hyperlipidemia, and that the addition of fish oil is more effective for the prevention of coronary heart disease than HMG-CoA reductase inhibitors alone.",1998.0,0,0 3403,9804052,Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar?,U Christians; W Jacobsen; L C Floren,"3-Hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.88) inhibitors are the most effective drugs to lower cholesterol in transplant patients. However, immunosuppressants and several other drugs used after organ transplantation are cytochrome P4503A (CYP3A, EC 1.14.14.1) substrates. Pharmacokinetic interaction with some of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, specifically lovastatin and simvastatin, leads to an increased incidence of muscle skeletal toxicity in transplant patients. It is our objective to review the role of drug metabolism and drug interactions of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin. In the treatment of transplant patients, from a drug interaction perspective, pravastatin, which is not significantly metabolized by CYP enzymes, and fluvastatin, presumably a CYP2C9 substrate, compare favorably with the other statins for which the major metabolic pathways are catalyzed by CYP3A.",1998.0,1,1 3404,9806100,Are there potential non-lipid-lowering uses of statins?,D C Wheeler,"Recent clinical trials have demonstrated beyond doubt that statins are effective in the prevention of acute coronary events. Critical analysis of these studies suggests that the benefits of statin therapy cannot be fully explained on the basis of reductions in plasma cholesterol levels. Accumulating knowledge of the actions of these drugs shows that they may prevent several processes that eventually lead to plaque rupture and the development of occlusive thrombosis, the basis of acute coronary events. Hence, statins may correct endothelial dysfunction (thus protecting against ischaemic injury), stabilise existing plaques and modify the coagulation pathway, thereby reducing the likelihood of a sudden vascular event. At a cellular level, these drugs inhibit the synthesis not just of cholesterol, but of other compounds important in cell proliferation. Antiproliferative effects have been demonstrated in vitro and may broaden the applications of statins to the treatment of noncardiovascular diseases. Finally, preliminary clinical studies indicate that as a result of immunosuppressive actions, statins may reduce the incidence of rejection following organ transplantation.",1998.0,0,0 3405,9807971,Short-term efficacy and tolerability of combination therapy with lovastatin and acipimox in Chinese patients with type 2 diabetes mellitus and mixed dyslipidemia.,G T Ko; T W Mak; V T Yeung; D C Chan; C W Lam; L W Tsang; C C Chow; C S Cockram,"In type 2 diabetes, it is not uncommon to find an elevated serum triglyceride and/or reduced high-density lipoprotein (HDL) cholesterol levels; elevated total cholesterol levels often occur as well. To evaluate the short-term efficacy and tolerability of combination therapy with lovastatin and acipimox in Chinese patients with type 2 diabetes who have mixed dyslipidemia, an open-label 6-month trial was conducted. All patients had type 2 diabetes (n = 33) with total cholesterol > or = 6.2 mmol/L and fasting triglyceride > or = 2.8 mmol/L, which had been confirmed twice and persisted for at least 12 weeks after introduction of diet control. After a 4-week run-in period, they were given lovastatin 40 mg daily at night for 12 weeks. Acipimox 250 mg three times a day was then added for a further 12 weeks. After 12 weeks of treatment with lovastatin alone, improvement was observed in total cholesterol (21% reduction), triglyceride (32% reduction), low-density lipoprotein (LDL) cholesterol (5.5% reduction), HDL cholesterol (11.6% elevation), apolipoprotein A-I (4.6% elevation), and apolipoprotein B (20.5% reduction). The addition of acipimox to lovastatin for an additional 12 weeks further reduced serum total cholesterol, triglyceride, LDL cholesterol, and apolipoprotein B, but this additional decrease was not statistically significant. However, HDL cholesterol and apolipoprotein A-I levels were significantly increased by the addition of acipimox (a 14.2% and 9.0% elevation, respectively). Serum creatine phosphokinase increased slightly after 12 weeks of lovastatin but decreased to a concentration similar to baseline after 12 weeks of combination treatment. No patients reported muscle pain or weakness or other side effects. Combination treatment with lovastatin and acipimox appears to be a safe and effective therapy in patients with type 2 diabetes and mixed dyslipidemia, and has particular benefit in elevating serum HDL cholesterol and apolipoprotein A-I levels.",1998.0,0,0 3406,9808592,How do we best treat patients with ischemic heart disease?,C J Pepine; P C Deedwania,,1998.0,0,0 3407,9809932,The effect of hormone replacement therapy alone and in combination with simvastatin on plasma lipids of hypercholesterolemic postmenopausal women with coronary artery disease.,E Sbarouni; Z S Kyriakides; ,"This study sought to compare hormone replacement therapy (HRT), simvastatin and their combination in the management of hypercholesterolemia in postmenopausal women with coronary artery disease (CAD). Lipid-lowering therapy reduces mortality in hypercholesterolemic women with CAD. In postmenopausal women HRT seems to increase survival, particularly those with ischemic heart disease, and this is partly due to changes in lipid levels. We studied 16 postmenopausal women with CAD and fasting total cholesterol <200 mg/dl and low-density lipoprotein (LDL) cholesterol <130 mg/dl. We compared HRT (0.625 mg of conjugated estrogen and 2.5 mg of medroxyprogesterone acetate daily) with simvastatin (20 mg daily) and their combination in a randomized, crossover, placebo-controlled study. Each treatment period was 8 weeks long with a 4-week washout interval between treatments. Simvastatin, HRT and their combination significantly reduced total and LDL cholesterol by 35%, 13%, and 33% and 45%, 20%, and 46%, respectively, compared to placebo (p < 0.001). However, simvastatin and the combination was superior to HRT (p < 0.001), and none of our patients had total cholesterol <180 mg/dl and LDL cholesterol <100 mg/dl on HRT alone. High-density lipoprotein cholesterol was not significantly affected by any of the active treatments, and triglycerides were lower during simvastatin therapy compared to placebo (p < 0.01). Apolipoprotein B was significantly reduced by simvastatin, alone and combined with HRT, by 39% and 35%, respectively, compared to placebo (p < 0.001). Alone and in combination with simvastatin, HRT significantly increased apolipoprotein A-I by 11% and 12%, respectively, compared to placebo (p < 0.05) and decreased lipoprotein (a) by 23% and 33%, respectively, compared to placebo (p < 0.05), whereas simvastatin had no significant effect on either of these parameters. In hypercholesterolemic postmenopausal women with CAD, HRT exerts beneficial effects on plasma lipids but the levels currently recommended for secondary prevention are not achieved. Hormone replacement therapy combined with simvastatin is well tolerated and extremely effective, as the two therapies seem to be additive.",1998.0,0,0 3408,9812207,Hyperlipidaemia and cardiovascular disease.,A V Sussekov,,1998.0,0,0 3409,9812209,Therapy and clinical trials.,P S Bachorik,,1998.0,0,0 3410,9816194,"Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer.",A Thibault; D Samid; A C Tompkins; W D Figg; M R Cooper; R J Hohl; J Trepel; B Liang; N Patronas; D J Venzon; E Reed; C E Myers,"Lovastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (the major regulatory enzyme of the mevalonate pathway of cholesterol synthesis), displays antitumor activity in experimental models. We therefore conducted a Phase I trial to characterize the tolerability of lovastatin administered at progressively higher doses to cancer patients. From January 1992 to July 1994, 88 patients with solid tumors (median age, 57 +/- 14 years) were treated p.o. with 7-day courses of lovastatin given monthly at doses ranging from 2 to 45 mg/kg/day. The inhibitory effects of lovastatin were monitored through serum concentrations of cholesterol and ubiquinone, two end products of the mevalonate pathway. Concentrations of lovastatin and its active metabolites were also determined, by bioassay, in the serum of selected patients. Cyclical treatment with lovastatin markedly inhibited the mevalonate pathway, evidenced by reductions in both cholesterol and ubiquinone concentrations, by up to 43 and 49% of pretreatment values, respectively. The effect was transient, however, and its magnitude appeared to be dose independent. Drug concentrations reached up to 3.9 micrometer and were in the range associated with antiproliferative activity in vitro. Myopathy was the dose-limiting toxicity. Other toxicities included nausea, diarrhea, and fatigue. Treatment with ubiquinone was associated with reversal of lovastatin-induced myopathy, and its prophylactic administration prevented the development of this toxicity in a cohort of 56 patients. One minor response was documented in a patient with recurrent high-grade glioma. Lovastatin given p.o. at a dose of 25 mg/kg daily for 7 consecutive days is well tolerated. The occurrence of myopathy, the dose-limiting toxicity, can be prevented by ubiquinone supplementation. To improve on the transient inhibitory activity of this dosing regimen on the mevalonate pathway, alternative schedules based on uninterrupted administration of lovastatin should also be studied.",1998.0,0,0 3411,9816550,"The effect of cholesterol reduction with fluvastatin on aortic compliance, coronary calcification and carotid intimal-medial thickness: a pilot study.",S M Forbat; R P Naoumova; P S Sidhu; C Neuwirth; M MacMahon; G R Thompson; S R Underwood,"Regression of atheroma with reduction of cholesterol levels is recognized to occur, but less is known about reversal of sclerosis. Non-invasive indices of sclerosis have largely been based on carotid ultrasound measurements. To measure aortic compliance, coronary calcification and carotid intimal-medial thickness during reduction of cholesterol level in patients with and without coronary artery disease. We studied 64 hypercholesterolaemic patients, 24 with and 40 without