record_id,pubmedID,title,authors,abstract,year,label_included,label_abstract_screening
1,10203431,Quality of life in arthritis patients using nonsteroidal anti-inflammatory drugs.,I Wiklund,"Arthritis is a painful and disabling condition. To suppress the pain and the inflammatory process, patients are often chronic nonsteroidal anti-inflammatory drug (NSAID) users. Chronic use of NSAIDs may induce peptic ulcer, dyspeptic problems and heartburn. Therefore, these patients are often provided with treatment to relieve and/or protect against gastrointestinal problems. Rheumatic disorders also affect a range of health-related quality of life domains. In one study, patients with NSAID-associated gastroduodenal lesions complained about lack of energy, sleep disturbances, emotional distress and social isolation in addition to pain and mobility limitations. The degree of distress and dysfunction differed markedly from scores in an unselected population. Clinical trial data suggest that acid-suppressing therapy with omeprazole is superior to therapy with misoprostol and ranitidine in healing gastroduodenal lesions and preventing abdominal pain, heartburn and indigestion symptoms during continued NSAID treatment. Because arthritic patients are severely incapacitated by their condition regarding most aspects of health-related quality of life, it is important to offer a treatment that is effective in healing and preventing NSAID-induced ulcers and gastrointestinal symptoms during continued NSAID treatment without further compromising the patients' quality of life. Treatment with omeprazole once daily has been shown to be superior to that with ranitidine and misoprostol in this respect.",2000.0,0,0
2,10234601,The safety profile of nonprescription ibuprofen in multiple-dose use: a meta-analysis.,D E Kellstein; J A Waksman; S A Furey; G Binstok; S A Cooper,"A meta-analysis was performed to compare the incidence of adverse experiences (AEs) during the multiple-dose use of nonprescription ibuprofen to a placebo. Eight studies, with doses ranging from 800 to 1200 mg/day and durations of 1 to 10 days, met the criteria for inclusion. AEs were classified according to COSTART, except that ""abdominal pain"" was conservatively reassigned to the digestive system. In each study, the overall AE frequency among ibuprofen-treated subjects (n = 1094) was numerically less than or equal to the placebo (n = 1093). Pooled across all studies, placebo subjects reported AEs significantly (p = 0.018) more often (31.7%) than ibuprofen subjects (27.4%). The frequency of digestive system AEs was comparable (p = 0.420) for the placebo (11.0%) and ibuprofen (12.1%); there was no significant difference for any specific digestive system AE. AE frequency in the ""body-as-a-whole"" category was significantly higher (p < 0.001) in the placebo (20.4%) than in ibuprofen (14.8%). The number of severe AEs in all of these categories was lower for ibuprofen than for the placebo. These data indicate that nonprescription ibuprofen has an excellent side effect profile in multiple-dose use, with a frequency of gastrointestinal AEs comparable to a placebo.",1999.0,0,1
3,10325662,,,,,0,0
4,10369404,"Comparative efficacy and safety of nimesulide and diclofenac in patients with acute shoulder, and a meta-analysis of controlled studies with nimesulide.",W Wober,"Adverse events, particularly gastrointestinal, partially offset the therapeutic value of NSAIDs. The abilities of nimesulide to inhibit COX-2 preferentially and to exert other novel anti-inflammatory actions are consistent with good efficacy and safety. This is borne out by a double-blind multicentre comparison of nimesulide and diclofenac in 122 patients with acute shoulder, and by a meta-analysis of various nimesulide trials. At the end of the 14 day double-blind study, nimesulide was at least as effective as diclofenac (investigator ratings: good/very good in 79.0% of patients given nimesulide, and 78.0% with diclofenac; patient ratings: good/very good in 82.3 and 78.0% respectively). Four patients (6.5%) dropped out in the nimesulide group (two early recovery, one lack of effect, one adverse event), compared with 13 (21.7%) in the diclofenac group, due mainly to adverse events (P=0.003). Global tolerability was judged by the investigators to be good/very good in 96.8% of the nimesulide group compared with 72.9% of those given diclofenac. Judgements by the patients were 96.8 and 78.0% respectively. Both differences are highly significant statistically. The meta-analysis demonstrates that nimesulide given for 2 weeks is far more efficacious than placebo in treating osteoarthritis, and is at least comparable to other NSAIDs The benefit-risk ratio for nimesulide was better in all individual studies since 100 mg nimesulide twice daily was about equal to placebo in safety and tolerability, especially regarding gastrointestinal adverse events.",1999.0,0,1
5,10369405,"Economic comparison of nimesulide and diclofenac, and the incidence of adverse events in the treatment of rheumatic disease in Greece.",L Liaropoulos,"In Greece a 15-day treatment of rheumatic disease with diclofenac costs 56% more than treatment with nimesulide. This is due to the lower incidence of gastrointestinal adverse events with nimesulide, and the absence of serious gastrointestinal complications leading to hospitalization, which more than offset the higher acquisition cost of nimesulide. The average saving by using nimesulide instead of diclofenac is about US$21 per patient for a 15-day treatment period.",1999.0,0,0
6,10380773,Occurrence of allergic conditions in asthmatics with analgesic intolerance.,A F Kalyoncu; G Karakaya; A A Sahin; Y I Bariş,"The study aimed to determine whether allergic conditions accompany analgesic intolerance. A total of 132 analgesic-intolerant patients with bronchial asthma admitted to the adult allergy unit from January 1991 to October 1997 and 103 patients with bronchial asthma randomly selected from among the asthmatics referred to our department between January and October 1997 were enrolled in the study. Those having analgesic intolerance and bronchial asthma were accepted as group I; patients having only asthma were accepted as group II. A standard questionnaire was completed for all the patients. Physical examination, routine skin prick tests, determination of total IgE levels and blood type, and oral analgesic provocation tests were also performed. The results showed that some allergic conditions were significantly more common in group I (22.7% and 7.8% for food allergy/intolerance [P<0.05], 16.7% and 7.8% for antibiotic allergy, 16.7% and 2.9% for dermographism, 9.8% and 1.0% for metal allergy, and 9.1% and 1.0% for chronic urticaria for groups I and II, respectively [P<0.001]). In addition, the mean of the total IgE level in the serum was higher in group I than group II (77.6 and 53.7 IU/ml; P<0.05), and the cumulative analgesic consumption was more in group I (14.2+/-17.1 and 9.1+/-12.5 boxes; P<0.05). Dermographism; chronic urticaria; antibiotic, metal, and food allergy; high levels of total IgE; and a high amount of cumulative analgesic consumption may be the conditions accompanying analgesic intolerance in asthmatics.",1999.0,0,0
7,10383505,Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen.,F L Lanza; M F Rack; T J Simon; H Quan; J A Bolognese; M E Hoover; F R Wilson; S E Harper,"Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxygenase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity. To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin. Healthy subjects (n = 170; age range 18-54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score >/= 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population. The percentage of subjects who developed a mucosal score >/= 2 in the MK-0966 group (12%) was significantly lower (P < 0.001) than that in the ibuprofen (71%) and aspirin (94%) groups, and was similar to that in the placebo group (8%). Only ibuprofen and aspirin significantly (P < 0.0001) reduced baseline thromboxane B2 levels. All treatments were generally well tolerated. In this acute short-term endoscopic study, MK-0966 250 mg q.d. (a dose at least 10 times higher than that demonstrated to reduce the signs and symptoms of osteoarthritis) produced significantly less gastrointestinal mucosal damage than either ibuprofen 800 mg t.d.s. or aspirin 650 mg q.d.s. and was comparable to placebo in this regard.",1999.0,0,0
8,10440619,"Analgesic efficacy of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain: a randomized, controlled trial.",B W Morrison; S Christensen; W Yuan; J Brown; S Amlani; B Seidenberg,"Previous data have suggested that rofecoxib, a cyclooxygenase (COX)-2-specific inhibitor, had analgesic effects similar to those of the nonsteroidal anti-inflammatory drugs when tested in the post-dental surgery pain model. The objective of this parallel-group, double-masked, randomized, placebo- and active comparator-controlled clinical trial was to assess more fully the analgesic efficacy of rofecoxib in the treatment of postoperative dental pain. After dental surgery, 151 patients (50.3% women; mean age, 18.3 years; 93.4% white) experiencing moderate-to-severe pain were to receive a single dose of placebo, rofecoxib 50 mg, or ibuprofen 400 mg. Analgesic efficacy was assessed for up to 24 hours postdose using self-administered questionnaires. Tolerability was assessed using spontaneous reports of adverse experiences, physical findings, and laboratory measurements. The results of this study demonstrated that rofecoxib 50 mg was more effective than placebo on all measures of analgesic efficacy. Rofecoxib 50 mg exhibited overall analgesic effects, onset of analgesia, and peak analgesic effects that were not significantly different from those of ibuprofen 400 mg, with a significantly longer duration of action (P < 0.05). We concluded that rofecoxib was efficacious in the treatment of postoperative dental pain and that COX-2-derived prostanoids play a role in treatment of the pain associated with dental surgery.",1999.0,0,0
9,10485502,Efficacy and tolerability of the specific cyclooxygenase-2 inhibitor DFP compared with naproxen sodium in patients with postoperative dental pain.,K Gottesdiener; D R Mehlisch; M Huntington; W Y Yuan; P Brown; B Gertz; S Mills,"DFP [3-(2-propyloxy)-(4-methyl-sulfonylphenyl)-(5,5-dimethyl)-fu ranone] is a highly specific cyclooxygenase-2 inhibitor (>2500-fold selective in transfected Chinese hamster ovary cell assays) that has demonstrated efficacy in preclinical models of pain and inflammation. The present single-dose, randomized, double-masked, double-dummy, placebo-controlled, parallel-group study was undertaken to compare DFP 5, 25, and 50 mg with naproxen sodium 550 mg and with placebo in 196 patients (mean age, 25.8 years; 187 [95.4%] males) who experienced moderate-to-severe pain after surgical removal of > or =2 third molars. Overall analgesic effect, duration of effect, time to onset of analgesic effect, peak analgesic effect, and tolerability were assessed over a 24-hour postdose period. Both DFP 25 and 50 mg, as well as the active comparator, naproxen sodium 550 mg, were significantly more effective than placebo. The onset of analgesic effect in the DFP 25-mg, DFP 50-mg, and naproxen sodium 550-mg groups did not differ significantly. DFP was generally well tolerated in single doses up to 50 mg. DFP 50 mg was efficacious in the treatment of postoperative dental pain and was indistinguishable from the active comparator, naproxen sodium 550 mg.",1999.0,0,0
10,10491346,Non-steroidal anti-inflammatory drugs and renal response to exercise: a comparison of indomethacin and nabumetone.,N V Olsen; N G Jensen; J M Hansen; N J Christensen; N Fogh-Andersen; I L Kanstrup,"Nabumetone, a newer non-steroidal anti-inflammatory drug (NSAID) which preferentially blocks cyclo-oxygenase-2 activity, may be less nephrotoxic than indomethacin. This study tested whether nabumetone has effects different from those of indomethacin on exercise-induced changes in renal function and the renin-aldosterone system. In a randomized fashion, ten subjects were studied after indomethacin (100 mg), nabumetone (1 g) or no medication (control) administered orally at 22.00 hours on the day before each study day, and again at 8.00 hours upon arrival at the laboratory. Renal function was studied at baseline, during graded 20-min exercise sessions at 25%, 50% and 75% of the maximal oxygen uptake rate, and subsequently during two 1-h recovery periods. Heart rate, arterial blood pressure, cardiac output and plasma catecholamines at rest and during exercise were not altered by indomethacin or nabumetone. Indomethacin decreased urinary rates of excretion of 6-oxo-prostaglandin F(1alpha) (6-oxo-PGF(1alpha)) and thromboxane B(2) in all study periods. Nabumetone decreased 6-oxo-PGF(1alpha) excretion during and after exercise. Excretion rates for PGE(2) did not change. Neither indomethacin nor nabumetone changed baseline values or exercise-induced decreases in renal plasma flow or glomerular filtration rate. Indomethacin, but not nabumetone, decreased sodium excretion, urine flow rate and free water clearance. The renal response to exercise, however, remained unchanged. In contrast with nabumatone, indomethacin decreased the plasma renin concentration. Thus, during exercise, nabumetone may decrease the excretion of 6-oxo-PGF(1alpha) by inhibition of cyclo-oxygenase-1 or by inhibition of specific exercise-induced activation of cyclo-oxygenase-2, or both. None of the drugs changed the renal response to exercise. Inhibition by indomethacin of angiotensin II and thromboxane A(2) synthesis may, during exercise, counterbalance renal vasoconstriction caused by blockade of vasodilatory prostaglandins.",1999.0,0,0
11,10500058,"A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Rofecoxib Osteoarthritis Endoscopy Study Group.",L Laine; S Harper; T Simon; R Bath; J Johanson; H Schwartz; S Stern; H Quan; J Bolognese,"Prostaglandin production in the normal gastrointestinal tract, believed to be critical for mucosal integrity, is mediated by cyclooxygenase (COX)-1, whereas prostaglandin production at inflammatory sites seems to occur via induction of COX-2. We hypothesized that COX-2-specific inhibition with rofecoxib (25 mg once daily) in the treatment of patients with osteoarthritis would cause fewer gastroduodenal ulcers than an equally effective dose of ibuprofen (800 mg 3 times a day), a nonspecific COX inhibitor. A total of 742 osteoarthritis patients without ulcers on baseline endoscopy were randomly assigned to receive rofecoxib (25 or 50 mg once daily), ibuprofen (800 mg 3 times daily), or placebo. Endoscopy was repeated at 6, 12, and 24 weeks. At 16 weeks, by study design, 95% of the placebo group and 5% of the other groups were discontinued. The cumulative incidence of gastroduodenal ulcers >/=3 mm with rofecoxib (25 or 50 mg once daily) was significantly (P < 0.001) lower than with ibuprofen and was statistically equivalent to placebo at week 12 (placebo, 9.9%; 25 mg rofecoxib, 4.1%; 50 mg rofecoxib, 7.3%; and ibuprofen, 27.7%). At 24 weeks, ulcer rates were 25 mg rofecoxib, 9. 6%; 50 mg rofecoxib, 14.7%; and ibuprofen, 45.8% (P < 0.001, ibuprofen vs. 25 and 50 mg rofecoxib). Rofecoxib, at doses 2-4 times the dose demonstrated to relieve symptoms of osteoarthritis, caused significantly less gastroduodenal ulceration than ibuprofen, with ulcer rates comparable to placebo.",1999.0,1,1
12,10511349,"Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: a randomized controlled trial.",B W Morrison; S E Daniels; P Kotey; N Cantu; B Seidenberg,"To determine whether rofecoxib is effective for treating primary dysmenorrhea and whether cyclooxygenase-2 is involved in the pathophysiology of primary dysmenorrhea. A double-masked, randomized, placebo and active-comparator-controlled clinical trial including 127 subjects with histories of primary dysmenorrhea was conducted in an outpatient clinical research center. Subjects were randomly assigned to placebo, rofecoxib 25 or 50 mg followed by 25 mg every 24 hours as needed, or naproxen sodium 550 mg every 12 hours as needed for up to 3 days. Subjects took all four treatments in a balanced, complete-block, crossover design. Measurements included self-administered questionnaires of analgesic efficacy, spontaneous reports of adverse experiences, physical examinations, and laboratory safety tests. Rofecoxib 25 and 50 mg provided analgesic efficacy greater than placebo (P < or = .006) for the primary endpoint of total pain relief over the first 8 hours. For other efficacy endpoints (sum of the pain intensity difference over the first 8 hours, subject's global evaluation, peak pain relief, peak pain intensity difference, and time to remedication) both doses of rofecoxib were better than placebo (P < or = .006) and were not distinguishable from naproxen sodium for all efficacy endpoints. All treatments were well tolerated. Rofecoxib effectively treated primary dysmenorrhea, and cyclooxygenase-2-derived prostanoids play a role in the pathophysiology of primary dysmenorrhea.",1999.0,0,0
13,10515650,Defining disease activity in ankylosing spondylitis: is a combination of variables (Bath Ankylosing Spondylitis Disease Activity Index) an appropriate instrument?,A Calin; J P Nakache; A Gueguen; H Zeidler; H Mielants; M Dougados,"Disease activity has been defined using a self-administered instrument, focusing on fatigue, axial pain, peripheral pain, enthesopathy and morning stiffness [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)]. This validated instrument is simple and takes 40 s to complete, but whether the index is an accurate expression of the component parts, or whether additional weighting would enhance its efficacy, is unclear. Four hundred and seventy-three patients with ankylosing spondylitis received placebo or active non-steroidal anti-inflammatory drug (NSAID) for 6 weeks, and changes between entry and completion were captured by BASDAI and the individual components. Principle component analysis (PCA) was used to explore the best combinations of variables in decreasing order of explained total dispersion and to assess whether a single sum (or algebraic expression) best defined disease activity status. At entry, the correlation between BASDAI and the first axis was 0.99, 0.11 with the second, and zero thereafter. Data at study end and relating to change revealed a 100% correlation (R = 1) between the first axis and the sum, with zero for the remainder. The data support BASDAI as being a valid and appropriate composite to define disease activity in ankylosing spondylitis. Developed as a simple sum of its components, BASDAI has excellent content validity.",1999.0,0,0
14,10555907,"Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. Rofecoxib Osteoarthritis Pilot Study Group.",E W Ehrich; T J Schnitzer; H McIlwain; R Levy; F Wolfe; M Weisman; Q Zeng; B Morrison; J Bolognese; B Seidenberg; B J Gertz,"To determine the efficacy and safety of the cyclooxygenase 2 (COX-2) specific inhibitor, rofecoxib in patients with osteoarthritis (OA) of the knee. Rofecoxib, 25 mg or 125 mg once daily, was compared with placebo in a 6 week, double blind, parallel group, randomized, multicenter study of 219 patients with knee OA. Both doses of rofecoxib produced clinically significant improvement as assessed by primary (e.g., WOMAC Pain Subscale 0-100 mm, decrease from baseline: placebo: 7.1 mm; rofecoxib 25 mg: 28.1 mm, rofecoxib 125 mg: 28.0 mm; p < 0.001 rofecoxib vs placebo) and secondary efficacy (p < 0.05) criteria compared with placebo. Clinical improvement with the 25 mg dose was similar to that with the 125 mg dose. Both rofecoxib doses were generally well tolerated. Specific inhibition of COX-2 by 25 and 125 mg rofecoxib, administered once daily, resulted in clinically meaningful improvements in patients with OA. This study confirms that COX-2 derived prostanoids are important clinical mediators of pain and other symptoms of knee OA and that inhibition of COX-1 is not required to provide clinical benefit.",1999.0,0,1
15,10555933,Evaluation of the functional status aspects of health-related quality of life of patients with osteoarthritis treated with celecoxib.,S Z Zhao; J I McMillen; J A Markenson; S D Dedhiya; W W Zhao; J T Osterhaus; S S Yu,"To evaluate the functional status of patients with signs and symptoms of osteoarthritis of the knee after treatment with celecoxib compared with placebo and naproxen. Prospective, randomized, double-blind, parallel-group, 12-week trial. Multicenter study conducted at 71 sites in the United States and Canada. One thousand four patients with active osteoarthritis of the knee in a flare state. Patients were assigned randomly to one of five treatment groups: placebo; celecoxib 50 mg twice/day, 100 mg twice/day, and 200 mg twice/day; and naproxen 500 mg twice/day. The Western Ontario and McMaster Universities Osteoarthritis Index was used to measure functional status. At the end of the treatment period, patients in the four active treatment groups had significantly better functional status than those receiving placebo. Patients treated with celecoxib 100 mg twice/day had significantly better improvements in pain scores than those treated with placebo and naproxen. Celecoxib was better than placebo and comparable with naproxen in improving aspects of functional status in patients with osteoarthritis.",1999.0,1,1
16,10560596,"Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial.",W G Bensen; J J Fiechtner; J I McMillen; W W Zhao; S S Yu; E M Woods; R C Hubbard; P C Isakson; K M Verburg; G S Geis,"To compare the efficacy and safety of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, with those of naproxen, a nonsteroidal anti-inflammatory drug (NSAID), and placebo in the treatment of osteoarthritis of the knee. In this multicenter, randomized, double-blind, placebo-controlled trial, 1003 patients with symptomatic osteoarthritis of the knee were randomly assigned to receive celecoxib at doses of 50, 100, or 200 mg twice a day; naproxen, 500 mg twice a day; or placebo for 12 weeks. Patients were evaluated with standard measures of efficacy 2 to 7 days after discontinuing previous NSAID or analgesic therapy and after 2, 6, and 12 weeks of treatment with the study drug. Celecoxib treatment led to significant improvement in the signs and symptoms of osteoarthritis as determined by all efficacy measures. Significant pain relief occurred within 2 days of the initiation of treatment, and maximum anti-inflammatory and analgesic activity, evident within 2 weeks, was sustained throughout the 12-week study. All celecoxib doses were efficacious compared with placebo, although the 50-mg twice-daily dosage regimen was minimally effective. The higher doses of celecoxib (100 and 200 mg twice a day) were similarly efficacious, and the magnitude of improvement observed with these dosing regimens was comparable to that seen with naproxen at a dose of 500 mg twice a day. All doses of celecoxib and naproxen were well tolerated. COX-2 inhibition with celecoxib is an effective approach for the treatment of osteoarthritis, as seen by clinical improvement in signs and symptoms comparable to treatment with naproxen.",1999.0,1,1
17,10566562,"Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial.",K Malmstrom; S Daniels; P Kotey; B C Seidenberg; P J Desjardins,"Pain is a common complaint, often occurring in conjunction with inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used analgesic agents in ambulatory patients. In recent studies, the cyclooxygenase-2 (COX-2) inhibitor rofecoxib demonstrated analgesic effects similar to those of NSAIDs in the treatment of acute pain and primary dysmenorrhea. The present randomized, single-dose, double-blind, double-dummy, placebo- and active-comparator-controlled, parallel-group study was undertaken to compare the analgesic efficacy of the COX-2 inhibitors rofecoxib 50 mg and celecoxib 200 mg with that of ibuprofen 400 mg and placebo in patients with postoperative dental pain. Two hundred and seventy-two patients experiencing pain after the removal of > or =2 third molars were randomized according to pain severity (moderate vs severe) to receive a single dose of placebo (n = 45), rofecoxib 50 mg (n = 90), celecoxib 200 mg (n = 91), or ibuprofen 400 mg (n = 46). Using a patient diary, patients recorded pain intensity, pain relief, and global evaluations throughout the 24-hour period after dosing. The overall analgesic effect, onset of action, peak effect, and duration of effect were evaluated, with the primary end point being total pain relief over 8 hours (TOPAR8). The safety profile was assessed on the basis of physical findings, laboratory results, and spontaneous reports of adverse experiences. The results showed that compared with celecoxib, rofecoxib had superior analgesic effects on all measures of analgesic efficacy, including overall analgesic effect (TOPAR8, 18.3 vs. 12.5; P<0.001), time to onset of effect (30 vs. 60 minutes; P = 0.003), peak pain relief (score, 2.8 vs 2.3; P<0.05), and duration of effect (>24 vs. 5.1 hours; P<0.001). In addition, rofecoxib's analgesic efficacy was similar to that of ibuprofen (TOPAR8, 18.3 vs. 17.0; P = 0.460), but the duration was longer (P<0.05); with ibuprofen, the time to on set was 24 minutes, peak pain relief score was 2.9, and duration of analgesic effect was 8.9 hours. The safety profile was similar across all treatment groups. Thus rofecoxib provided analgesic efficacy superior to that of celecoxib and comparable to that of ibuprofen in the treatment of patients with acute postoperative dental pain.",1999.0,0,0
18,10566565,"The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis. Phase II Rofecoxib Rheumatoid Arthritis Study Group.",T J Schnitzer; K Truitt; R Fleischmann; P Dalgin; J Block; Q Zeng; J Bolognese; B Seidenberg; E W Ehrich,"Nonsteroidal anti-inflammatory drugs. (NSAIDs) inhibit both cyclooxygenase (COX)-1 and COX-2 isoenzymes and are effective in the treatment of inflammatory disorders. This 8-week, double-masked, placebo-controlled trial was undertaken to assess the safety profile, tolerability, and effective dose range of once-daily rofecoxib, a COX-2-specific inhibitor, in the treatment of rheumatoid arthritis (RA). After a 3- to 15-day washout of prior NSAID therapy, 658 patients were randomly allocated to receive placebo or rofecoxib 5 mg, 25 mg, or 50 mg once daily. Safety profile, tolerability, and efficacy were evaluated after 2, 4, and 8 weeks of therapy. Six hundred fifty-eight patients (168, 158, 171, and 161 in the placebo and 5-mg, 25-mg, and 50-mg rofecoxib groups, respectively) were enrolled at 79 clinical centers in the United States. Mean age was 55 years, mean duration of RA was 10 years, and 506 (77%) of the 658 patients were female. All groups had similar baseline demographic characteristics. Patients taking rofecoxib 25 and 50 mg showed significant clinical improvement compared with those taking placebo; 43.9% in the rofecoxib 25-mg group and 49.7% in the rofecoxib 50-mg group completed the treatment period and achieved an American College of Rheumatology 20 response (P = 0.025 and 0.001 vs. placebo, respectively). The 5-mg dose of rofecoxib did not differ significantly from placebo. Patients in the rofecoxib 25- and 50-mg groups showed significant improvement in key individual efficacy measurements, including patient global assessment of pain, patient and investigator global assessment of disease activity, and Stanford Health Assessment Questionnaire Disability Index (P<0.05 vs placebo). Compared with placebo, significantly fewer patients in the 25-mg and 50-mg rofecoxib groups discontinued therapy because of lack of efficacy (P = 0.02 and P = 0.032, respectively). Our results show that rofecoxib 25 and 50 mg once daily was effective and generally well-tolerated in patients with RA.",1999.0,0,1
19,10580457,Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial.,L S Simon; A L Weaver; D Y Graham; A J Kivitz; P E Lipsky; R C Hubbard; P C Isakson; K M Verburg; S S Yu; W W Zhao; G S Geis,"In vitro studies have shown that celecoxib inhibits cyclooxygenase 2 (COX-2) but not COX-1, suggesting that this drug may have anti-inflammatory and analgesic activity without adverse upper gastrointestinal (GI) tract effects that result from COX-1 inhibition. To test whether celecoxib has efficacy as an anti-inflammatory and analgesic with reduced GI tract mucosal damage compared with conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis. Randomized, multicenter, placebo-controlled, double-blind trial lasting 12 weeks, with follow-up at weeks 2, 6, and 12, from September 1996 thorugh February 1998. Seventy-nine clinical sites in the United States and Canada. A total of 1149 patients aged 18 years or older with symptomatic rheumatoid arthritis who met inclusion criteria were randomized; 688 (60%) of these completed the study. Patients were randomized to receive celecoxib, 100 mg, 200 mg, or 400 mg twice per day (n = 240, 235, and 218, respectively); naproxen, 500 mg twice per day (n = 225); or placebo (n = 231). Improvement in signs and symptoms of rheumatoid arthritis as assessed using standard measures of efficacy and GI tract safety as assessed by upper GI tract endoscopy before and after treatment, compared among treatment groups. All dosages of celecoxib and naproxen significantly improved the signs and symptoms of arthritis compared with placebo. Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of initiating treatment and was sustained throughout the 12 weeks. The incidence of endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4 (4%) of 99, and the incidences across all dosages of celecoxib were not significantly different (P>.40): 9 (6%) of 148 with 100 mg twice per day, 6 (4%) of 145 with 200 mg twice per day, and 8 (6%) of 130 with 400 mg twice per day. In contrast, the incidence with naproxen was 36 (26%) of 137, significantly greater than either placebo or celecoxib (P<.001). The overall incidences of GI tract adverse effects were 19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200 mg, and 400 mg twice per day, respectively; and 31 % for naproxen. In this study, all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidenced by less frequent incidence of endoscopic ulcers compared with naproxen.",2001.0,1,1
20,10580458,Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs.,M J Langman; D M Jensen; D J Watson; S E Harper; P L Zhao; H Quan; J A Bolognese; T J Simon,"Nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) toxic effects, such as upper GI tract perforations, symptomatic gastroduodenal ulcers, and upper GI tract bleeding (PUBs), are thought to be attributable to cyclooxygenase 1 (COX-1) inhibition. Rofecoxib specifically inhibits COX-2 and has demonstrated a low potential for causing upper GI injury. To compare the incidence of PUBs in patients with osteoarthritis treated with rofecoxib vs NSAIDs. Prespecified analysis of all 8 double-blind, randomized phase 2b/3 rofecoxib osteoarthritis trials conducted from December 1996 through March 1998, including one 6-week dose-ranging study, two 6-week efficacy studies vs ibuprofen and placebo, two 1-year efficacy studies vs diclofenac, two 6-month endoscopy studies vs ibuprofen and placebo, and one 6-week efficacy study vs nabumetone and placebo. Multinational sites. Participants Osteoarthritis patients (N = 5435; mean age, 63 years [range, 38-94 years]; 72.9% women). Rofecoxib, 12.5, 25, or 50 mg/d (n = 1209, 1603, and 545, respectively, combined) vs ibuprofen, 800 mg 3 times per day (n = 847), diclofenac, 50 mg 3 times per day (n = 590); or nabumetone, 1500 mg/d (n = 127) (combined). Cumulative incidence of PUBs for rofecoxib vs NSAIDs, based on survival analysis of time to first PUB diagnosis, using PUBs that met pre-specified criteria judged by a blinded, external adjudication committee. The incidence of PUBs over 12 months was significantly lower with rofecoxib vs NSAIDs (12-month cumulative incidence, 1.3% vs 1.8%; P = .046; rate per 100 patient-years, 1.33 vs 2.60; relative risk, 0.51; 95% confidence interval, 0.26-1.00). The cumulative incidence of dyspeptic GI adverse experiences was also lower with rofecoxib vs NSAIDS over 6 months (23.5% vs 25.5%; P = .02), after which the incidence rates converged. In a combined analysis of 8 trials of patients with osteoarthritis, treatment with rofecoxib was associated with a significantly lower incidence of PUBs than treatment with NSAIDs.",2001.0,0,1
21,10588920,Selective cyclo-oxygenase-2 inhibitors aggravate ischaemia-reperfusion injury in the rat stomach.,N Maricic; K Ehrlich; B Gretzer; R Schuligoi; M Respondek; B M Peskar,"1. Effects of indomethacin, the selective cyclo-oxygenase (COX)-2 inhibitors NS-398 and DFU, and dexamethasone on gastric damage induced by 30 min ischaemia followed by 60 min reperfusion (I-R) were investigated in rats. Modulation of gastric levels of COX-1 and COX-2 mRNA by I-R was evaluated using Northern blot and reverse transcription-polymerase chain reaction. 2. I-R-induced gastric damage was dose-dependently aggravated by administration of indomethacin (1 - 10 mg kg(-1)), NS-398 (0.4 - 4 mg kg(-1)) or DFU (0.02 - 2 mg kg(-1)) as assessed macroscopically and histologically. 3. Likewise, administration of dexamethasone (1 mg kg(-1)) significantly increased I-R damage. 4. Low doses of 16, 16-dimethyl-prostaglandin(PG)E(2), that did not protect against ethanol-induced mucosal damage, reversed the effects of the selective COX-2 inhibitors, indomethacin and dexamethasone. 5. I-R had no effect on gastric COX-1 mRNA levels but increased COX-2 mRNA levels in a time-dependent manner. Dexamethasone inhibited the I-R-induced expression of COX-2 mRNA. 6. I-R was not associated with a measurable increase in gastric mucosal formation of 6-keto-PGF(1alpha) and PGE(2). PG formation was substantially inhibited by indomethacin (10 mg kg(-1)) but was not significantly reduced by NS-398 (4 mg kg(-1)), DFU (2 mg kg(-1)) or dexamethasone (1 mg kg(-1)). 7. The findings indicate that selective COX-2 inhibitors and dexamethasone markedly enhance gastric damage induced by I-R. Thus, whereas COX-2 has no essential role in the maintenance of gastric mucosal integrity under basal conditions, COX-2 is rapidly induced in a pro-ulcerogenic setting and contributes to mucosal defence by minimizing injury. This suggests that in certain situations selective COX-2 inhibitors may have gastrotoxic effects.",2000.0,0,0
22,10606360,"Celecoxib, a specific COX-2 inhibitor, has no significant effect on methotrexate pharmacokinetics in patients with rheumatoid arthritis.",A Karim; D S Tolbert; T L Hunt; R C Hubbard; K M Harper; G S Geis,"To determine the effects of celecoxib, a specific inhibitor of cyclooxygenase 2 (COX-2) on the renal clearance and plasma pharmacokinetic profile of stable methotrexate (MTX) doses in patients with rheumatoid arthritis (RA). Fourteen adult female patients with RA taking a stable weekly dose of MTX (5 to 15 mg/wk) for a minimum of 3 months were randomized to receive concomitantly either celecoxib (200 mg BID) or placebo for a period of 7 days in a single blind, 2 period crossover study of MTX pharmacokinetics and renal clearance. The plasma pharmacokinetic profile of MTX did not change significantly when celecoxib or a placebo was coadministered. The mean renal clearance of MTX alone, 7.98+/-2.18 l/h, was virtually unchanged by coadministration of celecoxib (7.94+/-1.61 l/h) or placebo (7.97+/-1.19 l/h). Celecoxib has no significant effect on the pharmacokinetics or renal clearance of MTX in patients with RA, although these results should be confirmed in prospective studies of elderly and renally impaired patients.",2000.0,0,0
23,10609620,The use of nimesulide in patients with acetylsalicylic acid and nonsteroidal anti-inflammatory drug intolerance.,S Bavbek; G Celik; D Ediger; D Mungan; Y S Demirel; Z Misirligil,"Intolerance or idiosyncrasy to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) is a crucial problem because these drugs are frequently used in medical treatment. In this study, we tested whether nimesulide, a selective cyclooxygenase-2 (COX-2) inhibitor, might be a valid alternative for patients with histories of adverse reaction to ASA or NSAIDs. A single-blind, placebo-controlled oral challenge procedure was applied to 60 adult patients (19 male, 41 female; with a mean age of 40.31 +/- 10.44 years, range 20-68 years) with a reliable history of ASA/NSAIDs-intolerance. According to history, the clinical presentations of intolerance were urticaria/angioedema in 32 patients, anaphylactoid reaction in 2 patients, respiratory reaction in 19 patients, and respiratory and cutaneous reaction in 7 patients. Atopy was confirmed by means of skin prick test with inhalant allergens. Oral challenge protocol was started with 25 mg of nimesulide and the remaining 75 mg was given 1 hr later. During the challenge procedure, blood pressure, pulse, nasoocular, pulmonary, and cutaneous symptoms were monitored. Of the 60 patients tested, 55 (91.7%) tolerated the drug with no adverse reaction. Only five (8.3%) patients demonstrated a positive response to oral challenge. The clinical presentations of intolerance to nimesulide were urticaria/angioedema in three patients, mild rhinitis in one patient, and mild dyspnea in one patient. The atopy prevalence was higher, with a ratio of 41.7%, in patients with ASA/NSAIDs intolerance than that of the healthy adult population in Turkey (p < 0.05). We believe that nimesulide can be used as an alternative drug for patients with ASA/NSAIDs intolerance.",1999.0,0,0
24,10609815,Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison.,P Emery; H Zeidler; T K Kvien; M Guslandi; R Naudin; H Stead; K M Verburg; P C Isakson; R C Hubbard; G S Geis,"Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase (COX), which leads to suppression of COX-1-mediated production of gastrointestinal-protective prostaglandins. Gastrointestinal injury is a common outcome. We compared the efficacy, safety, and tolerability of long-term therapy with celecoxib, a COX-1 sparing inhibitor of COX-2, with diclofenac, a non-specific COX inhibitor. 655 patients with adult-onset rheumatoid arthritis of at least 6 months' duration were randomly assigned oral celecoxib 200 mg twice daily or diclofenac SR 75 mg twice daily for 24 weeks. Anti-inflammatory and analgesic activity and tolerability were assessed at baseline, every 4 weeks, and at week 24. We assessed gastrointestinal safety by upper-gastrointestinal endoscopy within 7 days of the last treatment dose at centres where the procedure was available. Analysis was by intention-to-treat. 430 patients underwent endoscopy (celecoxib n=212, diclofenac n=218). The two drugs were similar in management of rheumatoid arthritis pain and inflammation. Gastroduodenal ulcers were detected endoscopically in 33 (15%) patients treated with diclofenac and in eight (4%) in the celecoxib group (p<0.001). The rate of withdrawal for any gastrointestinal-related adverse event, most commonly abdominal pain, diarrhoea, and dyspepsia, was nearly three times higher in the diclofenac-treated group than in the celecoxib group (16 vs 6%; p<0.001). Celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac, with a lower frequency of upper gastrointestinal ulceration or gastrointestinal adverse events, and tolerability was better.",2000.0,1,1
25,10626810,Synergistic effects of new chemopreventive agents and conventional cytotoxic agents against human lung cancer cell lines.,A F Soriano; B Helfrich; D C Chan; L E Heasley; P A Bunn; T C Chou,"Non-small cell lung cancer (NSCLC) cells have constitutively high expression of cytosolic phospholipase A2 (cPLA2) and cyclooxygenase (COX) 2. These NSCLC cells also have increased prostaglandin expression (PGE2). Many lung cancers also express 12-lipoxygenase RNA and 12-lipoxygenase protein and biosynthesize 12(S)-hydroxyeicosatetraenoic acid, which correlates with their metastatic potential. Several studies have demonstrated that COX-1 and COX-2 inhibitors could inhibit the in vitro growth of human lung cancer cell lines. In this report, we evaluated the growth-inhibitory effects of sulindac sulfide, a COX-1 and COX-2 inhibitor; exisulind (sulindac sulfone), a novel proapoptotic agent that does not inhibit COX enzymes; and nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor on human lung cancer cell lines. We compared these effects with those of 13-cis-retinoic acid, a chemoprevention agent, and with the cytotoxic chemotherapeutic agents paclitaxel and cisplatin, alone or in combination. Our goal was to develop new chemoprevention and treatment strategies. Each of the six agents tested inhibited the in vitro growth of three NSCLC and three SCLC cell lines at the highest concentration. Paclitaxel was the most potent agent (IC50 = 0.003-0.150 microM); sulindac sulfide, NDGA, and 13-cis-retinoic acid had intermediate potency (IC50 = 4-80 microM), and cisplatin and exisulind were the least potent (IC50 = 150-500 microM). Combination studies showed synergistic interactions for sulindac sulfide, exisulind, and NDGA with paclitaxel, cisplatin, and 13-cis-retinoic acid, regardless of drug-resistance phenotype. At high concentrations, the combination of 13-cis-retinoic acid and each of the five other drugs resulted in a strong synergistic effect. These studies provide a rationale for chemoprevention (exisulind +/- retinoic acid +/- NDGA) and therapeutic (exisulind +/- paclitaxel +/- cisplatin) studies in patients at risk for, or with, lung cancer.",2001.0,0,0
26,10638109,,,,,0,0
27,10644275,"Do cyclooxygenase-2 inhibitors provide benefits similar to those of traditional nonsteroidal anti-inflammatory drugs, with less gastrointestinal toxicity?",M Feldman; A T McMahon,,2000.0,0,0
28,10645754,Immunologic tolerability profile of celecoxib.,R Patterson; A E Bello; J Lefkowith,"Celecoxib is primarily an inhibitor of cyclooxygenase (COX) 2 and, at therapeutic concentrations in humans, does not inhibit the COX-1 isoenzyme. The present meta-analyses explore the incidence of allergic reactions with celecoxib in patients in the North American and international arthritis trials, in patients with a history of hypersensitivity reactions to sulfonamides, and in patients receiving medications containing sulfonamides. Data were obtained from 11,008 patients in 14 double-masked trials of celecoxib in arthritis ranging from 4 to 24 weeks in duration. Results demonstrate that the incidence of allergic reactions with celecoxib was not statistically different from that seen with placebo or active comparators (nonsteroidal anti-inflammatory drugs [NSAIDs]) when data from the entire cohort were analyzed. The subset of patients with a history of sulfonamide hypersensitivity reactions had a 3-fold to 6-fold higher incidence of dermatologic reactions than did the entire arthritis trial cohort. Although dermatologic reactions occurred with greater frequency in patients with a history of sulfonamide hypersensitivity, the trend was consistent across all 3 treatment groups (celecoxib, NSAIDs, and placebo). According to these data and structural and metabolic differences between sulfonamides, the potential for cross-allergenicity between celecoxib and other sulfonamide-containing medications appears comparable to that of placebo and nonsulfonamide-containing NSAIDs. Additionally, the risk of allergic reactions with celecoxib appears comparable to that of placebo and comparator NSAIDs. Prospective trials are needed to confirm these findings.",2000.0,0,1
29,10664917,"Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial.",P T Leese; R C Hubbard; A Karim; P C Isakson; S S Yu; G S Geis,"Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit cyclooxygenase-1 (COX-1), an enzyme critical to normal platelet function, and COX-2, which mediates inflammatory response mechanisms. Celecoxib, an antiarthritic agent that inhibits COX-2 but spares COX-1 at therapeutic doses, is expected to have minimal effects on platelet function. A double-blind, randomized, placebo-controlled study of 10 days' duration was conducted in 24 healthy adults to compare the effects on platelet function of a supratherapeutic dose of celecoxib (600 mg bid) with a standard dose of naproxen (500 mg bid), a conventional NSAID. Ex vivo platelet aggregation in response to standard agonists (collagen, arachidonate, or U46619 [a thromboxane A2 receptor agonist]), bleeding time, and serum thromboxane B2 (TxB2) level were measured. Unlike celecoxib or placebo, naproxen produced statistically significant reductions in platelet aggregation and serum TxB2 levels and increased bleeding time. The results indicate that even at supratherapeutic doses, celecoxib will not interfere with normal mechanisms of platelet aggregation and hemostasis, supporting the premise that celecoxib is COX-1 sparing relative to conventional NSAIDs.",2000.0,0,0
30,10693877,"Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double-blind, placebo-controlled trial. The Rofecoxib Osteoarthritis Endoscopy Multinational Study Group.",C Hawkey; L Laine; T Simon; A Beaulieu; J Maldonado-Cocco; E Acevedo; A Shahane; H Quan; J Bolognese; E Mortensen,"This randomized, double-blind study tested the hypothesis that rofecoxib, a drug that specifically inhibits cyclooxygenase 2, would cause fewer gastroduodenal ulcers than ibuprofen (in a multicenter trial), and its side effects would be equivalent to those of placebo (in a prespecified analysis combining the results with another trial of identical design). Seven hundred seventy-five patients with osteoarthritis were randomized to receive rofecoxib at a dosage of 25 mg or 50 mg once daily, ibuprofen 800 mg 3 times daily, or placebo. Gastroduodenal ulceration was assessed by endoscopy at 6, 12, and (for active treatment) 24 weeks. The primary and secondary end points were the incidence of gastroduodenal ulcers at 12 and 24 weeks, respectively. Ulcers were significantly less common (P < 0.001) following treatment with rofecoxib (25 mg or 50 mg) than with ibuprofen after 12 weeks (5.3% and 8.8% versus 29.2%, respectively) or 24 weeks (9.9% and 12.4% versus 46.8%, respectively). In the combined analysis, the 12-week ulcer incidence with 25 mg rofecoxib (4.7%) and with placebo (7.3%) satisfied prespecified criteria for equivalence. At 2-4 times the therapeutically effective dose, rofecoxib caused fewer endoscopically detected ulcers than did ibuprofen. Rofecoxib at a dose of 25 mg (the highest dose recommended for osteoarthritis) satisfied prespecified criteria for equivalence to placebo.",2000.0,1,1
31,10695097,A comparison of nimesulide beta cyclodextrin and nimesulide in postoperative dental pain.,G Scolari; F Lazzarin; C Fornaseri; V Carbone; S Rengo; M Amato; D Cicciù; D Braione; S Argentino; A Morgantini; C Bassetti; M Tramèr; G C Monza,"The aim of this study was to assess the efficacy and tolerability of single doses of nimesulide beta cyclodextrin compared with nimesulide in patients with dental pain following surgical procedures. This was a randomised, double-blind, between-patient, multicentre study involving 148 outpatients suffering from moderate to severe pain, who received single doses of either 400 mg nimesulide beta cyclodextrin or 100 mg nimesulide. The principal criterion for efficacy was pain intensity assessed on a visual analogue scale (VAS) 15 minutes after drug intake. Pain intensity was further evaluated 30, 45, 90, 120, 180, 240 and 360 minutes after dosing. Pain relief was evaluated at the same time points by means of a categorical scale. The time point of first pain relief, the use of rescue medication and the global evaluation of efficacy were also recorded. The reduction in pain intensity was significantly more pronounced in the nimesulide beta cyclodextrin group at 15, 30, 45 and 60 minutes (p < 0.01). Pain relief was significantly greater (p < 0.05) and more rapid with nimesulide beta cyclodextrin. In the patient overall assessment of efficacy, nimesulide beta cyclodextrin and nimesulide were rated excellent or good by 95% and 92% respectively; only one patient in the nimesulide beta cyclodextrin group needed rescue medication. Both study drugs were effective and well tolerated in the treatment of acute dental pain, with nimesulide beta cyclodextrin showing a faster onset of analgesic action.",2000.0,0,0
32,10743445,Effect of meloxicam on postoperative pain after abdominal hysterectomy.,J P Thompson; P Sharpe; S Kiani; O Owen-Smith,"We studied 36 patients, allocated randomly to receive meloxicam 15 mg rectally (n = 18) or placebo suppository (n = 18) before total abdominal hysterectomy in a double-blind study. Visual analogue scores for pain at rest (P < 0.005), on movement (P < 0.05) and on coughing (P < 0.05) were significantly decreased in the meloxicam group during the first 24 h after surgery. Mean 24-h PCA morphine requirements were 33.2 (SD 16.9) mg and 38.2 (20.8) mg in the meloxicam and placebo groups, respectively (ns). There was no difference in the incidence of nausea, vomiting or sedation between groups.",2000.0,0,0
33,10769425,[Concept for nationwide cooperation in planning and implementing multicenter studies].,R Rau,"In Germany, good clinical multicenter studies that are not supported by pharmaceutical companies are rarely performed. Good supranational industry-sponsored studies are usually aimed at the registration of new (expensive) drugs. The preconditions for co-operation in conducting industry-independent studies which are of interest for the scientific community have been improved substantially in Germany by instituting the working group of co-operating arthritis centers, the so-called core documentation where 32,000 patients with rheumatic conditions were documented in 1997 and the institution of a sophisticated information system (""RheumaNet""). The executive board of the German Rheumatology Association has set up an ""ad hoc commission"" that agreed to institute a ""Committee for the Coordination of Clinical Studies in Rheumatic Diseases"". In this committee rheumatologists subspecialized from medicine, orthopedic, pediatrics working in universities, hospitals and private practice as well as specialists in statistics and epidemiology shall be represented. In principle this committee is independent of the co-operating arthritis centers and the RheumaNet. All members of the German Rheumatology Association are invited to cooperate with this committee by contributing to the clinically important questions and participating in clinical studies. The committee has to define key questions in rheumatology and shall plan and organize multicenter studies to answer these questions. In addition, study protocols of pharmaceutical companies may be examined as to their importance, quality, and feasibility.",2000.0,0,0
34,10788528,Cost-effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs)-what makes a NSAID good value for money?,N Freemantle,,2000.0,0,1
35,10811855,Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation.,B F McAdam; I A Mardini; A Habib; A Burke; J A Lawson; S Kapoor; G A FitzGerald,"To examine the role of cyclooxygenase (COX) isozymes in prostaglandin formation and oxidant stress in inflammation, we administered to volunteer subjects placebo or bolus injections of lipopolysaccharide (LPS), which caused a dose-dependent increase in temperature, heart rate, and plasma cortisol. LPS caused also dose-dependent elevations in urinary excretion of 2,3-dinor 6-keto PGF(1alpha) (PGI-M) and 11-dehydro thromboxane B(2) (Tx-M). Platelet COX-1 inhibition by chronic administration of low-dose aspirin before LPS did not alter the symptomatic and febrile responses to LPS, but the increment in urinary PGI-M and Tx-M were both partially depressed. Pretreatment with ibuprofen, a nonspecific COX inhibitor, attenuated the febrile and systemic response to LPS and inhibited prostanoid biosynthesis. Both celecoxib, a selective COX-2 inhibitor, and ibuprofen attenuated the pyrexial, but not the chronotropic, response to LPS. Experimental endotoxemia caused differential expression of the COX isozymes in monocytes and polymorphonuclear leucocytes ex vivo. LPS also increased urinary iPF(2alpha)-III, iPF(2alpha)-VI, and 8,12-iso-iPF(2alpha)-VI, isoprostane (iP) indices of lipid peroxidation, and none of the drugs blunted this response. These studies indicate that (a) although COX-2 predominates, both COX isozymes are induced and contribute to the prostaglandin response to LPS in humans; (b) COX activation contributes undetectably to lipid peroxidation induced by LPS; and (c) COX-2, but not COX-1, contributes to the constitutional response to LPS in humans.",2000.0,0,0
36,10817549,"Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Rofecoxib Phase III Protocol 035 Study Group.",G W Cannon; J R Caldwell; P Holt; B McLean; B Seidenberg; J Bolognese; E Ehrich; S Mukhopadhyay; B Daniels,"To compare the clinical efficacy of rofecoxib, a specific inhibitor of cyclooxygenase 2 (COX-2), with that of diclofenac in patients with osteoarthritis (OA) and to evaluate the safety and tolerability of rofecoxib. We performed a randomized, double-blind, active comparator-controlled trial in 784 adults with OA of the knee or hip. Patients were randomized to 1 of 3 treatment groups: 12.5 mg of rofecoxib once daily, 25 mg of rofecoxib once daily, and 50 mg of diclofenac 3 times daily. Clinical efficacy and safety were evaluated over a 1-year continuous treatment period. Rofecoxib at dosages of 12.5 and 25 mg demonstrated efficacy that was clinically comparable to that of diclofenac, as assessed by all 3 primary end points according to predefined comparability criteria. Results from secondary end points were consistent with those of the primary end points. There were small statistical differences favoring diclofenac for 2 of the end points. All treatments were well tolerated. Rofecoxib was well tolerated and provided efficacy that was clinically comparable, according to predefined statistical criteria, to that of 150 mg of diclofenac per day in this 1-year study. Specific inhibition of COX-2 provided therapeutic efficacy in OA.",2000.0,1,1
37,10823362,"Efficacy and tolerability of meloxicam in an observational, controlled cohort study in patients with rheumatic disease.",F Degner; R Sigmund; H Zeidler,"Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase-2 without affecting platelet aggregation. The goal of this study was to assess the efficacy and tolerability of meloxicam under natural prescribing conditions for up to 6 months. This was a multicenter, prospective, observational cohort study. Participating centers were randomized to 1 of 2 groups: the meloxicam-only group, and the group who received comparator NSAIDs (ie, diclofenac, ibuprofen, piroxicam, or indomethacin). A total of 4526 patients received either meloxicam (n = 2530) or a comparator NSAID (n = 1996). Treatment groups were comparable in terms of observed efficacy measures. Meloxicam patients had significantly lower rates of reported gastrointestinal (GI) adverse drug reactions (1.80% vs 3.20%; P = 0.003), including dyspepsia (0.08% vs 0.35%; P = 0.049), abdominal pain (0.91% vs 1.90%; P = 0.006), gastritis (0.08% vs 0.60%; P = 0.002), and GI bleeding (0.08% vs 0.50%; P = 0.007), compared with those receiving comparator NSAIDs. There was evidence that meloxicam was prescribed preferentially to patients who had not responded to NSAIDs previously, who had previously experienced NSAID-induced side effects (and so were at high risk for developing NSAID-induced GI toxicity), or who were more seriously impaired. The nonrandomized and unblinded nature of this study limits the conclusions that can be drawn concerning efficacy or tolerability. Nevertheless, the study results are consistent with the favorable GI tolerability seen with meloxicam in double-blind comparative trials.",2000.0,0,1
38,10826459,Effects of celecoxib and naproxen on renal function in the elderly.,A Whelton; G Schulman; C Wallemark; E J Drower; P C Isakson; K M Verburg; G S Geis,"To compare the effects of celecoxib, a cyclooxygenase 2-specific inhibitor, with the nonspecific cyclooxygenase 1 and 2 inhibitor naproxen on renal function in 29 healthy elderly subjects in a single-blind, randomized, crossover study. Subjects received either celecoxib, 200 mg twice daily, for 5 days followed by celecoxib, 400 mg twice daily, for the next 5 days, or they received naproxen, 500 mg twice daily, for 10 days. After a 7-day washout, subjects were crossed over to receive the other regimen. After the first dose, the trend was for a greater decrease in glomerular filtration rate with naproxen (-5.31 mL/min per 1.73 m2) compared with celecoxib (-0.86 mL/min per 1.73 m2). The treatment difference became statistically significant on day 6 (-7.53 vs -1.11 mL/min per 1.73 m2 for naproxen and celecoxib, respectively; P=.004). Urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion was significantly reduced from baseline across the treatment interval with both celecoxib and naproxen (P< or =.04). There were no significant differences in prostaglandin excretion between these 2 agents (P> or =.07). Small, transient decreases (P<.05) in urinary sodium excretion were observed after the initiation of both celecoxib and naproxen treatment. Sodium excretion values returned to baseline by the end of the study. The results indicate that cyclooxygenase 2-specific inhibition in healthy elderly subjects may spare renal hemodynamic function, although the effects on sodium excretion, as well as urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion, appear to be similar to those of nonspecific cyclooxygenase inhibitors such as naproxen.",2000.0,0,0
39,10851109,"Treatment of acute low back pain with the COX-2-selective anti-inflammatory drug nimesulide: results of a randomized, double-blind comparative trial versus ibuprofen.",T Pohjolainen; A Jekunen; L Autio; H Vuorela,"A prospective, randomized double-blind comparative trial. To evaluate the efficacy and tolerability of nimesulide, a cyclooxygenase (COX)-2-selective anti-inflammatory agent versus ibuprofen in patients with acute lumbosacral back pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been more effective than placebo in patients with uncomplicated acute low back pain in previous randomized controlled trials. The efficacy and tolerability of a new COX-2-selective anti-inflammatory drug have not yet been established. One hundred four patients aged 18-65 years with acute low back pain were enrolled. The patients were randomly allocated either to oral nimesulide (100 mg twice daily for 10 days) or oral ibuprofen (600 mg three times daily for 10 days). Outcome measures on a visual analog scale were an average of the pain intensity and the pain relief, stiffness in the back, functional status, and the results of physical examinations. All side effects were recorded at each visit. With both study therapies, there was a clear improvement in all measured parameters of the pain and back function parameters measured from the third day of treatment onward. The patients' capacity for daily tasks, showed improvement in both groups (P < 0. 001), but a statistically significant difference was found between the two groups in favor of the nimesulide group (P < 0.05) after 10 days. Nimesulide was more effective than ibuprofen in improved lateral bending measurements (P = 0.026). Nimesulide and ibuprofen provided similar degrees of improvement in the modified Schober tests and in the pain intensity and back stiffness scores. More gastrointestinal side effects were reported with ibuprofen than nimesulide, and the comparison showed a trend (P = 0.067). Ten side effects occurred in the nimesulide group in 7 (13%) patients and 13 in the ibuprofen group in 11 (21%) patients. The results confirmed that the COX-2-selective inhibitor nimesulide is an effective and well-tolerated agent for use in general practices to treat acute low back pain. The incidence of gastrointestinal side effects seems to be lower with nimesulide than with ibuprofen.",2000.0,0,0
40,10868317,Celecoxib does not significantly alter the pharmacokinetics or hypoprothrombinemic effect of warfarin in healthy subjects.,A Karim; D Tolbert; A Piergies; R C Hubbard; K Harper; C B Wallemark; M Slater; G S Geis,"The objective of this study was to determine the effects of celecoxib, an anti-inflammatory/analgesic agent that primarily inhibits COX-2 and not COX-1 at therapeutic doses, on the steady-state pharmacokinetic profile and hypoprothrombinemic effect of racemic warfarin in healthy volunteers. Twenty-four healthy adult volunteers on maintenance doses of racemic warfarin (2-5 mg daily), stabilized to prothrombin times (PT) 1.2 to 1.7 times pretreatment PT values for 3 consecutive days, were randomized to receive concomitant celecoxib (200 mg bid) or placebo for 7 days in an open-label, multiple-dose, randomized, placebo-controlled, parallel-group study of warfarin pharmacokinetics and PT. Steady-state exposure of S- and R-warfarin (area under the curve [AUC]) and maximum plasma concentration (Cmax) in subjects receiving celecoxib were within 2% to 8% of the warfarin AUC and Cmax in subjects receiving placebo during the concomitant treatment period. In addition, PT values were not significantly different in subjects receiving warfarin and celecoxib concomitantly compared with subjects receiving warfarin and placebo. In conclusion, concomitant administration of celecoxib has no significant effect on PT or steady-state pharmacokinetics of S- or R-warfarin in healthy volunteers.",2000.0,0,0
41,10871971,A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Rofecoxib/Ibuprofen Comparator Study Group.,R Day; B Morrison; A Luza; O Castaneda; A Strusberg; M Nahir; K B Helgetveit; B Kress; B Daniels; J Bolognese; D Krupa; B Seidenberg; E Ehrich,"Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). It is not known whether a specific inhibitor of COX-2 will provide efficacy in osteoarthritis (OA) comparable with NSAIDs. Therefore, we compared the efficacy and safety of the rofecoxib, which specifically inhibits COX-2, with those of the NSAID ibuprofen in patients with OA. To compare the clinical efficacy and tolerability of rofecoxib (12.5 and 25 mg once daily) with ibuprofen (800 mg 3 times daily). A randomized, double-blind trial of 809 adults with OA was conducted. Patients with OA in whom the knee or hip was the primary source of pain were randomized to 1 of 4 treatment groups on demonstration of disease activity: placebo; rofecoxib, 12.5 or 25 mg once daily; or ibuprofen, 800 mg 3 times daily. Clinical efficacy and safety were monitored during a 6-week treatment period. Both doses of rofecoxib demonstrated efficacy clinically comparable with ibuprofen as assessed by 3 primary end points (pain walking on a flat surface [Western Ontario and McMaster Universities Osteoarthritis Index], patient global assessment of response to therapy, and investigator global assessment of disease status) according to predefined comparability criteria. Both rofecoxib doses and the ibuprofen dose provided significantly (P<.001) greater efficacy than placebo on all primary end points. Results from secondary end points were consistent with those of the primary end points. All treatments were well tolerated; the overall incidence rates of clinical adverse experiences were not significantly different (P>.05) among the treatment groups. Rofecoxib was well tolerated and provided clinical efficacy comparable with a high dose of the NSAID ibuprofen.",2000.0,1,1
42,10874062,"The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.",G Steinbach; P M Lynch; R K Phillips; M H Wallace; E Hawk; G B Gordon; N Wakabayashi; B Saunders; Y Shen; T Fujimura; L K Su; B Levin; L Godio; S Patterson; M A Rodriguez-Bigas; S L Jester; K L King; M Schumacher; J Abbruzzese; R N DuBois; W N Hittelman; S Zimmerman; J W Sherman; G Kelloff,"Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2. We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. At base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P=0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P=0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P=0.33 for the comparison with placebo) and 14.6 percent (P=0.09), respectively. The incidence of adverse events was similar among the groups. In patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps.",2000.0,0,0
43,10877012,"Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans.",M Depré; E Ehrich; A Van Hecken; I De Lepeleire; A Dallob; P Wong; A Porras; B J Gertz; P J De Schepper,"Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (Vioxx), characterized in vitro as a COX-2 inhibitor. Four panels of healthy men (n = 8 per panel) were administered rofecoxib (n = 6) (25, 100, 250, 375 mg) or placebo (n = 2) once daily on day 1 and days 3-14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time points post-dose. Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9 h to 17.5 h after multiple dosing with an accumulation ratio close to 2 for all doses. COX-2 inhibitory activity as assessed by average inhibition of whole blood lipopolysaccharide-stimulated prostaglandin E2 over the 8-h post-dose period on day 14 was 0.3, 67, 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatment groups, respectively. No treatment group showed significant inhibition of COX-1 as assessed by thromboxane B2 generation in clotting whole blood. Side effects were mild and transient. The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis.",2000.0,0,0
44,10877734,"Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial.",S K Swan; D W Rudy; K C Lasseter; C F Ryan; K L Buechel; L J Lambrecht; M B Pinto; S C Dilzer; O Obrda; K J Sundblad; C P Gumbs; D L Ebel; H Quan; P J Larson; J I Schwartz; T A Musliner; B J Gertz; D C Brater; S L Yao,"Most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1), whose inhibition is associated with gastrointestinal ulceration, and COX-2, whose inhibition is associated with therapeutic benefits. Although agents that do not produce COX-1 activity may have fewer adverse effects, targeted disruption of the COX-2 allele in mice has resulted in severe renal problems, suggesting that COX-2 inhibition may also produce adverse effects. To determine the effect of rofecoxib, a member of the coxib class of drugs and a specific inhibitor of the COX-2 enzyme, on renal function in elderly patients. A randomized, three-period, single-dose crossover study and a randomized, parallel-group, multiple-dose study. Clinical research units. 75 patients 60 to 80 years of age. In the first study, single doses of rofecoxib, 250 mg (about 5-fold to 20-fold the recommended dose); indomethacin, 75 mg; and placebo were administered to 15 patients. In the second study, multiple doses of rofecoxib, 12.5 or 25 mg/d; indomethacin, 50 mg three times daily; or placebo were administered to 60 patients. Patients in both studies received a low-sodium diet Glomerular filtration rate, creatinine clearance, and urinary and serum sodium and potassium values. Compared with placebo, single doses of rofecoxib and indomethacin decreased the glomerular filtration rate by 0.23 m/s (P < 0.001) and 0.18 mL/s (P = 0.003), respectively. In contrast, respective decreases of 0.14, 0.13, and 0.10 mL/s were observed after multiple doses of rofecoxib, 12.5 mg/d (P = 0.019); rofecoxib, 25 mg (P = 0.029), and indomethacin (P = 0.086) were administered. Changes in creatinine clearance and serum and urinary sodium and potassium were less pronounced. The effects of COX-2 inhibition on renal function are similar to those observed with nonselective NSAIDs. Thus, COX-2 seems to play an important role in human renal function.",2000.0,0,1
45,10902749,Determining minimally important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis.,M Kosinski; S Z Zhao; S Dedhiya; J T Osterhaus; J E Ware,"To define clinically meaningful changes in 2 widely used health-related quality of life (HQL) instruments in studies of patients with rheumatoid arthritis (RA). Patients with RA (n = 693) who were enrolled in 2 double-blind, placebo-controlled clinical trials completed the Short Form 36 (SF-36) modified health survey and the Health Assessment Questionnaire (HAQ) disability index at baseline and 6-week followup assessments. Data on 5 RA severity measures were also collected at baseline and at 6 weeks (patient and physician global assessments, joint swelling and tenderness counts, and global pain assessment). Comparison of changes in the SF-36 scales and HAQ scores was made between groups of patients known to differ in the level of change on each RA severity measure. With few exceptions, changes in the SF-36 and HAQ scores were different between patients who differed in the level of change on each RA severity measure. Changes in the SF-36 and HAQ scores were more strongly related to changes in the patient and physician global assessments and patient pain assessment than to changes in the joint swelling and tenderness counts. Based on these results, minimally important changes in the SF-36 scales and HAQ disability scores were determined, which will be useful in interpreting HQL results in clinical trials.",2000.0,0,1
46,10925968,"Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor.",J L Goldstein; F E Silverstein; N M Agrawal; R C Hubbard; J Kaiser; C J Maurath; K M Verburg; G S Geis,"The aim of this study was to assess the rate of upper gastrointestinal (UGI) ulcer complications (bleeding, perforation, or gastric outlet obstruction) associated with celecoxib, a specific COX-2 inhibitor, compared with the rate associated with nonspecific, nonsteroidal anti-inflammatory drugs (NSAIDs). A pooled analysis was conducted of 14 multicenter, double-blind, randomized, controlled trials (RCTs) and a separate analysis of one long-term open label trial that assessed the efficacy and safety of celecoxib for symptomatic treatment of arthritis. The RCTs enrolled 11,008 patients with osteoarthritis or rheumatoid arthritis treated for 2-24 wk; the long-term open label trial enrolled 5,155 patients receiving celecoxib for a maximum of 2 yr. In the RCTs, patients were randomly assigned to receive placebo (n = 1,864; 208 patient-years), celecoxib 25-400 mg b.i.d. (n = 6,376; 1,020 patient-years), or a comparator NSAID (n = 2,768; 535 patient-years); NSAIDs were naproxen 500 mg b.i.d., diclofenac 50 or 75 mg b.i.d., or ibuprofen 800 mg t.i.d.). In the long-term, open-label trial, patients received celecoxib 100-400 mg b.i.d. for up to 2 yr (n = 5,155; 5,002 patient-years). The principal outcome measure of this analysis was development of a UGI ulcer complication, which was prospectively defined as bleeding, perforation, or gastric outlet obstruction. Ulcer complications were assessed and adjudicated by persons blinded to the patient's treatment assignment or the study in which the patient participated. In the RCTs, UGI ulcer complications occurred in no placebo patients (0 of 1,864 patients), in 2 of 6,376 celecoxib patients (0.03%), and in 9 of 2,768 patients receiving an NSAID (0.33%), corresponding to annual incidences of 0.20% for celecoxib (p > 0.05 vs placebo) and 1.68% for NSAIDs (p = 0.002 vs celecoxib and placebo). In the long-term open-label trial, nine UGI ulcer complications occurred, for an incidence of 0.17% and an annualized incidence of 0.18%. The incidence of UGI ulcer complications associated with celecoxib was 8-fold lower than with nonspecific NSAIDs. The incidence of ulcer complications observed in celecoxib-treated patients was similar to that in patients receiving placebo in the RCTs, and to that in non-NSAID users reported in the literature.",2000.0,0,1
47,10955327,"Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo.",W G Bensen; S Z Zhao; T A Burke; R A Zabinski; R W Makuch; C J Maurath; N M Agrawal; G S Geis,"To determine the upper gastrointestinal (GI) tolerability of celecoxib, naproxen, and placebo in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). An analysis of 5, 12-week, randomized, double blind, parallel group, placebo controlled clinical trials was conducted. In these trials, patients were randomized to: naproxen 500 mg bid (n = 1,099), placebo (n = 1,136), celecoxib 50 mg bid (n = 690) (subtherapeutic dose), celecoxib 100 mg (n = 1,131) or 200 mg bid (n = 1,125) (therapeutic dose), or celecoxib 400 mg bid (n = 434) (supratherapeutic dosage). The incidence and time until moderate to severe abdominal pain, dyspepsia, nausea, and any of the aforementioned 3 upper GI symptoms (composite endpoint) were determined using time-to-event analysis. The cumulative incidences of moderate to severe abdominal pain, dyspepsia, or nausea (composite endpoint) were: naproxen 500 mg (12.0%; 95% CI 9.9%-14.0%), celecoxib 50 mg bid (7.1%; 95% CI 5.0%-9.2%), celecoxib 100 mg bid (7.8%; 95% CI 6.0%-9.5%), celecoxib 200 mg bid (8.1%; 95% CI 6.4%-9.9%), celecoxib 400 mg bid (6.0%; 95% CI 3.6%-8.4%), and placebo (8.5%; 95% CI 6.5%-10.8%). After controlling for independent predictors of the composite endpoint, relative risks (RR) for the various treatments relative to naproxen 500 mg bid were: celecoxib 50 mg (RR 0.54; 95% CI 0.37-0.77; p < 0.001), celecoxib 100 mg (RR 0.60; 95% CI 0.45-0.80; p < 0.001), celecoxib 200 mg bid (RR 0.63; 95% CI 0.47-0.83; p = 0.001), celecoxib 400 mg bid (RR 0.56; 95% CI 0.35-0.89; p = 0.015), and placebo (RR 0.63; 95% CI 0.47-0.85; p = 0.002). After controlling for independent predictors of the composite endpoint, celecoxib treatment group patients did not differ from placebo patients when reporting the composite endpoint, with p values ranging from 0.40 to 0.96. The upper GI tolerability of celecoxib is superior to naproxen. A dose-response relationship between celecoxib and upper GI symptoms was not apparent.",2001.0,0,1
48,10962812,[Celecoxib vs indomethacin and acute gastric lesions in rats].,O M Laudanno; J M Esnarriaga; J A Cesolari; C B Maglione; L J Aramberry; J S Sambrano; G Piombo; L Rista,"In 5 random groups of Wistar rats (n = 15 for each group), ulcerogenic doses of NSAIDs COX-1-COX-2 inhibitors such as indomethacin were compared with Celecoxib (COX-2 inhibitor); the production of antrum gastric ulcers and bowel and colon necrotic areas was studied. Celecoxib was given each 12 hs orally and subcutaneously during 5 days and gastrointestinal lesions were not found; in contrast, Celecoxib given after indomethacin aggravated antrum gastric ulcers (p < 0.001); intestinal massive necrosis and death were observed in all the rats. We conclude that Celecoxib does not induce gastrointestinal lesions in healthy mucosa; in contrast, Celecoxib amplifies the gastrointestinal lesions induced by indomethacin.",2000.0,0,0
49,10971303,Steady-state pharmacokinetics of lithium in healthy volunteers receiving concomitant meloxicam.,D Türck; G Heinzel; G Luik,"This open, controlled study investigated the effect of concomitant 15 mg oral meloxicam on the pharmacokinetics of lithium in healthy male volunteers. On days 1-14 lithium was coadministered with meloxicam to 16 volunteers; on days 10-14 lithium was administered in individualized dosage regimes to achieve stable lithium plasma concentrations in the lower therapeutic range of 0.3-0.7 mmol l(-1). A 12 h steady-state concentration profile for lithium was obtained at day 14, after which meloxicam was withdrawn. The lithium dose remained unchanged from day 15 to day 22, at which time a second lithium concentration profile was determined. Lithium and meloxicam were well tolerated throughout the study and all 16 volunteers completed the study. Lithium predose concentrations (Cpre,ss) and area under the curve (AUCss) values both increased by 21% (paired t-test P = 0.0002; 90% confidence intervals for test/reference ratios: 113-130% and 115-128%, respectively) when lithium was coadministered with meloxicam compared with values obtained for lithium alone. The geometric mean lithium Cpre,ss was 0.65 mmol l(-1) when coadministered with meloxicam and 0.54 mmol l(-1) for lithium alone. Lithium Cmax,ss values were increased by 16% by coadministration of meloxicam, from 0.97 mmol l(-1) to 1.12 mmol l(-1). The total plasma clearance of lithium was lower with concomitant meloxicam administration (82.5% of value for lithium alone). Meloxicam (15 mg) moderately increased the plasma concentration of lithium in healthy volunteers, but by a magnitude thought to be of low clinical relevance. Nevertheless, lithium plasma concentrations should be closely monitored in patients receiving concomitant meloxicam and lithium therapy.",2001.0,0,0
50,10974182,"A randomized trial measuring fecal blood loss after treatment with rofecoxib, ibuprofen, or placebo in healthy subjects.",R H Hunt; B Bowen; E R Mortensen; T J Simon; C James; A Cagliola; H Quan; J A Bolognese,"Gastrointestinal microbleeding, as assessed by the measurement of (51)chromium-labeled red blood cells, is a marker of the mucosal injury associated with the use of nonsteroidal anti-inflammatory drugs. This study tested the hypotheses that cyclooxygenase-2 specific inhibition with rofecoxib would cause less fecal blood loss than a therapeutic dose of ibuprofen and would be equivalent to placebo. In this randomized, double-blind group study, gastrointestinal blood loss was assessed by measurement of fecal (51)chromium radioactivity during a 1-week placebo baseline period and during 4 weeks of treatment with rofecoxib (25 mg or 50 mg once daily), ibuprofen (800 mg three times daily), or placebo in 67 healthy subjects. Gastrointestinal blood loss during treatment weeks 2 to 4 (versus the baseline period) was expressed as the geometric mean ratio of fecal radioactivity in weeks 2 to 4 compared with baseline. Ibuprofen caused significantly (P <0.001) greater gastrointestinal blood loss (geometric mean ratio of 5.2, 95% confidence interval [CI]: 4.2 to 6.3) than the 25-mg dose of rofecoxib (2.6, 95% CI: 2.2 to 3.1), the 50-mg dose of rofecoxib (2.6, 95% CI: 2.2 to 3.0), or placebo (2.1, 95% CI: 1.8 to 2.5). In contrast, gastrointestinal blood loss with both doses of rofecoxib were equivalent to placebo by a predetermined clinical similarity bound. In healthy subjects, treatment with rofecoxib, at 2 to 4 times the doses that are currently recommended for the treatment of patients with osteoarthritis, produced significantly less fecal blood loss than a therapeutic dose of ibuprofen and was equivalent to placebo.",2000.0,0,0
51,10979111,Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.,F E Silverstein; G Faich; J L Goldstein; L S Simon; T Pincus; A Whelton; R Makuch; G Eisen; N M Agrawal; W F Stenson; A M Burr; W W Zhao; J D Kent; J B Lefkowith; K M Verburg; G S Geis,"Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown. To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs. The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000. Three hundred eighty-six clinical sites in the United States and Canada. A total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months. Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (</=325 mg/d) was permitted. Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period. For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P =.09) and 2. 08% vs 3.54% (P =.02), respectively. For patients not taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P =.04) and 1.40% vs 2.91% (P =.02). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01% vs 2.12% (P =.92) and 4.70% vs 6.00% (P =.49). Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use. In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly. JAMA. 2000;284:1247-1255",2000.0,1,1
52,10986213,COX-2 inhibition with rofecoxib does not increase intestinal permeability in healthy subjects: a double blind crossover study comparing rofecoxib with placebo and indomethacin.,G Sigthorsson; R Crane; T Simon; M Hoover; H Quan; J Bolognese; I Bjarnason,"Acute and chronic use of non-steroidal anti-inflammatory drugs can increase intestinal permeability. Rofecoxib, which selectively inhibits cyclooxygenase 2 (COX-2), is a novel anti-inflammatory drug with the potential to produce minimal gastrointestinal toxic effects while retaining clinical efficacy. To assess the potential for rofecoxib to affect the intestine adversely, in comparison with placebo and indomethacin. Thirty nine healthy subjects (aged 24-30 years). We performed a four period crossover trial to assess intestinal permeability before and after seven days of treatment. Permeability was measured by the urinary ratio of chromium-51 labelled ethylene diamine tetraacetate ((51)CrEDTA)/L-rhamnose (five hour collection). Indomethacin 50 mg three times daily produced greater increases in intestinal permeability compared with placebo or rofecoxib (25 or 50 mg) (p< or = 0.001); rofecoxib was not significantly different from placebo. Mean day 7 to baseline ratios (95% confidence intervals) for (51)CrEDTA/L-rhamnose were 0.97 (0.82, 1.16), 0.80 (0.68, 0.95), 0.98 (0.82, 1.17), and 1.53 (1.27, 1.85) for placebo, rofecoxib 25 mg, rofecoxib 50 mg, and indomethacin groups, respectively. Rofecoxib was generally well tolerated. In this study, treatment for one week with indomethacin 50 mg three times daily significantly increased intestinal permeability compared with placebo, while treatment with rofecoxib 25 mg or 50 mg daily did not. The absence of a significant effect of rofecoxib on intestinal permeability at doses at least twice those recommended to treat osteoarthritis was consistent with other studies that have demonstrated little or no injury to the gastrointestinal mucosa associated with rofecoxib therapy.",2001.0,0,0
53,10990235,The prevention of chronic NSAID induced upper gastrointestinal toxicity: a Cochrane collaboration metaanalysis of randomized controlled trials.,A Rostom; G Wells; P Tugwell; V Welch; C Dubé; J McGowan,"To review the effectiveness of common interventions for the prevention of nonsteroidal antiinflammatory drug (NSAID) induced upper gastrointestinal (GI) toxicity. Randomized controlled clinical trials (RCT) of prostaglandin analogs, H2-receptor antagonists (H2RA), or proton pump inhibitors (PPI) for the prevention of chronic NSAID induced upper GI toxicity were identified through electronic databases, the Cochrane control trials register, conference proceedings, and by contacting content experts and companies. Outcome measures investigated were endoscopic ulcers, ulcer complications, symptoms, overall dropouts, dropouts due to symptoms, and study quality. Thirty-four RCT met the inclusion criteria. All doses of misoprostol significantly reduced the risk of endoscopic ulcers. Misoprostol 800 microg/day was superior to 400 microg/day for the prevention of endoscopic gastric ulcers (RR 0.18, RR 0.38, respectively; p = 0.0055). A dose-response relationship was not seen with duodenal ulcers. Misoprostol caused diarrhea at all doses, although significantly more at 800 than 400 microg/day (p = 0.0012). Misoprostol was the only prophylactic agent documented to reduce ulcer complications. Standard doses of H2RA were effective at reducing the risk of endoscopic duodenal (RR 0.24, 95% CI 0.10-0.57) but not gastric ulcers (RR 0.73, 95% CI 0.50-1.09). Both double dose H2RA and PPI were effective at reducing the risk of endoscopic duodenal and gastric ulcers (RR 0.44, 95% CI 0.26-0.74 and RR 0.37, 95% CI 0.27-0.51, respectively, for gastric ulcer) and were better tolerated than misoprostol. Misoprostol, PPI, and double dose H2RA are effective in preventing chronic NSAID related endoscopic gastric and duodenal ulcers. Lower doses of misoprostol are less effective and are still associated with diarrhea. Only misoprostol 800 microg/day has been directly shown to reduce the risk of ulcer complications.",2001.0,0,0
54,10994617,"Comparison of the intestinal toxicity of celecoxib, a selective COX-2 inhibitor, and indomethacin in the experimental rat.",J A Tibble; G Sigthorsson; R Foster; I Bjarnason,"It is suggested that the gastrointestinal toxicity of conventional non-steroid anti-inflammatory drugs (NSAIDs) is due to a 'topical' effect in addition to inhibition of the mucosal constitutive cyclo-oxygenase-1 (COX-1) enzyme. COX-2 selective inhibitors have been shown to have excellent gastrointestinal tolerability, but it is not known whether this is due to their selectivity and/or a lack of a 'topical' effect. We assessed the effects of celecoxib (a highly selective COX-2 inhibitor) on key pathophysiologic events in NSAID enteropathy. The 'topical' effects of indomethacin and celecoxib were assessed in vitro (coupled mitochondrial respiration) and in vivo (mitochondrial electron microscopy) and the consequences by study of intestinal permeability (51-Cr-labelled ethylenediamine-tetraacetic acid urinary excretion) and inflammation. We also assessed intestinal prostanoid levels (prostaglandin E, PGE) and the propensity of the drugs to induce intestinal ulcers. Indomethacin uncoupled mitochondrial oxidative phosphorylation in vitro and in vivo, caused a significant (P < 0.0001) increase in intestinal permeability, caused mucosal inflammation and a 90% decline in intestinal PGE levels, and was associated with multiple small intestinal ulcers. Celecoxib caused no significant increase in any of these parameters, did not decrease intestinal PGE levels, and caused no intestinal ulcers. The intestinal tolerability of celecoxib appears to be due to a combination of the absence of a 'topical' damaging effect and selective COX inhibition.",2001.0,0,0
55,11002624,A comparative study of subsyde-CR versus meloxicam in rheumatic disorders.,B R Patel,"A prospective, randomised comparative clinical study was conducted in adult patients of either sex presenting with articular and non-articular rheumatic conditions commonly encountered in clinical practice Rheumatoid arthritis, osteo-arthritis, cervical spondylosis, and lumbago/sciatica were the most frequent conditions encountered in both the groups, followed by others like tenosynovitis, frozen shoulder, prolapsed disc, fibrositis, myositis, sprains, strains and so on. The drugs that were employed for therapy were diclofenac in a controlled release formulation employing the DRCM technology (subsyde-CR) and meloxicam in a standard formulation marketed in our country. Both drugs were well tolerated and found to be effective in reducing the signs and symptoms of the disease entities throughout the study period, but subsyde-CR was observed to produce a somewhat greater reduction in signs and symptoms scores that meloxicam, a difference that could be possibly attributed to the greater efficacy of subsyde-CR in non-articular rheumatic conditions. On the basis of the available literature on diclofenac and meloxicam as well as the DRCM technology in formulating subsyde-CR, it is reasonable to conclude that a controlled release formulation of diclofenac based on the DRCM technology offers a safe and effective alternative to other non-steroidal anti-inflammatory drugs such as meloxicam.",2001.0,0,0
56,11003104,Alternative therapies for arthritis of the knee: a triumph of hope over reason?,J M Cuckler,,2001.0,0,0
57,11003457,Multiple sensitivity to NSAID.,R Asero,,2001.0,0,0
58,11020910,"Does nimesulide induce gastric mucosal damage? ""A double-blind randomized placebo-controlled trial"".",S Kapicioglu; A H Baki; M Sari; F Ozdemir; H Kavgaci,"In this study, it was aimed to examine the effect of nimesulide, a selective inhibitor of cox-2 enzyme, to the gastric mucosa and to correlate its effect with aspirin. This study was planned as double-blind, randomized and placebo-controlled. Mean age of voluntary persons (n = 32) was 42.3 +/- 2.7. Divided into 3 groups of volunteers were given randomized placebo (n = 10), aspirin (n = 10) (500 mg aspirin, Bayer) and nimesulide (n = 12) (100 mg mesulid, Pfizer) with 50 mL of water after 12 hours fasting period at 08.00 am. Gastroduodenoscopy was performed to the volunteers 3 hours after each therapy. Endoscopic scores of groups were; placebo: 0.20 +/- 0.13, aspirin: 2.8 +/- 0.46, nimesulide: 1.41 +/- 0.51. Lesion scores both in the aspirin group when compared with nimesulide and placebo groups (P < 0.00002, < 0.03), and in the nimesulide group when compared with the placebo group (P < 0.01) were significantly high. The positivity of Helicobacter pylori of groups was found; 67% in placebo, 72% in aspirin, 71% in nimesulide and there was no statistically significant difference in the groups. It was shown that nimesulide causes significantly serious gastric mucosal lesion when compared with placebo. The lesion score of nimesulide was found less than aspirin. According to the findings, nimesulide should be given carefully just as other analgesics due to the probability of causing gastric lesion.",2001.0,0,1