coronary artery disease. All were administered fluvastatin for 1 year. Aortic compliance was assessed using magnetic resonance and coronary calcification score was determined by electron beam computed tomography. Carotid intimal-medial thickness in 34 patients was measured by carotid ultrasound means. There was a rise in high-density lipoprotein cholesterol level and falls in total cholesterol level, low-density lipoprotein cholesterol level, low: high-density lipoprotein ratio, triglyceride level and very-low-density lipoprotein cholesterol level. Coronary artery disease patients had a higher coronary calcification score (442 +/- 551) than did other patients (269 +/- 724, P = 0.0002). For both groups there was a small rise in coronary calcification score during the study. Mean aortic compliance rose and blood pressure and carotid intimal-medial thickness fell. Analysis revealed significant correlations between change in mean aortic compliance and changes in high-density lipoprotein level (r = 0.3, P = 0.036), very-low-density lipoprotein level (r = -0.31, P = 0.038) and low: high-density lipoprotein ratio (r = -0.35, P = 0.014). There was no significant difference in these changes between the two patient groups. An improvement in aortic compliance over 1 year indicates that increase in high-density lipoprotein level, decrease in very-low-density lipoprotein level and improvement in low: high-density lipoprotein ratio caused by administration of fluvastatin beneficially influenced vascular pathophysiology in hypercholesterolaemic patients with and without coronary artery disease. In those patients studied with carotid ultrasound means, carotid intimal-medial thickness decreased from 1.09 to 0.87 mm (P = 0.004), corroborating these results.",1998.0,0,0 3412,9820992,Differences in the treatment of coronary heart disease between countries as revealed in the Scandinavian Simvastatin Survival Study (4S),O Faergeman; J Kjekshus; T Cook; K Pyörälä; L Wilhelmsen; G Thorgeirsson; T R Pedersen,"To assess differences in treatment of ischaemic heart disease in the Scandinavian countries. The Scandinavian Simvastatin Survival Study (4S) lasted 5.4 years and showed that death rates in 4444 patients with coronary heart disease were 30% lower in those treated with simvastatin to lower serum cholesterol than in those given placebo. Apart from this main result, the 4S provided detailed information on rates of death and other manifestations of coronary heart disease, as well as on use of non-lipid forms of therapy. There were substantial differences in 4S placebo group rates of mortality, coronary deaths and major coronary events between countries. Surgical and medical therapy varied importantly between countries. Major inter-country differences in rates of death and myocardial infarction in patients with coronary heart disease were likely to be due to a composite of differences in baseline characteristics including smoking. They occurred in a setting of very uneven exploitation of the potential for improving survival of patients with ischaemic heart disease.",1998.0,0,0 3413,9822090,Coronary stenting in cardiac allograft vasculopathy.,S P Jain; S R Ramee; C J White; M R Mehra; H O Ventura; S Zhang; J S Jenkins; T J Collins,"The purpose of this study was to evaluate acute angiographic success, in-hospital complications and long-term outcome after intracoronary stenting in patients with cardiac allograft vasculopathy. The application of conventional interventional modalities to treat discrete lesions in patients with cardiac allograft vasculopathy is associated with higher procedural morbidity, mortality and higher restenosis compared to atherosclerotic coronary artery disease. Elective coronary stenting has been shown to lower restenosis rates and improve long-term outcome in selected patients with native coronary artery disease; however, its safety and efficacy in reducing restenosis in patients with cardiac allograft vasculopathy is unknown. Ten patients with 19 discrete lesions in a major coronary artery without diffuse distal disease underwent intracoronary stenting using Palmaz-Schatz stents. The average stent size was 3.4 mm, and the stent/artery ratio was 0.99+/-0.07. Eight of ten (80%) patients received antiplatelet therapy (aspirin plus ticlopidine) only. Procedural success was 100% with no in-hospital stent thrombosis, Q-wave myocardial infarction or death. Minimal luminal diameter increased from 0.83+/-0.38 mm to 3.23+/-0.49 mm after stenting. Diameter stenosis decreased from 74.91+/-11.52% to 5.90+/-4.09% after stenting. Follow-up angiography was performed in 8 of 10 (80%) patients and 16 of 19 (84%) lesions. Target lesion revascularization was required in 2 of 10 (20%) patients and 3 of 16 (19%) lesions. Allograft survival was 7 of 10 (70%) at the end of 22+/-11 months follow-up. Intracoronary stenting can be performed safely with excellent angiographic success in selected patients with cardiac allograft vasculopathy. The restenosis rate appears to be low despite the aggressive nature of the disease. A multicenter study with a larger number of patients is required to assess its efficacy in reducing restenosis and improving allograft survival.",1998.0,0,0 3414,9822880,Antithrombotic therapy and venous graft disease.,A E Schussheim; V Fuster,"Venous graft disease is a thromboproliferative process and places a serious limitation on the symptom-free survival of patients after coronary artery bypass grafting. The efficacy of antithrombotics, especially during the first year after surgery, is suggested by an understanding of the four described phases of disease development. Studies examining the usefulness of hemostatic factors, such as lipoprotein (a) and fibrinogen, in identifying patients at added risk for graft occlusion are reviewed. Aspirin begun within the first day after surgery remains the mainstay of current preventive therapy, but the potential for other antiplatelet agents alone or in combination is explored. In a two-by-two trial, the efficacy of low-dose oral anticoagulation with warfarin (Coumadin) was equivocal. Aggressive cholesterol reduction decreased progression and need for revascularization by 30%. Future examinations are needed to define the optimal intensity and timing of therapy and to explore the role of newer, more potent antithrombotic agents.",1998.0,0,0 3415,9823789,Advances in the medical management of acute coronary syndromes.,C P Cannon,"Many advances in the treatment of acute coronary syndromes have been realized over recent years. In ST elevation myocardial infarction, new aggressive thrombolytic regimens improve early reperfusion and improve survival. The current focus is on bolus thrombolysis, glycoprotein IIb/IIIa inhibition, and low-molecular-weight heparin as adjuncts. In unstable angina and non-ST elevation myocardial infarction, two major advances are IIb/IIIa inhibition and low-molecular-weight heparin, each of which significantly improves the outcome of patients and which have just been approved for use by the Food and Drug Administration. Following acute coronary syndromes, cholesterol lowering with statin drugs has a major effect, even in the large group of patients with average cholesterol levels. Use of clopidogrel, a more potent antiplatelet agent than aspirin, appears to decrease recurrent ischemic events, which has highlighted the potential benefits of oral IIb/IIIa inhibitors, which are much more potent antiplatelet agents. An additional focus has been on ensuring that patients actually receive the currently available medications. With a great number of new medical treatments, the outcome of patients with acute coronary syndromes has improved and will continue to improve as we enter the next millennium.",1998.0,0,0 3416,9825949,Drug interactions of lipid-altering drugs.,H E Bays; C A Dujovne,"The use of lipid-altering drugs has been shown to reduce the progression of atherosclerotic lesions and reduce the risk of atherosclerotic events (such as myocardial infarction and stroke). In general, these lipid-altering drugs are well tolerated but there is the potential for drug interactions. For example, HMG-CoA reductase inhibitors may interact with macrolides, azalides, azole antifungals and cyclosporin. Resins (such as cholestyramine and colestipol) may impair the absorption of many concurrent medications. Fibrates have potential drug interactions with warfarin, furosemide (frusemide), oral hypoglycaemics and probenecid. Nicotinic acid (niacin) may have potential drug interactions with high dose aspirin (acetylsalicylic acid), uricosuric agents (such as sulfapyrazone) and alcohol (ethanol). Finally, probucol may have potential drug interactions with antidysrhythmics, tricyclic antidepressants and phenothiazines. In addition, lipid-altering drugs, used in combination, may have the potential for drug interactions, enhancing some of the risks of adverse effects, such as myositis and hepatotoxicity. Therefore, in order to use lipid-altering drugs in the most effective, and safest manner, it is important for the clinician to have an understanding of the mechanisms of potential drug interactions, which drug interactions may theoretically occur, and specifically, which spe cific drug interactions have already been described.",1998.0,1,1 3417,9826956,Regaining perspective in weight management.,L Kuritzky,,1998.0,0,0 3418,9826960,Detecting and correcting hyperlipidemia.,R R Hall,"The dangers of elevated serum cholesterol levels--and in particular, of increased concentrations of small, dense lipoproteins--have been fully delineated. Although effective therapies are available, too many physicians fail to look for hypercholesterolemia, or fail to treat it effectively. Adhering to therapeutic guidelines and encouraging patient compliance can be lifesaving.",1998.0,0,0 3419,9830386,The short life and rapid death of a novel antihypertensive and antianginal agent.,H Krum; J J McNeil,,1998.0,0,0 3420,9834769,"Treating to meet NCEP-recommended LDL cholesterol concentrations with atorvastatin, fluvastatin, lovastatin, or simvastatin in patients with risk factors for coronary heart disease.",D Hunninghake; R G Bakker-Arkema; J P Wigand; M Drehobl; H Schrott; J L Early; P Abdallah; S McBride; D M Black,"Our study compared use of atorvastatin, fluvastatin, lovastatin, and simvastatin for lowering low-density lipoprotein (LDL) cholesterol concentration in patients at risk for coronary heart disease (CHD). The goal was to reach the LDL cholesterol levels recommended by the National Cholesterol Education Program (NCEP). A combined total of 344 men and women took part in this 54-week, multicenter, open-label, randomized, parallel-group, active-controlled, treat-to-target study. Patients were selected on the basis of their LDL cholesterol concentration and their risk for CHD. During treatment, doses were titrated at 12-week intervals to a maximum of 80 mg per day of atorvastatin and lovastatin, or 40 mg per day of fluvastatin and simvastatin, with colestipol added if necessary to attain the NCEP-recommended LDL cholesterol concentration. At the starting dose, atorvastatin decreased plasma LDL cholesterol significantly (P < .05) compared with the other reductase inhibitors, and the percentage of patients reaching target LDL cholesterol concentration at the starting dose was significantly greater in the atorvastatin group (P < .05). Overall, a significantly (P < .05) greater percentage (95%) of atorvastatin-treated patients achieved target LDL cholesterol concentration. The safety profile was similar among all reductase inhibitors tested. At the starting dose, a significantly (P < .05) greater percentage of atorvastatin-treated patients at risk for CHD reached the target LDL cholesterol concentration than patients with treated with other reductase inhibitors.",1998.0,1,1 3421,9841303,Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.,Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group,"In patients with coronary heart disease and a broad range of cholesterol levels, cholesterol-lowering therapy reduces the risk of coronary events, but the effects on mortality from coronary heart disease and overall mortality have remained uncertain. In a double-blind, randomized trial, we compared the effects of pravastatin (40 mg daily) with those of a placebo over a mean follow-up period of 6.1 years in 9014 patients who were 31 to 75 years of age. The patients had a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter. Both groups received advice on following a cholesterol-lowering diet. The primary study outcome was mortality from coronary heart disease. Death from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P<0.001). Overall mortality was 14.1 percent in the placebo group and 11.0 percent in the pravastatin group (relative reduction in risk, 22 percent; 95 percent confidence interval, 13 to 31 percent; P<0.001). The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin; these outcomes included myocardial infarction (reduction in risk, 29 percent; P<0.001), death from coronary heart disease or nonfatal myocardial infarction (a 24 percent reduction in risk, P<0.001), stroke (a 19 percent reduction in risk, P=0.048), and coronary revascularization (a 20 percent reduction in risk, P<0.001). The effects of treatment were similar for all predefined subgroups. There were no clinically significant adverse effects of treatment with pravastatin. Pravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.",1998.0,0,0 3422,9841599,Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial.,S J Lewis; L A Moye; F M Sacks; D E Johnstone; G Timmis; J Mitchell; M Limacher; S Kell; S P Glasser; J Grant; B R Davis; M A Pfeffer; E Braunwald,"A majority of all myocardial infarctions occur in patients who are 65 years of age or older and have average cholesterol levels, but little information is available on whether cholesterol lowering in such patients reduces the rate of recurrent cardiovascular disease. To determine whether pravastatin reduces the rate of recurrent cardiovascular events in older patients. Subset analysis of a randomized, controlled trial. 80 hospitals and affiliates in the United States and Canada. 1283 patients aged 65 to 75 years who had had myocardial infarction and had a plasma total cholesterol level less than 6.2 mmol/L (240 mg/dL) and a low-density lipoprotein cholesterol level of 3.0 to 4.5 mmol/L (115 to 174 mg/dL). Pravastatin, 40 mg/d, or placebo. Five-year event rates of major coronary events (coronary death, nonfatal myocardial infarction, angioplasty, or bypass surgery) and stroke. Major coronary events occurred in 28.1% of placebo recipients and 19.7% of pravastatin recipients (difference, 9.0 percentage points [95% CI, 4 to 13 percentage points]; relative risk reduction, 32%; P < 0.001). Coronary death occurred in 10.3% of the placebo group and in 5.8% of the pravastatin group (difference, 4.6 percentage points [CI, 1.9 to 6.5 percentage points]; relative risk reduction, 45%; P = 0.004). Stroke incidence was 7.3% in the placebo group and 4.5% in the pravastatin group (absolute reduction, 2.9 percentage points [CI, 0.3 to 4.5 percentage points]; relative reduction, 40%; P = 0.03). The numbers of older patients needed to treat for 5 years were 11 (CI, 8 to 24) to prevent a major coronary event and 22 (CI, 15 to 53) to prevent a coronary death. For every 1000 older patients treated, 225 cardiovascular hospitalizations would be prevented compared with 121 hospitalizations in 1000 younger patients. In older patients with myocardial infarction and cholesterol levels in the average range, pravastatin is associated with a clinically important reduction in risk for major coronary events and stroke. Given the high cardiovascular event rate in older patients, the potential for absolute benefit in this age group is substantial.",1998.0,0,0 3423,9842411,Unstable atherosclerotic plaque. Pathophysiology and therapeutic guidelines.,G Berkenboom,"Plaque disruption promoted by local inflammation and oxidative stress seem to be the triggering mechanisms of acute coronary syndromes. Oxidized low-density lipoproteins (LDL) play a key role in this inflammatory process. Within the inflammatory region, angiotensin-converting enzyme (ACE) accumulation has been described, leading to enhanced production of local angiotensin II which stimulates adhesion molecule expression and increases oxidative stress (leading to excessive degradation of EDNO). According to recent clinical trials, drugs like statins or ACE inhibitors seem promising and could stabilize the plaque, probably by attenuation of the inflammatory process. Finally, as thrombus formation also plays a role in these acute coronary syndromes, another approach may be the use of antithrombotic therapy.",1998.0,0,0 3424,9843456,Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators.,R B Goldberg; M J Mellies; F M Sacks; L A Moyé; B V Howard; W J Howard; B R Davis; T G Cole; M A Pfeffer; E Braunwald,"Although diabetes is a major risk factor for coronary heart disease (CHD), little information is available on the effects of lipid lowering in diabetic patients. We determined whether lipid-lowering treatment with pravastatin prevents recurrent cardiovascular events in diabetic patients with CHD and average cholesterol levels. The Cholesterol And Recurrent Events (CARE) trial, a 5-year trial that compared the effect of pravastatin and placebo, included 586 patients (14.1%) with clinical diagnoses of diabetes. The participants with diabetes were older, more obese, and more hypertensive. The mean baseline lipid concentrations in the group with diabetes--136 mg/dL LDL cholesterol, 38 mg/dL HDL cholesterol, and 164 mg/dL triglycerides--were similar to those in the nondiabetic group. LDL cholesterol reduction by pravastatin was similar (27% and 28%) in the diabetic and nondiabetic groups, respectively. In the placebo group, the diabetic patients suffered more recurrent coronary events (CHD death, nonfatal myocardial infarction [MI], CABG, and PTCA) than did the nondiabetic patients (37% versus 25%). Pravastatin treatment reduced the absolute risk of coronary events for the diabetic and nondiabetic patients by 8.1% and 5.2% and the relative risk by 25% (P=0.05) and 23% (P<0.001), respectively. Pravastatin reduced the relative risk for revascularization procedures by 32% (P=0.04) in the diabetic patients. In the 3553 patients who were not diagnosed as diabetic, 342 had impaired fasting glucose at entry defined by the American Diabetes Association as 110 to 125 mg/dL. These nondiabetic patients with impaired fasting glucose had a higher rate of recurrent coronary events than those with normal fasting glucose (eg, 13% versus 10% for nonfatal MI). Recurrence rates tended to be lower in the pravastatin compared with placebo group (eg, -50%, P=0.05 for nonfatal MI). Diabetic patients and nondiabetic patients with impaired fasting glucose are at high risk of recurrent coronary events that can be substantially reduced by pravastatin treatment.",1998.0,0,1 3425,9845852,,,,,0,0 3426,9851392,Increased thrombotic vascular events after change of statin.,M Thomas; J Mann,,1998.0,0,0 3427,9852713,Tolerability and effects of high doses acipimox as additional lipid-lowering therapy in familial hypercholesterolemia.,P M Stuyt; H A Kleinjans; A F Stalenhoef,"Acipimox, a derivative of nicotinic acid, lowers serum lipid levels by reducing the production of very-low-density and low-density lipoproteins (LDL). We studied the additional lipid-lowering effect of high doses of acipimox in 12 patients with severe familial hypercholesterolemia (FH) who were on treatment with an HMG CoA reductase inhibitor, in some cases in combination with a resin. There was a significant reduction in total serum cholesterol (-9%), LDL-cholesterol (-9%) and serum triglycerides (-21%) when the standard doses of acipimox (750 mg/day) was added to treatment with simvastatin (and a resin). However, higher doses had no further hypolipidemic effect. In concordance with the reduction of serum cholesterol and LDL-cholesterol there was a significant decrease in apolipoprotein (apo)-B (-11%). There was no change in HDL-cholesterol, apo-A1 and lipoprotein(a). Acipimox in high doses up to 2250 mg/d was well tolerated except for initial gastric complaints and of flushing; because of these side effects one patient dropped out of the study. Acipimox in high doses, which were well tolerated, has no additional lowering effect on LDL-levels compared to the standard dose in patients with severe FH who are already treated with simvastatin.",1998.0,0,0 3428,9856659,A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme.,J Larner; J Jane; E Laws; R Packer; C