59,11028250,"Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers.",A Van Hecken; J I Schwartz; M Depré; I De Lepeleire; A Dallob; W Tanaka; K Wynants; A Buntinx; J Arnout; P H Wong; D L Ebel; B J Gertz; P J De Schepper,"Steady-state inhibitory activity of rofecoxib (Vioxx) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was -2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were -5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11-dehydro TXB2, a COX-1-derived product. These data support the contention that rofecoxib is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1.",2001.0,0,0
60,11040354,Nonsteroidal anti-inflammatory drug-induced acute gastric injury in Helicobacter pylori gastritis in Mongolian gerbils.,S Takahashi; T Fujita; A Yamamoto,"We examined the acute ulcerogenic effects of indomethacin and N-(2, cyclohexyloxy-4-nitrophenyl)methane sulfonamide (NS-398) on the gastric mucosa in Helicobacter pylori-infected Mongolian gerbils. H. pylori infection for 4 and 12 weeks caused moderate and severe gastritis, respectively, with cyclooxygenase-2 expression and an increase in prostaglandin E(2) production. In normal animals, gastric injury was caused by indomethacin, but not by NS-398. At 4 weeks infection, gastric lesions were synergistically aggravated by indomethacin, and NS-398 at high doses. However, at 12 weeks, the synergistic effects of indomethacin and NS-398 with H. pylori were not observed. Indomethacin and NS-398 at high doses inhibited prostaglandin E(2) production in both normal and the infected mucosa. NS-398 at low dose reduced only the H. pylori-increased prostaglandin production. These results suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) synergistically aggravate gastric lesions in moderate H. pylori gastritis, but not in severe gastritis. Cyclooxygenase-2 inhibition only might not induce acute gastric injury in H. pylori gastritis.",2001.0,0,0
61,11041902,"Safety and efficacy of meloxicam in the treatment of osteoarthritis: a 12-week, double-blind, multiple-dose, placebo-controlled trial. The Meloxicam Osteoarthritis Investigators.",D Yocum; R Fleischmann; P Dalgin; J Caldwell; D Hall; P Roszko,"Meloxicam (Mobic; Boehringer Ingelheim, Ridgefield, Conn) is an enolic acid derivative of the oxicam group of nonsteroidal anti-inflammatory drugs (NSAIDs) whose mechanism of action may be related to prostaglandin (cyclooxygenase) synthetase inhibition. In previous studies, meloxicam has been found to be safe and effective in the treatment of osteoarthritis (OA) at doses of 7.5 to 15 mg daily. To evaluate a lower dose and a different patient population, we evaluated the efficacy and safety of 3 doses of meloxicam vs placebo and diclofenac for the treatment of OA among patients with symptom exacerbations. In this double-blind, double-dummy, parallel-group, multicenter study, 774 patients with confirmed OA of the hip or knee and a flare were randomized and treated with daily oral administration of meloxicam tablets (at dosages of 3.75, 7.5, or 15 mg/d), diclofenac (100 mg [50 mg twice daily]), or placebo. Treatment was for 12 weeks, with regular assessments for drug safety and efficacy. Safety was assessed by evaluation of adverse events, vital signs, and laboratory data. Primary efficacy variables included the Western Ontario and McMaster University Osteoarthritis (WOMAC) index, the patient's overall assessment of pain, and the patient's and investigator's overall assessment of disease activity. The incidence of all adverse events was lower at each dosage of meloxicam than for diclofenac but greater than for placebo. However, the incidence of gastrointestinal adverse events and dropout rates because of such events was the same for meloxicam as for placebo and lower than for diclofenac. Meloxicam, at 7.5 and 15 mg/d, and diclofenac were statistically significantly more effective than placebo for all end points, while the 3.75-mg/d dosage of meloxicam did not always reach statistical significance for all end points. Efficacy was evident after 2 weeks of treatment, improved with increasing doses, and was maintained until the end of the trial. Meloxicam is a safe and effective medication for the symptomatic treatment of OA. The data support consideration of 7.5 to 15 mg of meloxicam once daily to treat the pain and stiffness of OA, with gastrointestinal tolerability comparable to that of placebo. Arch Intern Med. 2000;160:2947-2954",2001.0,0,1
62,11041909,Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis.,D J Watson; S E Harper; P L Zhao; H Quan; J A Bolognese; T J Simon,"Most nonsteroidal anti-inflammatory drugs (NSAIDs) are nonselective cyclooxygenase (COX-1 and COX-2) inhibitors and are associated with a variety of upper gastrointestinal (GI) tract symptoms. The roles of COX-1 and COX-2 in the pathogenesis of these symptoms are unclear. To test whether COX-2 inhibition with rofecoxib would have greater GI tolerability than nonselective COX-1 and COX-2 inhibition, we compared the incidences of (1) treatment discontinuations for GI adverse events (AEs) and (2) prespecified dyspeptic-type GI AEs among patients with osteoarthritis treated with rofecoxib vs NSAIDs. A prespecified, combined analysis of investigator-reported GI AEs in all 8 double-blind, randomized, phase 2b/3 osteoarthritis trials of rofecoxib was conducted. Patients included men and women with osteoarthritis (N = 5435); there was no upper age limit for entry. Treatments tested included rofecoxib, 12.5, 25, or 50 mg (combined), vs ibuprofen, diclofenac, or nabumetone (combined). Primary outcomes were the time (by survival analysis) to (1) treatment discontinuation due to GI AEs and (2) first reported dyspeptic-type GI AE. Between-treatment comparisons were made by log-rank test. The number of treatment discontinuations caused by GI AEs during 12 months was significantly lower (P=.02) with rofecoxib vs NSAIDs (8.2 vs 12.0 per 100 patient-years; relative risk, 0.70; 95% confidence interval, 0.52-0.94). The incidence of prespecified dyspeptic-type GI AEs during the first 6 months was significantly lower (P=.02) with rofecoxib vs NSAIDs (69.3 vs 85.2 per 100 patient-years; relative risk, 0.85; 95% confidence interval, 0.74-0.97). However, the difference between treatments in dyspeptic-type GI AEs was attenuated after 6 months. Rofecoxib was associated with a lower incidence of treatment discontinuations due to GI AEs over 12 months and a lower incidence of dyspeptic-type GI AEs over 6 months than treatment with nonselective COX inhibitors, or NSAIDs. Arch Intern Med. 2000;160:2998-3003",2001.0,0,1
63,11049912,Postoperative analgesic effects of celecoxib or rofecoxib after spinal fusion surgery.,S S Reuben; N R Connelly,"Nonsteroidal antiinflammatory drugs are recommended for the multimodal management of postoperative pain and may have a significant opioid-sparing effect after major surgery. The analgesic efficacy of the cyclooxygenase-2 nonsteroidal antiinflammatory drugs, celecoxib and rofecoxib, have not been evaluated after major orthopedic surgery. This study was designed to determine whether the administration of a preoperative dose of celecoxib or rofecoxib to patients who have undergone spinal stabilization would decrease patient-controlled analgesia (PCA) morphine use and/or enhance analgesia. We evaluated 60 inpatients undergoing spine stabilization by one surgeon. All patients received PCA morphine. The patients were divided into three groups. Preoperatively, they were given oral celecoxib 200 mg, rofecoxib 50 mg, or placebo. The outcome measures included pain scores and 24-h morphine use at six times during the first 24 postoperative h. The total dose of morphine and the cumulative doses for each of the six time periods were significantly more in the placebo group than in the other two groups. The morphine dose was significantly less in five of the six time intervals in the rofecoxib group compared with the celecoxib group. The pain scores were significantly less in the rofecoxib group than in the other two groups at two of the six intervals, and less than the placebo group in an additional interval. Although both rofecoxib and celecoxib produce similar analgesic effects in the first 4 h after surgery, rofecoxib demonstrated an extended analgesic effect that lasted throughout the 24-h study. We thus recommend that rofecoxib be used as a preoperative component of pain management that includes PCA morphine in patients undergoing spine stabilization surgery. The cyclooxygenase-2-specific nonsteroidal antiinflammatory drugs, celecoxib and rofecoxib, both demonstrate an opioid-sparing effect after spinal fusion surgery. Celecoxib resulted in decreased morphine use for the first 8 h after surgery, whereas rofecoxib demonstrated less morphine use throughout the 24-h study period.",2001.0,0,0
64,11060833,Evaluation of intravenous parecoxib for the relief of acute post-surgical pain.,K K Jain,"Parecoxib is a prodrug of valdecoxib, which is a potent and selective inhibitor of COX-2. Intravenous preparation of parecoxib is in Phase III clinical trials for the management of acute and severe post-surgical pain. It is the only COX-2 inhibitor that is available in a parenteral formulation. Clinical results compare parecoxib with ketorolac, a NSAID, which is the only non-narcotic analgesic available in parenteral formulation that can be administered for the relief of moderate to severe acute pain. Pharmacokinetic studies have shown that parecoxib is converted to valdecoxib within a short time following administration by im. or iv. injection. In clinical trials, parecoxib compares favourably with ketorolac and produces less gastric or duodenal ulcers, the predominant adverse effect, than ketorolac. Parecoxib, thus, fulfils some of the desirable characteristics of an ideal non-narcotic analgesic for severe post-surgical pain and has application in other acutely painful conditions. Parecoxib is expected to be filed for approval before the end of 2000 and is expected to be introduced in the market in 2001. It has favourable prospects for a fair share of the post-surgical pain relief market which is valued at approximately US$ 1 billion for the year 2000.",2001.0,0,0
65,11073508,Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis.,S Derry; Y K Loke,"To assess the incidence of gastrointestinal haemorrhage associated with long term aspirin therapy and to determine the effect of dose reduction and formulation on the incidence of such haemorrhage. Meta-analysis of 24 randomised controlled trials (almost 66 000 participants). Aspirin compared with placebo or no treatment, for a minimum of one year. Incidence of gastrointestinal haemorrhage. Gastrointestinal haemorrhage occurred in 2.47% of patients taking aspirin compared with 1.42% taking placebo (odds ratio 1.68; 95% confidence interval 1.51 to 1.88); the number needed to harm was 106 (82 to 140) based on an average of 28 months' therapy. At doses below 163 mg/day, gastrointestinal haemorrhage occurred in 2.30% of patients taking aspirin compared with 1.45% taking placebo (1.59; 1.40 to 1.81). Meta-regression showed no relation between gastrointestinal haemorrhage and dose. For modified release formulations of aspirin the odds ratio was 1.93 (1.15 to 3.23). Long term therapy with aspirin is associated with a significant increase in the incidence of gastrointestinal haemorrhage. No evidence exists that reducing the dose or using modified release formulations would reduce the incidence of gastrointestinal haemorrhage.",2001.0,0,0
66,11085526,Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models.,C S Williams; A J Watson; H Sheng; R Helou; J Shao; R N DuBois,"Nonsteroidal anti-inflammatory drugs have potential for use in the prevention and/or treatment of colorectal cancer. We have studied the cytotoxic effect of a specific COX-2 inhibitor, celecoxib, against LLC, HCA-7, and HCT-15 cells grown in cell culture and have compared these results with its effect on HCA-7 cells grown as xenografts in nude mice. ""High-dose"" celecoxib (>20 microM) reduced the viability of all three cell lines in vitro as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometric analysis demonstrated that this loss of viability was attributable to the induction of apoptosis. Significantly, concentrations of the drug <10 microM had no effect on cell viability in vitro. The cytotoxic effects of high-dose celecoxib were independent of COX-2 inhibition because similar effects were observed in cox-2 (+/+), cox-2 (+/-) and cox-2 (-/-) fibroblasts. A plasma concentration of 2.3+/-0.7 microM was achieved when celecoxib (1250 mg/kg of chow) was fed to animals ad libitum. Despite a lack of toxicity at 2-3 microM celecoxib in vitro, there was attenuation of HCA-7 xenograft growth in vivo. Celecoxib had no effect on apoptosis, cell division, or the epithelial architecture of the normal gut in treated mice. These results support the need for additional clinical evaluation of celecoxib for treatment and/or prevention of colorectal cancer in humans.",2001.0,0,0
67,11087881,Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.,C Bombardier; L Laine; A Reicin; D Shapiro; R Burgos-Vargas; B Davis; R Day; M B Ferraz; C J Hawkey; M C Hochberg; T K Kvien; T J Schnitzer; VIGOR Study Group,"Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups. In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor.",2001.0,1,1
68,11093446,Minimal perceptible clinical improvement with the Western Ontario and McMaster Universities osteoarthritis index questionnaire and global assessments in patients with osteoarthritis.,E W Ehrich; G M Davies; D J Watson; J A Bolognese; B C Seidenberg; N Bellamy,"To determine the minimal perceptible clinical improvement (MPCI) in patients with osteoarthritis (OA) with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, and patient and investigator global assessment of disease status in randomized clinical trials for treatment of OA. Subjects with OA of the knee or hip were randomized to receive either rofecoxib 12.5 or 25 mg once daily, ibuprofen 800 mg 3 times daily, or placebo for 6 weeks. The WOMAC and global assessments were completed at baseline and Weeks 2, 4, and 6. A patient global assessment of response to therapy (0 to 4 scale) was used to ""anchor"" the WOMAC scores. MPCI was defined as the difference in mean change from baseline in WOMAC (100 mm normalized visual analog scale, VAS) between patients with 0 = ""None"" global response to therapy and patients with 1 = ""Poor"" global response to therapy. MPCI was determined to be 9.7, 9.3, and 10.0 mm for the WOMAC pain, physical function and stiffness subscales, respectively, and 11.1 mm for WOMAC question 1: Pain walking on a flat surface. The MPCI for the investigator was 0.4 with investigator assessment of disease status reported on a 0 to 4 Likert scale. Of note, the estimated MPCI for the WOMAC and investigator globals were similar irrespective of treatment, sex, age, or geographic region. In this analysis, mean changes of roughly 9 to 12 mm (100 mm normalized VAS) on WOMAC scales were perceptible changes to patients with hip and knee OA. A mean decrease of 0.4 in global disease status (0 to 4 Likert scale) as assessed by the investigator corresponded to the patients' MPCI. Understanding the minimal perceptible differences may permit a better assessment of the clinical relevance of therapeutic interventions in OA.",2001.0,0,1
69,11115219,"Rofecoxib, a new cyclooxygenase 2 inhibitor, shows sustained efficacy, comparable with other nonsteroidal anti-inflammatory drugs: a 6-week and a 1-year trial in patients with osteoarthritis. Osteoarthritis Studies Group.",K Saag; D van der Heijde; C Fisher; A Samara; L DeTora; J Bolognese; R Sperling; B Daniels,"Rofecoxib, a cyclooxygenase 2 inhibitor (sometimes known as a specific cyclooxygenase 2 inhibitor or Coxib), is used in osteoarthritis (OA). Published information indicates rofecoxib's improved gastrointestinal safety profile over nonselective nonsteroidal anti-inflammatory agents (NSAIDs). To evaluate the efficacy and safety of rofecoxib in treating OA in 2 studies. Two randomized, double-blind, parallel-group studies in patients with OA of the knee or hip were conducted using identical entry criteria and end points. A 6-week placebo-controlled trial in 736 patients compared 12.5 and 25 mg of rofecoxib once daily with 800 mg of ibuprofen 3 times daily, and a 1-year study compared 12.5 and 25 mg of rofecoxib once daily with 50 mg of diclofenac 3 times daily in 693 patients. Rofecoxib, at 12.5 and 25 mg, demonstrated efficacy clinically comparable with ibuprofen, assessed by 3 primary end points according to predefined comparability criteria. Both rofecoxib doses and ibuprofen provided significantly greater efficacy than placebo on all primary end points at 6 weeks. Both rofecoxib doses and diclofenac showed similar efficacy over 1 year. All treatments were well tolerated. Rofecoxib is effective in treating OA with once-daily dosing for 6 weeks and 1 year. Rofecoxib was generally safe and well-tolerated in OA patients for 6 weeks and 1 year. Arch Fam Med. 2000;9:1124-1134",2001.0,1,1
70,11144988,Effect of rofecoxib on the pharmacokinetics of digoxin in healthy volunteers.,J I Schwartz; M De Smet; P J Larson; R Verbesselt; D L Ebel; R Lins; S Lens; A G Porras; B J Gertz,"The authors examined the effect of the cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, at steady state on the pharmacokinetics of digoxin following a single dose in healthy subjects. Each healthy subject (N = 10) received rofecoxib (75 mg once daily) or placebo for 11 days in a double-blind, randomized, balanced, two-period crossover study. A single 0.5 mg oral dose of digoxin elixir was administered on the 7th day of each 11-day period. Each treatment period was separated by 14 to 21 days. Samples for plasma and urine immunoreactive digoxin concentrations were collected through 120 hours following the digoxin dose. No statistically significant differences between treatment groups were observed for any of the calculated digoxin pharmacokinetic parameters. For digoxin AUC(0-infinity), AUC(0-24), and Cmax, the geometric mean ratios (90% confidence interval) for (rofecoxib + digoxin/placebo + digoxin) were 1.04 (0.94, 1.14), 1.02 (0.94, 1.09), and 1.00 (0.91, 1.10), respectively. The digoxin median tmax was 0.5 hours for both treatments. The harmonic mean elimination half-life was 45.7 and 43.4 hours for rofecoxib + digoxin and placebo + digoxin treatments, respectively. Digoxin is eliminated renally. The mean (SD) cumulative urinary excretion of immunoreactive digoxin after concurrent treatment with rofecoxib or placebo was 228.2 (+/- 30.8) and 235.1 (+/- 39.1) micrograms/120 hours, respectively. Transient and minor adverse events occurred with similar frequency on placebo and rofecoxib treatments, and no treatment-related pattern was apparent. Rofecoxib did not influence the plasma pharmacokinetics or renal elimination of a single oral dose of digoxin.",2001.0,0,0
71,11171823,Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen.,A A Shah; B Thjodleifsson; F E Murray; E Kay; M Barry; G Sigthorsson; H Gudjonsson; E Oddsson; A B Price; D J Fitzgerald; I Bjarnason,"Selective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs. We compared the biochemical and gastrointestinal effects of nimesulide, a potent and selective COX-2 inhibitor, with naproxen which exhibits no selectivity. Thirty six healthy volunteers were randomised to nimesulide 100 mg or naproxen 500 mg twice daily for two weeks in a double blind, crossover study with a washout between treatments. Gastrointestinal side effects were assessed by endoscopy, and by estimation of small intestinal absorption-permeability and inflammation. Comparisons were made between variables at the end of each treatment phase. Nimesulide caused significantly less gastric injury using the modified Lanza score (p<0.001) as well as reduced duodenum injury (p=0.039). Nimesulide had lower visual analogue scores (VAS) for haemorrhage and erosive lesions in the stomach (p<0.001) and for mucosal injection in the duodenum (p=0.039). Naproxen increased excretion of calprotectin, a marker of intestinal inflammation (5.5 (1.2) to 12.1 (2.1) mg/l) while nimesulide had no effect (treatment difference p=0.03). Naproxen abolished platelet aggregation to arachidonic acid and suppressed serum thromboxane B(2) (TXB(2)) by 98%, indices of COX-1 activity. In contrast, nimesulide had no significant effect on platelet aggregation, although it reduced serum TXB(2) by 29%. Production of prostaglandin E(2) and prostacyclin by gastric biopsies, also COX-1 dependent, was inhibited by naproxen, but not by nimesulide. COX-2 activity, determined as endotoxin induced prostaglandin E(2) formation in plasma, was markedly suppressed by both treatments. Nimesulide has preferential selectivity for COX-2 over COX-1 in vivo at full therapeutic doses and induces less gastrointestinal damage than that seen with naproxen in the short term.",2001.0,0,1
72,11172701,Gastrointestinal sparing anti-inflammatory drugs--effects on ulcerogenic and healing responses.,K Takeuchi; A Tanaka; K Suzuki; H Mizoguchi,"The use of nonsteroidal antiinflammatory drugs (NSAIDs) is associated with a wide array of alterations in gastrointestinal integrity and function. Various approaches have been taken to developing NSAIDs with reduced gastrointestinal toxicity, and few have been successfully reduced the incidence of adverse reactions. These include cyclooxygenase-2 (COX-2) selective inhibitors and nitric oxide (NO)-releasing NSAIDs. Especially, much has been written about the potential of COX-2 inhibitors as anti-inflammatory and analgesic agents that lack the gastrointestinal side effects of traditional NSAIDs. COX-2 expression is most evident at sites of inflammation, while COX-1 accounts for the majority of prostaglandin synthesis in the normal gastrointestinal tract. However, there are distinct examples of circumstances in which COX-2-derived prostaglandins play a role in the maintenance of gastrointestinal mucosal integrity, particularly when the mucosa is injured, and the delineation of COX-1 and COX-2 might not be quite as clear as has been suggested. On the other hand, the rational behind the NO-releasing NSAIDs is that the NO released from the derivatives will exert beneficial effects on the gastrointestinal mucosa. This approach has been successfully demonstrated to lessen the incidence of gastrointestinal damage and to promote the healing of gastric ulcers. The present article overviews the roles of COX and NO in housekeeping functions of the gastrointestinal mucosa in various circumstances, and the effects of gastrointestinal sparing NSAIDs, mainly COX-2 selective inhibitors and NO-releasing derivatives of NSAIDs, on the ulcerogenic and healing responses in the gastrointestinal mucosa of experimental animals.",2001.0,0,0
73,11185674,"A new cyclooxygenase-2 inhibitor, rofecoxib (VIOXX), did not alter the antiplatelet effects of low-dose aspirin in healthy volunteers.",H E Greenberg; K Gottesdiener; M Huntington; P Wong; P Larson; L Wildonger; L Gillen; E Dorval; S A Waldman,"The present study examined whether rofecoxib (VIOXX), a new specific inhibitor of cyclooxygenase-2 (COX-2), would interfere with the desired antiplatelet effects of aspirin. Thus, the effects of rofecoxib on inhibition of ex vivo serum-generated thromboxane B2 (TXB2) and platelet aggregation by low doses (81 mg) of aspirin were examined in healthy volunteers. This was a double-blind, randomized, placebo-controlled, parallel study of two treatment groups (n = 12 per group) in which subjects received 50 mg of rofecoxib or placebo for 10 days in a blinded fashion. Subjects also received 81 mg aspirin once on each of days 4 through 10 in an open-label fashion. Blood for measurement of serum TXB2 production and platelet aggregation studies was collected on day 1 (prior to rofecoxib/placebo), on day 4 (prior to aspirin), and on day 10 (before and 4 hours following the seventh dose of aspirin). Platelet-derived serum TXB2 (COX-1 assay) was measured in blood clotted for 1 hour at 37 degrees C. Platelet aggregation was independently induced employing 1 mM arachidonic acid and 1 microgram/mL collagen as agonists. Rofecoxib administered alone had no significant effect on serum TXB2 production or platelet aggregation (day 4). TXB2 production was inhibited 98.4% by aspirin coadministered with either rofecoxib or placebo (day 10). Similarly, platelet aggregation induced by arachidonic acid was inhibited 93.7% and 93.5% by aspirin coadministered with either rofecoxib or placebo, respectively (day 10). The comparable values for inhibition of collagen-induced platelet aggregation were 86.8% and 90.8%, respectively. No important clinical or laboratory adverse experiences were observed. In conclusion, rofecoxib alone (50 mg QD for 4 days) did not inhibit serum TXB2 production or platelet aggregation. In addition, rofecoxib (50 mg QD for 10 days) did not alter the antiplatelet effects of low-dose aspirin (inhibition of platelet aggregation and TXB2 production). Rofecoxib was generally well tolerated when administered alone or in combination with low-dose aspirin.",2001.0,0,0
74,11212158,"Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug.",M Dougados; J M Béhier; I Jolchine; A Calin; D van der Heijde; I Olivieri; H Zeidler; H Herman,"To evaluate the short-term efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis (AS). The study was a 6-week randomized, double-blind, placebo-controlled trial with 3 treatment arms: placebo, ketoprofen 100 mg twice daily, and celecoxib 100 mg twice daily. Patients who had AS according to the modified New York criteria, without peripheral synovitis and with active disease (pain > or =40 mm on a 100-mm visual analog scale [VAS] and an increase in pain of at least 30% after nonsteroidal antiinflammatory drug withdrawal) were eligible for study. Primary outcome measures were change in pain intensity (VAS) and change in functional impairment (Bath Ankylosing Spondylitis Functional Index [BASFI]). Of the 246 randomized patients, 76 were allocated to receive placebo, 90 ketoprofen, and 80 celecoxib. There were no statistically significant differences between treatment groups at study entry. During the 6 weeks of the study, the decrease in pain and functional impairment was greater in the active treatment groups than in the placebo group, with a trend in favor of celecoxib when the 2 active treatments were compared. The mean changes were -13 mm, -21 mm, and -27 mm (P = 0.006) for pain and 1, -6, and -12 (P = 0.0008) for BASFI score in the placebo, ketoprofen, and celecoxib groups, respectively. During treatment, the number of patients reporting epigastric pain was 6 (8%), 13 (14%), and 10 (13%) in the placebo, ketoprofen, and celecoxib groups, respectively. The results of this study confirm the clinically relevant antiinflammatory effect of celecoxib at a 200-mg daily dosage, with significant improvement of both pain and function in patients with AS.",2001.0,1,1
75,11219386,"New functions for Cox-2 in health and disease: report of ""The Third International Workshop on Cox-2"", Ka'upelehu, Kona, Hawaii, USA, 30 August to 2 September 1999.",F A Wollheim,,2001.0,0,0
76,11231941,"Rofecoxib, a COX-2 inhibitor, does not inhibit human gastric mucosal prostaglandin production.",N J Wight; K Gottesdiener; N M Garlick; C T Atherton; S Novak; B J Gertz; N A Calder; J Cote; P Wong; A Dallob; C J Hawkey,"Rofecoxib, an inhibitor of the inducible cyclooxygenase (COX)-2 enzyme, appears not to cause acute gastroduodenal injury or chronic ulceration. To attribute this to COX-2 selectivity with sparing of gastric mucosal prostaglandin synthesis requires direct proof. Twenty-four healthy, nonsmoking Helicobacter pylori-negative volunteers were randomized to 1 of 2 separate concurrent blinded crossover studies. Sixteen volunteers received rofecoxib, 50 mg once daily, for 5 days in one treatment period and placebo in the other. Eight volunteers similarly received naproxen, 500 mg twice daily, and placebo. On day 5 of each period, antral mucosal prostaglandin E2 (PGE2) synthesis was measured by radioimmunoassay after vortexing for 3 minutes. Whole blood COX-1 activity was measured as serum thromboxane (TXB)2- and COX-2 activity as lipopolysaccharide (LPS)-induced PGE2. Naproxen decreased gastric mucosal PGE2 synthesis by 65% (90% confidence interval [CI], 53%-74%; P = 0.001 vs. placebo) in contrast to an 18% increase after rofecoxib (90% CI, -11% to 57%; P = 0.313 vs. placebo). Naproxen also significantly inhibited both serum TXB2 by 94% and LPS-induced PGE2 production by 77% (both P < or = 0.002 vs. placebo), but rofecoxib only inhibited COX-2-dependent LPS-induced PGE(2) (by 79%; P < 0.001 vs. placebo). Rofecoxib (50 mg) lacked naproxen's ability to reduce the availability of gastroprotective prostaglandins.",2001.0,0,0
77,11235018,"Anti-arthritic effects of KF20444, a new immunosuppressive compound inhibiting dihydroorotate dehydrogenase, on rat collagen-induced arthritis.",K Kobayashi; A Nakashima; H Nagata; H Nakajima; K Yamaguchi; S Sato; I Miki,"A newly synthesized inhibitor of pyrimidine de novo biosynthesis, KF20444 (6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5H-benzo [6,7] cyclohepta [1,2-b] quinoline-8-carboxylic acid), was evaluated as an inhibitor of dihydroorotate dehydrogenase (DHO-DHase) and tested in the rat collagen-induced arthritis (CIA) model. Female Sprague Dawley rats, 5 weeks-old, were used for evaluation of KF20444 in the CIA model. Arthritis was evaluated by arthritis score, serum anti-type II collagen antibody titer, body weight loss, radiographical and histological changes. KF20444 was orally administered 5 times per week (0.3, 1, 3 mg/kg/day). KF20444 inhibited rat liver dihydroorotate dehydrogenase in vitro with Ki = 8.5 +/- 3.2 nM, which was a comparable effect to that of brequinar sodium (Ki = 25.3 +/- 5.3 nM). The anti-proliferative effect of KF20444 was caused by cell cycle arrest at the S-phase. Treatment with 3 mg/kg/day of KF20444 completely prevented the development of CIA based on reduction of the arthritis score. The 50% effective dose (ED50) of KF20444 on arthritis score was 0.64 mg/kg. KF20444 ameliorated body weight loss associated with disease onset. The compound also inhibited the increase in serum anti-type II collagen antibody level, and reduced both pannus formation and bone erosion. Importantly, KF20444 suppressed the development of arthritis, even when it was administered after booster immunization of collagen. KF20444 is a novel immunosuppressant which inhibits DHO-DHase and its effects in CIA suggest that it could be useful in the treatment of rheumatoid arthritis.",2001.0,0,0
78,11236293,Celecoxib--a rational alternative to NSAIDs.,I Moodley; G Hirsch,,2001.0,0,0
79,11237777,The use of anti-inflammatory drugs in cancer pain.,S Mercadante,"The role of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer pain has been well established in the treatment of mild pain and also alone or in association with opioids for the treatment of moderate to severe pain. Acutely, NSAIDs may be more than mild analgesics, and may provide additional analgesia when combined with opioids. However, NSAIDs have ceiling effects and there is no therapeutic gain from increasing dosages beyond those recommended. As there is no clearly superior NSAID, the choice should be based on experience and the toxicity profile that probably relates to the COX-1:COX-2 ratio. Among the older drugs, ibuprofen seems to have these properties.Non-steroidal anti-inflammatory drugs have been shown to have an opioid-sparing effect. Although the value of a simple narcotic-sparing effect may be questioned in cancer pain treatment, the use of NSAIDs may be useful when the increase in opioid dosage determine the occurrence of opioid toxicity. Like opioids, NSAIDs should not be considered analgesics for a specific type or cause of pain. There is a lack of evidence for any difference between different routes of NSAIDs administration. The long-term toxicity of NSAIDs in cancer pain is poorly defined due to a lack of studies. A variety of strategies have been used in an attempt to reduce the risks associated with NSAID therapy. Those NSAIDs that are weak COX-1 inhibitors may be preferred. In addition, concomitant administration of misoprostol is recommended in patients at increased risk for upper gastrointestinal complications.",2001.0,0,0
80,11248083,Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice.,D Praticò; C Tillmann; Z B Zhang; H Li; G A FitzGerald,"The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substantially in humans. Because deletion of the PGI(2) receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF(1alpha) by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI(2) biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.",2002.0,0,0
81,11252686,Celecoxib versus diclofenac in the management of osteoarthritis of the knee.,F McKenna; D Borenstein; H Wendt; C Wallemark; J B Lefkowith; G S Geis,"A clinical trial was conducted in 600 patients with OA of the knee to test the hypothesis that the specific COX-2 inhibitor, celecoxib, has equivalent efficacy and a superior tolerability/safety profile when compared to diclofenac, the current worldwide standard of care. Patients were administered celecoxib 100 mg BID, diclofenac 50 mg TID or placebo for 6 weeks in a multicentre, double-blind. placebo-controlled trial. Primary efficacy measures (index joint pain by VAS, WOMAC index) indicated statistically significant improvement versus placebo for both celecoxib and diclofenac and no statistically significant differences between celecoxib and diclofenac. American Pain Society (APS) measures to assess the rapidity of onset of action showed statistically significant and comparable pain relief versus placebo within 24 h for both celecoxib and diclofenac. More diclofenac patients reported GI side effects than patients treated with either placebo or celecoxib. Diclofenac-treated patients experienced statistically significant elevations in mean hepatic transaminases and serum creatinine and reductions in haemoglobin concentration when compared to placebo, events not observed with celecoxib. Celecoxib 200 mg daily is as effective as diclofenac 150 mg daily for relieving signs and symptoms of OA of the knee, including pain, and has a rapid onset of action. However, celecoxib appears to have a superior safety and tolerability profile.",2001.0,1,1
82,11252687,Tolerability profiles of rofecoxib (Vioxx) and Arthrotec. A comparison of six weeks treatment in patients with osteoarthritis.,E Acevedo; O Castañeda; M Ugaz; A D Beaulieu; B Pons-Estel; F Caeiro; N Casas; M Garza-Elizondo; F Irazoque; W Hinojosa; S Gutierrez-Ureña; K Vandormael; D B Rodgers; M Laurenzi,"To compare the incidence of selected spontaneously reported adverse events (AEs) in patients with osteoarthritis (OA) treated with rofecoxib (VIOXX, 12.5 mg qd) or Arthrotec (diclofenac 50 mg/misoprostol 200 mcg bid). Double-blind, parallel-group, 6-week study of patients aged > or = 40 years with a clinical diagnosis of OA treated with rofecoxib or Arthrotec. Primary endpoint: self-reported diarrhea; secondary endpoints: abdominal pain, discontinuations due to AEs, GI AEs and NSAID-type GI AEs (ie., acid reflux, dyspepsia, epigastric discomfort, heartburn, nausea, vomiting). Among 483 patients (80.3% females, mean age 62.1), the rofecoxib group vs the Arthrotec group respectively reported diarrhea 6.2% vs 16.2% (p<0.001); drug-related diarrhea 3.7% vs 16.2% (p<0.001); one or more clinical AEs 52.9% vs 73.0% (p<0.001); GI AEs 28.9% vs 48.5% (p<0.001); NSAID-type GI AEs 18.6% vs 29.9% (p=0.004); discontinuations due to abdominal pain 0.4% vs 3.7% (p<0.05); and discontinuations due to any AE 4.1% vs 9.1% (p=0.029). No significant differences were observed in efficacy. Rofecoxib 12.5 mg qd has improved GI tolerability and similar efficacy compared to Arthrotec (diclofenac 50 mg/misoprostol 200 mcg bid).",2001.0,1,1
83,11262983,"Antipyretic effects of nimesulide, paracetamol and ibuprofen-paracetamol.",A Lal; S Gomber; B Talukdar,"The antipyretic effect of nimesulide has not been adequately compared with paracetamol and ibuprofen-paracetamol combination in children. Hence, a randomized, double blind, and parallel groups' design and multicenter study was conducted on children with respiratory tract infections. Eighty-nine patients with temperatures above 38.5 degrees C were randomly administered nimesulide (1.5 mg/kg/dose), paracetamol (10.0 mg/kg/dose), or ibuprofen-patients combination (10.0 mg/kg/dose), thrice daily for five days. The axillary temperature was recorded at the baseline and at different time intervals post administration of drugs. The hematological and biochemical investigations were performed at the basal level and at the end of the treatment period. The adverse drug reactions were monitored during the trial. All the drugs produced a significant fall in temperature as compared to their respective basal values (p < 0.001). However, on looking at the change in temperatures at different time intervals from the respective basal levels, no significant difference was found among all the drugs. Surprisingly, nimesulide had a tendency to raise serum glutamate pyruvate transaminase and serum glutamate oxaloacetate transaminase levels as compared to its baseline values. There was no marked adverse effect of the drugs on other hematological and biochemical parameters investigated. No other serious adverse reaction occurred in the study. Ibuprofen-paracetamol combination, nimesulide, and paracetamol had almost similar antipyretic effects in children.",2001.0,0,0
84,11273789,Effect of the cyclooxygenase-2 inhibitor celecoxib on bronchial responsiveness and cough reflex sensitivity in asthmatics.,P V Dicpinigaitis,"Cyclooxygenase (COX), an essential enzyme in the pathway of prostaglandin formation from arachidonic acid, exists in two isoforms. Cyclooxygenase-1 (COX-1) is expressed under normal physiologic conditions, whereas COX-2, the inducible isoform, is associated with inflammation. Recent studies have linked COX-2 induction to the asthmatic inflammatory response, but potentially beneficial results, such as enhanced production of antiinflammatory and bronchoprotective substances, may also occur. The aim of the present study was to investigate the effect of selective COX-2 inhibition on bronchial responsiveness and cough reflex sensitivity. Eight adult subjects with stable asthma underwent spirometry, bronchoprovocation challenge with methacholine, and cough challenge testing with capsaicin, before and after a 7 day course of the COX-2 inhibitor celecoxib (200 mg orally, twice daily) and placebo, in a randomized, double-blind, crossover fashion. No significant changes in pulmonary function, bronchial responsiveness, or cough reflex sensitivity were induced by celecoxib. It appears, therefore, that 1 week of therapy with celecoxib does not significantly affect basal airway tone, nor the afferent airway receptors controlling bronchoconstriction and cough. However, the results of this trial cannot be extrapolated to subjects with severe asthma, or those suffering an asthmatic exacerbation. In such conditions of enhanced inflammatory response, the role of selective COX-2 inhibition remains to be elucidated.",2001.0,0,0
85,11276797,Epidemiology and pharmacoeconomic implications of non-steroidal anti-inflammatory drug-associated gastrointestinal toxicity.,T M MacDonald,"Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed and used, especially to treat patients with osteoarthritis and rheumatoid arthritis. Since their introduction as a therapeutic class, a large body of literature has accumulated on the side-effects of these drugs. NSAIDs, through their inhibition of prostaglandin synthesis, can affect the renal and cardiovascular systems. However, the majority of reported side-effects are related to the gastrointestinal (GI) system, and the occurrence of these GI events adds significantly to the disease burden. Several factors have been identified that contribute to the risk of an NSAID-associated GI event. However, when considering risk, especially in clinical trials or observational studies, it is necessary to distinguish between baseline risk and NSAID-attributable risk, since this distinction can affect the results and conclusions of the study; NSAID-attributable risk is present in subjects who have few or no risk factors for upper GI toxicity. Safer NSAIDs, such as the new specific cyclooxygenase-2 inhibitors, when targeted to the appropriate patient (i.e. those with NSAID-attributable risk), should lead to improved outcomes and reduced costs.",2001.0,0,1
86,11276798,Celecoxib clinical profile.,L Tive,"Celecoxib is the first COX-2-specific inhibitor approved for relief of the signs and symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA), as well as for treatment of familial adenomatous polyposis. For both OA and RA, celecoxib has been shown to be significantly superior in efficacy to placebo and similar in efficacy to traditional non-steroidal anti-inflammatory drugs. Its advantage, however, is its gastrointestinal (GI) safety. Randomized clinical trials as well as long-term outcomes studies have demonstrated that the GI safety profile of celecoxib is superior to that of traditional NSAIDs and similar to that of placebo. Additionally, the renal and cardiovascular safety of celecoxib has also become apparent, as well as its efficacy, tolerability and safety in the elderly population.",2001.0,0,1
87,11276799,Health economic models: a question of balance--summary of an open discussion on the pharmacoeconomic evaluation of non-steroidal anti-inflammatory drugs.,M F Drummond,"Pharmacoeconomics and pharmacoeconomic models are increasingly being used to guide health care decisions. In designing and using these models, an appropriate balance must be struck between scientific rigour and model transparency. It is therefore important to consider carefully how the various model components, such as model perspective, internal and external validity, and choice of comparators and outcomes, should be integrated into the model. These factors are discussed in relation to the pharmacoeconomic evaluation of non-steroidal anti-inflammatory drugs.",2001.0,0,0
88,11276801,Overview of the arthritis Cost Consequence Evaluation System (ACCES): a pharmacoeconomic model for celecoxib.,D Pettitt; J L Goldstein; A McGuire; J S Schwartz; T Burke; N Maniadakis,"Pharmacoeconomic analyses have become useful and essential tools for health care decision makers who increasingly require such analyses prior to placing a drug on a national, regional or hospital formulary. Previous health economic models of non-steroidal anti-inflammatory drugs (NSAIDs) have been restricted to evaluating a narrow range of agents within specific health care delivery systems using medical information derived from homogeneous clinical trial data. This paper summarizes the Arthritis Cost Consequence Evaluation System (ACCES)--a pharmacoeconomic model that has been developed to predict and evaluate the costs and consequences associated with the use of celecoxib in patients with arthritis, compared with other NSAIDs and NSAIDs plus gastroprotective agents. The advantage of this model is that it can be customized to reflect local practice patterns, resource utilization and costs, as well as provide context-specific health economic information to a variety of providers and/or decision makers.",2001.0,0,1
89,11276803,The Swedish ACCES model: predicting the health economic impact of celecoxib in patients with osteoarthritis or rheumatoid arthritis.,U Haglund; P Svarvar,"The Arthritis Cost Consequence Evaluation System (ACCES) pharmacoeconomic model was used to evaluate the economic and health impact of the recent introduction of celecoxib for treatment of osteoarthritis (OA) and rheumatoid arthritis (RA) in Sweden. The model demonstrates that use of celecoxib can be expected to reduce the incidence of gastrointestinal adverse events, resource utilization and treatment costs. In a cost-effectiveness analysis, celecoxib demonstrated economic dominance (i.e. improved health at reduced cost) compared with the currently available alternatives for OA, and demonstrated economic dominance against a clinically relevant base-case scenario for RA. In sensitivity analyses, the results were shown to be relatively robust; celecoxib demonstrated economic dominance or favourable cost-effectiveness ratios in all analyses. Based on these data, it can be concluded that the use of celecoxib in Sweden will provide societal benefits by improving health care at reduced cost for patients with OA and RA.",2001.0,0,1
90,11281823,The status of ongoing trials for mild cognitive impairment.,J J Sramek; A E Veroff; N R Cutler,"Mild cognitive impairment (MCI) is a term used to describe memory decline or other specific cognitive impairment in individuals who do not have dementia or significant impairment of other cognitive functions beyond that expected for their age or education. It has been suggested that as much as 38% of the elderly population would meet criteria for MCI and although the associated memory deficits are mild, the fact that up to 15% of MCI patients, particularly those with a particular type of memory impairment, convert to Alzheimer's disease (AD) annually has prompted serious attention. Despite the high conversion rate, MCI cannot be used synonymously with early or mild AD, as patients with AD are impaired not only in memory performance but in other cognitive domains as well; they meet diagnostic criteria for dementia. However, since there is a high conversion rate from MCI to AD, it is likely many with MCI have the underlying neuropathology of AD, though they do not yet meet clinical diagnostic criteria. Therefore, treatment strategies developed for AD, specifically acetylcholinesterase inhibitors and Cox-2 inhibitors, have been among the first employed to treat MCI. It is hoped that by impeding the progression of MCI in this manner, fewer patients will convert to AD. This article will give a brief overview of the condition of mild cognitive impairment and an account of trial methodology and current treatment strategies being employed for MCI.",2001.0,0,0
91,11293555,Comparison of once-daily and twice-daily administration of celecoxib for the treatment of osteoarthritis of the knee.,G W Williams; R C Hubbard; S S Yu; W Zhao; G S Geis,"The purpose of this study was to compare the efficacy and tolerability of a celecoxib 200 mg QD regimen with a 100 mg BID regimen in patients with osteoarthritis (OA) of the knee. Patients enrolled in this prospective, double-blind, placebo-controlled, parallel-group, multicenter study were randomly assigned to receive celecoxib 100 mg BID, celecoxib 200 mg QD, or placebo for 6 weeks. Assessments of OA severity (Patient's and Physician's Global Assessments of Arthritis, Patient's Assessment of Arthritis Pain-Visual Analog Scale, Lequesne Osteoarthritis Severity Index, and the Western Ontario and McMaster Universities Osteoarthritis Index) were performed at baseline and at week 2 and/or 6. Patients who discontinued treatment underwent assessments at the time of withdrawal from the study. Of the 718 patients enrolled, 243 received celecoxib 100 mg BID, 231 received celecoxib 200 mg QD, and 244 received placebo. For all measures of efficacy, at all assessments, improvements from baseline in both celecoxib groups were superior to that seen in the placebo group (P < 0.05). No significant differences in efficacy between the celecoxib groups were observed. The overall incidence of adverse events was similar in the 2 celecoxib treatment groups. Dosing regimens of celecoxib 200 mg QD and 100 mg BID are equally effective and well tolerated in patients with OA of the knee. The availability of 2 effective regimens provides patients and physicians with increased flexibility in the selection of an appropriate dosing regimen for celecoxib therapy.",2002.0,0,1
92,11293556,Efficacy and tolerability of celecoxib versus hydrocodone/acetaminophen in the treatment of pain after ambulatory orthopedic surgery in adults.,J S Gimbel; A Brugger; W Zhao; K M Verburg; G S Geis,"Current outpatient management of postoperative pain includes the use of oral opioid analgesics or nonsteroidal anti-inflammatory drugs; however, both types of medications are associated with side effects that can limit their usefulness in the outpatient setting. Two studies with identical protocols assessed the single- and multiple-dose analgesic efficacy and tolerability of celecoxib, a specific cyclooxygenase-2 inhibitor, in the treatment of acute pain after orthopedic surgery. These were multicenter, randomized, placebo- and active-controlled, double-blind, parallel-group trials conducted between January and June 1998. Both consisted of a single-dose assessment period (SDAP) and a multiple-dose assessment period (MDAP). In the SDAP, patients who had undergone orthopedic surgery received a single oral dose of celecoxib 200 mg, hydrocodone 10 mg/acetaminophen 1000 mg, or placebo within 24 hours after the end of anesthesia, with pain assessments conducted over the following 8-hour period. In the MDAP, extending from 8 hours after the first dose of study medication up to 5 days, patients who had received < or =1 dose of rescue medication during the SDAP continued on study medication (placebo recipients were rerandomized to active treatment), which could be taken up to 3 times a day as needed. A total of 418 patients were enrolled in the 2 trials. During the SDAP, 141 patients received celecoxib, 136 received hydrocodone/acetaminophen, and 141 received placebo. During the MDAP, 185 patients received celecoxib and 181 received hydrocodone/acetaminophen. When the combined data were analyzed, mean pain intensity difference (PID) scores generally favored the active treatments over placebo from 1 to 6 hours (with the exception of 1.5 hours) after dosing (P < or = 0.016) and favored celecoxib over the other treatments at 7 and 8 hours after dosing (P < 0.001). The active treatments demonstrated superior summed PID scores through 8 hours (P < 0.001), significantly shorter median times to onset of analgesia (P < 0.05), and significantly longer median times to first use of rescue medication (P < 0.05). During the MDAP, more hydrocodone/acetaminophen-treated patients (20%) than celecoxib-treated patients (12%) required rescue medication (P < 0.05), and the celecoxib group had significantly lower maximum pain intensity scores (P < 0.001, days 2-5), required fewer doses of study medication (P < or = 0.01, days 3-5), and had superior scores on a modified American Pain Society Patient Outcome Questionnaire (P < or = 0.013). In addition, a significantly lower proportion of celecoxib-treated patients experienced adverse events (43%) compared with hydrocodone/acetaminophen-treated patients (89%; P < 0.001). Over 8 hours, patients with moderate to severe pain after orthopedic surgery experienced comparable analgesia with single doses of celecoxib and hydrocodone/acetaminophen. Over a 5-day period, oral doses of celecoxib 200 mg taken 3 times a day demonstrated superior analgesia and tolerability compared with hydrocodone 10 mg/acetaminophen 1000 mg taken 3 times a day. Most patients required no more than 2 daily doses of celecoxib 200 mg for the control of their postorthopedic surgical pain.",2002.0,0,0
93,11304662,"Cyclooxygenase-2--specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients.",A Whelton; J G Fort; J A Puma; D Normandin; A E Bello; K M Verburg; SUCCESS VI Study Group,"Arthritis and hypertension are common comorbid conditions affecting elderly adults. Use of nonsteroidal anti-inflammatory drugs in patients treated with antihypertensive medication can lead to destabilization of blood pressure control and other cardiorenal events. The potential for similar interactions with cyclooxygenase-2-specific inhibitors has not been fully explored. The authors evaluated the cardiorenal safety of two new cyclooxygenase-2-specific inhibitors, celecoxib and rofecoxib. This study was a 6-week, randomized, parallel-group, double-blind trial in patients with osteoarthritis who were > or =65 years of age and were taking antihypertensive agents. Patients received once-daily celecoxib 200 mg or rofecoxib 25 mg. The primary endpoints were the development of edema, changes in systolic blood pressure, and changes in diastolic blood pressure as measured at any time point in the study. Measurements occurred at baseline and after 1, 2, and 6 weeks of treatment. Eight hundred ten patients received study medication (celecoxib, n = 411; rofecoxib, n = 399). Nearly twice as many rofecoxib- compared with celecoxib-treated patients experienced edema (9.5% vs. 4.9%, P = 0.014). Systolic blood pressure increased significantly in 17% of rofecoxib- compared with 11% of celecoxib-treated patients (P = 0.032) at any study time point. Diastolic blood pressure increased in 2.3% of rofecoxib- compared with 1.5% of celecoxib-treated patients (P = 0.44). At week 6, the change from baseline in mean systolic blood pressure was +2.6 mmHg for rofecoxib compared with -0.5 mmHg for celecoxib (P = 0.007). Patients taking antihypertensive therapy and receiving cyclooxygenase-2-specific inhibitors should be monitored for the development of cardiorenal events. Patients receiving celecoxib experienced less edema and less destabilization of blood pressure control compared with those receiving rofecoxib.",2001.0,1,1
94,11316141,"Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis.",J L Goldstein; P Correa; W W Zhao; A M Burr; R C Hubbard; K M Verburg; G S Geis,"Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin production by inhibiting cyclooxygenase (COX); they are believed to cause gastroduodenal damage by inhibiting the COX-1 isoform and to have analgesic and anti-inflammatory effects by inhibiting the COX-2 isoform. As compared to conventional NSAIDs, celecoxib, a COX-2 specific inhibitor, has been shown in previous single posttreatment endoscopy studies to be associated with lower gastroduodenal ulcer rates. In response to concerns that such studies may under-represent ulceration rates, the present serial endoscopy study was designed to compare cumulative gastroduodenal ulcer rates associated with the use of celecoxib to those of naproxen, a conventional NSAID. In this double-blind, parallel-group, multicenter study, 537 patients with osteoarthritis (OA) or rheumatoid arthritis (RA) were randomized to treatment with celecoxib 200 mg b.i.d. (n = 270) or naproxen 500 mg b.i.d. (n = 267) for 12 wk. Gastroduodenal damage was determined from esophagogastroduodenoscopy after 4, 8, and 12 wk of therapy. Arthritis efficacy was evaluated with Patient's and Physician's Global Assessments. Gastroduodenal ulcer rates after celecoxib and naproxen treatment were 4% versus 19% in the 0-4 wk interval (p < 0.001), 2% versus 14% in the 4-8 wk interval (p < 0.001), and 2% versus 10% in the 8-12 wk interval (p < 0.001), respectively. After 12 wk of treatment, the cumulative incidence of gastroduodenal ulcers was 9% with celecoxib and 41% with naproxen. In the celecoxib group, gastroduodenal ulcers were significantly associated with Helicobacter pylori status (p < 0.05), concurrent aspirin usage (p = 0.001), and a history of ulcer (p = 0.010), but not with disease type (OA/RA), age, gender, other relevant medical histories, or concurrent corticosteroid or disease-modifying antirheumatic drugs usage (p > 0.05). Celecoxib produced a significantly lower incidence rate of both gastric (p < 0.001) and duodenal (p < 0.030) ulcers. The two agents produced similar improvements in Patient's and Physician's Global Assessments of arthritis efficacy. The incidence of adverse events and withdrawal rates did not differ significantly between treatments. As compared to naproxen (500 mg b.i.d.), use of celecoxib (200 mg b.i.d.), a COX-2 specific agent, at the recommended RA dose and twice the most frequently prescribed OA dose, was associated with lower rates of gastric, duodenal, and gastroduodenal ulcers but had comparable efficacy, in patients with OA and RA.",2001.0,1,1
95,11317165,"Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor.",A Whelton; C J Maurath; K M Verburg; G S Geis,"The novel cyclooxygenase- (COX)-2 inhibitor celecoxib is an effective treatment for the signs and symptoms of osteoarthritis and rheumatoid arthritis. Conventional treatment for these debilitating conditions routinely involves the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs), which are nonspecific inhibitors of COX-1 and COX-2. Numerous studies suggest that inhibition of renal prostaglandin synthesis by NSAIDs is deleterious to kidney function, particularly in high-risk patients. As celecoxib inhibits COX-2 and spares COX-1 at therapeutic doses, we hypothesized that it may offer an improved renal safety profile in patients at risk for NSAID-induced renal toxicity. This article represents a post hoc analysis of the renal safety of celecoxib, using the safety database generated during its clinical development program. This analysis includes data from more than 50 clinical studies involving more than 13,000 subjects. Most subjects were enrolled in randomized, controlled trials (of up to 12 weeks' duration); however, more than 5000 subjects received celecoxib for as long as 2 years in a long-term, open-label study at as much as twice the maximum recommended dosage. The overall incidence of renal adverse events after celecoxib was greater than that after placebo but similar to that after NSAIDs. The most common events reported after celecoxib, namely, peripheral edema (2.1%), hypertension (0.8%), and exacerbation of preexisting hypertension (0.6%), were not time- or dose-related. Peripheral edema was not associated with increased weight or blood pressure. Furthermore, there was no evidence of drug-drug interactions between celecoxib and concomitant angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, calcium channel blockers, or diuretics. We conclude that celecoxib is well tolerated by patients who may be at risk for NSAID-induced renal toxicity, such as the elderly and those with hypertension or preexisting chronic heart disease.",2001.0,0,1
96,11321358,"Acute effects of the anti-inflammatory cyclooxygenase-2 selective inhibitor, flosulide, on renal plasma flow and glomerular filtration rate in rats.",A Turull; C Piera; J Queralt,"Nephrotoxicity of nonsteroidal anti-inflammatory drugs is associated with other risk factors (volume-depletion) and may be secondary to functional changes mediated by the inhibition of renal cyclooxygenases. Acute anti-inflammatory doses of flosulide and indomethacin were determined on carrageenan paw edema and its effects on renal plasma flow (RPF) and glomerular filtration rate (GFR) were studied in normovolemic and hypovolemic rats. In normovolemic rats, flosulide increased RPF and GFR (25 mg/kg) and indomethacin (5-10 mg/kg) was without effect. Volume-depleted rats were obtained by oral furosemide (32 mg/kg), urinary eicosanoids were determined. After furosemide, plasma volume, RPF and GFR and PGE2 decreased. Treatment of hypovolemic rats with flosulide (5-25 mg/kg) or indomethacin 10 mg/kg reduced RPF and GFR. Flosulide at 5 mg/kg reduced 6-keto-PGF1alpha whereas at 25 mg/kg and after indomethacin at 10 mg/kg a fall in 6-keto-PGF1alpha and TXB2 appeared. Our data suggest that acute COX-2 selective inhibition may alter renal function.",2001.0,0,0
97,11322018,[Liver damage and nonsteroidal anti-inflammatory drugs: case non-case study in the French Pharmacovigilance Database].,M P Bareille; J L Montastruc; M Lapeyre-Mestre,"This study investigates the relationship between exposure to non-steroidal anti-inflammatory drugs (NSAIDs) and liver injuries using the French Pharmacovigilance Database. We use the case/non-case methodology, where 'cases' were reports of the reactions of interest (liver injuries as recorded in the database according to the WHO-ART classification including cytolytic and cholestatic hepatitis, acute hepatitis, liver enzyme elevations). 'Non-cases' were all reports of reactions other than these being studied. Amineptine and acetaminophen were used as 'positive controls'. Among the 42,913 adverse drug reactions recorded in the database between January 1995 and December 1997, 5708 (13 per cent) were liver injuries. In comparison with other drugs in the database, liver injuries were inversely associated with exposure to NSAIDs, whatever the class of the drugs (OR 0.3 [0.3-0.4]). In contrast, liver injuries were significantly related to acetaminophen (OR 2.1 [1.9-2.3]), and amineptine (OR 14.0 [10.5-18.7]). Naproxen and diclofenac were associated with a higher frequency of liver injuries, respectively 15.7 per cent and 11.5 per cent. The risk associated with NSAIDs alone significantly decreased when the analysis was performed after exclusion of hepatotoxic drugs associated with NSAIDs (except for naproxen). The present results show the low frequency of liver damage associated with NSAIDs. The main factor appears to be concomitant exposure to other hepatotoxic drugs.",2001.0,0,0
98,11329096,Comparative efficacy and safety of nimesulide versus piroxicam in osteoarthritis with special reference to chondroprotection.,S Sharma; S Rastogi; V Gupta; D Rohtagi; P Gulati,"The efficacy and tolerability profile of nimesulide was assessed in a double-blind, piroxicam-controlled trial in 49 patients with osteoarthritis of the knee joint. Nimesulide was administered orally as 100 mg twice daily, and piroxicam was administered as 20 mg orally in the morning and placebo in the evening. These patients were stratified into two groups: clinical assessment and magnetic resonance imaging evaluation of the knee. All patients were followed for 8 weeks with clinical assessment every 2 weeks; of these, 11 patients were selected for magnetic resonance imaging evaluation, and they were treated for 24 weeks. The principal efficacy parameters were improvement in osteoarthritis severity index, joint tenderness, swelling, and functional capacity of the patients. The final judgment of efficacy was made by the physician. Nimesulide improved all primary and secondary efficacy parameters with an activity comparable to piroxicam. Significant reduction in joint swelling and tenderness was observed as early as 2 weeks in the two treatment groups; however, a greater number of patients were relieved in nimesulide group. At 8 and 24 weeks, the number of patients with no joint swelling were 66.7% versus 50% and 80% versus 66.7% in the nimesulide and piroxicam groups (P <.05). Functional capacity at 8 weeks improved in 72.2% of nimesulide and 44.4% of piroxicam recipients. Mild adverse effects, mainly gastrointestinal, considered possibly related to treatment were recorded in 4 patients treated with nimesulide and in 12 patients treated with piroxicam. No significant change in the articulating cartilage of the tibiofemoral joint was observed over a 24-week period with either treatment. Nimesulide was as efficacious as piroxicam in reducing the inflammatory indices, and both drugs were equally well tolerated.",2001.0,0,0
99,11331167,"Preoperative oral rofecoxib does not decrease postoperative pain or morphine consumption in patients after radical prostatectomy: a prospective, randomized, double-blinded, placebo-controlled trial.",J J Huang; A Taguchi; H Hsu; G L Andriole; A Kurz,"To evaluate the analgesic efficacy of the rofecoxib po before radical prostatectomy. Prospective, randomized, double-blinded, placebo-controlled trial. Teaching hospital. Anesthetic management was standardized. Patients received either a 50-mg rofecoxib capsule or a placebo capsule po 1 hour before induction of anesthesia. Patient-generated 10-cm visual analog scale (VAS) scores for pain were assessed at 1, 2, 4, 6, 8, and 24 hours after surgery. Morphine consumption was recorded from a patient-controlled analgesia device at the same time. A patient-generated overall pain relief score was obtained at 24 hours after surgery. We were unable to detect any differences between study groups with respect to postoperative morphine consumption, VAS score, or overall pain relief score. When rofecoxib is used po in maximum recommended doses before surgery, it does not provide significant analgesia that results in reduction in pain scores or analgesic requirements for patients after radical prostatectomy.",2001.0,0,0
100,11332239,[Tolerability of a selective cyclooxygenase-2-inhibitor (rofecoxib) in patients with intolerance reactions to nonsteroidal anti-inflammatory agents].,T M Zollner; S Ahlbach; R Kaufmann; W H Boehncke,"Pseudoallergic reactions triggered by nonsteroidal anti-inflammatory drugs (NSAIDs) are common and caused by inhibition of the enzyme cyclooxygenase-1, whereas their therapeutic effects are mediated by inhibition of cyclooxygenase-2. This study analyzed the tolerability of the selective cyclooxygenase-2-inhibitor rofecoxib in patients who encountered pseudoallergic reactions to NSAIDs. 37 patients (12 males, 25 females, mean age 35 years [15-75 years]) with a history of pseudoallergic reactions to NSAIDs underwent standardized skin prick, scratch and patch tests along with oral placebo-controlled blinded exposure to rofecoxib (maximum single dose 12.5 mg, cumulative dose 25 mg). 23 patients had skin reactions, 4 times respiratory symptoms were documented, and in 10 cases cutaneous as well as respiratory symptoms were reported. Salicylic acid was identified as the most common trigger for a pseudoallergic reaction (n = 28). In 9 cases several non-steroidal antiphlogistics of different chemical groups caused symptoms. All skin tests showed negative results. Oral challenge with rofecoxib was tolerated by all 37 patients without adverse effects. Given the high incidence of pseudoallergic reactions to NSAIDs the use of selective cyclooxygenase-2-inhibitors represents a therapeutic alternative as well as a means of prevention of the described reactions.",2001.0,0,0
101,11336575,Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis.,N M Davies; T W Gudde; M A de Leeuw,"The discovery of the two isoenzymes of cyclooxygenase (COX) has recently lead to the development and clinical introduction of specific inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib, onto the market. Celecoxib is an effective anti-inflammatory, analgesic and antipyretic agent therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. In addition, celecoxib has some novel therapeutic and pharmacological activities. Celecoxib inhibits anti-apoptotic kinase activation and is the first specific COX-2 inhibitor to be marketed for familial adenomatous polyposis, an inheritable predisposition for colorectal cancer. Celecoxib is not without gastrointestinal (GI) side effects but demonstrates markedly reduced GI ulceration in clinical trials when compared to traditional non-specific non-steroidal anti-inflammatory drugs (NSAIDs). The specific COX-2 inhibitors each have distinctive pharmacokinetic properties. Celecoxib can be given either once or twice daily. Racial differences in drug disposition, and pharmacokinetic changes in elderly patients, patients with chronic renal insufficiency and patients with mild to moderate hepatic impairment, are evident with celecoxib. Despite the specific action of these drugs, there remains the potential for significant drug interactions. Celecoxib has demonstrated interactions with fluconazole, lithium and warfarin. Increased clinical vigilance should be maintained when co-prescribing medications with celecoxib until further clinical experience is gained. Celecoxib represents a major therapeutic advance in terms of GI safety. However, long-term safety in other organ systems, safety with concomitant drug administration, and pharmacoeconomic benefits still remain to be proven.",2002.0,0,0
102,11345810,Renal safety of combined cyclooxygenase 2 (COX-2) inhibitor and angiotensin II receptor blocker administration in mild volume depletion.,T Kistler; P M Ambühl,"Drugs that either inhibit prostaglandin synthesis or antagonise angiotensin II effects are likely to impair renal function, especially in patients with an activated renin-angiotensin-aldosterone system. Of the former, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, and newer agents with cyclooxygenase 2 (COX-2) specific inhibition may have fewer renal side effects compared to non-selective NSAIDs. We therefore investigated whether combination of a COX-2 inhibitor with an angiotensin II subtype 1 (AT1) receptor blocker is safe with regard to preservation of normal renal function in a state of slight volume contraction. Mild volume depletion was induced by a salt-restricted diet in 5 healthy volunteers who were then given a single dose of 400 mg celecoxib, a COX-2 inhibitor, alone or in combination with 150 mg irbesartan, an AT1 receptor blocker. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by measuring inulin and PAH clearance respectively, along with plasma renin activity (PRA) and urinary electrolyte excretion before and over 100 minutes after drug administration. PRA was high prior to drug administration, indicating slight salt depletion, and dropped by 65% after intake of celecoxib alone (p = 0.008) but only by 25% after combined intake with irbesartan (p = n.s.). GFR was not affected either by celecoxib alone or by combined administration with irbesartan. In contrast, ERPF increased by 28% 80 minutes after simultaneous drug intake (p = 0.029), but not after celecoxib alone. Renal sodium and potassium excretion did not significantly change under celecoxib alone or in combination with irbesartan. Selective COX-2 inhibition by celecoxib in combination with an AT1 receptor blocker (irbesartan) has no acute adverse effects on renal haemodynamics and renal salt handling in slightly volume-depleted subjects with normal renal function. Moreover, our data obtained in humans appear to confirm the co-regulatory interaction of COX-2 and angiotensin II in the control of renin release, as suggested by animal studies.",2001.0,0,0
103,11346221,Endoscopic comparison of the gastroduodenal safety and the effects on arachidonic acid products between meloxicam and piroxicam in the treatment of osteoarthritis.,D M Chang; T H Young; C T Hsu; S Y Kuo; T C Hsieh,"Our objective was to evaluate the efficacy, the gastroduodenal safety, and the effects on arachidonic acid products of meloxicam, a new acidic enolic non-steroidal anti-inflammatory drug which preferentially inhibits cyclo-oxygenase-2 over cyclo-oxygenase-1, versus piroxicam in patients with osteoarthritis of the knee. Meloxicam 7.5 mg or piroxicam 20 mg daily was administered for 4 weeks in this double-blind parallel-groups randomised study. The efficacy for pain relief of the two tested medications was assessed by means of visual analogue scale and other clinical parameters. Pre- and post-treatment endoscopies were performed, and the findings were scored and recorded. The gastric fluid was aspirated at each time and prostaglandin E2, thromboxane B2 and leukotriene B4 were determined by ELISA. There was no significant difference between the groups regarding the primary efficacy. Changes in endoscopic findings by means of Lanza score showed statistically significant differences between the two treatment groups in favour of meloxicam at all sites--gastric, duodenal and total. Within-group comparisons showed a statistically significant difference (worsening) in gastric and total score with piroxicam, but no significant difference with meloxicam. The frequency of clinically relevant cases (total score >2) also showed a statistically significant worsening in the piroxicam group. The better GI tolerability of meloxicam was also suggested by fewer adverse GI events and no withdrawals due to adverse events compared with piroxicam. The pre-/post-study gastric juice concentration of PGE2, TXB2, and LTB4 in the meloxicam group was 135.2 +/- 85.8/71.2 +/- 32.2, 116.3 +/- 81.7/99.4 +/- 107.5 and 388 +/- 321/223 +/- 98 pg/ml respectively. The pre-/post-study gastric juice concentration of PGE2, TXB2 and LTB4 in the piroxicam group was 105.7 +/- 43.1/68.2 +/- 34.9, 94.0 +/- 50.9/105.9 +/- 121.1 and 625 +/- 1574/828 +/- 1464 pg/ml, respectively. Both meloxicam and piroxicam significantly inhibited gastric PGE2 levels after 4 weeks' treatment; however, there was no difference between these two groups. Neither of these medications had an effect on TXB2. Only meloxicam inhibited LTB4 concentration significantly, and the between-groups difference was significant. Meloxicam 7.5 mg once daily had better gastrointestinal tolerability and an efficacy comparable to that of piroxicam 20 mg over 4 weeks in patients with osteoarthritis of the knee.",2001.0,0,0
104,11367984,"[Effect of celecoxib, a COX-2 inhibitor, in familial adenomatous polyposis].",B Wullen; A Mühlhöfer; W G Zoller,,2001.0,0,0
105,11385116,Evaluation of the tocolytic effect of a selective cyclooxygenase-2 inhibitor in a mouse model of lipopolysaccharide-induced preterm delivery.,M Sakai; K Tanebe; Y Sasaki; K Momma; S Yoneda; S Saito,"The inflammatory process is known to cause preterm delivery. Recently, a cyclooxygenase (COX)-2 inhibitor has been developed as an anti-inflammatory drug with few side-effects. We evaluated the COX-2 inhibitor, Celecoxib, for its tocolytic effects and side-effects on dams and pups using a lipopolysaccharide (LPS)-induced preterm delivery mouse model (preterm delivery rates; 95%). With administration of Celecoxib (50, 10, 1 and 0.3 mg/kg), the preterm labour rate was significantly reduced to 18, 30, 36 and 60% respectively. The prostaglandin F(2alpha)(PGF(2alpha)) and PGE(2) concentrations in murine uterine tissue 4 and 10 h after LPS treatment with Celecoxib (10 and 1 mg/kg) were significantly lower than those in the LPS-treated group without CELECOXIB: With administration of 10 or 100 mg/kg Celecoxib, the fetal ductus arteriosus was constricted significantly in preterm and near-term rats, although constriction rates in preterm rats were significantly lower than those in near-term rats. Reproductive and renal functions in offspring whose mothers were treated with LPS and Celecoxib were normal. These data demonstrate that Celecoxib could be used as a new therapy for preterm labour. However, careful attention to constriction of the fetal ductus arteriosus should be given.",2001.0,0,0
106,11390425,T-cell involvement in drug-induced acute generalized exanthematous pustulosis.,M Britschgi; U C Steiner; S Schmid; J P Depta; G Senti; A Bircher; C Burkhart; N Yawalkar; W J Pichler,"Acute generalized exanthematous pustulosis (AGEP) is an uncommon eruption most often provoked by drugs, by acute infections with enteroviruses, or by mercury. It is characterized by acute, extensive formation of nonfollicular sterile pustules on erythematous background, fever, and peripheral blood leukocytosis. We present clinical and immunological data on four patients with this disease, which is caused by different drugs. An involvement of T cells could be implied by positive skin patch tests and lymphocyte transformation tests. Immunohistochemistry revealed a massive cell infiltrate consisting of neutrophils in pustules and T cells in the dermis and epidermis. Expression of the potent neutrophil-attracting chemokine IL-8 was elevated in keratinocytes and infiltrating mononuclear cells. Drug-specific T cells were generated from the blood and skin of three patients, and phenotypic characterization showed a heterogeneous distribution of CD4/CD8 phenotype and of T-cell receptor Vbeta-expression. Analysis of cytokine/chemokine profiles revealed that IL-8 is produced significantly more by drug-specific T cells from patients with AGEP compared with drug-specific T cells from patients that had non-AGEP exanthemas. In conclusion, our data demonstrate the involvement of drug-specific T cells in the pathomechanism of this rather rare and peculiar form of drug allergy. In addition, they indicate that even in some neutrophil-rich inflammatory responses specific T cells are engaged and might orchestrate the immune reaction.",2001.0,0,0
107,11393589,Nimesulide aggravates kainic acid-induced seizures in the rat.,T Kunz; E H Oliw,"Treatment of rats with kainic acid (10 mg/kg, intraperitoneally) triggers limbic seizures. Cyclooxygenase-2 mRNA is expressed in the hippocampus and cortex after 8 hr and marked cell loss occurs after 72 hr in the CA1-CA3 areas of the hippocampus. We examined the effect of the cyclooxygenase-2 inhibitor, nimesulide (N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide), on kainate-induced seizures and delayed neurotoxicity. Nimesulide (10 mg/kg, intraperitoneally) was well tolerated given alone or 6-8 hr after kainate. However, pretreatment with nimesulide augmented seizures and increased the mortality rate from approximately 10% to 69%. We examined the effect of nimesulide on delayed cell loss after 72 hr in the surviving animals with histological staining. Cell loss did not seem to be reduced in animals treated with nimesulide 6-8 hr after kainate, but in the surviving animals pretreated with nimesulide less cell loss occurred. We conclude that nimesulide should be used with caution as an antiinflammatory drug in patients with convulsive disorders.",2002.0,0,0
108,11413920,[The selective Cox-2 inhibition by rofecoxib reduces risk of severe gastrointestinal complications of anti-inflammatory therapy by more than 50%].,H Kellner,,2001.0,0,0
109,11424902,Neurotoxicity as a mechanism for neurodegenerative disorders: basic and clinical aspects.,W Danysz,"This three day meeting focused on chronic neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amylotrophic lateral sclerosis (ALS). It attracted 69 participants from 10 countries with dominance of Chile and USA. Neurodegeneration and its prevention increasingly gain in importance as the number of people affected increases year-by-year. The meeting addressed various basic aspects having pragmatic implications such as: oxidative stress, inflammatory reaction, glial activation, role of glutamatergic system and apoptosis using a plethora of in vitro and in vivo methods.",2001.0,0,0
110,11425807,Induction of delayed follicular rupture in the human by the selective COX-2 inhibitor rofecoxib: a randomized double-blind study.,M Pall; B E Fridén; M Brännström,"The aims of the present study were to examine whether periovulatory administration of a cyclo-oxygenase (COX)-2 inhibitor affects human ovulation and endocrine parameters. Thirteen healthy women, 30-40 years of age, without hormonal treatment and with regular menstrual cycles (27-34 days), were given the selective COX-2 inhibitor rofecoxib (n = 6) or placebo (n = 7) in a random double-blind fashion. In an initial control cycle, serial hormonal analyses, detection of a measurable mid-cycle urine LH peak and transvaginal ultrasound scans were performed to confirm normal ovulatory and endocrinological cyclic patterns, in all participating women. During the subsequent treatment cycle, serial ultrasound scans were performed. When the dominant follicle reached 14-16 mm in diameter, 25 mg rofecoxib or placebo was taken orally, once daily for 9 consecutive days, during which follicle size was monitored daily by ultrasound scans and serial hormone analyses were performed. Four of the six women who received rofecoxib demonstrated delayed follicle rupture, >48 h after the LH peak, when compared with the placebo group, who all had follicular rupture >36 h after the detected LH peak. No differences in peripheral serum concentrations of progesterone, oestradiol, LH and FSH were observed between placebo and rofecoxib groups, when analysed at specified time intervals. This study suggests that selective COX-2 inhibition has a negative, local effect on human ovulation, resulting in delayed follicular rupture, without affecting peripheral hormonal cyclicity.",2001.0,0,0
111,11439734,Effect of rofecoxib therapy on measures of health-related quality of life in patients with osteoarthritis.,E W Ehrich; J A Bolognese; D J Watson; S X Kong,"Bodily pain and physical disability can negatively impact health-related quality of life (HRQL) in patients with osteoarthritis (OA). To assess the effects of treatment with a new agent, rofecoxib, on HRQL in patients with OA. Randomized, double-blind, 6-week clinical trial comparing treatment with rofecoxib, 5 to 50 mg, with placebo in 672 patients with OA of the hip or knee. Patient HRQL was assessed at baseline and at the end of treatment using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). At 6 weeks, mean change from baseline in all SF-36 mental and physical health domain scores demonstrated significant improvement with rofecoxib use (P < .05 for all doses for all SF-36 domains), with evidence of a dose-response relation. Improvements in mental and physical HRQL domains with rofecoxib treatment were significantly greater than those with placebo treatment (P < .05 for each dose of rofecoxib vs placebo for all domains except general health) and highly correlated with improvements observed using disease-specific OA outcome measures such as the Western Ontario and McMaster Universities Osteoarthritis Index-visual Analog 3.0 OA index pain and physical function subscales. The effect of rofecoxib vs placebo treatment on mental health largely disappeared after adjustment for improvement in OA disease-specific measures. Rofecoxib treatment increased physical and mental HRQL domain scores on the SF-36. Improvements in mental health with rofecoxib use primarily resulted from effective treatment of OA (i.e., reduction in pain and improvement in physical function).",2001.0,0,1
112,11465874,Parecoxib (parecoxib sodium).,S M Cheer; K L Goa,"Parecoxib (parecoxib sodium) is an injectable pro drug of valdecoxib, which is a potent and selective inhibitor of cyclo-oxygenase-2. Intravenous (IV) or intramuscular (IM) parecoxib >20 mg has analgesic activity superior to that of placebo and similar to that of IV or IM ketorolac 30 or 60 mg well controlled trials in patients with postoperative dental pain (n = 304 to 457). In a well controlled trial (n = 202), IV parecoxib 20 or 40mg showed analgesic activity greater than that of placebo and IV morphine 4mg and similar to that of IV ketorolac 30 mg following gynaecological surgery Following orthopaedic surgery, the analgesic activity of IV parecoxib 20 or 40mg was similar to that of IV ketorolac 30 mg and superior to that of IV morphine 4 mg or placebo in well controlled trials (n = 175 and 208). IV parecoxib (40 mg twice daily for 7 days) produced significantly fewer gastrointestinal erosions and/or ulcers than ketorolac (15 mg 4 times a day for 5 days) in healthy volunteers in a well controlled trial; effects on upper gastrointestinal mucosa were similar for parecoxib and placebo. Parecoxib is well tolerated after dental, gynaecological or orthopaedic surgery. The most common adverse events irrespective of treatment (parecoxib, ketorolac or placebo) after dental surgery were nausea, alveolar osteitis, dizziness and headache. Nausea, abdominal pain, headache, abdominal fullness, dizziness, back pain, fever, hypoactive bowel sounds, vomiting, tachycardia, somnolence, abnor mal breath sounds and pruritus occurred in > or = 10% of parecoxib recipients after gynaecological surgery. Similar results were seen in placebo recipients.",2002.0,0,0
113,11475491,Rofecoxib: new preparation.  A disappointing NSAID analgesic.,,"(1) Rofecoxib, a nonsteroidal antiinflammatory drug, is licensed in France for symptom relief in osteoarthritis. It is promoted by MSD-Chibret as a ""specific inhibitor of type 2 cyclooxygenases (COX-2)"". (2) The clinical dossier includes trials versus other antiinflammatory drugs, but the reports available are generally vague. Rofecoxib has not been compared with paracetamol. (3) In these trials rofecoxib 12.5-25 mg/day was no more effective than the comparators (ibuprofen or diclofenac) used at maximal recommended doses. (4) Relative to other nonsteroidal antiinflammatory drugs prescribed at high doses to selected patients in the controlled conditions of clinical trials, rofecoxib only moderately reduces the risk of severe gastrointestinal reactions (1.3% versus 1.8% after a year of treatment) and dyspeptic disorders (23.5% versus 25.5%). (5) Questions persist on other adverse effects, especially those potentially affecting the kidneys and heart. (6) Rofecoxib is subject to the same precautions (pregnancy, interactions, etc.) as other nonsteroidal antiinflammatory drugs.",2001.0,0,0
114,11488693,Meloxicam in hypersensitivity to NSAIDs.,E Nettis; R Di Paola; A Ferrannini; A Tursi,,2001.0,0,0
115,11494927,Cyclooxygenase (COX-2) selective inhibitors. Any better than NSAIDs?,A Nguyen; A Chaiton,,2001.0,0,1
116,11505178,Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs.,L A García Rodríguez; S Hernández-Díaz,"Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with an increase in upper gastrointestinal complications. There is no agreement, however, on whether all conventional NSAIDs have a similar relative risk (RR), and epidemiologic data are limited on acetaminophen. We studied the association between these medications and the risk of upper gastrointestinal bleed/perforation in a population-based cohort of 958,397 persons in the United Kingdom between 1993 and 1998. Our nested case-control analysis included 2,105 cases and 11,500 controls. RR estimates were adjusted for several factors known to be associated with upper gastrointestinal bleed/perforation. Compared with non-users, users of acetaminophen at doses less than 2 gm did not have an increased risk of upper gastrointestinal complications. The adjusted RR for acetaminophen at doses greater than 2 gm was 3.6 [95% confidence interval (95% CI) = 2.6-5.1]. The corresponding RRs for low/medium and high doses of NSAIDs were 2.4 (95% CI = 1.9-3.1) and 4.9 (95% CI = 4.1-5.8). The RR was 3.1 (95% CI = 2.5, 3.8) for short plasma half-life, 4.5 (95% CI = 3.5-5.9) for long half-life, and 5.4 (95% CI = 4.0-7.1) for slow-release formulations of NSAIDs. After adjusting for daily dose, the differences in RR between individual NSAIDs tended to diminish except for apazone. Users of H2 receptor antagonists, omeprazole, and misoprostol had RRs of 1.4 (95% CI = 1.2-1.8), 0.6 (95% CI = 0.4-0.9), and 0.6 (95% CI = 0.4-1.0), respectively. Among NSAID users, use of nitrates was associated with an RR of 0.6 (95% CI = 0.4-1.0).",2001.0,0,0
117,11509060,Risk of cardiovascular events associated with selective COX-2 inhibitors.,D Mukherjee; S E Nissen; E J Topol,"Atherosclerosis is a process with inflammatory features and selective cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects by virtue of inhibiting inflammation. However, by decreasing vasodilatory and antiaggregatory prostacyclin production, COX-2 antagonists may lead to increased prothrombotic activity. To define the cardiovascular effects of COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients without coronary artery disease, we performed a MEDLINE search to identify all English-language articles on use of COX-2 inhibitors published between 1998 and February 2001. We also reviewed relevant submissions to the US Food and Drug Administration by pharmaceutical companies. Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials with approximately 1000 patients each. The results from VIGOR showed that the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P =.002). There was no significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than that in the placebo group of a recent meta-analysis of 23 407 patients in primary prevention trials (0.52%): 0.74% with rofecoxib (P =.04 compared with the placebo group of the meta-analysis) and 0.80% with celecoxib (P =.02 compared with the placebo group of the meta-analysis). The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors. Further prospective trial evaluation may characterize and determine the magnitude of the risk.",2001.0,0,1