Myers; M Shaffrey,"Malignant gliomas are thought to be highly dependent on the mevalonate pathway for cell growth. Lovastatin, a cholesterol-lowering drug, inhibits not only the rate-limiting step in the mevalonate pathway (hepatic hydroxymethyl glutaryl coenzyme A reductase), but also the prenylation of several key regulatory proteins including ras and the small guanosine triphosphate binding proteins. Therefore, from August 1994 through March 1996, 18 patients with either anaplastic glioma or glioblastoma multiforme were entered into a trial testing the safety of high-dose lovastatin with or without radiation. Although the response data is too premature to evaluate activity, the fact that high doses of lovastatin are well tolerated with concurrent radiation suggests that central nervous system toxicity will not be a significant limiting toxicity as more selective farnesyltransferase inhibitors are brought into the clinic as radiation sensitizers.",1998.0,0,0 3429,9856919,Cost-effectiveness of statins.,D M Huse; M W Russell; J D Miller; D F Kraemer; R B D'Agostino; R C Ellison; S C Hartz,"Currently, 6 hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are marketed in the United States (US). Given the wide variation in the prices and efficacy of statins, formal cost-effectiveness analysis may improve drug selection decisions. To assess the cost-effectiveness of statin therapy in primary and secondary prevention of coronary heart disease, we developed a model of the costs and consequences of lipid-regulating therapy and estimated the incremental cost-effectiveness of 5 statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) at usual starting doses versus no therapy. Drug effects on serum lipids were assessed using data approved by the US Food and Drug Administration for product labeling. Annual risks of coronary event occurrence were estimated using Framingham Heart Study coronary risk equations developed for use in this model. Current estimates of direct medical costs of coronary heart disease were used to assign costs to health states and acute coronary events. Main outcome measurements were net cost (statin therapy minus savings in coronary heart disease treatment), gain in life expectancy, and cost per life-year saved. The maximum gain in life expectancy was achieved with atorvastatin, which also had a lower net cost than lovastatin, pravastatin, and simvastatin. Compared with fluvastatin, atorvastatin's greater effectiveness is attained at a lower cost per life-year saved. The cost-effectiveness of HMG-CoA reductase inhibition in primary and secondary prevention of coronary heart disease has been improved with the introduction of atorvastatin.",1998.0,0,0 3430,9859160,"[Statins (HMG-CoA reductase inhibitors), cholesterol and stroke].",J Marta-Moreno; C Echeandia; A Oliveros-Cid; A Figuerola; S Mola,"The HMG-CoA reductase inhibitors (known as statins) have been shown to reduce morbi-mortality of vascular origin, including transitory ischemic accidents and cerebral infarcts, in a large group of patients. The implications, both clinical and of costs, oblige us to consider analysis of the existing evidence and the answers to a number of questions arising in a field which has not yet received much attention from neurologists.",1998.0,0,0 3431,9861520,"Elderly patients with hypercholesterolaemia: a double-blind study of the efficacy, safety and tolerability of fluvastatin.",M Lye; R Valacio; J P Reckless; A K Ghosh; I N Findlay; M K Ghosh; A P Passmore; R A Fulcher,"Coronary heart disease is a major cause of morbidity and mortality in the elderly, a rapidly growing section of the population. Elderly patients have been excluded from most preventative risk factor trials. We evaluated fluvastatin, a fully synthetic hydroxymethyl glutaryl coenzyme A reductase inhibitor, in white patients older than 60 years, in seven hospital centres. After an 8-week cholesterol-decreasing diet phase, patients were allocated to groups to receive fluvastatin 40 mg daily (n = 33) or placebo (n = 36) given for 12 weeks. All patients had low-density lipoprotein cholesterol concentrations > or = 4.1 mmol/l 1 week before they were allocated to a treatment at random. After receiving randomised treatment for 12 weeks, 50 patients then received fluvastatin 40 mg daily on an open basis for a further 12 weeks. Mean +/- SD age was 70.7 +/- 5.2 years for fluvastatin patients and 68.3 +/- 5.6 years for placebo. Mean +/- SD percentage changes in lipid concentrations from randomisation to the end of 12 weeks were calculated (n = 63) by intent-to-treat analysis. Total cholesterol decreased by 21.64 +/- 8.7% in the fluvastatin group and by 2.91 +/- 7.25% in the placebo group (P < 0.01); high-density lipoprotein cholesterol increased by 4.98 +/- 10.84% in the fluvastatin group and decreased by 0.05 +/- 8.68% in the placebo group (P = 0.05); low-density lipoprotein cholesterol decreased by 27.14 +/- 8.45% in the fluvastatin group and by 2.16 +/- 9.68% in the placebo group (P < 0.01); very-low-density lipoprotein cholesterol decreased by 30.70 +/- 30.65% in the fluvastatin group and by 9.80 +/- 28.6% in the placebo group (P < 0.01); triglyceride decreased by 18.13 +/- 17.35% in the fluvastatin group and by 2.97 +/- 21.85% in the placebo group (P < 0.01). There were no statistically significant differences between treatment groups for any other biochemical or haematological parameters. Adverse events were mainly mild, diminishing with continued treatment, and no event was serious by standard criteria. Patient-assessed tolerability after randomised treatment was 'very good' for 18 fluvastatin patients and for 26 placebo patients (P = 0.79). Seven patients withdrew from the 12-week follow-up (four from the fluvastatin group and three from the placebo group). We conclude that fluvastatin decreases lipid concentrations effectively and safely in elderly patients, producing clinically significant decreases in total cholesterol, low-density lipoprotein cholesterol, triglyceride and, especially, very-low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol moderately.",1998.0,0,0 3432,9863541,Cholesteryl ester transfer in hypercholesterolaemia: fasting and postprandial studies with and without pravastatin.,C Contacos; P J Barter; L Vrga; D R Sullivan,"Subjects with hypercholesterolaemia (HC) have increased fasting cholesteryl ester transfer protein (CETP) activity and accelerated cholesteryl ester transfer (CET) from HDL to apo B-containing lipoproteins. The aim of this study was to examine the effects of postprandial lipaemia and pravastatin treatment on plasma triglycerides (TG) and CETP activity and on CET and LDL Stokes' diameter in primary HC (n = 19, total cholesterol > or =6.5, LDL-cholesterol > or =4.5, TG <4.0 mmol/l). Samples were collected fasting and 6 h after an oral fat load (0.88 g/kg body weight) after 6 weeks therapy with placebo or pravastatin 40 mg nocte according to a double-blind randomized cross-over study. Apart from significant reductions in plasma total cholesterol, LDL-cholesterol apo B and TG. pravastatin significantly reduced CETP activity in both the fasting (mean +/- SD, 37.9+/-12.2 to 32.0+/-10.3 nmol/ml plasma per h) and postprandial state (35.5+/-11.3 to 31.3+/-9.5 nmol/ml plasma per h) compared to equivalent placebo phases. CETP activity did not change during postprandial lipaemia despite a significant 45-55% increase in CET to triglyceride-rich lipoproteins (TRL) of d <1.006 g/ml. LDL Stokes' diameter was unchanged postprandially or by pravastatin. The mass of TRL was the strongest contributor to variation in CET in both fasting and postprandial plasma, accounting for at least 77% of the variance of CET. Postprandial TRL-TG was the strongest contributor to variation in fasting LDL Stokes' diameter in untreated HC (54%) whilst HDL-cholesterol was the strongest fasting contributor to variation (45%) for placebo- and pravastatin-treated HC. We conclude that pravastatin may reduce the atherogenicity of the lipoprotein profile in HC by reducing CETP activity. Furthermore, CET is strongly influenced by postprandial lipaemia which may have a cumulative effect on LDL size.",1998.0,0,0 3433,9868585,Therapy and clinical trials.,K von Bergmann; P H Jones,,1998.0,0,0 3434,9868591,Primary and secondary prevention of coronary artery disease: a follow-up on clinical controlled trials.,M Kornitzer,"Most probably the decennia of the 1990s will be called the 'statin decennia' in the history of coronary heart disease prevention. Statins are effective, both in primary and secondary prevention of coronary heart disease, in middle-aged and older (< 76 years) men and women, in both diabetics and non-diabetics with coronary heart disease. Statins used in secondary prevention of coronary heart disease significantly reduce the risk of stroke. They also reduce daily attacks of myocardial ischemia. Pathogenetic pathways leading to 'biological plausibilities' of the statins favourable effects are multiple, which explains their rapid (less than 1 year) influence on coronary events. Until the results from new event trials become available, fibrates have very few indications as first line drug therapy in dyslipidemia. They should be considered in combined therapy with statins. The scientific evidence with statins is overwhelming and the question is no longer 'who should we treat?' but 'who can society afford to treat?'