118,11519771,Economic evaluation of rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs for the treatment of osteoarthritis.,J M Pellissier; W L Straus; D J Watson; S X Kong; S E Harper,"Results of phase III clinical trials of rofecoxib, a selective inhibitor of cyclooxygenase 2, have shown that osteoarthritis patients treated with rofecoxib had significantly fewer clinically significant gastrointestinal (GI) adverse events than those who received nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). This paper explores the potential economic implications of the use of rofecoxib versus nonselective NSAIDs for the treatment of osteoarthritis via a decision analytic model based on rofecoxib clinical data and the published literature. Base-case 1-year analyses were done with data on GI adverse events, specifically perforations, ulcers, and bleeds (PUBs), obtained from a prespecified pooled analysis of the rofecoxib clinical trials. Analyses were also performed using pooled results of two 12-week endoscopic surveillance trials, with adjustments for silent ulcers of 40% and 85%. Under base-case conditions, the expected cost savings in GI problems and comedications averted with rofecoxib versus NSAIDs was 0.81 dollars per day, representing an 85% offset of the difference in drug price. For rofecoxib versus NSAIDs, the expected cost per PUB avoided with rofecoxib was 4738 dollars, and expected cost per year of life saved was 18,614 dollars. In analyses based on endoscopic data, therapy with rofecoxib was less expensive than therapy with NSAIDs, regardless of silent ulcer adjustment. Results were most sensitive to prophylactic GI comedication rates, and were robust over a range of model assumptions and costs. In this analysis based on differences in clinically significant GI events for osteoarthritis patients, cost differences between rofecoxib and NSAIDs were markedly offset by expected cost savings in GI problems and comedications averted with rofecoxib. Costs per year of life saved with rofecoxib versus NSAIDs were well within accepted benchmarks for cost-effectiveness. When endoscopic data alone were considered, rofecoxib was cost saving across all assumptions about silent ulcer rates.",2002.0,0,1
119,11525777,Cyclooxygenase selectivity of non-steroid anti-inflammatory drugs in humans: ex vivo evaluation.,F Giuliano; J G Ferraz; R Pereira; G de Nucci; T D Warner,"We have recently described a novel assay to assess ex vivo the activity and selectivity on cyclooxygenase-1 and -2 (EC 1.14.99.1) of non-steroid anti-inflammatory drugs (NSAID) administered to rats [Br. J. Pharmacol. 126 (1999) 1824.]. Here, we have extended these studies to humans. Healthy male volunteers were given orally one of the following drugs (mg) for 5 days: etodolac (200 or 400 b.i.d.), meloxicam (7.5 or 15 q.d.), nimesulide (100 or 200 b.i.d.), nabumetone (500 or 1000 b.i.d.) or naproxen (500 b.i.d.). Blood samples were withdrawn from the volunteers before and up to 24 h after the last dose. Plasma obtained from the blood was tested for its ability to inhibit prostanoid formation in interleukin-1beta-treated A549 cells (cyclooxygenase-2 system) and human washed platelets (cyclooxygenase-1 system). Plasma from etodolac-treated subjects demonstrated a slight selectivity towards the inhibition of cyclooxygenase-2. This effect was more prominent in plasma from subjects receiving meloxicam or nimesulide. Plasma from nabumetone-treated subjects showed no or little selectivity towards cyclooxygenase-1 depending on the dose of drug administered, while plasma taken from subjects receiving naproxen was more active at inhibiting cyclooxygenase-1 than cyclooxygenase-2. In conclusion, we have demonstrated that this assay can be used to assess ex vivo the relative activity against cyclooxygenase-1 and cyclooxygenase-2 of NSAIDs consumed by human volunteers. It is to be hoped that data from such systems will aid in our understanding of the relationships between the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2 by NSAIDs and their reported efficacies and (gastrointestinal) toxicities.",2001.0,0,0
120,11563999,Influence of risk factors on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen in two randomized controlled trials.,C J Hawkey; L Laine; S E Harper; H U Quan; J A Bolognese; E Mortensen; Rofecoxib Osteoarthritis Endoscopy Multinational Study Group,"Highly selective inhibitors of the inducible cyclooxygenase-2 enzyme (coxibs) have been associated with less gastrotoxicity than nonselective NSAIDs in clinical studies. To evaluate the influence of risk factors for NSAID-induced gastrotoxicity on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen. We analysed pooled data from two identical double-blind, randomized, 12-week endoscopy studies which compared the gastroduodenal toxicity of placebo (n=371), rofecoxib 25 mg (n=390), rofecoxib 50 mg (n=379), and ibuprofen 2400 mg daily (n=376) in patients with osteoarthritis. The potential risk factors evaluated were: age (< 65, > or = 65 years), sex, race (white, nonwhite), Helicobacter pylori status, presence of gastroduodenal erosions at baseline, a history of upper gastrointestinal disease, prior NSAID use within 30 days of study entry, and smoking. We also evaluated these factors for possible association with the development of clinically-evident gastrointestinal perforations, ulcers or bleeds over 12 weeks. Across all treatment groups, the likelihood of detecting endoscopic ulcers, or of clinical presentation with a bleed, over 12 weeks was increased approximately 4-5-fold in patients with previous upper gastrointestinal disease (relative risk [95% confidence interval] of 4.2 [2.5, 7.1] for endoscopic ulcers; 3.8 [1.4, 10.6] for bleeds), or those with gastroduodenal erosions at baseline endoscopy (relative risk of 4.4 [2.6, 7.5] for endoscopic ulcers; 5.0 [1.9, 13.5] for bleeds). H. pylori infection did not increase the risk of endoscopic ulcers or bleeds (relative risk of 1.1 [0.8, 1.6] for endoscopic ulcers; 0.3 [0.1, 0.9] for bleeds). The risk factor sub-group effects were constant across all treatment groups, and the significantly higher incidence of ulcers with ibuprofen as compared to rofecoxib and placebo was maintained in all risk factor subgroups. Gastroduodenal erosions at baseline and a clinical history of upper gastrointestinal disease, but not H. pylori colonization, increased the risk for endoscopically-detected ulcers and clinical bleeds. Rofecoxib did not magnify the risk in any of the patient subgroups studied.",2002.0,0,0
121,11583480,A pharmacokinetic study of intramuscular (i.m.) parecoxib sodium in normal subjects.,A Karim; A Laurent; M E Slater; M E Kuss; J Qian; S L Crosby-Sessoms; R C Hubbard,"A single-center, double-blind, placebo-controlled, randomized study was conducted to determine the pharmacokinetics, safety, and tolerability of single, rising intramuscular (i.m.) doses and the single maximum tolerated dose of parecoxib sodium, a prodrug of the novel COX-2 selective anti-inflammatory analgesic drug valdecoxib, in 56 healthy male volunteers, ages 18 to 45 years inclusive. Cohorts of up to 6 subjects in each dose schedule were administered either parecoxib sodium (1 mg, 2 mg, 5 mg, 10 mg, 20 mg, or 40 mg) or matching placebo. Following i.m. administration, serial blood samples for measurement of plasma concentrations of parecoxib, valdecoxib, and valdecoxib metabolite (M1) were collected at predetermined intervals (from 15 minutes prior to dose and through 96 hours postdose). Urine collections were obtained for drug assay (from -12 to 0 hours, 0 to 12 hours, and 12 to 24 hours postdose). After i.m. administration, peak plasma concentrations of parecoxib were reached within 15 minutes and then declined rapidly as prodrug was converted to the active moiety, valdecoxib. Change in plasma concentrations of valdecoxib, which declined more slowly (t(1/2) = 5.4-9.9 hours), reflected transformation to several metabolites, one of which was the minor active metabolite M1. As measured by the AUC(0-infinity), Cmax, and XU(0-24) of valdecoxib, parecoxib sodium demonstrated dose proportionality when administered in the range of 1 mg to 40 mg of parecoxib. All single i.m. doses up to the maximum of 40 mg of parecoxib, as well as concentrations of up to 20 mg/ml, were well tolerated.",2002.0,0,0
122,11583481,Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients.,J I Schwartz; N G Agrawal; P H Wong; K A Bachmann; A G Porras; J L Miller; D L Ebel; M R Sack; G B Holmes; J S Redfern; B J Gertz,"Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase-2 (COX-2). Methotrexate is a disease-modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double-blind, placebo-controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days -1, 7, 14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days 1 to 21 only to maintain a double-blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7-hydroxymethotrexate. The AUC(0-infinity) geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day -1, day 14/day -1, and day 21/day -1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day -1). All AUC(0-infinity), GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7-hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.",2002.0,0,0
123,11587283,COX-2 inhibition and thrombotic tendency: a need for surveillance.,L G Cleland; M J James; L K Stamp; P S Penglis,"Cyclooxygenase-2 (COX-2) inhibitors belong to a new class of drugs which have anti-inflammatory efficacy similar to that of traditional non-steroidal anti-inflammatory drugs (NSAIDs), but are associated with a reduced incidence of adverse upper gastrointestinal events. Biochemical evidence that COX-2 inhibitors could promote or exacerbate a tendency to thrombosis is supported by recent results from clinical trials and case reports. Two agents in this class, celecoxib and rofecoxib, have been listed on the Pharmaceutical Benefits Scheme (PBS) for very broad indications in chronic arthropathies, suggesting that they will move into widespread community use. It is important to canvass the possibility that use of these agents could be associated with thrombotic events.",2001.0,0,1
124,11589257,"Upper gastrointestinal safety evaluation of parecoxib sodium, a new parenteral cyclooxygenase-2-specific inhibitor, compared with ketorolac, naproxen, and placebo.",S I Harris; M Kuss; R C Hubbard; J L Goldstein,"Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of ulcers and upper gastrointestinal (GI) ulcer complications, which has been attributed to the inhibition of cyclooxygenase-1. These risks are usually increased in elderly populations. Parecoxib sodium is an injectable prodrug of the cyclooxygenase-2-specific inhibitor valdecoxib that has exhibited analgesic activity in previous trials. The purpose of this study was to compare the GI safety and tolerability profile of parecoxib sodium with that of ketorolac, naproxen, and placebo in a 7-day endoscopic trial in elderly subjects. This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group study. After a normal baseline endoscopy, healthy elderly subjects aged 66 to 75 years were randomized to receive i.v. parecoxib sodium (10 mg BID), oral naproxen (500 mg BID), or placebo for 7 days, or placebo for 2 days followed by i.v. ketorolac (15 mg QID) for 5 days. Endoscopy was performed again after 7 days. Among the first 17 subjects enrolled, ulcers were observed in all treatment groups except the parecoxib sodium group (ketorolac, 4/4 subjects; naproxen, 2/4 subjects; and placebo, 2/5 subjects). Four subjects in the ketorolac group and 1 subject in the naproxen group had multiple gastric ulcers or combined gastric and duodenal ulcers. Because of the unexpectedly high incidence of gastroduodenal ulcers observed, the study was terminated early and the randomization blind broken. These findings suggest that elderly patients may be at risk for GI ulceration even after short-term use of the conventional NSAIDs ketorolac and naproxen.",2002.0,0,0
125,11589259,"Rofecoxib versus codeine/acetaminophen in postoperative dental pain: a double-blind, randomized, placebo- and active comparator-controlled clinical trial.",D J Chang; J R Fricke; S R Bird; N R Bohidar; T W Dobbins; G P Geba,"In recent studies of acute pain and primary dysmenorrhea, rofecoxib, a nonsteroidal anti-inflammatory drug that selectively targets the cyclooxygenase-2 enzyme, was found to be similar in efficacy to ibuprofen and naproxen sodium. The purpose of this study was to determine the analgesic efficacy of a single oral dose of rofecoxib 50 mg compared with the combination of codeine 60 mg/acetaminophen 600 mg in a model of postsurgical dental pain. In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate or severe pain after the surgical extraction of > or = 2 third molars, at least 1 of which was a mandibular impaction, were randomized to receive placebo, rofecoxib 50 mg, or codeine 60 mg/acetaminophen 600 mg. Patient evaluations of pain intensity, pain relief, and global assessments were recorded throughout the 24-hour period after dosing. The 2-stopwatch method was used to determine time to confirmed perceptible pain relief. The primary end point assessing overall analgesic effect was total pain relief over 6 hours (TOPAR6). Secondary end points were patient global assessment of response to therapy (PGART) at 6 hours, onset of analgesia, peak analgesic effect, and duration of analgesia. A total of 393 patients were enrolled; 182 received rofecoxib, 180 received codeine/acetaminophen, and 31 received placebo. The overall analgesic effect of rofecoxib 50 mg was greater than that of codeine 60 mg/acetaminophen 600 mg for TOPAR6 (12.4 vs 7.0; P < 0.001) and PGART at 6 hours (P < 0.001). The onset of analgesic effect was similar for rofecoxib and codeine/acetaminophen. Peak analgesic effect as measured by peak pain relief scores during the first 6 hours was significantly greater in the rofecoxib group compared with the codeine/acetaminophen group (P < 0.001), as was the duration of analgesic effect measured by the time to rescue analgesia (9.6 hours vs 2.3 hours, P < 0.001). Adverse events were reported in 33.0%, 46.1%, and 32.3% of patients treated with rofecoxib, codeine/acetaminophen, and placebo, respectively. The most common adverse events were nausea (6.0%, 25.0%, and 9.7%, respectively) and vomiting (3.8%, 18.3%, and 6.5%, respectively). Significantly more patients in the codeine/acetaminophen group than in the rofecoxib group experienced adverse events overall (P < 0.050) and nausea in particular (P < 0.001). In this study of moderate to severe postoperative dental pain, the analgesic efficacy of rofecoxib 50 mg was greater than that of codeine/acetaminophen, with a lower incidence of adverse events and nausea.",2002.0,0,0
126,11600467,Acute gastrointestinal permeability responses to different non-steroidal anti-inflammatory drugs.,E Smecuol; J C Bai; E Sugai; H Vazquez; S Niveloni; S Pedreira; E Mauriño; J Meddings,"Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage both in the upper and lower gastrointestinal tract. New anti-inflammatory drugs have been developed in an attempt to improve their gastrointestinal side effect profile. Our objective was to compare the effect on gastrointestinal permeability of acute equieffective doses of four different NSAIDs; three were designed to reduce gastrointestinal mucosal injury. Healthy volunteers underwent sugar tests in a randomised fashion, 15 days apart, at: (1) baseline; (2) after two days of 75 mg slow release (microspheres) indomethacin; (3) after two days of 7.5 mg oral meloxicam which preferentially inhibits cyclooxygenase 2; and (4) after two days of 750 mg naproxen. A subgroup of subjects was tested after two days of 200 mg celecoxib. In each test, subjects ingested a solution containing sucrose, lactulose, and mannitol and sucralose, to evaluate gastroduodenal, intestinal, and colonic permeability, respectively. Gastric permeability was significantly affected by naproxen (p<0.05) but not by slow release indomethacin, meloxicam, or celecoxib. Intestinal permeability was significantly increased by the first three NSAIDs (p<0.05) but not by celecoxib. Abnormal lactulose/mannitol ratios were observed in 42% of meloxicam treatments, in 62% during indomethacin, and in 75% of subjects treated with naproxen. Finally, colonic permeability, as measured by sucralose, was not significantly increased by any of the four drugs. Our study provides evidence that the newly developed NSAIDs reduce gastric mucosal permeability significantly. However, most produced significant alteration of small intestinal permeability. In contrast, our results suggest that celecoxib seems to exhibit the most desirable gastrointestinal side effect profile.",2002.0,0,0
127,11674895,Are NSAIDs more effective than acetaminophen in patients with osteoarthritis?,D Blandino,,2002.0,0,0
128,11696466,"Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib.",M A Konstam; M R Weir; A Reicin; D Shapiro; R S Sperling; E Barr; B J Gertz,"In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor rofecoxib, one study demonstrated a significant difference between rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with rofecoxib compared with those treated with placebo or nonselective NSAIDs. CV thrombotic events were assessed across 23 phase IIb to V rofecoxib studies. Comparisons were made between patients taking rofecoxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or another nonselective NSAIDs used in the development program (diclofenac, ibuprofen, and nabumetone). The major outcome measure was the combined end point used by the Antiplatelet Trialists' Collaboration, which includes CV, hemorrhagic, and unknown deaths; nonfatal myocardial infarctions; and nonfatal strokes. More than 28 000 patients, representing >14 000 patient-years at risk, were analyzed. The relative risk for an end point was 0.84 (95% CI: 0.51, 1.38) when comparing rofecoxib with placebo; 0.79 (95% CI: 0.40, 1.55) when comparing rofecoxib with non-naproxen NSAIDs; and 1.69 (95% CI: 1.07, 2.69) when comparing rofecoxib with naproxen. This analysis provides no evidence for an excess of CV events for rofecoxib relative to either placebo or the non-naproxen NSAIDs that were studied. Differences observed between rofecoxib and naproxen are likely the result of the antiplatelet effects of the latter agent.",2002.0,0,1
129,11698316,Postoperative analgesia is not different after local vs systemic administration of meloxicam in patients undergoing inguinal hernia repair.,J Rømsing; S Mysager; P Vilmann; J Sonne; N E Larsen; D stergaard,"To distinguish between local and systemic drug effects, we compared pain scores, analgesic consumption and plasma concentrations after local vs i.v. administration of meloxicam 7.5 mg in patients with inguinal hernia repair. In a double-blind, randomized study 56 patients received either local or i.v. meloxicam 7.5 mg. Postoperative pain was assessed with a visual analogue scale (VAS) at rest, on mobilization, and on coughing, the need for supplementary analgesics (fentanyl i.v. and/or acetaminophen-codeine tablets) was recorded, and blood samples were drawn during 24 hr after meloxicam administration. No significant differences were found between groups with respect to pain scores, or in the consumption of supplementary analgesics. Following local application of meloxicam, the peak plasma concentration (C(max)) of 0.5 +/- 0.2 mg*L(-1) achieved after 1.8 +/- 0.5 hr was much lower than the C(max) of 2.5 +/- 0.9 mg*L(-1) achieved immediately after i.v. administration (P <0.05). Mean meloxicam plasma concentration after infiltration was significantly lower than after i.v. doses for the first three hours after administration (P <0.05). We showed no differences in pain scores and analgesic consumption between local and i.v. administration of meloxicam 7.5 mg during the first 24 hr after herniorrhaphy, while plasma concentration of meloxicam was lower after local administration. These results indicate a lack of difference in pain relief after concentrating meloxicam at the hernia wound or after achieving high blood levels rapidly (i.v.). Local administration of meloxicam may confer an advantage over systemic administration by eliciting lower incidences of systemic adverse effects.",2002.0,0,0
130,11718158,Celecoxib in osteoarthritis and rheumatoid arthritis: new preparation. As disappointing as rofecoxib.,,"(1) The reference treatment for drug-based symptomatic relief of osteoarthritis and rheumatoid arthritis is paracetamol and low-dose ibuprofen. (2) The clinical file on celecoxib, a drug promoted as a selective COX-2 inhibitor, is bulky but fails to answer several practical questions, mainly because it lacks comparative trials against paracetamol and low-dose NSAIDs. (3) In osteoarthritis, three double-blind trials versus naproxen and placebo in a total of 3 258 patients show that the analgesic effect of celecoxib 200 mg/day is moderate and does not differ significantly from that of naproxen. Giving celecoxib in one or two daily doses makes no difference in terms of efficacy. (4) In rheumatoid arthritis, two double-blind trials against naproxen and placebo in a total of 2252 patients, and a double-blind trial versus sustained-release diclofenac, show that the symptomatic effect of celecoxib is moderate and no different from that of the comparator NSAIDs. (5) There is no evidence that the safety profile of celecoxib is very different from that of other NSAIDs. The advantage in terms of gastrointestinal adverse effects appears very slight. According to clinical trials and pharmacovigilance data, celecoxib is in no way exempt from the severe gastrointestinal adverse effects generally associated with NSAIDs. (6) In short, celecoxib changes nothing in the management of osteoarthritis and rheumatoid arthritis.",2002.0,0,0
131,11718436,Cox-2 inhibitors and cardiovascular risk: point and counterpoint.,B F Mandell,,2002.0,0,1
132,11718437,"Cox-2 inhibitors and cardiovascular risk: the data are inconclusive, and these drugs are needed.",J Lipani,,2002.0,0,1
133,11718438,Cox-2 inhibitors and cardiovascular risk: we defend our data and suggest caution.,D Mukherjee; S E Nissen; E J Topol,,2002.0,0,1
134,11739299,Cyclooxygenase-2 blockade does not impair endothelial vasodilator function in healthy volunteers: randomized evaluation of rofecoxib versus naproxen on endothelium-dependent vasodilatation.,S Verma; S R Raj; L Shewchuk; K J Mather; T J Anderson,"From a cardiovascular standpoint, the safety of cyclooxygenase-2 (COX-2) blockers has been a topic of increasing concern. This concern stemmed from observations indicating that the COX-2 isoform is the major source of endothelium-derived prostacyclin and, hence, that selective blockade of this enzyme may impair endothelial health. To investigate this matter, we examined the effects of 7 days of treatment with rofecoxib versus naproxen on endothelial function in healthy volunteers. Thirty-five healthy volunteers were randomized to receive 7-day treatment with either rofecoxib (25 mg/d, n=18) or naproxen (750 mg/d, n=17). Vascular response measurements were conducted using forearm strain-gauge plethysmography. Changes in forearm blood flow in response to the endothelium-dependent vasodilator acetylcholine (3, 10, and 30 microg/min) and the endothelium-independent vasodilator sodium nitroprusside (1 and 10 microg/min) were assessed before and after treatment. Acetylcholine evoked a dose-dependent increase in forearm blood flow in all groups. Importantly, treatment resulted in no change in acetylcholine-mediated increases in forearm blood flow in either group (naproxen, P=0.27; rofecoxib, P=0.58). Similarly, there was no change in forearm blood flow in response to sodium nitroprusside (naproxen, P=0.55; rofecoxib, P=0.63). We herein describe, for the first time, the effects of COX-2-selective inhibition on endothelium-dependent vasodilatation in healthy adults. COX-2 blockade, when used at the doses employed therapeutically (which are known to inhibit vascular prostacyclin production) did not result in significant changes in endothelial vasodilator responses in healthy volunteers. The effects of COX-2 inhibitors on vasodilator responses in patients with coronary artery disease remain to be determined.",2002.0,0,0
135,11752357,Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.,F Catella-Lawson; M P Reilly; S C Kapoor; A J Cucchiara; S DeMarco; B Tournier; S N Vyas; G A FitzGerald,"Patients with arthritis and vascular disease may receive both low-dose aspirin and other nonsteroidal antiinflammatory drugs. We therefore investigated potential interactions between aspirin and commonly prescribed arthritis therapies We administered the following combinations of drugs for six days: aspirin (81 mg every morning) two hours before ibuprofen (400 mg every morning) and the same medications in the reverse order; aspirin two hours before acetaminophen (1000 mg every morning) and the same medications in the reverse order; aspirin two hours before the cyclooxygenase-2 inhibitor rofecoxib (25 mg every morning) and the same medications in the reverse order; enteric-coated aspirin two hours before ibuprofen (400 mg three times a day); and enteric-coated aspirin two hours before delayed-release diclofenac (75 mg twice daily) Serum thromboxane B(2) levels (an index of cyclooxygenase-1 activity in platelets) and platelet aggregation were maximally inhibited 24 hours after the administration of aspirin on day 6 in the subjects who took aspirin before a single daily dose of any other drug, as well as in those who took rofecoxib or acetaminophen before taking aspirin. In contrast, inhibition of serum thromboxane B(2) formation and platelet aggregation by aspirin was blocked when a single daily dose of ibuprofen was given before aspirin, as well as when multiple daily doses of ibuprofen were given. The concomitant administration of rofecoxib, acetaminophen, or diclofenac did not affect the pharmacodynamics of aspirin The concomitant administration of ibuprofen but not rofecoxib, acetaminophen, or diclofenac antagonizes the irreversible platelet inhibition induced by aspirin. Treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin.",2002.0,0,1
136,11753007,"Effects of parecoxib, a parenteral COX-2-specific inhibitor, on the pharmacokinetics and pharmacodynamics of propofol.",Andra Ibrahim; Sang Park; Jennifer Feldman; Aziz Karim; Evan D Kharasch,"Parecoxib, a cyclooxygenase-2-specific inhibitor with intended perioperative analgesic and antiinflammatory use, is a parenterally administered inactive prodrug undergoing rapid hydrolysis in vivo to the active cyclooxygenase-2 inhibitor valdecoxib. Both parecoxib and valdecoxib inhibit human cytochrome P450 2C9 (CYP2C9) activity in vitro. Thus, a potential exists for in vivo interactions with other CYP2C9 substrates, including propofol. This investigation determined the influence of parecoxib on the pharmacokinetics and pharmacodynamics of bolus dose propofol in human volunteers. This was a randomized, balanced crossover, placebo-controlled, double-blind, clinical investigation. Twelve healthy 21- to 37-yr-old subjects were studied after providing institutional review board-approved written informed consent. Each subject received a 2-mg/kg intravenous propofol bolus 1 h after placebo (control) or 40 mg intravenous parecoxib on two occasions. Venous concentrations of propofol, parecoxib, and parecoxib metabolites were determined by mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Pharmacodynamic measurements included clinical endpoints, cognitive function (memory, Digit-Symbol Substitution Tests), subjective self-assessment of recovery (Visual Analog Scale) performed at baseline, 15, 30, 60 min after propofol, and sedation depth measured by Bispectral Index. Propofol plasma concentrations were similar between placebo- and parecoxib-treated subjects. No significant differences were found in pharmacokinetic parameters (Cmax, clearance, elimination half-life, volume of distribution) or pharmacodynamic parameters (clinical endpoints [times to: loss of consciousness, apnea, return of response to voice], Bispectral Index scores, Digit-Symbol Substitution Test scores, memory, Visual Analog Scale scores, propofol EC(50)). Single-bolus parecoxib, in doses to be used perioperatively, does not alter the disposition or the magnitude or time course of clinical effects of bolus propofol. Effects on a propofol infusion were not evaluated.",2002.0,0,0
137,11754119,Quantification of nimesulide in human plasma by high-performance liquid chromatography/tandem mass spectrometry. Application to bioequivalence studies.,R E Barrientos-Astigarraga; Y B Vannuchi; M Sucupira; R A Moreno; M N Muscará; G De Nucci,"A method based on liquid chromatography with negative ion electrospray ionization and tandem mass spectrometry is described for the determination of nimesulide in human plasma. Liquid-liquid extraction using a mixture of diethyl ether and dichloromethane was employed and celecoxib was used as an internal standard. The chromatographic run time was 4.5 min and the weighted (1/x) calibration curve was linear in the range 10.0-2000 ng x ml(-1). The limit of quantification was 10 ng x ml(-1), the intra-batch precision was 6.3, 2.1 and 2.1% and the intra-batch accuracy was 3.2, 0.3 and 0.1% for 30, 300 and 1200 ng x ml(-1) respectively. The inter-batch precision was 2.3, 2.8 and 2.7% and the accuracy was 3.3, 0.3 and 0.1% for 30, 300 and 1200 ng x ml(-1) respectively. This method was employed in a bioequivalence study of one nimesulide drop formulation (nimesulide 50 mg x ml(-1) drop, Medley S/A Indústria Farmacêutica, Brazil) against one standard nimesulide drop formulation (Nisulid, 50 mg x ml(-1) drop, Astra Médica, Brazil). Twenty-four healthy volunteers (both sexes) took part in the study and received a single oral dose of nimesulide (100 mg, equivalent to 2 ml of either formulation) in an open, randomized, two-period crossover way, with a 2-week washout interval between periods. The 90% confidence interval (CI) for geometric mean ratios between nimesulide and Nisulid were 93.1-109.6% for C(max), 87.7-99.8% for AUC(last) and 88.1-99.7% for AUC(0-infinity). Since the 90% CI for the above-mentioned parameters were included in the 80-125% interval proposed by the US Food and Drug Administration, the two formulations were considered bioequivalent in terms of both rate and extent of absorption.",2002.0,0,0
138,11754710,,,,,1,1
139,11764220,Precision of composite measures of osteoarthritis efficacy in comparison to that of individual endpoints.,J A Bolognese; E W Ehrich; T J Schnitzer,"Osteoarthritis (OA) clinical studies generally employ various endpoints to evaluate a spectrum of disease manifestations. Compared with individual endpoints, a composite measure might (1) provide a uniform outcome measure of OA efficacy with greater face validity, (2) address multiplicity, and (3) enhance precision. Combinations of endpoints were analyzed to investigate precision of composite measures of OA efficacy. We reanalyzed three 6 week, placebo controlled, double blind, parallel group studies (2 by the same protocol) of the cyclooxygenase-2 (COX-2) specific inhibitor rofecoxib. The average change from baseline at study weeks 2, 4, and 6 was assessed for 10 individual response variables, including patient and investigator global assessments, WOMAC 3.0V OA Index pain, stiffness and physical function subscales, graded study joint tenderness, and rescue analgesic use. Relationships among variables were evaluated using pairwise correlations and principal components analysis. The precision of variables to differentiate rofecoxib from placebo was evaluated using effect size (i.e., mean difference between rofecoxib versus placebo divided by pooled SD). Correlations among all pairs of response variables ranged from 0.5 to 0.9, except those with tenderness (0.4 to 0.6) and those with analgesic use (0.2 to 0.4). The first principal component explained about 70% of the total variability, with weights generally similar (0.17 for rescue analgesic use, 0.25 for tenderness, and 0.30 to 0.37 for the others). These results indicate that nearly all measures are closely related. Based on these results, various linear combinations of the 9 endpoints were formed and their precision to discriminate active treatment from placebo was compared to that of the individual endpoints. Effect sizes of the individual endpoints ranged from 0.6 to 1.1; those of the composites from 0.7 to 0.9. The results were very consistent between study protocols. In comparison to individual endpoints, composite analyses of OA clinical endpoints do not increase precision to discriminate active treatment from placebo.",2002.0,0,0
140,11772800,The preemptive analgesic effect of rofecoxib after ambulatory arthroscopic knee surgery.,Scott S Reuben; Shailesh Bhopatkar; Holly Maciolek; Wanda Joshi; Joseph Sklar,"Nonsteroidal antiinflammatory drugs (NSAIDs) provide effective postoperative analgesia after arthroscopic knee surgery. Some investigators have suggested that the preemptive administration of NSAIDs may reduce postoperative analgesic requirements and hypersensitivity. We evaluated the analgesic effect of administering rofecoxib either before or after surgical incision in patients undergoing arthroscopic knee surgery under local anesthesia. Sixty patients undergoing arthroscopic meniscectomy were randomized into three groups. All patients received intraarticular bupivacaine 0.25% pre- and postsurgery together with IV sedation using midazolam and propofol. The Preincisional group received a single 50 mg dose of rofecoxib 1 h before surgery, the Postincisional group received rofecoxib 50 mg after the completion of surgery, and the Placebo group received a placebo tablet before surgery. Pain scores, the time to first opioid use, and 24-h analgesic use were recorded. Analgesic duration, defined as the time from completion of surgery until first opioid use, was significantly longer in those patients receiving pre- (803 +/- 536 min) versus postincisional (461 +/- 344 min) rofecoxib or placebo (318 +/- 108 min). The 24 h acetaminophen/oxycodone use was less in the Preincisional group (1.5 +/- 0.6 pills) versus the Postincisional group (3.3 +/- 1.3 pills) or the Placebo group (5.5 +/- 1.6 pills). Pain scores with movement were lower in the Preincisional group at all postoperative time intervals. We conclude that rofecoxib provides effective postoperative analgesia for arthroscopic meniscectomy. Further, the administration of rofecoxib 50 mg before surgery provides a longer duration of postoperative analgesia, less 24 h opioid use, and lower incidental pain scores compared with administering the drug after the completion of surgery. The administration of rofecoxib 50 mg before arthroscopic knee surgery provides a longer duration of analgesia, less 24-h opioid use, and lower pain scores than administering the drug after the completion of surgery.",2002.0,0,0
141,11782819,"Valdecoxib, a COX-2-specific inhibitor, is an efficacious, opioid-sparing analgesic in patients undergoing hip arthroplasty.",Frederic Camu; Tessa Beecher; David P Recker; Kenneth M Verburg,"Opioid agents are highly effective analgesics after orthopedic surgery but are associated with several adverse effects. Valdecoxib is a new, highly selective cyclooxygenase (COX)-2-specific inhibitor with a rapid onset of action and significant analgesic properties that is being developed for the management of acute pain. The objective of this study was to demonstrate the opioid-sparing efficacy of valdecoxib as part of a multimodal treatment of pain associated with hip arthroplasty. This multicenter, multiple-dose, double-blind, parallel-group study compared the opioid-sparing effects, analgesic efficacy, and safety of 20- and 40-mg doses of valdecoxib twice daily with placebo in patients receiving morphine by patient-controlled analgesia after hip arthroplasty. Study medication was first administered 1 to 3 hours preoperatively. The total amount of morphine administered, pain intensity, and patient's global evaluation of study medication were assessed over a period of 48 hours. Patients receiving 20 or 40 mg valdecoxib twice daily required on average 40% less morphine than those receiving placebo after hip arthroplasty. Pain intensity levels and patient satisfaction were significantly improved in both valdecoxib groups compared with placebo. Valdecoxib and placebo were equally well tolerated. Pre- and postoperative administration of valdecoxib reduces the amount of morphine required for postoperative pain relief and provides greater analgesic efficacy compared with morphine alone. Thus, valdecoxib has significant clinical utility for acute pain management in orthopedic surgery patients.",2002.0,0,0
142,11792343,"Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone).",Alise S Reicin; Deborah Shapiro; Rhoda S Sperling; Eliav Barr; Qinfen Yu,"Aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and specific cyclooxygenase-2 (COX-2) inhibitors each have distinctive effects on COX-1-mediated thromboxane biosynthesis, the major determinant of platelet aggregation. It is unclear whether these effects are associated with differences in thrombogenic risks. To compare the risk for thrombotic cardiovascular events among patients receiving rofecoxib, nonselective NSAIDs, and placebo, cardiovascular safety was assessed in 5,435 participants in 8 phase IIB/III osteoarthritis trials. The median treatment exposure was 31/2 months. The primary end point assessed was the risk of any arterial or venous thrombotic cardiovascular adverse event (AE). A second analysis assessed differences in the Anti-Platelet Trialists' Collaboration (APTC) events, a cluster end point that consists of the combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2) myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic cardiovascular AEs were reported with rofecoxib, placebo, and comparator nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100 patient-years in the rofecoxib treatment group compared with 2.27/100 patient-years in the combined nonselective NSAID group. In trials that compared rofecoxib with placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the rofecoxib group compared with 2.57/100 patient-years in the placebo group. Consistent with the risks of cardiovascular AEs, similar rates of APTC events were reported with rofecoxib, placebo, and comparator nonselective NSAIDs. Thus, in the rofecoxib osteoarthritis development program, there was no difference between rofecoxib, comparator nonselective NSAIDs, and placebo in the risks of cardiovascular thrombotic events.",2002.0,0,1
143,11802750,"Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole.",David Y Graham; Naurang M Agrawal; Donald R Campbell; Marian M Haber; Cyndy Collis; Nancy L Lukasik; Bidan Huang; NSAID-Associated Gastric Ulcer Prevention Study Group,"Studies that report prevention of ulcer recurrence among long-term users of nonsteroidal anti-inflammatory drugs (NSAIDs) that do not stratify for Helicobacter pylori status may not be generalizable to the large population of individuals without H pylori. This was a prospective, double-blind, multicenter, active- and placebo-controlled study among 537 patients without H pylori who were long-term users of NSAIDs and who had a history of endoscopically documented gastric ulcer. Patients were randomized to receive placebo, 200 microg of misoprostol 4 times a day, or 15 or 30 mg of lansoprazole once daily for 12 weeks. Ulcer status was determined by endoscopy at 4, 8, and 12 weeks. Patients receiving lansoprazole (15 or 30 mg) remained free from gastric ulcer longer than those who received placebo (P<.001) but for a shorter time than those who received misoprostol. By week 12, the percentages of gastric ulcer-free patients were as follows: placebo, 51% (95% confidence interval [CI], 41.1%-61.3%); misoprostol, 93% (95% CI, 87.2%-97.9%); 15-mg lansoprazole, 80% (95% CI, 72.5%-87.3%); and 30-mg lansoprazole, 82% (95% CI, 75.0%-89.6%). A significantly higher proportion of patients in the misoprostol group reported treatment-related adverse events and early withdrawal from the study. When the impact of withdrawals on ulcer development was considered (as failures), therapy was successful for 69% for each of the active treatment groups and 35% for the placebo group. Proton pump inhibitors such as lansoprazole are superior to placebo for the prevention of NSAID-induced gastric ulcers but not superior to misoprostol, 800 microg/d. When the poor compliance and potential adverse effects associated with misoprostol are considered, proton pump inhibitors and full-dose misoprostol are clinically equivalent.",2002.0,1,1
144,11803730,Comparative efficacy and safety of celecoxib and naproxen in the treatment of osteoarthritis of the hip.,A J Kivitz; R W Moskowitz; E Woods; R C Hubbard; K M Verburg; J B Lefkowith; G S Geis,"Osteoarthritis (OA) is responsible for more disability of the lower extremities in the elderly than any other disease in the US. The pain associated with OA is the primary symptom leading to disability in these patients. Current ACR guidelines recommend consideration of acetaminophen for mild-to-moderate pain and conventional non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 specific inhibitors for moderate-to-severe OA symptoms. The aim of this study was to compare the efficacy and safety of the COX-1 sparing, COX-2 specific inhibitor, celecoxib, with the conventional NSAID naproxen, and placebo, in the treatment of OA of the hip. In this multicenter, randomized, placebo-controlled trial, 1061 patients with symptomatic OA of the hip were randomized to receive celecoxib at doses of 100 mg, 200 mg, or 400 mg/day; naproxen 1000 mg/day; or placebo, for 12 weeks. Patients were evaluated using standard measures of efficacy at baseline, 2-4 days after discontinuing previous NSAID or analgesic therapy, and after 2, 6, and 12 weeks of treatment. All doses of celecoxib and naproxen significantly improved the symptoms of OA, at all time points compared with placebo. This sustained treatment effect of celecoxib was dose dependent. In terms of pain relief and improvement in functional capacity, celecoxib 200 mg/day and 400 mg/day were similarly efficacious and were comparable to naproxen. Both drugs were generally well tolerated. Celecoxib at a dose of 200 mg/day is as effective as a standard therapeutic dose of the conventional NSAID, naproxen, in reducing the pain associated with OA of the hip.",2002.0,1,1
145,11805921,Evaluation of the safety and efficacy of the perioperative administration of rofecoxib for total knee arthroplasty.,Scott S Reuben; Richard Fingeroth; Robert Krushell; Holly Maciolek,"Nonsteroidal anti-inflammatory drugs (NSAIDs) frequently are discontinued before elective total knee arthroplasty (TKA) because of the increased incidence of perioperative bleeding. Rofecoxib, a selective cyclooxygenase 2 inhibitor, does not interfere with the coagulation system and may be a safer NSAID for patients undergoing TKA. In this study, 100 patients undergoing elective TKA discontinued their use of NSAIDs 10 days before surgery and were assigned randomly to receive either placebo (n = 50) or rofecoxib (n = 50), 25 mg daily for 5 consecutive days starting 3 days before surgery. The administration of rofecoxib resulted in improved preoperative pain scores and no significant increase in the incidence of perioperative bleeding or international normalized ratio compared with placebo. Rofecoxib does not need to be discontinued before elective TKA.",2002.0,0,0