. Health economics are indeed pivotal in the use of statins and public health authorities have to find answers according to their resources or innovative strategies, including new aspects in dietary advice (the 'Mediterranean diet'?).",1998.0,0,0 3435,9869855,Non-immune factors in chronic rejection. Is there a role for hypolipemic drugs?,L Paczek; M Bill; J Wyzgał; L Gradowska; Z Gałazka; Z Gaciong,,1998.0,0,0 3436,9874052,Effects of pravastatin on thoracic aortic atherosclerosis in patients with heterozygous familial hypercholesterolemia.,C E Pitsavos; K I Aggeli; J D Barbetseas; I N Skoumas; S G Lambrou; A A Frogoudaki; C I Stefanadis; P K Toutouzas,"Data regarding the effects of plasma lipid lowering on the evolution of thoracic aortic atherosclerosis (TAA) are scarce. In this study, we performed transesophageal echocardiography to characterize TAA in 16 newly diagnosed patients with heterozygous familial hypercholesterolemia and to follow its evolution after 2 years of statin treatment. TAA was graded as follows: grade I = normal intima; grade II = increased intimal echo density without thickening; grade IIIA = increased intimal echo density with single atheromatous plaque < or = 3 mm; grade IIIB = multiple plaques < or = 3mm; grade IV = > or = 1 plaque >3 mm; and grade V = mobile or ulcerated plaques. Baseline aortic intimal morphology was grade I in one patient, grade II in 4, grade IIIA in 6, grade IIIB in 3, and grade IV in 2 patients. Hypolipidemic treatment resulted in significant reductions in plasma total cholesterol and low-density lipoprotein (LDL) cholesterol. Follow-up aortic morphology was grade I in 5 patients, grade II in 2, grade IIIA in 3, grade IIIB in 3, and grade IV in 3 patients. TAA remained stable in 7 patients, progressed in 3, and regressed in 6 patients. TAA evolved in a uniform manner in the ascending aorta, aortic arch, and descending aorta. Patients with TAA regression were younger (39+/-14 vs 52+/-8 years, p=0.038) and had a greater decrease in plasma LDL cholesterol as a result of treatment (138+/-56 vs 73+/-55 mg/dl, p=0.036) than patients with TAA stability or progression. These observations support the hypothesis that hypolipidemic treatment may favorably affect the course of TAA in patients with heterozygous familial hypercholesterolemia.",1999.0,0,0 3437,9879865,Coronary artery surgery: the end of the beginning.,F D Loop,"In each of the first three decades of myocardial revascularization, conventional treatment has been revised completely. This lecture comments on three areas of discovery that have shaped the evolution of myocardial revascularization: science, technology development, and revascularization. The discoveries in all three areas are inexorably interrelated. The single greatest lesson learned so far is that conduit performance carries more prognostic weight than any other factor. We have observed that vein graft atherosclerosis is predictable, and that the first-generation lipid lowering drugs have a favorable effect in patients who achieve marked LDL reduction. Biologically better revascularization begins with use of the internal thoracic artery for grafting to the anterior descending coronary artery. As the results of internal thoracic artery grafting are widely reported, arterial bypass revascularization has expanded, notably by radial and gastroepiploic arteries. The results of bilateral internal thoracic artery grafting are discussed, including large-scale registry results of internal thoracic artery usage in the United States. The internal thoracic artery is significantly underutilized. Diabetes affects both endoluminal and surgical revascularization. The new pharmacology in cardiology interventions shows promise in diminishing restenosis and thrombosis even in diabetic patients. Conversely, extended internal thoracic artery grafting may also benefit diabetic patients. Now we are entering a new age of minimally invasive coronary surgery. We have passed through the early stages of mini-thoracotomy, and we are moving on to access through 1-cm ports, intrathoracic cannulation, antegrade and retrograde myocardial protection, and computer guided three-dimensional vision and instrumentation. The potential for robotic control adds greater precision, ease of use, and safety. This new technology will be integrated with diagnostic information, intraoperative monitoring, anesthesia and perfusion data, cost accounting, and surgical note transcription. The operating room of the future will package intraoperative information and is adaptable to all surgical specialties. The future of coronary artery surgery will depend on minimally invasive techniques, all-arterial grafting, and selective lipid modification to reduce progressive atherosclerosis. The conclusion of this decade marks the end of the beginning. The new generation of cardiothoracic surgeons will share in an array of technology and research unmatched in previous decades.",1999.0,0,0 3438,9884398,Use of sildenafil (Viagra) in patients with cardiovascular disease. Technology and Practice Executive Committee.,M D Cheitlin; A M Hutter; R G Brindis; P Ganz; S Kaul; R O Russell; R M Zusman,,2000.0,0,0 3439,9884814,Clinical pharmacokinetics of mibefradil.,H A Welker; H Wiltshire; R Bullingham,"Mibefradil, a tetralol derivative, is a new long-acting calcium antagonist used for the treatment of patients with hypertension and chronic stable angina pectoris. The drug is virtually completely metabolised, with less than 3% of an oral dose excreted unchanged in urine. Its metabolism occurs via parallel pathways, which fall into 2 broad categories: esterase-catalysed hydrolysis (producing the major plasma metabolite) and cytochrome P450 (CYP) 3A4-mediated oxidation. Plasma protein binding is greater than 99.5%, predominantly to alpha 1-acid glycoprotein. Oral multiple dose administration of mibefradil 50 or 100 mg once daily is associated with inhibition of the CYP3A4 pathway of metabolism, increasing the half-life and bioavailability of the parent compound. The intensity of the inhibition of CYP similarly results in numerous clinically relevant drug interactions which ultimately motivated the voluntary withdrawal of mibefradil from the market. With multiple oral doses of 50 to 100 mg once daily, the time to maximum plasma concentration was approximately 2.4 hours, absolute bioavailability was around 80%, clearance was 5.7 to 7.5 L/h, oral terminal exponential volume of distribution was 180 L, and terminal exponential half-life was 22 hours (ranging between 17 and 25 hours). A NONMEM sparse data analysis indicated that apparent clearance is not affected by race, gender, age or bodyweight. Renal function does not affect the pharmacokinetics of mibefradil.",1999.0,0,0 3440,9884817,,,,,0,0 3441,9885777,Do lipid lowering drugs reduce the risk of coronary heart disease?,L B Pritzker,"Historically, a wide range of drugs have been used to treat hyperlipidemias. These include fibrates whose main action is to lower plasma triglycerides; bile-acid sequestering resins introduced to reduce plasma cholesterol; and more recently a family of statins designed to inhibit the rate-limiting enzyme of cholesterol biosynthesis, HMG-CoA reductase. Early trials employing rather small numbers of subjects with established coronary artery disease (CAD) demonstrated that lipid reduction was often but not always associated with a lowered incidence of clinical end-points, including death and non-fatal myocardial infarction. However, significant angiographic benefit was rarely demonstrated in these investigations. More recent trials based on statins have shown a reduction in clinical events not only in patients with CAD, but also in healthy subjects given these drugs for primary prevention. Differences in design, duration, the role of confounders such as risk factors other than lipids, and the frequently poor correlation between angiographic changes and clinical outcomes are discussed.",1999.0,0,0 3442,9892586,Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators.,J F Plehn; B R Davis; F M Sacks; J L Rouleau; M A Pfeffer; V Bernstein; T E Cuddy; L A Moyé; L B Piller; J Rutherford; L M Simpson; E Braunwald,"The role of lipid modification in stroke prevention is controversial, although increasing evidence suggests that HMG-CoA reductase inhibition may reduce cerebrovascular events in patients with prevalent coronary artery disease. To test the hypothesis that cholesterol reduction with pravastatin may reduce stroke incidence after myocardial infarction, we followed 4159 subjects with average total and LDL serum cholesterol levels (mean, 209 and 139 mg/dL, respectively) who had sustained an infarction an average of 10 months before study entry and who were randomized to pravastatin 40 mg/d or placebo in the Cholesterol and Recurrent Events (CARE) trial. Using prospectively defined criteria, we assessed the incidence of stroke, a prespecified secondary end point, and transient ischemic attack (TIA) over a median 5-year follow-up period. Patients were well matched for stroke risk factors and the use of antiplatelet agents (85% of subjects in each group). Compared with placebo, pravastatin lowered total serum cholesterol by 20%, LDL cholesterol by 32%, and triglycerides by 14% and raised HDL cholesterol by 5% over the course of the trial. A total of 128 strokes (52 on pravastatin, 76 on placebo) and 216 strokes or TIAs (92 on pravastatin, 124 on placebo) were observed, representing a 32% reduction (95% CI, 4% to 52%, P=0.03) in all-cause stroke and 27% reduction in stroke or TIA (95% CI, 4% to 44%, P=0.02). All categories of strokes were reduced, and treatment effect was similar when adjusted for age, sex, history of hypertension, cigarette smoking, diabetes, left ventricular ejection fraction, and baseline total, HDL, and LDL cholesterol and triglyceride levels. There was no increase in hemorrhagic stroke in patients on pravastatin compared with placebo (2 versus 6, respectively). Pravastatin significantly reduced stroke and stroke or TIA incidence after myocardial infarction in patients with average serum cholesterol levels despite the high concurrent use of antiplatelet therapy.",1999.0,0,0 3443,9893719,Lipids and stroke: neglect of a useful preventive measure?,J A Papadakis; D P Mikhailidis; A F Winder,"The epidemiological studies linking lipid variables and stroke are reviewed. These studies indicate that serum total cholesterol (TC) levels are associated positively with thrombotic and negatively with haemorrhagic strokes. Relationships for other lipid fractions are not as clearly defined. The results of trials with lipid lowering drugs suggest that only statins effectively reduce the incidence of stroke. Differences between trial results may be due to variation in the extent of reduction of TC levels. Possible underlying mechanisms for benefit and the apparent superiority of statins are also discussed. The reduction in the risk of thrombotic stroke with statins is most evident through meta-analyses (p < 0.001) and less impressive in individual trials (p < 0.03). This difference is largely attributable to the small number of events in trials primarily aimed at evaluating ischaemic heart disease (IHD) reduction. This also means that benefit may be limited to those with established IHD. IHD and thrombotic