146,11809254,Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study.,Wayne A Ray; C Michael Stein; Kathi Hall; James R Daugherty; Marie R Griffin,"Non-aspirin, non-steroidal anti-inflammatory drugs (NANSAIDs) have complex effects that could either prevent or promote coronary heart disease. Comparison of the NANSAID rofexocib with naproxen showed a substantial difference in acute myocardial infarction risk, which has been interpreted as a protective effect of naproxen. We did an observational study to measure the effects of NANSAIDs, including naproxen, on risk of serious coronary heart disease. We used data from the Tennessee Medicaid programme obtained between Jan 1, 1987, and Dec 31, 1998, to identify a cohort of new NANSAID users (n=181 441) and an equal number of non-users, matched for age, sex, and date NANSAID use began. Both groups were 50-84 years of age, were not resident in a nursing home, and did not have life-threatening illness. The study endpoint was hospital admission for acute myocardial infarction or death from coronary heart disease. During 532634 person-years of follow-up, 6362 cases of serious coronary heart disease occurred, or 11.9 per 1000 person-years. Multivariate-adjusted rate ratios for current and former use of NANSAIDs were 1.05 (95% CI 0.97-1.14) and 1.02 (0.97-1.08), respectively. Rate ratios for naproxen, ibuprofen, and other NANSAIDs were 0.95 (0.82-1.09), 1.15 (1.02-1.28), and 1.03 (0.92-1.16), respectively. There was no protection among long-term NANSAID users with uninterrupted use; the rate ratio among current users with more than 60 days of continuous use was 1.05 (0.91-1.21). When naproxen was directly compared with ibuprofen, the current-use rate ratio was 0.83 (0.69-0.98). Absence of a protective effect of naproxen or other NANSAIDs on risk of coronary heart disease suggests that these drugs should not be used for cardioprotection.",2002.0,0,0
147,11823092,Why do cyclo-oxygenase-2 inhibitors cause cardiovascular events?,Richard J Bing; Magdalena Lomnicka,"This report confirms evidence that selective nonsteroidal anti-inflammatory drugs (NSAIDs), such as celecoxib, can lead to thrombotic cardiovascular events. Aspirin, a nonselective COX-1 (cyclo-oxygenase) and COX-2 inhibitor may result in gastric toxicity. For this reason, selective COX-2 inhibitors have been developed to reduce erosion of the gastric mucosa. Both selective and nonselective NSAIDs reduce prostacyclin formation in the infarcted heart; they accomplish this by tipping the balance of prostacyclin/thromboxane in favor of thromboxane, a prothrombotic eicosanoid. The relative increase in thromboxane, coupled with a diminution in prostacyclin in infarcted heart muscle, can lead to the development of thrombotic cardiovascular events. This may be prevented by the addition of a nitric oxide donor to NSAIDs.",2002.0,0,0
148,11831545,Effect of rofecoxib on the pharmacokinetics of chronically administered oral contraceptives in healthy female volunteers.,Jules I Schwartz; Peggy H Wong; Arturo G Porras; David L Ebel; Thomas R Hunt; Barry J Gertz,"The effect of rofecoxib, a highly selective cyclooxygenase (COX)-2 inhibitor, on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET), two common components of a combination oral contraceptive product, was examined. A double-blind, two-period crossover study was conducted in 18 healthy women who received ORTHO-NOVUM 1/35, a combination of EE (35 microg) and NET (1 mg), concurrently for 14 days with either 175 mg rofecoxib or matching placebo during two consecutive menstrual cycles. Plasma was sampled for EE, NET, sex hormone binding globulin (SHBG), and albumin. The AUC(0-24 h) geometric mean ratio (GMR: rofecoxib/placebo) with corresponding 90% confidence interval (CI) of EE and NET was 1.13 (1.06, 1.19) and 1.18 (1.13, 1.24), respectively. The Cmax GMR of EE and NET was 1.06 (0.98, 1.16) and 1.04 (0.99, 1.09), respectively. In each case, the 90% CIs satisfied the predefined bioequivalence limits of (0.80, 1.25). Measures of SHBG and albumin and routine clinical and laboratory safety parameters showed no clinically meaningful changes. The addition of rofecoxib to the oral contraceptive was not associated with any clinically important changes in EE or NET pharmacokinetics and thus would not be anticipated to influence the efficacy of this contraceptive regimen.",2002.0,0,0
149,11835924,"Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac.",William B White; Gerald Faich; Andrew Whelton; Clement Maurath; Nancy J Ridge; Kenneth M Verburg; G Steven Geis; James B Lefkowith,"It has been hypothesized that cyclooxygenase 2 specific inhibitors may increase the risk of cardiovascular (CV) thromboembolic events because of their inhibition of vascular prostacyclin synthesis and lack of an effect on platelet thromboxane A(2) production and aggregation. Thus, we analyzed the data for celecoxib and nonsteroidal anti-inflammatory drugs (NSAIDs) from the Celecoxib Long-term Arthritis Safety Study to determine the incidences of serious CV thromboembolic events. This trial included 3,987 persons randomized to celecoxib 400 mg twice daily (2,320 person-years of exposure) and 3,981 persons randomized to either ibuprofen 800 mg 3 times daily or diclofenac 75 mg twice daily (2,203 person-years). Because acetylsalicylic acid (ASA) use for CV risk prophylaxis (< or =325 mg/day) was permitted, separate analyses were performed for all patients and those not taking ASA. The incidences of serious CV thromboembolic events (myocardial infarction, stroke, CV deaths, and peripheral events) were similar, and not significantly different, between celecoxib and NSAID comparators (combined or individually) for all patients as well as the subgroup of patients not taking ASA. This observation was true both for all serious CV thromboembolic events, as well as for individual events. No increase in myocardial infarction was apparent, even in patients not taking ASA who were candidates for secondary prophylaxis for myocardial infarction. The relative risks for celecoxib versus NSAIDs for serious CV thromboembolic events were 1.1 for all patients and 1.1 for the subgroup of patients not taking ASA (95% confidence interval 0.7 to 1.6 and 0.6 to 1.9, respectively). In addition, the incidences of adverse CV events such as hypertension, edema, and congestive heart failure were similar to, or significantly lower than, NSAID comparators regardless of the use of ASA. Thus, these analyses demonstrate no increased risk of serious CV thromboembolic events associated with celecoxib compared with conventional NSAIDs and therefore do not support the hypothesis of a class adverse effect of cyclooxygenase 2 specific inhibitors on the CV system.",2002.0,0,1
150,11846050,Quality of life in chronic NSAID users: a comparison of the effect of omeprazole and misoprostol.,N Yeomans; I Wilson; G Långström; C Hawkey; J Naesdal; A Walan; I Wiklund,"To compare the impact on quality of life (QoL) of omeprazole and misoprostol during healing, and omeprazole, misoprostol, and placebo during maintenance treatment in chronic NSAID users with NSAID-associated gastroduodenal lesions. Validated baseline and follow-up QoL questionnaires were completed by 610 patients (healing: after 4/8 weeks; maintenance: after 6 months). Patients with arthritis being treated with NSAIDs have a poor QoL. Rheumatoid arthritis causes more joint problems and physical mobility limitations than osteoarthritis. Chronic NSAID use causes heartburn and dyspepsia. QoL improved on both treatments (about equally on two general QOL scales), but omeprazole relieved gastrointestinal symptoms more than misoprostol, particularly reflux, abdominal pain and indigestion symptoms. During maintenance, both treatments maintained QoL, but misoprostol induced diarrhoea. QoL in arthritis patients on chronic NSAID treatment is destroyed. Omeprazole is superior to misoprostol for relief and prevention of NSAID-associated gastrointestinal symptoms allowing continued NSAID treatment without compromising the patients' QoL.",2002.0,0,0
151,11846190,Gingival crevicular fluid matrix metalloproteinase-8 levels following adjunctive use of meloxicam and initial phase of periodontal therapy.,Nurcan Buduneli; Saynur Vardar; Gül Atilla; Timo Sorsa; Hanne Luoto; Haluk Baylas,"The purpose of the present study was to assess the effects of adjunctive meloxicam on the matrix metalloproteinase-8 (MMP-8) levels of gingival crevicular fluid (GCF) in chronic periodontitis patients following the initial phase of periodontal therapy. Twelve chronic periodontitis patients received 7.5 mg meloxicam, and 10 patients received placebo tablets together with scaling and root planing in a 1 x 1 regimen for 10 days. Scaling and root planing were performed on day 3 of drug intake. The MMP-8 levels in GCF samples obtained before and on day 10 of drug intake were determined by using the immunofluorescence assay. Plaque index (PI), papilla bleeding index (PBI), and GCF MMP-8 levels were compared within each patient group, between the 2 patient groups, and also with a clinically healthy control group using non-parametric statistical analyses. Both meloxicam and placebo groups showed statistically significant reductions in PBI, PI, and GCF MMP-8 levels on day 10 compared to baseline (P<0.01). The GCF MMP-8 level on day 10 in the meloxicam group was similar to the clinically healthy control group (P>0.05), while it was significantly higher in the placebo group (P<0.01). Positive correlations were found between MMP-8 total amounts and PBI scores at baseline and day 10 of drug intake in the patient groups. Meloxicam showed a tendency to reduce GCF MMP-8 levels in vivo within the first 10 days when used as an adjunct in the initial phase of periodontal treatment that consists of scaling and root planing. Verification of this effect on collagenase-2 downregulation, as well as on the clinical periodontal parameters in long-term studies using larger test and control groups, is needed to provide further support for the adjunctive use of selective cyclooxygenase (COX)-2 inhibitors in the treatment of chronic periodontitis.",2002.0,0,0
152,11874389,Limitation of the in vitro whole blood assay for predicting the COX selectivity of NSAIDs in clinical use.,Hubert Blain; Christelle Boileau; Françoise Lapicque; Emmanuelle Nédélec; Damien Loeuille; Cécile Guillaume; Alain Gaucher; Claude Jeandel; Patrick Netter; Jean-Yves Jouzeau,"To assess if the inhibitory potency of nonsteroidal anti-inflammatory drugs (NSAIDs) on cyclooxygenase (COX) isoenzymes, when given therapeutically in humans, can be predicted from their in vitro concentration-response curves using the whole blood assay. Twenty-four healthy male volunteers aged 20--27 years were recruited. Inhibition of blood COX isoenzymes was determined in vitro before any drug intake and ex vivo after single and repeated intake of either 7.5 mg meloxicam once, 400 mg ibuprofen three times daily or 75 mg diclofenac SR once, taken in a randomized cross-over design. Production of thromboxane B2 (TXB2) during clotting and of prostaglandin E2 (PGE2) during endotoxin exposure served as indicators of platelet COX-1 and monocyte COX-2 activity, respectively. Drugs were determined in plasma by h.p.l.c., with a chiral separation of ibuprofen and free fractions after equilibrium dialysis. Intra-subject variation for COX-1 and COX-2 at baseline was at 26 +/- 18% and 18 +/- 13% respectively, and intersubject variation at 39% and 36%, respectively. The ratios of IC50s and, at best, of IC80s revealed diclofenac and meloxicam as selective COX-2 inhibitors and ibuprofen as a preferential COX-1 inhibitor in vitro. However, after oral intake, ibuprofen inhibited ex vivo COX-2 by 80% whereas diclofenac inhibited COX-1 by 70%. Meloxicam inhibited COX-1 from 30 to 55% depending on the repetition of the dose and increase in plasma concentrations. Using in vitro dose--response curves, the in vivo inhibitory potency of diclofenac was estimated adequately from its circulating concentration ([-0.18, 0.21] for COX-1 and [-0.13, -0.03] for COX-2) but this was not the case for ibuprofen on COX-2 ([-0.14, 0.27]) and meloxicam on COX-1 ([0.31, 1.05]). The limited predictability of the system was not improved through considering the unbound fraction of the drugs or the variable chiral inversion of ibuprofen. Assessment of COX-2 selectivity based on in vitro studies and pharmacological modelling has a limited clinical relevance. There is a need to investigate COX selectivity at therapeutic plasma concentrations of NSAIDs using the ex vivo whole blood assay.",2002.0,0,0
153,11897288,Fatal allergic vasculitis associated with celecoxib.,F Schneider; F Meziani; C Chartier; M Alt; A Jaeger,"We report on the occurrence of a rare and as yet unforseeable adverse reaction to treatment with celecoxib, a cyclooxygenase-2 (COX-2) selective, non-steroidal, anti-inflammatory drug. A previously healthy adult suffered fatal acute multiple organ failure presumably after diffuse allergic vasculitis with diffuse necrotic purpura. Although no conclusive proof is available, such a reaction could have been triggered by at least one of two mechanisms: an allergic reaction linked to the chemical structure of celecoxib; or an interaction of the drug with synthesis of endothelial eiconasoids leading to an imbalance between vasoactive end products, resulting in widespread rise to local thrombosis.",2002.0,0,0
154,11897923,Valdecoxib is more efficacious than rofecoxib in relieving pain associated with oral surgery.,James Fricke; John Varkalis; Sam Zwillich; Rebecca Adler; Eliot Forester; David P Recker; Kenneth M Verburg,"Inhibition of the cyclooxygenase (COX)-2 enzyme has been shown previously to reduce pain and inflammation. Valdecoxib is a new highly selective COX-2 inhibitor with a rapid onset of action and significant analgesic properties. This study compared the analgesic efficacy of valdecoxib and rofecoxib in treating postoperative pain in patients undergoing oral surgery. This randomized, double-blind, placebo-controlled study compared the efficacy of 40 mg valdecoxib with that of 50 mg rofecoxib and placebo. Efficacy was assessed by the onset of analgesia, pain intensity levels, and pain relief over 24 hours, time-weighted sum of total pain, sum of pain intensity difference, the percentage of patients requiring rescue medication and experiencing regimen failure, and patients' global evaluation. Patients receiving valdecoxib experienced a significantly quicker onset of analgesia, significantly improved pain relief, and lower pain intensity compared with patients receiving rofecoxib and greater satisfaction with their study medication after a single dose. Valdecoxib also demonstrated efficacy that was superior to that of rofecoxib with respect to the percentage of patients requiring rescue medication or experiencing regimen failure (p < or =.05). Valdecoxib, rofecoxib, and placebo were equally well tolerated. This study demonstrates that valdecoxib provides significantly greater analgesic efficacy than rofecoxib in the management of pain after oral surgery.",2002.0,0,0
155,11906348,Anaphylaxis to celecoxib.,M Grob; W J Pichler; B Wüthrich,,2002.0,0,0
156,11907361,,,,,0,0
157,11908554,"Dose response and safety study of meloxicam up to 22.5 mg daily in rheumatoid arthritis: a 12 week multicenter, double blind, dose response study versus placebo and diclofenac.",Daniel E Furst; Karen S Kolba; Roy Fleischmann; Joel Silverfield; Maria Greenwald; Sanford Roth; David B Hall; Paul J Roszko; Meloxicam Rheumatoid Arthritis Investigators,"This Phase III, placebo and active controlled, multicenter trial evaluated the efficacy and safety of meloxicam 7.5, 15, and 22.5 mg daily for the treatment of rheumatoid arthritis (RA). A 12 week, randomized, double blind, double dummy, parallel group trial compared daily oral meloxicam 7.5, 15, and 22.5 mg to placebo (negative control) and diclofenac 75 mg BID (positive control). A total of 894 patients (18 years of age with confirmed RA who flared following an NSAID-free period) were randomized to be treated. Baseline scores for all endpoints were similar among the treatment groups. Patient assessments were at 0, 2, 4, 8, and 12 weeks or early termination. All treatment groups demonstrated significant improvement from baseline (p < 0.001). Meloxicam 7.5 and 22.5 mg was significantly superior to placebo in all 5 primary efficacy endpoints (swollen joint count, tender joint count, patient pain, patient and physician global; all p < 0.05). Diclofenac 150 mg was superior to placebo for 4 of 5 primary efficacy measures (all but swollen joint count; p < 0.05) and meloxicam 15 mg was superior for 3 of 5 primary endpoints (patient pain and patient and physician global). AUC of patient global, patient pain, and modified Health Assessment Questionnaire demonstrated dose-response (p < 0.04), while AUC ACR20 showed a qualitative trend in the same direction. The rate of gastrointestinal (GI) events during the 12 week trial for all doses of meloxicam and diclofenac did not differ significantly from placebo (23.2-32.0%). GI withdrawals were comparable and not significantly different across all treatment groups (4.3-5.7%). This trial demonstrated a dose response relationship for meloxicam 7.5, 15, and 22.5 mg using AUC measurement of response for the treatment of RA. All 3 doses of meloxicam. and positive control, were effective in the treatment of RA. The overall incidence rate of GI events did not differ significantly from placebo in either the meloxicam treatment groups or the positive control.",2002.0,1,1
158,11908558,Gastroprotective therapy and risk of gastrointestinal ulcers: risk reduction by COX-2 therapy.,Frederick Wolfe; Janice Anderson; Thomas A Burke; Lester M Arguelles; Dan Pettitt,"Proton pump inhibitors (PPI) and misoprostol decrease the risk of development of nonsteroidal antiinflammatory drug induced gastric ulcers and aid healing of upper gastrointestinal (GI) ulcers. H2 receptor antagonists (H2RA) are less effective for this task, but are widely used by patients and physicians for the treatment of GI symptoms and duodenal ulcers. Sucralfate is a weaker agent that is sometimes used for prophylaxis or treatment of upper GI ulcers. We investigated the effect of GI drugs and selective and nonselective NSAID on the incidence of GI ulcer development in a cohort of patients immediately after the release of celecoxib and rofecoxib to investigate the effect of confounding by indication when effective GI agents and cyclooxygenase 2 (COX-2)-specific inhibitors are prescribed to a high risk population. During a 6 month period of observation 8547 NSAID users were evaluated by mailed questionnaire concerning NSAID drug use and ulcer development. In the first half of 1999, patients took 12,177 separate NSAID courses. GI therapy that followed the development of upper GI ulcers was excluded from analysis. Ulcer reports were confirmed by followup validation. GI drugs were used concomitantly in this population by 42% of patients using an NSAID. GI drugs were associated with an increased risk of ulcer. But this risk was confined to PPI (OR 4.1, 95% CI 2.95, 5.69), and not to other GI drugs. Overall, patients using nonselective NSAID compared to those taking COX-2-specific inhibitors had an increased risk of upper GI ulcers (OR 2.12, 95% CI 1.43, 3.34). Patients taking nonselective NSAID plus PPI were also at increased risk for upper GI ulcers compared to those taking nonselective NSAID alone (OR 5.09. 95% CI 3.88, 6.67). Similarly, the risk of upper GI ulcers was increased in the nonselective NSAID plus PPI group (OR 3.83, 95% CI 2.32, 6.31) compared to the COX-2 plus PPI group. PPI use, but not other GI drug use, is a marker for increased susceptibility to ulcers among NSAID users. This risk of upper GI ulcers is increased in PPI users regardless of which NSAID is used (nonselective or COX-2-specific inhibitor). Although COX-2 use is associated with greater risk factors for upper GI ulcers due to channeling bias, COX-2 users have significantly fewer ulcers than equivalent nonselective NSAID users regardless of concomitant PPI utilization.",2002.0,0,0
159,11911727,Aseptic meningitis associated with rofecoxib.,Renan A Bonnel; Maria L Villalba; Claudia B Karwoski; Julie Beitz,"Rofecoxib is a nonsteroidal anti-inflammatory drug that is reported to act by selectively inhibiting cyclooxygenase-2. A review and analysis of reports sent to the Spontaneous Reporting System of the Food and Drug Administration, Rockville, Md, suggest that aseptic meningitis is associated with rofecoxib use. To our knowledge, there have been no published reports of aseptic meningitis occurring in association with rofecoxib use to date. We report 5 serious cases of aseptic meningitis associated with rofecoxib use.",2002.0,0,0
160,11929402,Dyspepsia tolerability from the patients' perspective: a comparison of celecoxib with diclofenac.,J L Goldstein; G M Eisen; T A Burke; B M Peña; J Lefkowith; G S Geis,"To compare celecoxib (800 mg/day, n=1997) with diclofenac (150 mg/day, n=1996) on dyspepsia-related tolerability. In one of the two protocols comprising the Celecoxib Long-Term Arthritis Safety Study, a randomized double-blind trial, patients completed the Severity of Dyspepsia Assessment Questionnaire at baseline and at weeks 4, 13, 26 and 52 for the following three scales: Pain Intensity, Non-Pain Symptoms and Satisfaction with Dyspepsia-Related Health. For the Pain Intensity scale, patients given diclofenac had significantly higher (worsening dyspepsia) mean changes, defined as follow-up minus baseline, than patients given celecoxib (P < 0.001, at all assessments). The mean changes in the Pain Intensity scale (scale, 2-47; higher score is higher pain intensity) were 0.99 (95% confidence interval (CI): 0.50, 1.48) for celecoxib and 2.76 (95% CI: 2.28, 3.25) for diclofenac at 4 weeks. Satisfaction was superior with celecoxib at all assessments (P < 0.001). At 4 weeks, the mean changes in the Satisfaction scale (scale, 7-35; higher score is higher satisfaction) were 0.02 (95% CI: - 0.26, 0.29) for celecoxib and - 0.72 (95% CI: - 1.00, - 0.45) for diclofenac. Diclofenac patients had significantly higher Non-Pain Symptoms at 4 weeks (P=0.005). Celecoxib, at two to four times the recommended dose, demonstrated a superior dyspepsia-related tolerability and satisfaction compared with standard dosages of diclofenac.",2002.0,0,0
161,11937958,[Celecoxib induced toxiderma with positive patch-test].,S Verbeiren; C Morant; H Charlanne; K Ajebbar; J Caron; P Modiano,"Celecoxib (Celebrex(R)) is a new generation non-steroidal anti-inflammatory drug, recently introduced in France. We report a maculopapular rash due to this drug with positive patch-tests. A forty year-old man received with 3 tablets/day of celecoxib for intercostal pain. Nine days after initiation of treatment a maculopapular rash appeared. At the end of treatment, the eruption persisted for two days, then rapidly improved within one week. Six weeks later, patch-tests with celecoxib diluted at 20 p. 100 in petrolatum were positive at 48 hours. Cutaneous reactions due to celecoxib are rare. In our case report, the delay, clinical aspect, improvement on withdrawal of treatment and positive patch test all emphasize the imputability of celecoxib. We wish to underline the possible cutaneous reactions with this new non-steroidal anti-inflammatory drug.",2002.0,0,0
162,11950252,"Efficacy and safety of the COX-2 specific inhibitor valdecoxib in the management of osteoarthritis of the hip: a randomized, double-blind, placebo-controlled comparison with naproxen.",W Makarowski; William W Zhao; Terry Bevirt; David P Recker,"Non-steroidal antiinflammatory agents are commonly used to treat pain and inflammation associated with osteoarthritis (OA), but have poor gastrointestinal (GI) tolerability. This study compared the efficacy of the COX-2 specific inhibitor valdecoxib with naproxen and placebo, in treating symptomatic OA of the hip. This multicenter, randomized, double-blind 12-week study compared the efficacy and tolerability of single daily doses of valdecoxib 5 mg and 10 mg with placebo or naproxen 500 mg BID. Efficacy was assessed by Patient's and Physician's Global Assessment of Arthritis, and the WOMAC (Western Ontario and McMasters) OA Individual and Composite Indices. The incidence of adverse events was monitored throughout the study. Valdecoxib was clinically and statistically superior to placebo for Patient's and Physician's Global Assessment of Arthritis and for all WOMAC OA Indices over the 12 week study period (P<or= 0.05). Valdecoxib 10 mg was similar to naproxen in terms of efficacy, and demonstrated greater numerical improvements compared with valdecoxib 5 mg. Valdecoxib 5 mg and 10 mg demonstrated similar tolerability compared to placebo and a lower incidence of GI-related adverse effects compared with naproxen. Single daily doses of valdecoxib 5 mg and 10 mg were similar to naproxen and superior to placebo, in treating symptomatic OA of the hip. Both doses of valdecoxib were well tolerated and demonstrated improved GI tolerability compared to naproxen.",2002.0,1,1
163,11950408,Evaluation of preoperative administration of the cyclooxygenase-2 inhibitor rofecoxib for the treatment of postoperative pain after lumbar disc surgery.,Alex Bekker; Paul R Cooper; Anthony Frempong-Boadu; Ramesh Babu; Thomas Errico; Allen Lebovits,"A combination of analgesics with different mechanisms of action may improve postoperative pain control and reduce the incidence of side effects. This study was designed to assess the efficacy of preoperative administration of rofecoxib (Vioxx; Merck & Co., Inc., Somerset, NJ) in reducing pain and opioid requirements after single-level lumbar microdiscectomy. A randomized, double-blind, placebo-controlled clinical trial was performed on 61 consenting patients who were considered American Society of Anesthesiologists Class I or II and who were scheduled for elective single-level lumbar microdiscectomy. Patients received either two doses of rofecoxib 50 mg or a placebo preoperatively. The outcome measures included morphine use in the postanesthesia care unit (PACU), discharge times, and side effect profile. Data were analyzed by use of independent sample t tests for continuous variables or chi(2) tests for categorical variables. A P value of <0.05 was considered significant. The two groups were comparable with respect to patient characteristics, intraoperative opioid and hypnotic consumption, and duration of surgery. Patients in the rofecoxib group required significantly less morphine postoperatively. Significantly more patients in the placebo group reported pain scores greater than 7 at admission to the PACU. Time to first request for analgesia was shorter in the placebo group, but the difference did not reach statistical significance. There were no significant differences between groups in the incidence of nausea, time to discharge from the PACU, or hospital stay. Preoperative rofecoxib is effective in reducing postoperative narcotic consumption in patients undergoing lumbar laminectomy. The use of rofecoxib does not shorten PACU length of stay or hospital discharge time. These outcome measures depend on multiple administrative factors.",2002.0,0,0
164,11961179,,,,,0,0
165,11967252,Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors.,William B White; Jeffrey Kent; Addison Taylor; Kenneth M Verburg; James B Lefkowith; Andrew Whelton,"Nonselective nonsteroidal anti-inflammatory agents have been shown to attenuate the antihypertensive efficacy of ACE inhibitors with average increases in systolic blood pressure (BP) of 5 to 10 mm Hg. Less is known about the specific cyclooxygenase-2 (COX-2) inhibitors now widely used for the treatment of arthritis. The objective of this study was to determine the effects of celecoxib compared with placebo on 24-hour BP levels in ACE inhibitor-treated patients with hypertension. This was a randomized, double-blind, placebo-controlled, parallel-group clinical trial involving 178 men and women (mean age, 53 years) with essential hypertension who were treated and controlled with lisinopril monotherapy (10 to 40 mg daily). Baseline BP values were obtained using 24-hour ambulatory recordings. Patients received either celecoxib, 200 mg twice daily (twice the recommended dose for osteoarthritis) (n=91), or placebo (n=87) for 4 weeks, and changes in the 24-hour BP, body weight, and clinical laboratory parameters were assessed. Mean changes from baseline in the 24-hour systolic and diastolic BP were 2.6/1.5+/-0.9/0.6 mm Hg on celecoxib versus 1.0/0.3+/-1/0.6 mm Hg on placebo (P=0.34 for systolic BP; P=0.45 for diastolic BP). The proportion of patients whose 24-hour BP increased by at least 5, 10, 15, or 20 mm Hg were also similar on celecoxib and placebo. No changes in body weight, serum creatinine, or potassium occurred in either group. Thus, these data demonstrate that high doses of celecoxib have no significant effect on the antihypertensive effect of the ACE inhibitor lisinopril. The placebo-subtracted changes observed in 24-hour BP (1.6/1.2 mm Hg) are less than what has been reported for nonselective nonsteroidal anti-inflammatory agents in ACE inhibitor-treated patients.",2002.0,0,0
166,11973187,The efficacy of premedication with celecoxib and acetaminophen in preventing pain after otolaryngologic surgery.,Tijani Issioui; Kevin W Klein; Paul F White; Mehernoor F Watcha; Margarita Coloma; Gary D Skrivanek; Stephanie B Jones; Kevin C Thornton; Bradley F Marple,"Non-opioid analgesics are often used to supplement opioids for the management of perioperative pain. In this randomized, double-blinded, placebo-controlled study, we examined the effects of acetaminophen and a cyclooxygenase type-2 inhibitor, celecoxib, when administered alone or in combination, before elective otolaryngologic surgery in 112 healthy outpatients. Subjects were assigned to 1 of 4 study groups: Group 1, placebo (vitamin C, 500 mg per os [PO]); Group 2, acetaminophen 2000 mg PO; Group 3, celecoxib 200 mg PO; or Group 4, acetaminophen 2000 mg and celecoxib 200 mg PO. All patients received a standardized anesthetic technique. During the postoperative period, pain was assessed using a 10-point verbal rating scale. Recovery times, the need for rescue analgesics, side effects, and patient satisfaction scores were also recorded. The combination of acetaminophen and celecoxib was significantly more effective than placebo in reducing postoperative pain. Celecoxib, when administered alone or in combination with acetaminophen, improved patients' satisfaction with their postoperative analgesia. With the combination of acetaminophen and celecoxib, an additional expenditure of $6.16 would be required to obtain complete satisfaction with postoperative pain management in one additional patient who would not have been completely satisfied if he/she had received the placebo. However, oral celecoxib or acetaminophen alone was not significantly more effective than placebo in reducing postoperative pain when administered before surgery. We conclude that oral premedication with a combination of acetaminophen (2000 mg) and celecoxib (200 mg) was highly effective in decreasing pain and improving patient satisfaction after outpatient surgery. Oral premedication with a combination of acetaminophen (2000 mg) and celecoxib (200 mg) was effective in decreasing pain and improving patient satisfaction after otolaryngologic surgery. However, acetaminophen (2000 mg) or celecoxib (200 mg) alone was not significantly more effective than placebo in reducing postoperative pain.",2002.0,0,0
167,11975819,Intraoral chilling versus oral sumatriptan for acute migraine.,M H Friedman; S J Peterson; C F Behar; Z Zaidi,"Migraine pathophysiology is associated with a dural inflammation. Recent evidence suggests that the primary inflammation occurs in a maxillary nerve segment, accessible intraorally. Local tenderness, related to symptom laterality, has been palpated consistently in asymptomatic migraine patients, and significant migraine relief has been obtained from chilling confined to this area. Thirty-five symptomatic episodic migraine patients were enrolled in this study, comparing 40 minutes of bilateral intraoral chilling, 50 mg of oral sumatriptan, and 40 minutes of sham (tongue) chilling. Hollow metal tubes chilled by circulating ice water were held in the maxillary molar periapical areas by the patient. Pain and nausea were recorded at baseline and 1, 2, 4, and 24 hours after start of treatment, using a numeric symptom-relief scale. Significant mean headache relief was obtained by maxillary chilling and sumatriptan at all four time intervals, with poor relief obtained by placebo. Maxillary chilling was more effective than sumatriptan at all four time intervals. Significant nausea relief was obtained by maxillary chilling and sumatriptan at posttreatment and 2 and 4 hours later. At 24 hours, some headache and nausea recurrence was noted with sumatriptan. The repeated-measures analysis of variance indicated that both treatments, drug (P = 0.024) and maxillary chilling (P = 0.001), reduced the headache, as compared with the control group. Tenderness suggests local inflammation associated with vasodilatation and edema. Because chilling can resolve local edema, these findings raise the possibility that an intraoral inflammation may be a factor in migraine etiology.",2002.0,0,0
168,11978928,Migratory pulmonary infiltrates in a patient with rheumatoid arthritis.,S Mehandru; R L Smith; G S Sidhu; N Cassai; C P Aranda,"The case history is described of an elderly man with rheumatoid arthritis receiving treatment with sulfasalazine and the cyclooxygenase-2 inhibitor celecoxib who presented with severe shortness of breath, cough, and decreased exercise tolerance. The chest radiograph showed unilateral alveolo-interstitial infiltrates and a biopsy specimen of the lung parenchyma showed changes consistent with acute eosinophilic pneumonia. Antibiotic treatment was unsuccessful, but treatment with steroids and discontinuation of sulfasalazine and celecoxib resulted in a marked clinical improvement confirmed by arterial blood gas analysis. The condition may have developed as an adverse reaction either to sulfasalazine or to celecoxib, although hypersensitivity to the latter has not previously been reported.",2002.0,0,0
169,12003391,Rofecoxib and cytomegalovirus in acute flare-up of ulcerative colitis: coprecipitants or coincidence?,Jason Goh; Derek Wight; Miles Parkes; Stephen J Middleton; John O Hunter,,2002.0,0,0
170,12003405,Acute pancreatitis associated with rofecoxib.,Ravi K Amaravadi; Brian C Jacobson; Daniel H Solomon; Michael A Fischer,,2002.0,0,0
171,12010890,"A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis.",R K S Phillips; M H Wallace; P M Lynch; E Hawk; G B Gordon; B P Saunders; N Wakabayashi; Y Shen; S Zimmerman; L Godio; M Rodrigues-Bigas; L-K Su; J Sherman; G Kelloff; B Levin; G Steinbach; FAP Study Group,"Non-selective cyclooxygenase (COX) inhibitors (non-steroidal anti-inflammatory drugs) inhibit large bowel carcinogenesis in patients with familial adenomatous polyposis (FAP). Their role in the duodenum of these patients is less certain. The disease modifying activity of specific COX-2 inhibitors has not been explored in humans. This was a randomised, double blind, placebo controlled study of celecoxib (100 mg twice daily (n=34) or 400 mg twice daily (n=32)) versus placebo (n=17), given orally twice daily for six months to patients with FAP. Efficacy was assessed qualitatively by blinded review of shuffled endoscopy videotapes comparing the extent of duodenal polyposis at entry and at six months and quantitatively by measurement of the percentage change in duodenal area covered by discrete and plaque-like adenomas from photographs of high and low density polyposis. Shuffled and blinded video review showed a statistically significant effect of 400 mg twice daily celecoxib compared with placebo treatment (p=0.033) with all five independent observers scoring a beneficial effect. Overall, patients taking celecoxib 400 mg twice daily showed a 14.5% reduction in involved areas compared with a 1.4% for placebo (p=0.436). However, patients with clinically significant disease at baseline (greater than 5% covered by polyps) showed a 31% reduction in involved areas with celecoxib 400 mg twice daily compared with 8% on placebo (p=0.049). A panel of five endoscopists found a significant reduction in duodenal polyposis after six months of treatment with celecoxib 400 mg twice daily. COX-2 inhibition may help this otherwise untreatable condition.",2002.0,0,0
172,12013363,Celecoxib-induced erythema multiforme with glyburide cross-reactivity.,Erika J Ernst; Jason A Egge,"Erythema multiforme is an acute inflammatory skin reaction that often is caused by drugs, especially sulfonamides and their derivatives. Celecoxib, a cyclooxygenase-2 inhibitor, is a sulfonamide derivative commonly prescribed to treat arthritis in patients who cannot tolerate or who have a contraindication for taking traditional nonsteroidal antiinflammatory agents. A 57-year-old man with a previously undocumented sulfa allergy experienced an allergic skin reaction and had difficulty breathing secondary to throat swelling. His condition was believed to be erythema multiforme associated with the introduction of celecoxib into his drug regimen. His drug therapy was discontinued, but a subsequent reaction occurred when the sulfonamide derivative glyburide was reintroduced. It is important for clinicians to obtain a careful history and perform a thorough medical evaluation in all patients receiving sulfonamides and their derivatives, as a potentially life-threatening allergic reaction may be prevented.",2002.0,0,0
173,12017395,"Comparison of the analgesic efficacy of rofecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: a randomized, placebo-controlled clinical trial.",David J Chang; Paul J Desjardins; Erluo Chen; Adam B Polis; Mary McAvoy; Sandra H Mockoviak; Gregory P Geba,"Rofecoxib is a selective cyclooxygenase-2 inhibitor indicated for the treatment of acute pain, with similar analgesic efficacy to ibuprofen and naproxen sodium. Diclofenac sodium is the most commonly prescribed nonsteroidal anti-inflammatory drug worldwide; it is effective for the treatment of pain as well as the signs and symptoms associated with the painful conditions of osteoarthritis and rheumatoid arthritis. The aim of this study was to compare the analgesic efficacy and tolerability of a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg, and placebo over 8-hour and 24-hour periods in patients with moderate to severe pain after oral surgery. In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate to severe pain after the surgical extraction of > or = 2 third molars were randomized to receive a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given every 8 hours), or placebo. Patients rated pain intensity, pain relief, and global assessments at prespecified times throughout the 24-hour period after initial dosing. Overall analgesic efficacy was determined by total pain relief over 8 hours (TOPAR8) and 24 hours (TOPAR24) and patient global assessments at 8 and 24 hours. Onset of analgesic effect was determined by using the 2-stopwatch method for confirmed perceptible pain relief. Peak analgesic effect was the maximum pain relief attained during the first 8 hours. The duration of analgesic effect was determined by median time to rescue analgesia use. A total of 305 patients were randomized to treatment: 121 received rofecoxib, 121 received diclofenac sodium, and 63 received placebo. The baseline demographics were similar among the groups. Overall, 61.3% experienced moderate pain and 38.7% experienced severe pain; 53.1% were female; and the mean age was 23.4 years. The overall analgesic efficacy, as assessed by TOPAR8, of a single dose of rofecoxib 50 mg was significantly greater than a single dose of enteric-coated diclofenac sodium 50 mg (20.5 vs 8.2) and placebo (20.5 vs 5.9). Patient global assessment at 8 hours was also significantly better for rofecoxib compared with enteric-coated diclofenac sodium and placebo. TOPAR24 was significantly greater for a single dose of rofecoxib 50 mg compared with 3 doses of enteric-coated diclofenac sodium 50 mg (64.1 vs 25.1) and placebo (64.1 vs 19.2). At 24 hours, the patient global assessment for rofecoxib was significantly better than that achieved with enteric-coated diclofenac sodium and placebo. The onset of analgesic effect was significantly more rapid for rofecoxib than for enteric-coated diclofenac sodium and placebo (median times: 31 minutes, >4 hours, and >4 hours, respectively). The peak analgesic effect was significantly greater for rofecoxib compared with enteric-coated diclofenac sodium (3.2 vs 1.5) and placebo (3.2 vs 1.1). The duration of analgesia was significantly longer for rofecoxib than enteric-coated diclofenac sodium (median times: >24 hours vs 1 hour and 37 minutes) and placebo (>24 hours vs 1 hour and 37 minutes). Enteric-coated diclofenac sodium was numerically greater than placebo for the key end points measuring overall efficacy (total pain relief and patient global assessment), but diclofenac sodium did not provide as much analgesic effect as expected for a drug effective for pain, osteoarthritis, and rheumatoid arthritis and did not differ significantly from placebo. Overall, both rofecoxib and enteric-coated diclofenac sodium were generally well tolerated, although the rofecoxib group had a significantly lower incidence of clinical and drug-related adverse events than the enteric-coated diclofenac sodium group. A single 50-mg dose of rofecoxib provided greater overall analgesic efficacy over 8 hours, more rapid onset of analgesia, greater maximum analgesic effect, and longer duration of effect than a single 50-mg dose of enteric-coated diclofenac sodium in patients with moderate to severe pain associated with oral surgery. Compared with 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg every 8 hours), a single dose of rofecoxib 50 mg provided greater overall analgesic efficacy over 24 hours.",2002.0,0,0
174,12022317,"Increase in lifetime adverse drug reactions, service utilization, and disease severity among patients who will start COX-2 specific inhibitors: quantitative assessment of channeling bias and confounding by indication in 6689 patients with rheumatoid arthritis and osteoarthritis.",Frederick Wolfe; Nancy Flowers; Thomas A Burke; Lester M Arguelles; Dan Pettitt,"Nonrandom assignment of therapy in observational studies and clinical practice can be accompanied by channeling bias and confounding by indication. This in turn can lead to unreliable conclusions about treatment effectiveness. Although widely acknowledged as important, no studies in rheumatology have measured the extent of these biases. We identified variables contributing to confounding and investigated the strength of the confounding effect. Analytical methods (propensity scores) are available to mitigate the effect of nonrandom assignment if the full extent of confounding can be understood. A population of 6637 patients with rheumatoid arthritis (RA) and osteoarthritis (OA) from the practices of 433 US rheumatologists completed 2 sets of detailed questionnaires concerning (1) the last 6 months in 1998 and (2) the first 6 months of 1999, generally prior to and after the release of celecoxib and rofecoxib. Patients who received the COX-2 specific inhibitors in period 2 were identified (n = 1517), and their characteristics were compared to the 5120 who did not start a new COX-2 specific inhibitor during Period 1. Patients starting a new COX-2 specific inhibitor had a greater lifetime history of adverse reactions of all kinds, but particularly gastrointestinal adverse drug reactions. They also had more severe scores for pain, functional disability, fatigue, helplessness, and global severity, and they used more inpatient and outpatients services than patients who would not switch to COX-2 specific inhibitors. Confounding by indication and channeling bias result in an overall increase in severity of about 25% for the above measures. Observational studies should account for these biases by a broadly defined propensity score that includes the variables identified in this report. These observations are germane to observational studies of disease modifying antirheumatic drugs and biologics, as well, and suggest the need for careful control of confounders when assessing treatment effects in rheumatic disease observational studies.",2002.0,0,0
175,12025527,"Efficacy of celecoxib in treating symptoms of viral pharyngitis: a double-blind, randomized study of celecoxib versus diclofenac.",L L M Weckx; J E Ruiz; J Duperly; G A Martínez Mendizabal; M B G Rausis; S L Piltcher; M Saffer; C Matsuyama; S Levy; J G Fort,"This study compared the efficacy and safety of the cyclooxygenase-2 specific inhibitor celecoxib with the conventional non-steroidal anti-inflammatory drug diclofenac in the symptomatic treatment of viral pharyngitis. Adult patients from 27 study centers in Latin America were treated with oral doses of celecoxib 200 mg once daily or 200 mg twice daily, or diclofenac 75 mg twice daily for 5 days in a double-blind, randomized study. The primary efficacy assessment was 'Throat Pain on Swallowing' on day 3. In addition, secondary quality-of-life assessments were performed on days 3 and 5. All adverse events and treatment-emergent signs and symptoms were recorded. Data from 313 patients were evaluable for efficacy (105 celecoxib 200 mg once daily, 107 celecoxib 200 mg twice daily, 101 diclofenac 75 mg twice daily). The upper 95% confidence limits for the visual analog scale of 'Throat Pain on Swallowing' on day 3 for celecoxib 200 mg once daily relative to diclofenac 75 mg twice daily, and celecoxib 200 mg twice daily relative to diclofenac 75 mg twice daily were 9.26 and 7.83, respectively. All secondary efficacy and quality-of-life measures were clinically similar for the three treatment groups, and no statistically significant differences were detected. The incidences of treatment-emergent adverse events and withdrawals due to adverse events were similar for all groups, but numerically higher among patients taking diclofenac than celecoxib. More patients in the diclofenac group reported gastrointestinal complaints (7.3%) compared with those in the celecoxib groups (4.3% in the celecoxib 200 mg once-daily group and 3.4% in the celecoxib 200 mg twice-daily group). In conclusion, 5 days of treatment with celecoxib 200 mg once daily is as effective as diclofenac 75 mg twice daily in the symptomatic treatment of viral pharyngitis. Celecoxib 200 mg once daily is also as effective as celecoxib 200 mg twice daily in this condition.",2003.0,0,0
176,12039807,Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs?,Peter Jüni; Anne W S Rutjes; Paul A Dieppe,,2002.0,0,0
177,12042193,Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia.,Norbert Müller; Michael Riedel; Constanze Scheppach; Bernd Brandstätter; Safet Sokullu; Karin Krampe; Markus Ulmschneider; Rolf R Engel; Hans-Jürgen Möller; Markus J Schwarz,"Abnormalities in the immune system in schizophrenia have been described. However, important findings such as high levels of activating cytokines in the CSF and signs of CNS inflammation have been controversial. The authors conducted a trial of the new selective cyclooxygenase-2 inhibitor celecoxib, an immunomodulatory drug, in schizophrenic patients to evaluate its therapeutic effects. In a prospective, double-blind evaluation, 50 patients with an acute exacerbation of schizophrenia were randomly assigned to either risperidone plus celecoxib or risperidone plus placebo. After a washout period, 25 patients received 2-6 mg/day of risperidone plus placebo and 25 received risperidone plus 400 mg/day of celecoxib for 5 weeks. The treatment effect was calculated by analysis of covariance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or risperidone dose or plasma level. Over 5 weeks, both groups of patients showed significant improvement in scores on the Positive and Negative Syndrome Scale and on all subscales. However, the celecoxib group showed significantly greater improvement in the total score. Additional treatment with celecoxib has significant positive effects on the therapeutic action of risperidone with regard to total schizophrenia psychopathology. Moreover, the fact that treatment with an immunomodulatory drug showed beneficial effects on schizophrenia symptoms indicates that immune dysfunction in schizophrenia is not just an epiphenomenon but is related to the pathomechanism of the disorder. However, a nonimmunological therapeutic effect of celecoxib mediated by the N-methyl-D-aspartic acid receptor has to be taken into account.",2002.0,0,0
178,12046048,Celecoxib-induced acute interstitial nephritis.,Justine Henao; Irfan Hisamuddin; Chike M Nzerue; Geetanjali Vasandani; Karlene Hewan-Lowe,"Data about the nephrotoxicity of selective cyclooxygenase-2 inhibitors are still evolving. Acute interstitial nephritis is a well-described complication of therapy with nonselective nonsteroidal anti-inflammatory drugs. We report a case of biopsy-proven acute interstitial nephritis in a 73-year-old diabetic woman, who had taken celecoxib for more than 1 year before presentation. She presented with clinical findings of subnephrotic proteinuria and acute renal failure that required dialysis. She recovered renal function with cessation of celecoxib therapy after 2 weeks. Other medications were reintroduced safely, without recurrence of renal failure. A kidney biopsy specimen showed acute interstitial nephritis with a prominent eosinophilic infiltrate in the interstitium. This case documents the occurrence of acute interstitial nephritis with celecoxib and emphasizes the need for continued vigilance and care in use of cyclooxygenase-2 inhibitors in high-risk patients.",2002.0,0,0
179,12047490,A comparison of the effects of nabumetone vs meloxicam on serum thromboxane B2 and platelet function in healthy volunteers.,D J W van Kraaij; A H I Hovestad-Witterland; M de Metz; E J Vollaard,"To compare the effects of nabumetone and meloxicam, two cyclo-oxygenase-2 (COX-2) preferential nonsteroidal anti-inflammatory drugs (NSAIDs), on platelet COX-1 activity and platelet function. Twelve healthy volunteers (3 male, 9 female, median age 22 years) participated in an open, randomized, cross-over trial of nabumetone 1000 mg twice daily vs meloxicam 7.5 mg twice daily during 1 week with 2 weeks wash-out. After a second 2 week wash-out period, one dose of indomethacin 50 mg was given as a positive control to check for NSAID induced inhibition of platelet function. COX-1 inhibition was measured as percentage inhibition of serum TXB2 generation in clotting whole blood, and as closure time with use of the platelet function analyser PFA-100. Data are reported as median with range. Paired variables were analysed using Wilcoxons signed rank test. TXB2 levels decreased significantly after all three medications, but percentage inhibition after nabumetone and indomethacin (88% and 97%, respectively) was significantly higher than after meloxicam (63%) (P<0.05). Closure times increased significantly after administration of all three medications (P<0.05). Increases in closure time after administration did not differ between nabumetone and meloxicam (24% and 14%, respectively), but were significantly larger after indomethacin administration (63%) (P<0.01). In the maximum registered dosage, nabumetone inhibits thromboxane production much more than meloxicam, signifying less COX-2 selectivity of the former. However, both nabumetone and meloxicam cause only minor impairment in platelet function in comparison with indomethacin and the difference between them is not significant.",2002.0,0,0
180,12049701,[Gynecomastia secondary to rofecoxib].,Joaquín Antón Martínez; Pilar Tejada González; Nora Gutiérrez Sanpedro; Pedro González Blanco,,2002.0,0,0
181,12077530,Erythema multiforme due to rofecoxib.,Rashmi Sarkar; Charandeep Kaur; Amrinder J Kanwar,,2002.0,0,0
182,12086565,,,,,0,0
183,12093262,Celecoxib-induced cholestatic hepatotoxicity in a patient with cirrhosis.,Paulo Alegria; Luís Lebre; Cristina Chagas,,2002.0,0,0
184,12093311,Renal failure associated with the use of celecoxib and rofecoxib.,Syed R Ahmad; Cindy Kortepeter; Allen Brinker; Min Chen; Julie Beitz,"Celecoxib and rofecoxib are two relatively new nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit the cyclo-oxygenase-2 (COX-2) isoenzyme at therapeutic concentrations. The nephrotoxic potential of selective COX-2 inhibitors has not been clearly established. This study was conducted in order to understand the association between acute renal failure and the two COX-2 inhibitors celecoxib and rofecoxib. A search was performed in the US Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS) to identify cases of renal failure submitted to the FDA. A MEDLINE search of the English language literature was also performed to identify published cases of renal failure associated with celecoxib and rofecoxib. One hundred twenty-two and 142 domestic US cases of celecoxib and rofecoxib-associated renal failure, respectively, were identified in the AERS database. The literature search identified 19 cases of acute renal impairment in association with celecoxib and rofecoxib. In addition, drug regulatory authorities in the UK, Canada, and Australia have received about 50 reports of renal failure with celecoxib and rofecoxib. Descriptive statistics of the AERS cases have been summarised in this report. Data from AERS and published case reports suggest that use of both these drugs is associated with renal effects similar to that of conventional nonselective NSAIDs. Physicians should be aware that serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short-term therapy with celecoxib and rofecoxib. Patients at greatest risk for renal injury are those with pre-existing renal impairment, heart failure, liver dysfunction, those taking diuretics and/or ACE inhibitors, and the elderly. Kidney function should be monitored closely for any signs of potential renal injuries soon after initiating treatment with these agents, especially in high-risk populations. In addition, healthcare practitioners should adequately warn patients of the signs and symptoms of serious renal toxicity, and of the need for them to see their physician promptly if they occur. Celecoxib and rofecoxib are not recommended for use in patients with advanced renal disease.",2002.0,0,0
185,12098171,Valdecoxib does not impair platelet function.,Philip T Leese; Sheela Talwalker; Jeffrey D Kent; David P Recker,"The platelet effects of a supratherapeutic dose of the new cyclooxygenase (COX)-2 specific inhibitor, valdecoxib (40 mg twice a day), naproxen 500 mg twice a day, diclofenac 75 mg twice a day, and placebo were compared in 62 healthy adult subjects in this 7(1/2) day single-center, randomized, placebo-controlled trial. Platelet aggregation responses (to arachidonate [AA], collagen, and adenosine diphosphate [ADP]), bleeding time, and serum thromboxane B(2) (TxB(2)) concentrations were measured at baseline and at regular intervals on days 1 and 8. Valdecoxib had no effect on platelet function. Naproxen and diclofenac significantly reduced the platelet aggregation response to AA and to a lesser extent collagen and ADP at most assessments compared with placebo. Naproxen significantly lowered serum TxB(2) levels. In contrast to standard doses of 2 nonsteroidal antiinflammatory drugs (NSAIDs), a supratherapeutic valdecoxib dosage does not impair platelet function (COX-1). Valdecoxib may be a safer analgesic option than conventional NSAIDs in patients for whom bleeding complications are a concern. (Am J Emerg Med 2002;20:275-281.",2002.0,0,0
186,12100094,Rizatriptan combined with rofecoxib vs. rizatriptan for the acute treatment of migraine: an open label pilot study.,A V Krymchantowski; J S Barbosa,"Rizatriptan is an effective and fast acting drug for the acute treatment of migraine. As with any other acute treatment for migraine, headache recurrence may occur in up to one-third of responders. Combination with non-steroidal anti-inflammatory drugs (NSAIDs) seems to reduce the incidence of headache recurrence in clinical practice. Rofecoxib is a member of a new class of NSAIDs, which selectively inhibits the COX-2 enzyme and therefore is associated with a lower risk of gastrointestinal side-effects; the drug has a long plasma half-life (17 h). This open label study compared rizatriptan with rizatriptan plus rofecoxib in the acute treatment of migraine. Fifty-six triptan naive patients from a tertiary centre (37 women and 19 men, ages 16-55 years, mean 35 years) with International Headache Society migraine were randomized into two groups. They were instructed to treat three consecutive moderate or severe attacks with either 10 mg rizatriptan (group 1: 18 women and 10 men) or with 10 mg rizatriptan plus 25 mg rofecoxib (group 2: 19 women and 9 men). The presence of headache and nausea at 1, 2 and 4 h, and of side-effects, use of rescue medication and recurrence were compared. Fifty-four patients completed the study. Group 1 treated 76 attacks and group 2 treated 81 attacks. Absence of headache at 1 h was seen in 19 attacks (25%) in group 1 and in 34 attacks (42%) in group 2 (P=0.082); at 2 h absence of headache was seen in 60% of group 1 attacks and in 76% of group 2 attacks (P=0.115). At 4 h, 75% of group 1 attacks and 88% of group 2 attacks were pain free (P=0.122). With regard to nausea, of those who had nausea at baseline, 31% and 49% of attacks in groups 1 and 2, respectively, were nausea free at 1 h (P=0.091), 75% and 79% at 2 h (P=0.736) and 82% and 91% (P=0.479) at 4 h. Recurrence, based on all attacks of those patients who achieved pain free at 4 h, was observed in 53% of group 1 and 20% of group 2 attacks (P<0.001). Sustained pain-free rates (for the 4-h time point) were 45.6% of group 1 and 78.9% of group 2 attacks. There were no significant differences with regard to rescue medication consumption after 4 h and side-effects in both groups. There was a non-significant trend for the combination group to have a higher response rate. The group treated with rizatriptan and rofecoxib had a lower recurrence rate than the group treated with rizatriptan. This study demonstrated that combining a fast acting triptan such as rizatriptan with rofecoxib reduced headache recurrence rates, was well tolerated and may be more effective than the use of rizatriptan alone. Double-blind, placebo-controlled studies are necessary to confirm these observations.",2002.0,0,0
187,12100776,Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis.,Alan Kivitz; Glenn Eisen; William W Zhao; Terry Bevirt; David P Recker,"We compared the efficacy and upper gastrointestinal safety of the cyclooxygenase-2-specific inhibitor valdecoxib with naproxen and placebo in treating moderate to severe osteoarthritis of the knee. This multicenter, randomized, double-blind, placebo-controlled study compared the efficacy and upper gastrointestinal tract safety of valdecoxib at dosages of 5, 10, and 20 mg once daily with placebo and naproxen at the dosage of 500 mg twice daily. We included patients who had been diagnosed with moderate to severe osteoarthritis of the knee according to the modified criteria of the American College of Rheumatology. The Patient's and Physician's Global Assessment of Arthritis (PaGAA, PhGAA), Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), and Western Ontario and McMaster's Universities (WOMAC) Osteoarthritis indices were assessed at baseline and at weeks 2, 6, and 12. Upper gastrointestinal ulceration was assessed by pre- and posttreatment endoscopies. Valdecoxib 10 and 20 mg once daily (but not 5 mg once daily) demonstrated similar efficacy to naproxen at 500 mg twice daily, and all 3 dosages were superior to placebo for the PaGAA, PhGAA, PAAP-VAS, and WOMAC Osteoarthritis indices at most assessments throughout the 12-week study (P <.05). The incidence of endoscopically proven ulcers was significantly higher in the naproxen group than in the 5- and 10-mg valdecoxib groups, but not in the 20-mg valdecoxib group. All 3 valdecoxib doses were comparable to placebo in ulcer incidence. Valdecoxib (10 and 20 mg once daily) is significantly superior to placebo and as effective as naproxen (500 mg twice daily) in improving moderate to severe osteoarthritis of the knee. Upper gastrointestinal tract safety of valdecoxib (5 and 10 mg) was comparable to that of placebo and significantly better than that of naproxen.",2002.0,1,1
188,12105157,"Efficacy assessment of meloxicam, a preferential cyclooxygenase-2 inhibitor, in acute coronary syndromes without ST-segment elevation: the Nonsteroidal Anti-Inflammatory Drugs in Unstable Angina Treatment-2 (NUT-2) pilot study.",Raul Altman; Hector L Luciardi; Juan Muntaner; Fatima Del Rio; Sofia G Berman; Ruben Lopez; Claudio Gonzalez,"Despite the use of heparin, aspirin, and other antiplatelet agents, acute coronary syndrome patients without ST-segment elevation remain at risk of cardiovascular thrombotic events. Given the role of inflammation in the pathogenesis of arterial thrombosis, we tested the hypothesis that the combination of meloxicam, a preferential COX-2 inhibitor, and heparin and aspirin would be superior to heparin and aspirin alone. In an open-label, randomized, prospective, single-blind pilot study, patients with acute coronary syndromes without ST-segment elevation were randomized to aspirin and heparin treatment (n=60) or aspirin, heparin, and meloxicam (n=60) during coronary care unit stay. Patients then received aspirin or aspirin plus meloxicam for 30 days. During the coronary care unit stay, the primary outcomes variable of recurrent angina, myocardial infarction, or death was significantly lower in the patients receiving meloxicam (15.0% versus 38.3%, P=0.007). The second composite variable (coronary revascularization procedures, myocardial infarction, and death) was also significantly lower in meloxicam-treated patients (10.0% versus 26.7%, P=0.034). At 90 days, the primary end point remained significantly lower in the meloxicam group (21.7% versus 48.3%, P=0.004), as did the secondary end point (13.3% versus 33.3%, P=0.015) and the need for revascularization alone (11.7% versus 30.0%, P=0.025). No adverse complications associated with the meloxicam treatment were observed. Meloxicam with heparin and aspirin was associated with significant reductions in adverse outcomes in acute coronary syndrome patients without ST-segment elevation. Additional larger trials are required to confirm the findings of this pilot study.",2002.0,0,0
189,12113843,"Fatal hyperkalemia related to combined therapy with a COX-2 inhibitor, ACE inhibitor and potassium rich diet.",Emile Hay; Hashmonai Derazon; Natalia Bukish; Leonid Katz; Igor Kruglyakov; Michael Armoni,"We describe the case of a 77-year old mildly hypertensive woman with no underlying renal disease who was admitted to the Emergency Department (ED) in a comatose state with fever. The patient had been on low dose enalapril and a potassium rich diet. Five days before admission, rofecoxib, a new selective COX-2 inhibitor nonsteroidal anti-inflammatory drug (NSAID), was added for leg pain. She was found to have severe hyperkalemia and died 90 min after her arrival. We cannot absolutely determine whether the COX-2 inhibitor was the dominant contributor to the development of hyperkalemia or the combination itself, with an intercurrent infection and some degree of dehydration. Physicians should be aware of this possible complication and only prescribe NSAIDs, including the new COX-2 drugs, to the elderly under close monitoring of kidney function and electrolyte tests.",2002.0,0,0
190,12151162,"Valdecoxib, a cyclooxygenase-2-specific inhibitor, is effective in treating primary dysmenorrhea.",Stephen E Daniels; Sheela Talwalker; Sarah Torri; Michael C Snabes; David P Recker; Kenneth M Verburg,"To compare the efficacy of the cyclooxygenase (COX)-2-specific inhibitor valdecoxib with naproxen sodium in treating menstrual pain associated with primary dysmenorrhea. This single-center, double-blind, placebo-controlled, randomized, crossover study compared the efficacy and safety of single oral doses of valdecoxib 20 mg and 40 mg with naproxen sodium 550 mg, or placebo, with an option of treatment for up to 3 days, twice daily. Efficacy was assessed by time-weighted sum of total pain relief, sum of pain intensity difference, time-specific pain relief, and pain intensity difference over 12 hours, time to rescue medication or first re-medication, the percentage of patients taking rescue medication, and patient's global evaluation of study medication. Mean time-weighted sum of total pain relief and sum of pain intensity difference were significantly superior to placebo for the first 8 and 12 hours after the initial dose of valdecoxib 20 mg (P <.01) and 40 mg (P <.001). Valdecoxib 20 mg and 40 mg were comparable to naproxen sodium 550 mg for all efficacy measures. Other differences in efficacy measures favoring the higher dose of valdecoxib did not achieve statistical significance, with the exception of sum of pain intensity difference-12. Both doses of valdecoxib were well tolerated. Both valdecoxib 20- and 40-mg doses were effective and well tolerated for the treatment of primary dysmenorrhea. Valdecoxib 20 mg and 40 mg demonstrate analgesic efficacy, based on onset, magnitude, and duration of analgesia that is similar to naproxen sodium, making it a potential choice for treating women with primary dysmenorrhea.",2002.0,0,0
191,12151676,Fatal haemorrhagic pulmonary oedema and associated angioedema after the ingestion of rofecoxib.,N P Kumar; G Wild; K A Ramasamy; J Snape,"Angioedema is a recognised side effect of rofecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor. But death resulting from a haemorrhagic pulmonary oedema after its ingestion has not been recorded. The case of a 60 year old man who died from haemorrhagic pulmonary oedema in the presence of angioedema after the ingestion of two doses of 12.5 mg of rofecoxib is reported.",2002.0,0,0
192,12151917,Efficacy and safety of intravenous parecoxib sodium in relieving acute postoperative pain following gynecologic laparotomy surgery.,Scott F Barton; Fred F Langeland; Michael C Snabes; Diane LeComte; Michael E Kuss; Shobha S Dhadda; Richard C Hubbard,"This study tested the hypothesis that an injectable cyclooxygenase (COX)-2-specific inhibitor will be at least as effective and well tolerated as a COX-nonspecific conventional nonsteroidal antiinflammatory drug (NSAID) by comparing the analgesic efficacy and tolerability of one intravenous dose of parecoxib sodium, an injectable prodrug of the novel COX-2-specific inhibitor, valdecoxib, with ketorolac and placebo in postoperative laparotomy surgery patients. Intravenous morphine, 4 mg, was studied as a positive analgesic control. In this multicenter, double-blinded, placebo-controlled study, women experiencing moderate-to-severe pain on the first day after abdominal hysterectomy or myomectomy received one intravenous dose of parecoxib sodium, 20 or 40 mg, ketorolac, 30 mg, morphine, 4 mg, or placebo. Analgesic efficacy and tolerability were evaluated for 24 h postdose or until patients, whose pain was not adequately controlled, opted to receive rescue analgesia. Two hundred two patients were enrolled. All treatment groups had comparable demographics and baseline pain status. All active treatments had an equally rapid time to onset of analgesia (10-23 min). Overall, each parecoxib sodium dose and ketorolac were significantly superior to morphine and placebo for most measures of analgesic efficacy at most time points, including a significantly longer (two- to threefold) time to rescue analgesia (P </= 0.05). All treatments were well tolerated. Single intravenous doses of parecoxib sodium, 20 mg and 40 mg, have comparable analgesic effects and are well tolerated after laparotomy surgery. Parecoxib sodium appears to be as effective as intravenous ketorolac, 30 mg, and superior to intravenous morphine, 4 mg.",2002.0,0,0
193,12162470,"Effects of meloxicam on platelet function in healthy adults: a randomized, double-blind, placebo-controlled trial.",Henry M Rinder; Jayne B Tracey; Magdalena Souhrada; Chao Wang; R Paul Gagnier; Chester C Wood,"Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1), thereby inhibiting platelet function via blockade of thromboxane A2 (TxA2) formation, and COX-2, the enzyme that mediates inflammatory responses. Meloxicam is a relatively COX-2-selective anti-arthritis drug that shows significant TxA2 inhibition, albeit less than traditional NSAIDs. A randomized, double-blind, placebo-controlled trial was conducted in 79 healthy adults to compare the effects of once-daily therapeutic (7.5 mg, 15 mg) and supratherapeutic (30 mg) doses of meloxicam with extended-release indomethacin (Indo-ER 75 mg once daily) on bleeding time, TxA2 formation, and platelet aggregation. The authors measured platelet aggregation to COX-1-dependent (ADP arachidonate) and COX-1-independent (high-dose collagen) agonists, bleeding time, serum TxB2, and clotting times (aPTT and PT) after 8 days' administration and at 3 and 6 hours after steady-state dosing. Meloxicam significantly decreased TxB2 production compared with placebo in a dose-dependent fashion, reaching a peak of 77% inhibition 6 hours after 30 mg meloxicam; Indo-ER blocked TxB2 formation by 96% at the same time point. However, neither acute nor 8 days' administration of meloxicam at any dose caused a significant increase in bleeding time or inhibition of platelet aggregation to any agonist when compared with placebo. By contrast, Indo-ER significantly increased the bleeding time and inhibited platelet aggregation to COX-1-dependent agonists 6 hours after dosing. Clotting times were unaffected by any drug. It was concluded that unlike nonselective NSAIDs, meloxicam's blockade of TxA2 formation (even at supratherapeutic doses) does not reach levels that result in decreased in vivo platelet function, as measured by bleeding time and aggregometry. In this study of healthy subjects, meloxicam did not interfere with platelet-mediated hemostasis.",2003.0,0,0
194,12162474,Efficacy and tolerability of nonprescription ibuprofen versus celecoxib for dental pain.,Geraldine Doyle; Shyamalie Jayawardena; Elizabeth Ashraf; Stephen A Cooper,"Many clinicians appear confused about the purported clinical advantages of the new generation COX-2 inhibitors compared to both over-the-counter and prescription nonsteroidal anti-inflammatory analgesic agents (NSAIDs). Infact, there is a paucity of published information comparing the safety and efficacy of these two classes of drugs when used to treat acute pain. This study was designed to compare the safety and analgesic efficacy of an over-the-counter (OTC) analgesic, ibuprofen (Advil Liqui-Gels), to the leading prescription COX-2 inhibitor celecoxib (Celebrex). Ibuprofen liquigel is an encapsulated, solubilized potassium salt of ibuprofen that has a higher Cmax and shorter tmax than traditional ibuprofen solid-dosage formulations. This trial evaluated the maximum approved OTC dosing regimen (400 mg x 3, q4-6h) of ibuprofen liquigels compared to a single dose of celecoxib (200 mg) and placebo in 174 patients with moderate orsevere pain following surgical extraction of impacted third molars. The study design was multiple dose, randomized (stratified by baseline pain and gender), placebo controlled, double blind, double dummy, and parallel group. The onset of pain relief was determined using a two-stopwatch procedure. Treatments were also compared using standard indices of pain intensity and pain relief. The study demonstrated assay sensitivity in that both active medications were significantly more effective than placebo for all efficacy measures. In comparing the two active medications, the time to meaningful relief was significantly shorter, and the mean 4-, 8-, and 12-hour summed pain relief combined with pain intensity difference scores were significantly higher for ibuprofen liquigels compared with celecoxib (p < 0.001). Analyses of other key efficacy variables, including the time to rescue medication and the patients' overall assessment of study medication, confirmed the superior efficacy of ibuprofen liquigels over celecoxib. Both active treatments were well tolerated, with no differences in incidence or severity of adverse events. Of particular interest, there were no differences in gastrointestinal-related side effects when comparing these doses of ibuprofen liquigels to celecoxib. In conclusion, ibuprofen liquigels were a significantly more effective analgesic and provided relief significantly faster compared with celecoxib in the treatment of postsurgical pain.",2003.0,0,0
195,12175641,,,,,0,0
196,12198057,"The influence of parecoxib, a parenteral cyclooxygenase-2 specific inhibitor, on the pharmacokinetics and clinical effects of midazolam.",Andra Ibrahim; Aziz Karim; Jennifer Feldman; Evan Kharasch,"Parecoxib, a parenteral cyclooxygenase-2 inhibitor, is undergoing clinical development as an analgesic/antiinflammatory drug for perioperative use. Parecoxib, an inactive prodrug, is hydrolyzed in vivo to valdecoxib, a substrate for hepatic cytochrome P450 (CYP) 3A4. Thus, potential exists for interactions with other CYP3A4 substrates. In this investigation, we determined the influence of parecoxib on the pharmacokinetics and clinical effects of midazolam, a CYP3A4 substrate, in volunteers. This was a randomized, balanced crossover, placebo-controlled, double-blinded clinical investigation. Twelve healthy subjects aged 23-41 yr were studied after providing IRB-approved informed consent. Midazolam 0.07 mg/kg IV infusion was administered 1 h after placebo (control) or parecoxib 40 mg IV. Venous midazolam concentrations were determined by using liquid chromatography-mass spectrometry/mass spectrometry assay. Pharmacokinetic variables were determined by noncompartmental analysis. Pharmacodynamic measurements included clinical end-points, cognitive function (memory; digit symbol substitution tests), subjective self-assessment of recovery (visual analog scales), and bispectral index. Midazolam plasma concentrations were similar between placebo and parecoxib-treated subjects. No differences were found in midazolam pharmacokinetics (maximal observed plasma concentration, clearance, elimination half-life, volume of distribution) or pharmacodynamics (clinical end-points, digit symbol substitution tests, memory, visual analog scales, bispectral index). Single-bolus parecoxib does not alter the pharmacokinetics or pharmacodynamics of midazolam infusion. Parecoxib did not affect CYP3A4 activity as assessed using midazolam clearance as the in vivo probe. Parecoxib, a parenteral cyclooxygenase-2 inhibitor intended for perioperative use as an analgesic/antiinflammatory drug, is a substrate for hepatic cytochrome P450 3A4. The potential for a drug interaction with midazolam, an in vivo CYP3A4 probe, was tested in healthy volunteers. Single-bolus parecoxib does not alter the pharmacokinetics or pharmacodynamics of midazolam.",2002.0,0,0
197,12209034,"Efficacy and safety of valdecoxib in treating the signs and symptoms of rheumatoid arthritis: a randomized, controlled comparison with placebo and naproxen.",W Bensen; A Weaver; L Espinoza; W W Zhao; W Riley; B Paperiello; D P Recker,"To compare the efficacy of the COX-2 specific inhibitor valdecoxib with the conventional NSAID naproxen and placebo in treating rheumatoid arthritis (RA). This multi-centre, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of valdecoxib 10 mg (n=209), 20 mg (n=212) or 40 mg once daily (q.d.) (n=221) with naproxen 500 mg b.i.d. (n=226) or placebo (n=222), in treating the signs and symptoms of RA. Efficacy was assessed by the number of patients responding to treatment according to the American College of Rheumatology-Responder Index (ACR-20). ACR-20 response was recorded for all randomized patients who received a single dose of study medication (above). Valdecoxib, at all administered doses, produced significant improvements in the ACR-20 Responder Index at weeks 2, 6 and 12 compared with placebo (P<or=0.01). Valdecoxib and naproxen did not differ in terms of ACR-20 response rate and the three doses of valdecoxib were similar to one another. All three doses of valdecoxib were well tolerated. Single daily doses of valdecoxib 10, 20 and 40 mg demonstrated efficacy that was superior to placebo and similar to naproxen in treating the signs and symptoms of RA. All three doses provided similar levels of efficacy.",2002.0,1,1
198,12211219,Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers.,Keith D Wilner; Margaret Rushing; Catherine Walden; Rebecca Adler; James Eskra; Robert Noveck; Ramon Vargas,"Celecoxib is a novel cyclooxygenase-2-specific inhibitor for the management of acute pain, primary dysmenorrhea, and the signs and symptoms of arthritis. This double-blind, placebo-controlled study in 16 healthy volunteers evaluated whether celecoxib alters the effect of concomitant aspirin on platelet function. Volunteers received celecoxib (400 mg/day) or placebo for 4 days. On day 5, they also received a single 325 mg dose of aspirin with either 200 mg celecoxib or placebo. Thromboxane and platelet aggregation response to adenosine 5'-diphosphate (ADP), collagen, and arachidonic acid were measured before the first dose of celecoxib or placebo (baseline) and before dosing and 2 and 8 hours post dose on day 5. There was no significant difference in thromboxane inhibition between the two groups (percent inhibition: placebo 99.4%, celecoxib 99.0%; p = 0.555). There was also no significant difference in the effect of aspirin on platelet aggregation due to ADP, collagen, or arachidonic acid between the groups. Therefore, these data indicate that celecoxib does not alter the effects of aspirin on platelet function.",2003.0,0,0
199,12211224,"Effects of celecoxib and diclofenac on blood pressure, renal function, and vasoactive prostanoids in young and elderly subjects.",Karin Dilger; Charlotte Herrlinger; Jörg Peters; Hannsjörg W Seyberth; Horst Schweer; Ulrich Klotz,"Cyclooxygenase (COX) inhibitors are among the most widely used drugs, especially in the elderly. It has been claimed that the new COX-2 inhibitors offer advantages in terms of drug safety. To test this hypothesis, the authors compared in a double-blind, randomized trial the effects of celecoxib (200 mg bid) and diclofenac (75 mg bid) on blood pressure and renal function in two groups (each n = 12) of young (mean age = 32 years) and elderly (mean age = 68 years) normotensive subjects. Changes from baseline in the 24-hour blood pressure profiles, parameters of the renin-angiotensin-aldosterone system, inulin clearance, urinary marker proteins, and eicosanoid excretion were monitored during the treatment period of 2 weeks. Comparison between celecoxib and diclofenac showed no significant difference in minor alterations of blood pressure. During daytime, there was a trend to elevation of mean arterial blood pressure (mmHg) by celecoxib in the elderly of 2.8 (95 % confidence interval [CI) = -2.5 to 8.2) in comparison with the young subjects of -1.3 (95% CI= -3.7 to 1.0); there was also a trend to elevation of mean arterial blood pressure by diclofenac in the elderly of 4.1 (95% CI= -1.2 to 9.4) in comparison with the young subjects of 0.4 (95% CI= -2.4 to 3.2). In both populations, the authors found no significant drug effects on the parameters of the renin-angiotensin-aldosterone system, inulin clearance, and urinary marker proteins. As expected, diclofenac reduced excretion of allprostanoids, whereas celecoxib did not affect production of TxB2 and its metabolites. Neither in young nor in elderly normotensive subjects were blood pressure and renal function significantly affected by a short-term treatment with standard doses of celecoxib and diclofenac. Therefore, normal aging appears not to represent a special risk factor in therapy with these two agents.",2003.0,0,0
200,12218521,"A single preoperative oral dose of valdecoxib, a new cyclooxygenase-2 specific inhibitor, relieves post-oral surgery or bunionectomy pain.",Paul J Desjardins; Vincent S Shu; David P Recker; Kenneth M Verburg; Clifford J Woolf,"The trend toward day-case surgery, with discharge on oral medication, has highlighted the need for effective and safe analgesics that facilitate a rapid recovery and discharge time. This study evaluated the analgesic efficacy, dose dependency, duration of action, and safety of the cyclooxygenase-2 specific inhibitor, valdecoxib, administered before oral or orthopedic surgery. Eligible healthy adult patients were scheduled to undergo either extraction of two impacted third molar teeth (n = 284) or bunionectomy surgery (n = 223) with local anesthesia in two randomized, double-blind, placebo-controlled studies conducted at three centers in the United States. Patients received a single, preoperatively administered oral dose of placebo or 10 (oral surgery only), 20, 40, or 80 mg valdecoxib. Analgesic efficacy was assessed postoperatively, over a 24-h treatment period, or until the patient required rescue medication. Efficacy measures included time to rescue medication, proportion of patients requiring such rescue, pain intensity, and the Patient's Global Evaluation of Study Medication. In both studies, all doses of valdecoxib produced analgesia with a duration (time to rescue analgesia) and magnitude (Pain Intensity, Patient's Global Evaluation) significantly greater than placebo. A dose-dependent effect was observed up to 40 mg valdecoxib, with an 80-mg dose providing no additional analgesic benefit. In both models, all doses of valdecoxib were well tolerated, with no clinically significant treatment-related gastrointestinal, renal, or platelet-derived adverse events, and no evidence of a dose-related increase in adverse events. Preoperative orally administered valdecoxib provides well-tolerated and effective analgesia for mild to moderate postoperative pain.",2002.0,0,0
201,12219273,[Allergic vasculitis following ingestion of celecoxib?].,D Gscheidel; M K Daspet; C J Le Coz; D Lipsker,A 76-year-old patient developed cutaneous vasculitis on the lower legs on the 8th day of treatment with the selective cox-2-inhibitor celecoxib (Celebrex((R))) and the proton-pump inhibitor omeprazole. The patient had no history of allergic reactions. The patient had already been treated previously with omeprazole without any side effects. A cutaneous biopsy confirmed the diagnosis of leucocytoclastic vasculitis. The purpuric skin lesions regressed within 3 weeks after withdrawing the two newly introduced drugs. We discuss the potential role of Celecoxib in triggering this vasculitis.,2002.0,0,0
202,12220285,Rofecoxib-induced instant aquagenic wrinkling of the palms.,K Robin Carder; William L Weston,"An 18-year-old woman presented with a 3-week complaint of exaggerated palmar wrinkling and swelling following brief exposure (1-2 minutes) of her hands to water. She had a history of mixed connective tissue disease and had been started on rofecoxib therapy 1 month prior to the onset of her skin symptoms. Discontinuation of rofecoxib was followed by resolution of symptoms within a period of 3 weeks. Similar palmar skin changes following water exposure have been reported to occur in cystic fibrosis and are thought to be due to increased salt content of the skin and secondary increased water-binding capacity. Rofecoxib is a selective COX-2 inhibitor that has been shown to increase sodium reabsorption in the kidney via effects on prostaglandin E2 and the renal vasculature. The COX-2 protein is also expressed in keratinocytes and plays a role in keratinocyte differentiation. Prostaglandin E2 also plays a role in keratinocyte proliferation and differentiation. Thus rofecoxib may cause increased sodium reabsorption in the skin, as it does in the kidney. The rofecoxib-associated elevation in skin sodium may increase keratin water-binding capacity and cause exaggerated aquagenic wrinkling of the skin, as occurs in cystic fibrosis.",2002.0,0,0
203,12222558,Toxic epidermal necrolysis after celecoxib therapy.,Peter Berger; Daniel Dwyer; Carmela E Corallo,"Toxic epidermal necrolysis (TEN) is a rare disease that is defined by extensive detachment of full-thickness epidermis. It most often is related to an adverse drug reaction. The drugs implicated in most cases of TEN have been sulfonamides, anticonvulsants, allopurinol, and some of the conventional nonsteroidal antiinflammatory agents. We describe a patient who developed a generalized desquamating rash after therapy with celecoxib.",2003.0,0,0
204,12242171,"Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials.",Jonathan J Deeks; Lesley A Smith; Matthew D Bradley,"To determine the efficacy, gastrointestinal safety, and tolerability of celecoxib (a cyclo-oxygenase 2 (COX 2) inhibitor) used in the treatment of osteoarthritis and rheumatoid arthritis. Systematic review of randomised trials that compared at least 12 weeks' celecoxib treatment with another non-steroidal anti-inflammatory drug (NSAID) or placebo and reported efficacy, tolerability, or safety. Trials identified from manufacturer and by searching electronic databases and evaluated according to predefined inclusion and quality criteria. Data combined through meta-analysis. 15 187 patients with osteoarthritis or rheumatoid arthritis.  Western Ontario and McMaster universities osteoarthritis index; American College of Rheumatology responder index and joint scores for rheumatoid arthritis. Tolerability: withdrawal rates for adverse effects. Gastrointestinal safety: incidence of ulcers, bleeds, perforations, and obstructions. Nine randomised controlled trials were included. Celecoxib and NSAIDS were equally effective for all efficacy outcomes. Compared with those taking other NSAIDs, in patients taking celecoxib the rate of withdrawals due to adverse gastrointestinal events was 46% lower (95% confidence interval 29% to 58%; NNT 35 at three months), the incidence of ulcers detectable by endoscopy was 71% lower (59% to 79%; NNT 6 at three months), and the incidence of symptoms of ulcers, perforations, bleeds, and obstructions was 39% lower (4% to 61%; NNT 208 at six months). Subgroup analysis of patients taking aspirin showed that the incidence of ulcers detected by endoscopy was reduced by 51% (14% to 72%) in those given celecoxib compared with other NSAIDs. The reduction was greater (73%, 52% to 84%) in those not taking aspirin. Celecoxib is as effective as other NSAIDs for relief of symptoms of osteoarthritis and rheumatoid arthritis and has significantly improved gastrointestinal safety and tolerability.",2002.0,0,0
205,12357161,Cost-efficacy of rofecoxib versus acetaminophen for preventing pain after ambulatory surgery.,Tijani Issioui; Kevin W Klein; Paul F White; Mehernoor F Watcha; Gary D Skrivanek; Stephanie B Jones; Jie Hu; Bradley F Marple; Caleb Ing,"Nonsteroidal antiinflammatory drugs are commonly administered as part of a multimodal regimen for pain management in the ambulatory setting. This randomized, double-blinded, placebo-controlled study was designed to compare the analgesic effect of oral rofecoxib, a cyclooxygenase-2 inhibitor, and acetaminophen when administered alone or in combination prior to outpatient otolaryngologic surgery. A total of 143 healthy outpatients undergoing elective otolaryngologic surgery were assigned to one of four study groups: group 1 = control (500 mg vitamin C); group 2 = 2 g acetaminophen; group 3 = 50 mg rofecoxib; or group 4 = 2 g acetaminophen and 50 mg rofecoxib. The first oral dose of the study medication was taken 15-45 min before surgery, and a second dose of the same medication was administered on the morning after surgery. Recovery times, side effects, and the need for rescue analgesics were recorded. Follow-up evaluations were performed at 24 and 48 h after surgery to assess postdischarge pain, analgesic requirements, nausea, and patient satisfaction with their postoperative pain management and quality of recovery. Peak pain scores and the need for rescue analgesic medication were used as the endpoints for estimating efficacy of the study drugs, while cost to achieve complete satisfaction with analgesia was used in the cost-effectiveness analysis. Premedication with rofecoxib (50 mg) was significantly more effective than either placebo or acetaminophen (2 g) in reducing the peak postoperative pain, the need for analgesic medication, and improving the quality of recovery and patient satisfaction. Moreover, the addition of acetaminophen failed to improve its analgesic efficacy. An expenditure for rofecoxib of 16.76 US dollars (95% confidence interval, 7.89 to 21.03 US dollars) and 30.24 US dollars (95% confidence interval, 5.25 to 54.20 US dollars) would obtain complete satisfaction with pain control in one additional patient who would not have been satisfied if placebo or acetaminophen, respectively, had been administered prior to surgery. Rofecoxib, 50 mg administered orally, decreased postoperative pain and the need for analgesic rescue medication after otolaryngologic surgery. The addition of 2 g oral acetaminophen failed to improve its analgesic efficacy.",2002.0,0,0