stroke share common risk factors and patients with one condition are at high risk of developing the other. Therefore, one additional reason for using statins in these patients is that these drugs can effectively prevent IHD-related events including deaths.",1999.0,0,0 3444,9894706,The management of hypercholesterolaemia in patients with coronary artery disease referred for coronary angiography.,F Saia; T P Chua; K M Fox,"There are clear benefits in treating hypercholesterolaemia in patients with ischaemic heart disease, especially those with previous myocardial infarction. Following publication of trial evidence and treatment guidelines for hypercholesterolaemia, we investigated the current practice of the management of hypercholesterolaemia in patients with coronary artery disease referred for coronary angiography by general physicians. We prospectively reviewed 156 consecutive patients (117 men; mean age 61.5+/-9.6 [S.D.] years) with a history of angina pectoris who attended the day case unit for coronary angiography in a 10 week period. Nearly a tenth of these patients had not been screened for hypercholesterolaemia in this study. Of those patients with a cholesterol level > or =5.5 mmol/l, almost a quarter were not on a statin or any other cholesterol-lowering therapy. Continued effort should be given to the screening and effective management of hypercholesterolaemia in patients with coronary artery disease.",1999.0,0,0 3445,9917082,Comparison of 24-hour ambulatory blood pressure data in hypertensive patients switched from nifedipine-GITS to nifedipine-CC.,R L Wurdeman; A N Mooss; S M Mohiuddin; B D Lucas; K L Ryschon; D E Hilleman,"To evaluate 24-hour blood pressure control and frequency of adverse effects in patients with mild to moderate hypertension switched from nifedipine gastrointestinal therapeutic system (Nif-GITS) to nifedipine coat core (Nif-CC). Open-label, prospective, switch study University-affiliated outpatient cardiology clinic. Twenty patients with mild to moderate essential hypertension, who were taking Nif-GITS 30, 60, or 90 mg/day for 8 weeks or longer. Patients stabilized with Nif-GITS 30, 60, or 90 mg were monitored over 24 hours with an ambulatory blood pressure monitor and were then switched to an equivalent dosage of Nif-CC. After 8 weeks+/-1 week taking Nif-CC, they were again monitored with a 24-hour blood pressure monitor. The 24-hour blood pressure load (percentage of values > 135/85 mm Hg for 24 hrs), daytime blood pressure load (percentage of values > 140/90 mm Hg from 7:00 A.M.-10:00 P.M.), nighttime blood pressure load (percentage of values > 120/80 mm Hg from 10:00 P.M.-7:00 A.M.), diurnal blood pressure variation, average 24-hour blood pressure, daytime blood pressure, nighttime blood pressure, mean blood pressure for the first 4 hours, and last 8 hours of the dosing interval were measured. Adverse effects such as headache, dizziness, and edema were also reported. No differences in average 24 hour-blood pressure readings were observed but significant differences in blood pressure control during the first 4 and last 8 hours of the dosing interval were seen. Systolic and diastolic blood pressures were higher after approximately 16 hours in patients switched from Nif-GITS to Nif-CC. Although Nif-CC caused a greater initial response, it was less effective than Nif-GITS after 16 hours. This could explain the lack of differences in average 24-hour blood pressure values between formulations. Of the 20 patients, 20% experienced increased headaches, 20% showed signs of increased peripheral edema, and 10% reported occasional dizziness after switching agents. Three patients discontinued Nif-CC, two as ordered by their primary care physician and one on his own due to headache. This study suggests that patients switched from Nif-GITS to Nif-CC could experience increased blood pressure during the night or toward the end of the dosing interval. They could also experience adverse effects such as headache, edema, and dizziness, which could result in more physician visits and put patients with other disease states such as coronary heart disease at increased risk.",2001.0,0,0 3446,9917116,Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial.,E A Stein; D R Illingworth; P O Kwiterovich; C A Liacouras; M A Siimes; M S Jacobson; T G Brewster; P Hopkins; M Davidson; K Graham; F Arensman; R H Knopp; C DuJovne; C L Williams; J L Isaacsohn; C A Jacobsen; P M Laskarzewski; S Ames; G J Gormley,"Heterozygous familial hypercholesterolemia (HeFH) is a common disorder associated with early coronary artery disease, especially in men. The age at which drug therapy should be started is still controversial, as is the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). To assess the lipid-lowering efficacy, biochemical safety, and effect on growth and sexual development of lovastatin in adolescent boys with HeFH. One-year, double-blind, placebo-controlled, balanced, 2-period, 2-arm randomized trial. In the first period (24 weeks), lovastatin was increased at 8 and 16 weeks and the dosage remained stable during the second period (24 weeks). The study was conducted between 1990 and 1994. Fourteen pediatric outpatient clinics in the United States and Finland. Boys aged 10 to 17 years with HeFH. Of 132 randomized subjects (67 intervention, 65 placebo), 122 (63 intervention, 59 placebo) and 110 (61 intervention, 49 placebo) completed the first and second periods, respectively. Lovastatin, starting at 10 mg/d, with a forced titration at 8 and 16 weeks to 20 and 40 mg/d, respectively, or placebo. The primary efficacy outcome measure was low-density lipoprotein cholesterol (LDL-C). Primary safety measures were growth and sexual development. Compared with placebo, LDL-C levels of patients receiving lovastatin decreased significantly (P<.001) by 17%, 24%, and 27% receiving dosages of 10, 20, and 40 mg/d, respectively, and remained 25 % lower than baseline at 48 weeks. Growth and sexual maturation assessed by Tanner staging and testicular volume were not significantly different between the lovastatin and placebo groups at 24 weeks (P = .85) and 48 weeks (P = .33); neither were serum hormone levels or biochemical parameters of nutrition. However, the study was underpowered to detect significant differences in safety parameters. Serum vitamin E levels were reduced with lovastatin treatment consistent with reductions in LDL-C, the major carrier of vitamin E in the circulation. This study in adolescent boys with HeFH confirmed the LDL-C-reducing effectiveness of lovastatin. Comprehensive clinical and biochemical data on growth, hormonal, and nutritional status indicated no significant differences between lovastatin and placebo over 48 weeks, although further study is required.",2001.0,0,0 3447,9918521,Vascular effects of estrogen and cholesterol-lowering therapies in hypercholesterolemic postmenopausal women.,K K Koh; C Cardillo; M N Bui; L Hathaway; G Csako; M A Waclawiw; J A Panza; R O Cannon,"Lipoproteins affect endothelium-dependent vasomotor responsiveness. Because lipoprotein effects of estrogen and cholesterol-lowering therapies differ, we studied the vascular responses to these therapies in hypercholesterolemic postmenopausal women. We randomly assigned 28 women to conjugated equine estrogen (CE) 0.625 mg, simvastatin 10 mg, and their combination daily for 6 weeks. Compared with respective baseline values, simvastatin alone and combined with CE reduced LDL cholesterol to a greater extent than CE alone (both P<0.05). CE alone and combined with simvastatin raised HDL cholesterol and lowered lipoprotein(a) to a greater extent than simvastatin alone (all P<0.05). Flow-mediated dilation of the brachial artery (by ultrasonography) improved (all P<0.001 versus baseline values) on CE (4.0+/-2.6% to 10.2+/-3.9%), simvastatin (4.3+/-2.4% to 10.0+/-3.9%), and CE combined with simvastatin (4.6+/-2.0% to 9.8+/-2.6%), but similarly among therapies (P=0.507 by ANOVA). None of the therapies improved the dilator response to nitroglycerin (all P>/=0.184). Only therapies including CE lowered levels of plasminogen activator inhibitor type 1 and the cell adhesion molecule E-selectin (all P<0. 05 versus simvastatin). Although estrogen and statin therapies have differing effects on lipoprotein levels, specific improvement in endothelium-dependent vasodilator responsiveness is similar. However, only therapies including estrogen improved markers of fibrinolysis and vascular inflammation. Thus, estrogen therapy appears to have unique properties that may benefit the vasculature of hypercholesterolemic postmenopausal women, even if they are already on cholesterol-lowering therapy.",2001.0,0,0 3448,9920511,Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group.,,"Clinical management of heterozygous familial hypercholesterolaemia is largely based on evidence from a small number of observational studies and extrapolation from the results of clinical trials of lipid-lowering in patients with polygenic hypercholesterolaemia The objectives of this study were (i) to determine the absolute and relative mortality of patients with treated heterozygous familial hypercholesterolaemia, (ii) to estimate the effect of changes in treatment efficacy on mortality trends over time, and (iii) to examine the implications of these findings for patient management. A cohort of 605 men and 580 women aged 20-79 years with heterozyous familial hypercholesterolaemia were recruited from 21 out-patient lipid clinics in the UK. Patients were followed prospectively from 1980 to 1995 for 8770 person-years. Absolute mortality was calculated, and relative risk was expressed as the ratio of the number of observed deaths to the number expected in the general population of England and Wales. Forty six of the 73 deaths were due to coronary heart disease. In women aged 20-39, despite treatment, the relative risk of a fatal coronary event was increased 125-fold (95% confidence intervals 15-451) and the annual coronary mortality was 0.17%. In men aged 20-39 the relative risk was increased 48-fold (17-105) and the annual coronary mortality was 0.46%. The relative risk decreased with age but the absolute risk increased. For men and women aged 60-79, the annual coronary mortality was 1.1% representing a significant excess mortality for women (relative risk 2.6, 1.3-4.5) but not for men (RR 1.1, 0.5-2.3). Non-coronary mortality was not increased at any age (RR for all ages 0.68, 0.45-0.99). There was a decline in the relative risk for coronary mortality in patients aged 20-59 from an eight-fold (4.8-7.2) increased risk before 1992 to 3.7 (1.6-7.2.) thereafter (P=0.08). The results suggest that the prognosis for patients with heterozygous familial hypercholesterolaemia has improved with the introduction of more effective treatment, and that lipid-lowering therapy is not associated with increased non-coronary mortality. These findings and the excess coronary mortality observed suggest that all affected adult men and post-menopausal women should be treated with HMG-CoA reductase inhibitors.",1999.0,0,0 3449,9922713,"[Antioxidative effects of fluvastatin, and its major metabolites].",A Nakashima; M Ohtawa; N Masuda; H Morikawa; T Bando,"Fluvastatin (FV) is a highly potent inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Recently, its antioxidant effect caused by inhibiting the formation of low density lipoproteins (LDL) in vitro has been reported. In this study, we reported the antioxidant effects of FV and its major metabolites in human (M-2, M-3, M-4, M-5, and M-7) on lipid peroxidation using rat liver microsomes. The extent of NADPH-induced microsomal (Ms) lipid peroxidation was determined by the thiobarbituric acid (TBA) assay. The antioxidant effect of each compound was shown as the percentage of inhibition on the formation of TBA reactive substances (TBARS) against the vehicle control. Probucol (PR), a potent antioxidant drug, was used as a reference control. The concentration of each compound in this experiment was set at 0.1 mM (final conc.). FV inhibited the formation of TBARS by 30 to 60% without depending on the used Ms concentrations (0.025-0.2 mg protein/ml). The antioxidant effects of M-2, M-3, and M-5 were comparable to that of FV at low Ms concentrations. At the highest Ms concentration, however, the antioxidant effects of these metabolites were considerably higher than that of FV. Inhibition of the formation of TBARS by M-4 or M-7 was approximately 30% of the control and independent of the used Ms concentrations. The antioxidant effect of PR was comparable to those of M-2, M-3, and M-5 in this study. Pravastatin (PV), a potent inhibitor of HMG-CoA reductase, reduced the formation of TBARS around 20% at 0.25 or 0.5 mg protein/ml of Ms concentrations. But the value of percentage of inhibition was around 5% at 0.1 or 0.2 mg protein/ml of Ms concentrations. In conclusion, the antioxidant effects of FV, M-2, M-3, and M-5 were found to be comparable to that of PR.",1999.0,0,0 3450,9923885,Lipid-lowering drugs and homocysteine.,M de Lorgeril; P Salen; F Paillard; P Lacan; G Richard,,1999.0,0,0 3451,9927392,Delayed response of myocardial flow reserve to lipid-lowering therapy with fluvastatin.,M Guethlin; A M Kasel; K Coppenrath; S Ziegler; W Delius; M Schwaiger,"Lipid-lowering therapy can improve endothelial function in patients with coronary artery disease (CAD) and hypercholesterolemia. Little is known about induced changes in myocardial microcirculation. This study prospectively investigated the temporal effects of lipid-lowering therapy with fluvastatin on coronary flow and flow reserve (CFR) in patients with CAD assessed by PET. In an open clinical trial, CFR was studied in 15 patients with angiographically documented multivessel CAD and hypercholesterolemia (LDL >160 mg/dL). Dynamic 13N-labeled ammonia PET imaging in conjunction with adenosine was used to assess regional and global CFR at baseline as well as at 2 and 6 months during treatment with fluvastatin (60 to 80 mg/d). Despite a rapid decrease in total cholesterol (29+/-6%) and LDL (37+/-9%), myocardial blood flow at rest and during stress was unchanged after 2 months of treatment (2.7+/-0.9 versus 2.5+/-0.6 mL x g-1 x min-1). At 6 months, stress blood flow as well as CFR increased significantly (3.4+/-1.0 mL x g-1 x min-1). No change in hemodynamic parameters was noted during the entire study. Nine of 15 patients increased CFR by >20%. All responders demonstrated improvement in anginal symptoms, whereas nonresponders stated no change (n=4) or worsening of symptoms (n=2). The improvement in CFR was not related to the amount of lipid lowering and was independent of the severity of stenoses. Improvement in stress blood flow and CFR is delayed compared with the lipid-lowering effect of fluvastatin, suggesting a slow recovery of the vasodilatory response to adenosine.",1999.0,0,0 3452,9928746,Target organ involvement in hypertensive patients in Eastern Sudan.,A A Hussain; A G Elzubier; M E Ahmed,"Hypertension has become a major cause of cardiovascular morbidity and mortality in both the developed and the developing nations. In a cross-sectional study we assessed the state of blood pressure (BP) control and the pattern of target organ complications in 198 Sudanese patients treated in a teaching hospital in Kassala town in Eastern Sudan, (mean age 53 years, 76% women). Excellent BP control (BP <140/90 mm Hg) was achieved in 46% of the patients. Stage 2 or Stage 3 target organ involvement, particularly albuminuria and ischaemic heart disease, were detected in one-third of the patients. These complications were found to be related to both the severity and the duration of hypertension as well as to the frequency of cigarette smoking. Factors such as poor compliance, adverse socioeconomic status, as well as obesity and cigarette smoking may account for poor BP control and hence the development of hypertensive complications. We conclude that optimal BP control is not yet achieved in the majority of hypertensives in the Sudan. Reasons for this failure should be identified and corrected in order to avoid hypertensive target organ damage.",1999.0,0,0 3453,9929747,The importance of randomized clinical trials and evidence-based medicine: a clinician's perspective.,H L Kennedy,"Clinical evaluation of therapies for patient care has evolved during the twentieth century from a variety of scientific methods. As a result of medical, political, and economic changes that occurred in the 1990s, randomized clinical trials and evidence-based methods are presently in the forefront of the physician's thinking in the decision-making process for therapeutic interventions. A new standard of patient care has emerged during this process. This report provides a clinician's viewpoint of the importance and interpretation of evidence-based methods and suggests a strategy when such evidence does not exist.",1999.0,0,0 3454,9929751,Long-term safety of pravastatin-gemfibrozil therapy in mixed hyperlipidemia.,E A Iliadis; R S Rosenson,"Combined HMG-CoA reductase inhibitor and fibric acid derivative therapy is often necessary for the effective reduction of concentrations of low-density lipoprotein (LDL) cholesterol and triglycerides in patients with mixed hyperlipidemia; however, the potential risk of myopathy has limited the use of these agents. This study evaluated long-term safety and efficacy of combined pravastatin and gemfibrozil therapy. Eighty-three patients with hyperlipidemia were treated with combined pravastatin and gemfibrozil therapy for a median of 44 months (range 9-78 months). Plasma lipids, serum liver function tests, creatinine, and creatinine kinase (CK) levels were measured every 3 to 4 months. One patient developed myalgia with a normal CK level after 4 months of combination therapy. Three patients had transient elevations in CK levels that ranged from 3 to 5 times the upper limits of ""normal"" and that returned to normal upon repeat testing. Liver function tests did not change significantly from baseline. In a subset of 26 previously untreated patients, combined pravastatin (mean daily dose 22 mg) and gemfibrozil (mean daily dose 1,154 mg) therapy lowered total cholesterol by 25% (p < 0.001), triglycerides by 53% (p = 0.0001), LDL cholesterol by 14% (p = 0.24), and increased high-density lipoprotein (HDL) cholesterol by 20% (p = 0.012). Pravastatin and gemfibrozil therapy is safe and efficacious in patients with mixed hyperlipidemia. The long-term safety results are consistent with other reports on follow-up of shorter duration.",1999.0,0,0 3455,9932614,Stroke risk factors and stroke prevention.,M S Elkind; R L Sacco,"Stroke is the third leading cause of death and the leading cause of chronic disability in the United States. In the past several decades, case series, case-control studies, and prospective cohort studies have successfully identified nonmodifiable risk markers for stroke, such as age, gender, race, ethnicity, heredity and several well-established modifiable risk factors for ischemic stroke. Hypertension, atrial fibrillation, other cardiac diseases, hyperlipidemia, diabetes, cigarette smoking, physical inactivity, carotid stenosis, and transient ischemic attack (TIA) are all potentially treatable conditions that predispose to stroke. Research on other putative stroke risk factors-including antiphospholipid antibodies, elevated homocysteine, alcohol, inflammation, and infection-is ongoing. Controlled trials have shown that stroke risk can be reduced by blood-pressure control, lipid-lowering agents, surgery for carotid stenosis, warfarin for atrial fibrillation, and antiplatelet agents. It is hoped that an improved understanding of stroke risk factors will reduce the future burden of stroke.",1999.0,0,0 3456,9935018,Influence of baseline lipids on effectiveness of pravastatin in the CARE Trial. Cholesterol And Recurrent Events.,M A Pfeffer; F M Sacks; L A Moyé; C East; S Goldman; D T Nash; J R Rouleau; J L Rouleau; B A Sussex; P Theroux; R J Vanden Belt; E Braunwald,"We sought to assess the influence of baseline lipid levels on coronary event rates and the effectiveness of pravastatin therapy in the Cholesterol And Recurrent Events (CARE) study. The CARE study cohort provided a relatively unique opportunity to examine the relation between lipid levels and clinical events in a post-myocardial infarction (MI) population with relatively low cholesterol and low density lipoprotein (LDL) cholesterol values. There were 4,159 patients with a previous infarct and a total cholesterol level <240 mg/dl, LDL cholesterol level 115 to 174 mg/dl and triglyceride level <350 mg/dl randomly allocated to placebo (n=2,078) or pravastatin 40 mg/day (n=2,081). Time to either coronary death or nonfatal MI (primary end point) or to the secondary end point, which included undergoing a coronary revascularization procedure, was determined as a function of baseline lipids (total, LDL, high density lipoprotein [HDL] cholesterol and triglyceride levels). Quartile analysis indicated important effects for LDL cholesterol, in which a higher LDL was associated with greater cardiac event rates (in the placebo group, every 25-mg/dl increment in LDL was associated with a 28% increased risk [5% to 56%, p=0.015]) in the primary event. The differential event rates with respect to baseline LDL cholesterol for placebo and pravastatin groups reduced the difference in clinical outcomes at lower LDL cholesterol levels. In both the placebo and pravastatin groups, an inverse relation between baseline HDL cholesterol and cardiac events was observed (10 mg/dl lower baseline HDL cholesterol level was associated with a 10% [0% to 19%, p=0.046] increase in coronary death or nonfatal MI). Within the LDL cholesterol levels in CARE (115 to 174 mg/dl), baseline values influenced both the risk of events in the placebo group as well as the clinical effectiveness of pravastatin therapy.",1999.0,0,0 3457,9949762,Celecoxib for arthritis.,,,1999.0,0,0 3458,9972199,Inadequate control of lipid levels in patients with a previous myocardial infarction.,C J Ellis; A Zambanini; J K French; M Denton; R Johnson; H Patel; H D White,"To access the current lipid management of late survivors of acute myocardial infarction. A systematic follow-up of all survivors who had previously been screened for enrolment into one of three randomised clinical trials in Auckland was undertaken from December 1995 to January 1997. All contacted survivors were asked to answer a questionnaire regarding their current therapy and were invited to undergo venepuncture for a lipid assay. Of the 1036 patients with acute myocardial infarction screened for enrolment in the three trials there were 984 (95%) who survived 30 days. At a median of 5.5 years (interquartile range 3.2-8.5) follow-up, 641 (86%) survivors agreed to have a fasting lipid test. The mean total cholesterol level was 5.7 +/- 1.1 mmol/L high density lipoprotein cholesterol 1.1 +/- 0.3 mmol/L, low density lipoprotein cholesterol 3.8 +/- 0.9 mmol/L and triglyceride level 1.9 +/- 1.1 mmol/L. Two hundred and seven (32%) patients were treated with a lipid-modifying agent. Four hundred and forty-five (69%) patients had a cholesterol level > or = 5.2 mmol/L 381 (59%) patients had a level > or = 5.5 mmol/L and 72 (11%) patients had a level > or = 7.0 mmol/L of whom 62 patients were not being treated with a lipid-modifying agent. For the 107 patients with coronary artery bypass grafts, the mean cholesterol level was 5.4 mmol/L and the mean low density lipoprotein cholesterol level was 3.7 +/- 0.9 mmol/L, with 57 (53%) patients not being treated with a ""statin"" or ""fibrate"". Lipid management is suboptimal in this high risk population of patients post-infarction and greater efforts need to be made to achieve better control. Diet is frequently inadequate in these patients at high risk and statin therapy is indicated.",1999.0,0,0 3459,9987704,The effect of converting from pravastatin to simvastatin on the pharmacodynamics of warfarin.,J C Lin; M K Ito; S N Stolley; A P Morreale; D B Marcus,"Forty-six adult patients maintained on warfarin therapy were converted from pravastatin to simvastatin. Mean international normalized ratio (INR) significantly increased from 2.42 to 2.74, p = 0.002. Although warfarin doses were reduced in 7 patients and increased in 4 patients following the post-conversion INR measurements, the pre- and postconversion median weekly warfarin dose of all 46 patients did not differ significantly. The number of patients with an INR > 3.0 increased significantly from 6 to 16 following the conversion. There was no report of unusual episodes of bleeding. The results indicate that antihyperlipidemic therapy can be changed safely from pravastatin to simvastatin in patients who are taking warfarin concomitantly. Additional anticoagulation monitoring is not necessary in institutions where patients are followed in formal anticoagulation clinics.",1999.0,0,0 3460,9988300,Underutilization of cardiac medications in the Pacemaker Selection in the Elderly study.,W S Aronow,,1999.0,0,0 3461,9988781,Squalene and its potential clinical uses.,G S Kelly,"Squalene, an isoprenoid compound structurally similar to beta-carotene, is an intermediate metabolite in the synthesis of cholesterol. In humans, about 60 percent of dietary squalene is absorbed. It is transported in serum generally in association with very low density lipoproteins and is distributed ubiquitously in human tissues, with the greatest concentration in the skin, where it is one of the major components of skin surface lipids. Squalene is not very susceptible to peroxidation and appears to function in the skin as a quencher of singlet oxygen, protecting human skin surface from lipid peroxidation due to exposure to UV and other sources of ionizing radiation. Supplementation of squalene to mice has resulted in marked increases in cellular and non-specific immune functions in a dose-dependent manner. Squalene may also act as a ""sink"" for highly lipophilic xenobiotics. Since it is a nonpolar substance, it has a higher affinity for un-ionized drugs. In animals, supplementation of the diet with squalene can reduce cholesterol and triglyceride levels. In humans, squalene might be a useful addition to potentiate the effects of some cholesterol-lowering drugs. The primary therapeutic use of squalene currently is as an adjunctive therapy in a variety of cancers. Although epidemiological, experimental and animal evidence suggests anti-cancer properties, to date no human trials have been conducted to verify the role this nutrient might have in cancer therapy regimens.",1999.0,0,0 3462,9989373,Comparison of the effects of pravastatin and lovastatin on sleep disturbance in hypercholesterolemic subjects.,B L Ehrenberg; S Lamon-Fava; K E Corbett; J R McNamara; G E Dallal; E J Schaefer,"We have studied the effects of two cholesterol-lowering medications, lovastatin and pravastatin, on different sleep parameters in hypercholesterolemic subjects. These medications are 3-hydroxy-methylglutaryl coenzyme A inhibitors. Only subjects who had complained of sleep disturbance while on previous treatment with lovastatin were enrolled. Sixteen subjects (11 men and 5 women) underwent a randomized, double-blind, three-way crossover treatment with lovastatin, pravastatin, and placebo. Each phase of the study lasted 4 weeks. A placebo wash-out period of 4 weeks separated each treatment phase. At the end of each treatment phase, subjects were admitted to the sleep laboratory for 2 consecutive nights. No statistical differences were detected during treatment with lovastatin, pravastatin, and placebo for sleep parameters such as total sleep time, total awake time, wake time after sleep onset, efficiency of sleep, and percent of different phases of sleep. Our study suggests that lovastatin and pravastatin do not have a significant effect on sleep parameters in hypercholesterolemic subjects that could explain their complaints of insomnia. Nevertheless, the subjects did have moderate sleep disturbances that could account for insomnia and most likely predate the use of HMG-CoA reductase inhibitors.",1999.0,0,0 3463,9989597,Determinants of plasma coenzyme Q10 in humans.,J Kaikkonen; K Nyyssönen; T P Tuomainen; U Ristonmaa; J T Salonen,"In the present study, we assessed the strongest determinants of plasma coenzyme Q10 (Qm10) in 518 men and women (aged 45-70 years) with a stepwise multivariate regression model. Male gender (P<0.001), serum cholesterol (P<0.001), serum gamma-glutamyltransferase (P<0.001), serum triglycerides (P< 0.001), age (P=0.017) and 4-day alcohol consumption (P=0.03) were the most important factors which were directly associated with plasma Q10). The intensity of conditioning exercise (P=0.03) and use of statins (P<0.05) showed an inverse association with plasma Q10. None of the assessed nutrients increased plasma Q10 levels significantly. Our results suggest that many confounding factors, in addition to serum cholesterol and triglycerides, should be taken into account when the role of plasma Q10 is examined in epidemiological research.",1999.0,0,0 3464,9989677,Dietary supplement or drug? The case of cholestin.,R J Havel,,1999.0,0,0 3465,9989957,Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy.,C M Ballantyne; J A Herd; L L Ferlic; J K Dunn; J A Farmer; P H Jones; J R Schein; A M Gotto,"BACKGROUND--Patients with coronary artery disease (CAD) commonly have low HDL cholesterol (HDL-C) and mildly elevated LDL cholesterol (LDL-C), leading to uncertainty as to whether the appropriate goal of therapy should be lowering LDL-C or raising HDL-C. METHODS AND RESULTS--Patients in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) had mildly to moderately elevated LDL-C; many also had low HDL-C, providing an opportunity to compare angiographic progression and the benefits of the HMG-CoA reductase inhibitor fluvastatin in patients with low versus patients with higher HDL-C. Of the 339 patients with biochemical and angiographic data, 68 had baseline HDL-C <0.91 mmol/L (35 mg/dL), mean 0.82+/-0.06 mmol/L (31. 7+/-2.2 mg/dL), versus 1.23+/-0.29 mmol/L (47.4+/-11.2 mg/dL) in patients with baseline HDL-C >/=0.91 mmol/L. Among patients on placebo, those with low HDL-C had significantly more angiographic progression than those with higher HDL-C. Fluvastatin significantly reduced progression among low-HDL-C patients: 0.065+/-0.036 mm versus 0.274+/-0.045 mm in placebo patients (P=0.0004); respective minimum lumen diameter decreases among higher-HDL-C patients were 0. 036+/-0.021 mm and 0.083+/-0.019 mm (P=0.09). The treatment effect of fluvastatin on minimum lumen diameter change was significantly greater among low-HDL-C patients than among higher-HDL-C patients (P=0.01); among low-HDL-C patients, fluvastatin patients had improved event-free survival compared with placebo patients. CONCLUSIONS--Although the predominant lipid-modifying effect of fluvastatin is to decrease LDL-C, patients with low HDL-C received the greatest angiographic and clinical benefit.",2001.0,0,0