206,12360461,Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis.,Loren Laine; Claire Bombardier; Christopher J Hawkey; Barry Davis; Deborah Shapiro; Christopher Brett; Alise Reicin,"Epidemiologic data indicate that the risk of nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) clinical events varies based on patients' clinical characteristics. The authors determined risk factors for NSAID-related clinical upper GI events and the event rates, absolute risk reductions, and numbers needed to treat for individual risk factors for a nonselective NSAID and a selective cyclooxygenase 2 inhibitor in a double-blind outcomes trial. Eight thousand seventy-six rheumatoid arthritis patients aged >or=50 years (or >or=40 on corticosteroid therapy) were randomly assigned to rofecoxib 50 mg daily or naproxen 500 mg twice daily for a median of 9 months. The development of clinical upper GI events (bleeding, perforation, obstruction, and symptomatic ulcer identified on clinically indicated work-up) was assessed. Significant risk factors included prior upper GI events, age >or=65, and severe rheumatoid arthritis (RR, 2.3-3.9). Patients administered naproxen who had prior upper GI complications or who were aged >or=75 years had 18.84 or 14.46 events per 100 patient-years, and the risk of events remained constant over time. The reduction in events with rofecoxib was similar in high- and low-risk subgroups (RR, 0.31-0.68). The number needed to treat with rofecoxib instead of naproxen to avert 1 GI event was 10-12 in highest risk patients (prior event, age >or=75 years, or severe rheumatoid arthritis), 17-33 in patients with other risk factors, and 42-106 in low-risk patients. NSAID-related GI events increase dramatically with risk factors such as prior events or older age. Ten to twelve high-risk patients need to be treated with a protective strategy such as the selective cyclooxygenase 2 inhibitor, rofecoxib, to avert a clinical GI event.",2002.0,0,0
207,12362101,Incidence of gastroduodenal ulcers associated with valdecoxib compared with that of ibuprofen and diclofenac in patients with osteoarthritis.,David H Sikes; Naurang M Agrawal; William W Zhao; Jeffrey D Kent; David P Recker; Kenneth M Verburg,"To determine whether valdecoxib, at chronic arthritis doses, has the characteristics of a cyclo-oxygenase 2 (COX-2) specific inhibitor, as measured by a reduced incidence of upper-gastrointestinal ulceration compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs). This double-blind, multicentre, placebo-controlled, parallel-group study compared the incidence of gastroduodenal ulcers associated with valdecoxib 10 mg daily (q.d.) and 20 mg q.d. with that of ibuprofen 800 mg three times daily (t.i.d.) or diclofenac 75 mg twice daily (b.i.d.) when administered over a 12-week period. The incidence of gastroduodenal ulcers was assessed by upper-gastrointestinal endoscopy, performed at baseline and again at the end of week 12 (or at early study termination). Efficacy assessments were performed at baseline and at weeks 2, 6 and 12 using Patient's and Physician's Global Assessments of Arthritis. A total of 1052 osteoarthritis patients were enrolled into the trial. The incidence of gastroduodenal ulcers over 12 weeks was 5% in patients receiving valdecoxib 10 mg q.d., 4% in patients receiving valdecoxib 20 mg q.d., 7% in patients receiving placebo, 16% in patients receiving ibuprofen 800 mg t.i.d. (P <0.05 v. placebo), and 17% in patients receiving diclofenac 75 mg b.i.d. (P <0.05 v. placebo). The incidence of gastroduodenal ulcers at week 12 seen in the ibuprofen 800 mg t.i.d. and diclofenac 75 mg b.i.d. groups was significantly higher than that in the valdecoxib 10 mg q.d. and valdecoxib 20 mg q.d. groups (P <0.05). The incidence rates of gastroduodenal ulcers were not significantly different between the valdecoxib treatment groups or between valdecoxib- and placebo-treated patients. Efficacy responses to valdecoxib 10 mg and 20 mg q.d. were significantly greater than placebo and comparable with both ibuprofen 800 mg t.i.d. and diclofenac 75 mg b.i.d. The results of the study demonstrate that valdecoxib has an upper-gastrointestinal safety profile typical of a COX-2 specific inhibitor. Overall, the data indicate that administration of valdecoxib offers similar efficacy for the treatment of osteoarthritis but improved upper-gastrointestinal safety compared with the conventional NSAIDs, ibuprofen and diclofenac, based on the significantly lower incidence of gastroduodenal ulcers detected by endoscopy.",2003.0,1,1
208,12369656,A placebo and active comparator-controlled trial of rofecoxib for the treatment of rheumatoid arthritis.,P P Geusens; K Truitt; P Sfikakis; P L Zhao; L DeTora; S Shingo; C S Lau; A Kalla; G Tate,"To evaluate the efficacy and tolerability of rofecoxib 25 mg and 50 mg once daily versus placebo and naproxen 500 mg twice daily in patients with RA. Eligible patients were randomized (double-blind) to placebo (n = 289), rofecoxib 25 mg (n = 306), 50 mg (n = 286) once daily, or naproxen (n = 142) for 12 weeks. Efficacy assessments included the ACR core set, with prespecified primary endpoints: patient and investigator global assessments of disease activity, tender and swollen joint counts. Investigator-reported adverse experiences, routine laboratory and vital sign measurements were monitored. Rofecoxib 25 mg, 50 mg, and naproxen provided similar treatment effects, significantly different from placebo, consistent with improvement, for all primary endpoints. Effects were evident at the earliest assessment (week 2) and sustained for 12 weeks. All treatments were generally well-tolerated. Rofecoxib 25 mg once daily had similar efficacy to naproxen 500 mg twice daily (a standard dose). No additional benefit was seen with 50 mg rofecoxib.",2002.0,0,0
209,12383990,COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease.,Wayne A Ray; C Michael Stein; James R Daugherty; Kathi Hall; Patrick G Arbogast; Marie R Griffin,"Results of premarketing and postmarketing trials have raised doubts about the cardiovascular safety of the non-steroidal anti-inflammatory drug (NSAID) rofecoxib, especially at doses greater than 25 mg. Between Jan 1, 1999, and June 30, 2001, we did a retrospective cohort study of individuals on the expanded Tennessee Medicaid programme (TennCare), in which we assessed occurrence of serious coronary heart disease (CHD) in non-users (n=202916) and in users of rofecoxib and other NSAIDs (rofecoxib n=24 132, other n=151 728). Participants were aged 50-84 years, lived in the community, and had no life-threatening non-cardiovascular illness. Users of high-dose rofecoxib were 1.70 (95% CI 0.98-2.95, p=0.058) times more likely than non-users to have CHD; among new users this rate increased to 1.93 (1.09-3.42, p=0.024). By contrast, there was no evidence of raised risk of CHD among users of rofecoxib at doses of 25 mg or less or among users of other NSAIDs.",2002.0,0,0
210,12395955,COX-2-specific inhibitors: prescribing patterns in a large managed care health system and strategies to minimize costs.,Rick A Weideman; Kevin C Kelly; Catherine L Kelley; Byron Cryer,"To determine the relative costs associated with the exclusive use of celecoxib versus rofecoxib in a large managed care system. A retrospective review of all calendar year 2000 prescriptions dispensed for celecoxib and rofecoxib in the Veterans Affairs (VA) system. The primary data points included drug strength, quantity dispensed, and days supply for the prescription. The cost minimization model described in Federal Practitioner (1999;16[4]:41-44) was used to calculate the cost savings. The mean once-daily dosing rates and their 95% confidence intervals were determined by binomial data analysis. Calendar year 2001 utilization and cost projections were derived by linear regression trend analysis. Current VA system costs per dose are celecoxib 100 mg $0.66; celecoxib 200 mg $1.32; rofecoxib (12.5 or 25 mg) $1.32; rofecoxib 50 mg $2.14. During calendar year 2000, the VA spent $13.8 million and $4.2 million on celecoxib and rofecoxib, respectively. The percentage of once-daily or less than once-daily dosing was celecoxib 100 mg (17%), celecoxib 200 mg (67%), celecoxib overall (49%), rofecoxib 12.5 mg (86%), rofecoxib 25 mg (94%), rofecoxib 50 mg (100%), and rofecoxib overall (93%). Based on current utilization, if all celecoxib prescriptions were changed to rofecoxib, the VA would have realized annual cost savings of $2.1 million in calendar year 2000. In calendar year 2001, projected cost savings could total $5.2 million. This potential savings is largely due to the high prevalence of twice-daily celecoxib dosing. The results of the cyclooxygenase-2 cost minimization analysis provide a compelling argument for the preferred use of rofecoxib in the VA system, and potentially in other managed care systems.",2002.0,0,0
211,12398962,Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or =65 years of age with systemic hypertension and osteoarthritis.,Andrew Whelton; William B White; Alfonso E Bello; Joseph A Puma; John G Fort; SUCCESS-VII Investigators,"Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), including the cyclooxygenase-2 (COX-2) specific inhibitors, with antihypertensive medication is common practice for many patients with arthritis. This study evaluated the effects of celecoxib 200 mg/day and rofecoxib 25 mg/day on blood pressure (BP) and edema in a 6-week, randomized, parallel-group, double-blind study in patients > or =65 years of age with osteoarthritis who were treated with fixed antihypertensive regimens. One thousand ninety-two patients received study medication (celecoxib, n = 549; rofecoxib, n = 543). Significantly more patients in the rofecoxib group compared with the celecoxib group developed increased systolic BP (change >20 mm Hg plus absolute value > or =140 mm Hg) at any time point (14.9% vs 6.9%, p <0.01). Rofecoxib caused the greatest increase in systolic BP in patients receiving angiotensin-converting enzyme inhibitors or beta blockers, whereas those on calcium channel antagonists or diuretic monotherapy receiving either celecoxib or rofecoxib showed no significant increases in BP. Clinically significant new-onset or worsening edema associated with weight gain developed in a greater percentage of patients in the rofecoxib group (7.7%) compared with the celecoxib group (4.7%) (p <0.05). Thus, in patients with controlled hypertension on a fixed antihypertensive regimen, careful monitoring of BP is warranted after the initiation of celecoxib or rofecoxib therapy.",2002.0,1,1
212,12401617,Analgesic effects of rofecoxib in ear-nose-throat surgery.,A Turan; S Emet; B Karamanlioğlu; D Memiş; N Turan; Z Pamukcu,"In this study we evaluated the analgesic efficacy and the opioid-sparing effect of rofecoxib in ear-nose-throat surgery patients. Patients undergoing nasal septal or sinus surgery were randomized to receive either oral placebo or rofecoxib 50 mg 1 h before surgery. All patients received propofol 0.8 mg/kg, fentanyl 1 microg/kg, and local anesthesia at the operative site. Sedation was maintained by a continuous infusion of propofol adjusted to maintain sedation at a 2-3 level on the Ramsey scale. Additional fentanyl 0.5-1 microg/kg was administered at the patient's request or if the verbal rating scale score was >4. Patient sedation and pain scores were obtained at 5, 15, 30 45, and 60 min during surgery and 30 min and 2, 4, 6, 12, and 24 h after completion of the procedure. During the postoperative period, diclofenac 75 mg IM was administered for analgesia at the patient's request or if the visual analog scale (VAS) rating for pain was more than 4. VAS pain scores, intraoperative fentanyl, and postoperative diclofenac requirements were significantly smaller in the rofecoxib group compared with the placebo group (P < 0.001). The times to first analgesic request were also significantly less in the rofecoxib group. We conclude that the preoperative administration of oral rofecoxib provided a significant analgesic benefit and decreased the need for opioids in patients undergoing nasal septal and nasal sinus surgery. The aim of this study was to evaluate the analgesic efficacy and opioid-sparing effect of rofecoxib, a new selective cyclooxygenase-2 inhibitor drug, in ear-nose-throat surgery patients. Preoperative administration of oral rofecoxib provided a significant analgesic benefit and decreased the need for opioids in patients undergoing nasal septal and nasal sinus surgery.",2002.0,0,0
213,12407655,Nephrotic syndrome and interstitial nephritis associated with celecoxib.,Arnold B Alper; Suzanne Meleg-Smith; N Kevin Krane,"Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known to cause fluid and electrolyte abnormalities and renal failure. NSAIDs also may cause an acute allergic interstitial nephritis (AIN) and the nephrotic syndrome, characterized by histologic pathology consistent with minimal change disease in patients with previously normal renal function. The nephrotoxic potential of cyclooxygenase 2 (COX-2) inhibitors has not been established because AIN associated with nephrotic syndrome has not been reported secondary to the COX-2 inhibitors. This case report describes the first case of AIN associated with nephrotic syndrome in a patient treated with the selective COX-2 inhibitor, celecoxib.",2002.0,0,0
214,12414874,Rapid potentiation of endothelium-dependent vasodilation by estradiol in postmenopausal women is mediated via cyclooxygenase 2.,A C Calkin; K Sudhir; S Honisett; M R I Williams; T Dawood; P A Komesaroff,"Estrogens influence cardiovascular function through direct and indirect effects and via genomic and nongenomic mechanisms. The pathways underlying the nongenomic mechanisms are not completely understood. Estrogen-induced responses in vascular cells have been shown to influence prostaglandins and cyclooxygenase (COX), a key enzyme in the production of prostaglandins, with two isoforms, COX-1 and COX-2. We investigated the effects of prostaglandins on the acute potentiation by 17beta-estradiol (E) of acetylcholine (ACh)-mediated vasodilation in the cutaneous vasculature. Using a double-blind placebo-controlled design, we assessed skin blood flow in 32 healthy, postmenopausal women by laser Doppler velocimetry with direct current iontophoresis of ACh and sodium nitroprusside before and after 6-wk treatment periods with aspirin (a nonspecific COX-1 and COX-2 inhibitor), diclofenac (predominantly a COX-2 inhibitor, which also inhibits COX-1), celecoxib (a specific COX-2 inhibitor), given at anti-inflammatory doses, or placebo. Blood flux values before iontophoresis of ACh did not differ between the treatment groups or after E administration, excluding a direct cutaneous vasodilator effect of the treatments or of E. Acute E administration enhanced the response to ACh after aspirin, diclofenac, and placebo; however, this effect was completely abolished with celecoxib treatment (P < 0.05). E had no effect on sodium nitroprusside-mediated vasodilation after any of the treatments. We conclude that the COX-2 pathway plays a specific role in the rapid E-induced potentiation of cholinergic vasodilation in postmenopausal women.",2002.0,0,0
215,12425513,Toxic epidermal necrolysis due to administration of celecoxib (Celebrex).,Bruce Friedman; Hermann K Orlet; Joseph M Still; Edward Law,"A 41-year-old woman was given celecoxib (Celebrex) for the treatment of carpal tunnel syndrome. An erythematous rash developed that progressed to exfoliative dermatitis, and the patient was diagnosed with toxic epidermal necrolysis. After transfer to the burn unit, she was treated with topical mupirocin calcium cream and bismuth tribromophenatein petrolatum gauze dressings. Her wounds healed well. This is the first case report of toxic epidermal necrolysis due to treatment with celecoxib of which we are aware.",2002.0,0,0
216,12462285,"A comparison of rofecoxib versus celecoxib in treating pain after dental surgery: a single-center, randomized, double-blind, placebo- and active-comparator-controlled, parallel-group, single-dose study using the dental impaction pain model.",Kerstin Malmstrom; James R Fricke; Paul Kotey; Barbara Kress; Briggs Morrison,"Rofecoxib and celecoxib, selective cyclooxygenase-2 inhibitors, have analgesic efficacy similar to that of nonselective nonsteroidal anti-inflammatory drugs. This study was designed to confirm earlier findings that the overall analgesic efficacy of rofecoxib 50 mg was superior to that of celecoxib 200 mg and to extend the comparison to include celecoxib 400 mg. In this single-center, randomized, double-blind, placebo- and active-comparator-controlled, parallel-group, single-dose study, patients who experienced moderate or severe pain after surgical extraction of at least 2 third molars received a single oral dose of either rofecoxib 50 mg, celecoxib 400 mg, celecoxib 200 mg, ibuprofen 400 mg, or placebo. Patients recorded scores of pain intensity, pain relief, and global assessment at prespecified time intervals throughout the 24-hour period after dosing. The end points were total pain relief (TOPAR) score over 8 hours (TOPAR8; primary end point), TOPAR score over 12 hours (TOPAR12), sum of pain intensity difference (SPID) over 8 and 12 hours (SPID8 and SPID12), patient's global assessment of study drug at 8 hours, time to confirmed perceptible pain relief (ie, time to onset of analgesic effect), peak pain intensity difference (PID), peak pain relief, time to first dose of rescue medication (ie, duration of analgesic effect), and percentage of patients using rescue medication. A total of 482 patients (358 females, 124 males; mean age, 22.1 years) were enrolled. Rofecoxib 50 mg (n = 151 patients) demonstrated significantly greater overall analgesic efficacy compared with celecoxib 400 mg (n = 151), as measured by TOPAR8 (least squares mean [SE] 17.2 [0.8] vs 15.0 [0.8]; P < 0.05) and TOPAR12 (25.3 [1.2] vs 21.0 [1.2]; P < 0.05), as well as a significantly longer duration of analgesic effect (P < 0.05). Time to onset of analgesic effect and peak analgesic effect were similar for rofecoxib 50 mg and celecoxib 400 mg. Rofecoxib also showed significantly greater overall analgesic efficacy than did celecoxib 200 mg (n = 90), including greater TOPAR8 scores (17.2 [0.8] vs 11.5 [1.1]; P < 0.001), faster onset of analgesic effect (P < 0.001), greater peak analgesic effect (P < 0.001 for peak pain relief and peak PID), and longer duration of analgesic effect (P < 0.001). The overall analgesic efficacy of rofecoxib 50 mg was similar to that of ibuprofen 400 mg (n = 45), except that the duration of analgesic effect of rofecoxib 50 mg was significantly longer (P < 0.001). All active treatments produced significantly greater overall analgesic efficacy compared with that of placebo (P < 0.001 for all scores [TOPAR8, TOPAR12, SPID8, SPID12, and patient's global assessment] for all study drugs). The adverse-events (AE) profile was generally similar in all treatment groups. The 3 most common AEs were nausea, postextraction alveolitis, and vomiting. In this study, rofecoxib 50 mg provided generally superior overall analgesic efficacy compared with that of celecoxib 400 and 200 mg, including a significantly longer duration of analgesic effect. The overall analgesic efficacy of rofecoxib 50 mg was generally similar to that of ibuprofen 400 mg, except for a significantly longer duration of analgesic effect.",2003.0,0,0
217,12487621,The second generation of COX-2 inhibitors: what advantages do the newest offer?,Dirk O Stichtenoth; Jürgen C Frölich,"The discovery of two cyclooxygenase (COX)-isoenzymes, a constitutive COX-1, serving homeostatic prostanoid synthesis, and an inducible COX-2, responsible for proinflammatory prostanoid production, led to the development of new non-steroidal anti-inflammatory drugs (NSAIDs), the selective COX-2 inhibitors, promising minimal NSAID-typical toxicity with full anti-inflammatory efficacy. So far, the strategy of selective COX-2 inhibition has been successful. Selective COX-2 inhibitors have significantly less gastrotoxicity and no effects on platelet aggregation. However, with regard to renal adverse events, selective COX-2 inhibitors do not offer a clinically relevant advantage over non-selective inhibitors. Moreover, concerns over the cardiovascular risk of selective COX-2 inhibitors have recently been raised. The second generation of COX-2 inhibitors with higher COX-2 selectivity was developed with the promise of further reduction of NSAID-typical adverse effects. The leading compounds are valdecoxib, parecoxib, etoricoxib and lumaricoxib. At the present time they have proven efficacy for the treatment of pain and inflammation. Parecoxib as a parenteral, highly selective COX-2 inhibitor has the potential to become the NSAID of choice for treatment of postoperative pain. In clinical trials, valdecoxib, parecoxib, etoricoxib and lumaricoxib have caused no more endoscopic ulcers than placebo. However, to date, no data on the clinically relevant endpoints perforation, symptomatic ulcer and bleeding are available. Furthermore, no definite conclusions on renal and cardiovascular safety are possible. Current evidence points to a marginal, if any, gain of safety compared with the first generation of COX-2 inhibitors. However, trials with the new COX-2 inhibitors offer the chance to address these open questions of highly selective COX-2 inhibition; that is, thrombogenic risk, sodium and water retention, and interference with tissue repair, in particular, healing of mucosal damage.",2003.0,0,0
218,12492220,Exacerbation of Crohn's colitis with severe colonic hemorrhage in a patient on rofecoxib.,Jean-Mar Gornet; Zahir Hassani; Robert Modiglian; Marc Lémann,,2003.0,0,0
219,12492248,Comparison of low-dose rofecoxib versus 1000 mg naproxen in patients with osteoarthritis. Results of two randomized treatment trials of six weeks duration.,R Myllykangas-Luosujärvi; H S Lu; S L Chen; D Choon; C Amante; C T Chow; G Pasero; Gy Genti; B Sarembock; C A F Zerbini; F Vrijens; A Moan; D B Rodgers; L De Tora; M Laurenzi; Naproxen 901 OF study group Naproxen 901 OC study group,"To compare the efficacy and safety of rofecoxib 12.5 mg once daily to naproxen 500 mg twice daily in patients > or = 40 years of age with knee or hip osteoarthritis (OA). Two identical 6-week, randomized, double-blind studies were conducted (1 in Africa, Australia, Europe, Canada, Mexico, & South America; 1 in Asia). Primary endpoints were pain walking on a flat surface, patient global assessment of response to therapy, and investigator global assessment of disease status. Overall, 944 patients participated. For all efficacy endpoints, treatment effects for rofecoxib and naproxen were comparable and seen at the first measures of efficacy. Both compounds were generally well-tolerated, with an improved gastrointestinal safety profile for rofecoxib versus naproxen. CONCLUSIONS In these studies, rofecoxib 12.5 mg once daily (the lowest indicated dose) and naproxen 500 mg twice daily showed similar treatment effects in OA patients. Rofecoxib and naproxen were generally well tolerated.",2003.0,1,1
220,12495363,,,,,0,0
221,12501222,Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis.,Francis K L Chan; Lawrence C T Hung; Bing Y Suen; Justin C Y Wu; Kenneth C Lee; Vincent K S Leung; Aric J Hui; Ka F To; Wai K Leung; Vincent W S Wong; S C Sydney Chung; Joseph J Y Sung,"Current guidelines recommend that patients at risk for ulcer disease who require treatment for arthritis receive nonsteroidal antiinflammatory drugs (NSAIDs) that are selective for cyclooxygenase-2 or the combination of a nonselective NSAID with a proton-pump inhibitor. We assessed whether celecoxib would be similar to diclofenac plus omeprazole in reducing the risk of recurrent ulcer bleeding in patients at high risk for bleeding. We studied patients who used NSAIDs for arthritis and who presented with ulcer bleeding. After their ulcers had healed, we randomly assigned patients who were negative for Helicobacter pylori to receive either 200 mg of celecoxib twice daily plus daily placebo or 75 mg of diclofenac twice daily plus 20 mg of omeprazole daily for six months. The end point was recurrent ulcer bleeding. In the intention-to-treat analysis, which included 287 patients (144 receiving celecoxib and 143 receiving diclofenac plus omeprazole), recurrent ulcer bleeding occurred in 7 patients receiving celecoxib and 9 receiving diclofenac plus omeprazole. The probability of recurrent bleeding during the six-month period was 4.9 percent (95 percent confidence interval, 3.1 to 6.7) for patients who received celecoxib and 6.4 percent (95 percent confidence interval, 4.3 to 8.4) for patients who received diclofenac plus omeprazole (difference, -1.5 percentage points; 95 percent confidence interval for the difference, -6.8 to 3.8). Renal adverse events, including hypertension, peripheral edema, and renal failure, occurred in 24.3 percent of the patients receiving celecoxib and 30.8 percent of those receiving diclofenac plus omeprazole. Among patients with a recent history of ulcer bleeding, treatment with celecoxib was as effective as treatment with diclofenac plus omeprazole, with respect to the prevention of recurrent bleeding. Renal toxic effects are common in high-risk patients receiving celecoxib or diclofenac plus omeprazole.",2003.0,1,1
222,12509627,A randomized double-blind pilot study comparing Doloteffin and Vioxx in the treatment of low back pain.,S Chrubasik; A Model; A Black; S Pollak,"This randomized, double-dummy, double-blind pilot study of acutely exacerbated low back pain was aimed to inform a definitive comparison between Doloteffin, a proprietary extract of Harpagophytum, and rofecoxib, a selective inhibitor of cyclo-oxygenase-2 (COX-2). Forty-four patients (phyto-anti-inflammatory drug-PAID-group) received a daily dose of Doloteffin containing, inter alia, 60 mg of harpagoside for 6 weeks and 44 (non-steroidal anti-inflammatory drug-NSAID-group) received 12.5 mg/day of rofecoxib. All were allowed rescue medication of up to 400 mg/day of tramadol. Several outcome measures were examined at various intervals to obtain estimates of effect size and variability that might be used to decide the most suitable principal outcome measure and corresponding numbers required for a definitive study. Forty-three PAID and 36 NSAID patients completed the study. Ten PAID and 5 NSAID patients reported no pain without rescue medication for at least 5 days of the 6th week of treatment. Eighteen PAID and 12 NSAID patients had more than a 50% reduction in the week's average of their pain scores between the 1st and 6th weeks. The mean percentage decrease from baseline in the pain component of the Arhus Index was 23 (S.D. 52) in PAID and 26 (S.D. 43) in NSAID. The corresponding measures for the overall Arhus Index were 11 (31) and 16 (24) and, for the Health Assessment Questionnaire, 7 (8) and 6 (7). Tramadol was used by 21 PAID patients and 13 NSAID patients. Fourteen patients in each group experienced 39 adverse effects, of which 28 (13 in PAID) were judged to some degree attributable to the study medications. Though no significant intergroup differences were demonstrable, large numbers will be needed to show equivalence.",2003.0,0,0
223,12511311,"A randomized, clinical trial comparing oral celecoxib 200 mg, celecoxib 400 mg, and ibuprofen 600 mg for acute pain.",David F Salo; Robert Lavery; Vikram Varma; Jennifer Goldberg; Tara Shapiro; Alan Kenwood,"Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used to treat pain. The objective of this study was to compare the efficacies of celecoxib and ibuprofen for the treatment of acute pain. The null hypothesis was that no difference between celecoxib and ibuprofen exists. The study was a prospective, randomized, double-blind, controlled clinical trial. After consent, patients rated their pain on a 100-mm visual analog scale (VAS) and categorical intensity pain scale. Patients were then randomized to receive 200-mg or 400-mg celecoxib or 600-mg ibuprofen (all orally). Patients were contacted 5 hours after receiving study medication when a second VAS score was recorded, along with categorical pain intensity, pain relief score, side effects, and number of rescue medications taken. The main outcome measures were change in visual analog pain and categorical pain intensity scores, and pain relief scores, at five hours. One hundred ten patients were evaluated and 105 were enrolled. Thirty-four received celecoxib 200 mg, 32 received celecoxib 400 mg, and 39 received ibuprofen 600 mg. Ninety-one were available for the five-hour VAS and 88 for the five-hour categorical pain intensity and pain relief analysis: The two patients who were unable to read a VAS were excluded, and two enrolled patients withdrew prior to medication. One patient was excluded because his injury was a fracture, and therefore did not meet the inclusion criteria. There was no statistical difference among the treatment groups in age, time from injury to medication, initial VAS score, percent lost to follow-up, or treatment with adjunctive therapy. There was no statistical difference in change of VAS among the groups at five hours: ibuprofen 600 mg (-23.8 mm [95% CI = -31.56 mm to -16.1 mm] [n = 32]), celecoxib 200 mg (-16.1 mm [95% CI = -24.3 mm to -7.98 mm] [n = 31]), and celecoxib 400 mg (-12.4 mm [95% CI = -23.1 mm to -1.8 mm] [n = 30]) (p = 0.16). There was no significant difference between the groups, at five hours, in change of categorical pain intensity (p = 0.11) or pain relief scores (p = 0.059), though the pain relief scale approached significance favoring ibuprofen. No significant difference exists among emergency department (ED) patients treated for acute pain, at five hours, with celecoxib 200 mg, celecoxib 400 mg, or ibuprofen 600 mg, though the power of the study to detect a change was low, 36%. However, the magnitude of pain relief for celecoxib, coupled with the cost of the medication, questions its use in the immediate ED setting.",2003.0,0,0
224,12512760,Acute pancreatitis: a rare complication of celecoxib.,G Nind; W Selby,,2003.0,0,0
225,12523925,Celecoxib-related renal papillary necrosis.,Laila Akhund; Robert J Quinet; Saliha Ishaq,"Selective cyclooxygenase 2 (COX-2) inhibitors are known to affect renal prostaglandins (epoprostenol and dinoprostone), which are at least in part COX-2 dependent. Consequently, adverse events including hypertension, peripheral edema, hypercalemia, hyponatremia, and acute renal failure have been reported to occur with the new COX-2-specific inhibitors. This case report posits celecoxib as a likely cause of renal papillary necrosis and alerts physicians to the possibility of this additional renal complication with COX-2-specific inhibitors.",2003.0,0,0
226,12534638,Population pharmacokinetic analysis of meloxicam in rheumatoid arthritis patients.,Ingolf Meineke; Dietrich Türck,"To perform a nonlinear mixed effect modelling (NONMEM) population pharmacokinetic analysis of meloxicam plasma concentrations in rheumatoid arthritis (RA) patients participating in three clinical trials, and to evaluate the effects of age, weight, gender and concomitant medications on meloxicam pharmacokinetics. Meloxicam was administered to RA patients once daily for 3 weeks or 6 months at doses between 7.5 and 60 mg. Plasma samples were obtained at least 7 days after the first dose and meloxicam plasma concentrations were quantified by h.p.l.c. NONMEM analysis was conducted on plasma samples derived from 586 patients. A one-compartmental model was found to describe the data adequately. For a typical subject in the population, a clearance of 0.377 l h-1 (95% confidence interval (CI) 0.0304-0.449) in males and 0.347 l h-1 (95% CI 0.274-0.419) in females was obtained. The volume of distribution was estimated to be 14.9 l. The findings were corroborated by subsequent analysis using WinBUGS. Analysis of covariates showed that age and gender both significantly (P < 0.005) affected clearance. The effect of age was relatively small and a dose adjustment of <10% was deemed unnecessary. Differences between males and females were attributed to differences in weight. No clinically relevant drug-drug interactions were found, although sulphasalazine and glucocorticoids both significantly (P < 0.005) affected meloxicam clearance (+19% and - 12%, respectively). The mechanisms by which these agents affect meloxicam clearance remain to be elucidated. The population pharmacokinetic meloxicam data from patients with RA gave similar results to those obtained from phase I trials. However, uncommon drug interactions may not be detected in phase I trials because of the small number of observations made.",2003.0,0,0
227,12540224,Effectiveness of prophylactic use of rofecoxib in comparison with ibuprofen on postendodontic pain.,V Gopikrishna; A Parameswaran,"The purpose of this study was to determine if prophylactic rofecoxib would significantly reduce postendodontic pain, when compared with ibuprofen or placebo. An additional objective was to establish if any relationship exists between periapical diagnosis and the need for additional medication after completion of pulpectomy. A total of 45 patients consented to a double-blind, single-dose oral administration of 50 mg of rofecoxib, 600 mg of ibuprofen, or a placebo before conventional root canal therapy. The root canal treatment was performed in two appointments. Patient-reported visual analog scale ratings of pain intensity were conducted upon initial clinical presentation and at 4, 8, 12, 24, 48, and 72 h after completion of pulpectomy. Results showed that at the 4- and 8-h periods, both rofecoxib and ibuprofen provided significantly better pain relief than placebo. At the 12- and 24-h periods, rofecoxib demonstrated significantly better pain relief than both ibuprofen and placebo. Patients with a periapical diagnosis of acute apical periodontitis showed a significantly increased need for additional medication after completion of pulpectomy compared with all other periapical diagnoses.",2003.0,0,0
228,12551863,Selective COX-2 inhibition improves endothelial function in coronary artery disease.,Rémy Chenevard; David Hürlimann; Markus Béchir; Frank Enseleit; Lukas Spieker; Matthias Hermann; Walter Riesen; Steffen Gay; Renate E Gay; Michel Neidhart; Beat Michel; Thomas F Lüscher; Georg Noll; Frank Ruschitzka,"There is an ongoing debate as to whether the gastrointestinal safety of COX-2 inhibition compared with nonsteroidal antiinflammatory drugs (NSAIDs) may come at the cost of increased cardiovascular events. In view of the large number of patients at cardiovascular risk requiring chronic analgesic therapy with COX-2 inhibitors for arthritic and other inflammatory conditions, the effects of selective COX-2 inhibition on clinically useful surrogates for cardiovascular disease, particularly endothelial function, need to be determined. Fourteen male patients (mean age, 66+/-3 years) with severe coronary artery disease (average of 2.6 vessels with stenosis >75%) undergoing stable background therapy with aspirin and statins were included. The patients received celecoxib (200 mg BID) or placebo for a duration of 2 weeks in a double-blind, placebo-controlled, crossover fashion. After each treatment period, flow-mediated dilation of the brachial artery, high-sensitivity C-reactive protein, oxidized LDL, and prostaglandins were measured. Celecoxib significantly improved endothelium-dependent vasodilation compared with placebo (3.3+/-0.4% versus 2.0+/-0.5%, P=0.026), whereas endothelium-independent vasodilation, as assessed by nitroglycerin, remained unchanged (9.0+/-1.6% versus 9.5+/-1.3%, P=0.75). High-sensitivity C-reactive protein was significantly lower after celecoxib (1.3+/-0.4 mg/L) than after placebo (1.8+/-0.5 mg/L, P=0.019), as was oxidized LDL (43.6+/-2.4 versus 47.6+/-2.6 U/L, P=0.028), whereas prostaglandins did not change. This is the first study to demonstrate that selective COX-2 inhibition improves endothelium-dependent vasodilation and reduces low-grade chronic inflammation and oxidative stress in coronary artery disease. Thus, selective COX-2 inhibition holds the potential to beneficially impact outcome in patients with cardiovascular disease.",2003.0,0,0
229,12553505,Prophylaxis of heterotopic ossification after total hip arthroplasty: a prospective randomized study comparing indomethacin and meloxicam.,Thomas Barthel; Bernd Baumann; Ulrich Nöth; Jochen Eulert,"We performed a randomized, prospective study on the prophylaxis of heterotopic ossification (HO) after total hip arthroplasty (THR), comparing indomethacin and the selective COX-2 inhibitor meloxicam. From the day after surgery, 272 patients were treated with 7.5 mg meloxicam, 15 mg meloxicam, or 2 x 50 mg indomethacin a day, for 14 days. After 6 months, radiographs of patients treated with 7.5 mg meloxicam showed that HO had occurred in one third. This treatment was therefore stopped after 26 patients have been assigned to this group. According to the intention-to-treat principle, patients given 15 mg meloxicam developed HO in 25% (20% Brooker grade I, 4% grade II and 1% grade III) and those given indomethacin in 10% (7% Brooker grade I, 1% grade II and 2% grade III), a statistically significant difference.",2003.0,0,0
230,12557133,Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use.,Loren Laine; Laurine G Connors; Alise Reicin; Christopher J Hawkey; Ruben Burgos-Vargas; Thomas J Schnitzer; Qinfen Yu; Claire Bombardier,"Epidemiologic studies suggest nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for lower gastrointestinal (GI) clinical events, but data from prospective trials are lacking. Cyclooxygenase (COX)-2-selective inhibitors decrease upper GI clinical events but the effect on lower GI events has not been determined. We performed a post hoc analysis of serious lower GI clinical events with a nonselective NSAID and a COX-2-selective agent in a prospective, double-blind, randomized GI outcomes trial. A total of 8076 rheumatoid arthritis patients 50 years or older (or 40 years or older on corticosteroid therapy) expected to require NSAIDs for 1 year or greater were randomly assigned to naproxen 500 mg twice daily or rofecoxib 50 mg daily. The rate of serious lower GI clinical events, defined as bleeding with a 2 g/dL drop in hemoglobin or hospitalization, or hospitalization for perforation, obstruction, ulceration, or diverticulitis, was determined. The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen (relative risk, 0.46; 95% confidence interval [CI], 0.22-0.93; P = 0.032). Serious lower GI events accounted for 39.4% of all serious GI events (complicated upper GI event or lower GI event) among patients taking naproxen and 42.7% among those taking rofecoxib. Serious lower GI events occurred at a rate of 0.9% per year in rheumatoid arthritis patients taking the nonselective NSAID naproxen, accounting for nearly 40% of the serious GI events that developed in these patients. Serious lower GI events were 54% lower with the use of the selective COX-2 inhibitor rofecoxib.",2003.0,0,0
231,12562444,"Review article: NSAIDs, gastroprotection and cyclo-oxygenase-II-selective inhibitors.",R Micklewright; S Lane; W Linley; C McQuade; F Thompson; N Maskrey,"In patients at high risk of NSAID-associated serious upper gastrointestinal complications, gastroprotection with misoprostol or a proton pump inhibitor should be considered. Only misoprostol, 800 micro g/day, has been shown to reduce serious upper gastrointestinal complications in a large clinical outcome trial. The benefit of Helicobacter pylori eradication in reducing NSAID-associated gastrointestinal toxicity is controversial, and routine testing for and eradication of H. pylori in NSAID users are not currently advised. The gastrointestinal safety of rofecoxib and celecoxib has been assessed in large clinical outcome trials which, on first analysis, show benefits over non-selective NSAIDs in the incidence of serious upper gastrointestinal complications. However, longer term gastrointestinal data from the celecoxib study (CLASS) and cardiovascular adverse event data from the rofecoxib study (VIGOR) have questioned the risk-benefit profile of these new drugs and, until they are better understood, it seems sensible not to use them routinely in large numbers of individuals. The gastrointestinal safety of meloxicam and etodolac has not been adequately assessed in such trials. Therefore, evidence for their use instead of non-selective NSAIDs, or instead of celecoxib or rofecoxib, is not robust.",2003.0,0,0
232,12580988,Safety profile of rofecoxib as used in general practice in England: results of a prescription-event monitoring study.,Deborah Layton; Jane Riley; Lynda V Wilton; Saad A W Shakir,"A postmarketing Prescription-Event Monitoring study was undertaken to monitor the safety of rofecoxib, a cyclo-oxygenase (COX)-2 selective inhibitor prescribed in primary care in England. Questionnaires requesting clinical event data were sent to prescribing physicians between February and November 2000, and the data analysed for all events. There were 15,268 patients identified, mean age 62 years, 67% female. The commonest specified indication was osteoarthritis (24%). Dyspepsia and nausea were the most frequently reported adverse events. A history of dyspeptic or upper gastrointestinal (GI) conditions, recent use of other nonsteroidal anti-inflammatory drugs (NSAIDs), use of selected concomitant gastroirritant drugs (NSAIDs, aspirin, anticoagulants, antiplatelet drugs), or gastroprotective drugs (misoprostol, antacids, proton-pump inhibitors, histamine-2 antagonists), and age (>/= 65 years) modified the risk of having minor GI events. During treatment or within 1 month of stopping, 110 serious GI events were reported (including 76 upper GI bleeds/peptic ulcers, one perforated colon), 101 thromboembolic events, three reports of acute renal failure, one each of Stevens-Johnson syndrome, severe anaphylaxis and angio-oedema. Doctors should continue to prescribe NSAIDs including COX-2 selective inhibitors with caution.",2003.0,0,0
233,12588209,Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly.,Muhammad Mamdani; Paula Rochon; David N Juurlink; Geoffrey M Anderson; Alex Kopp; Gary Naglie; Peter C Austin; Andreas Laupacis,"Recent debate has emerged regarding the cardiovascular safety of selective cyclooxygenase 2 inhibitors and the possible cardioprotective effect of naproxen sodium. We compared the rates of acute myocardial infarction (AMI) among elderly patients dispensed selective cyclooxygenase 2 inhibitors, naproxen, and nonselective nonnaproxen nonsteroidal anti-inflammatory drugs (NSAIDs). We conducted a population-based retrospective cohort study using administrative health care data from Ontario, Canada, from April 1, 1998, to March 31, 2001. We identified NSAID-naive cohorts of subjects aged 66 years and older in whom treatment was initiated with celecoxib (n = 15 271), rofecoxib (n = 12 156), naproxen (n = 5669), and nonnaproxen nonselective NSAIDs (n = 33 868), along with a randomly selected control cohort not exposed to NSAIDs (n = 100 000). Multivariate Cox proportional hazards models were used to compare AMI rates between study drug groups while controlling for potential confounders. Relative to control subjects, the multivariate model showed no significant differences in AMI risk for new users of celecoxib (adjusted rate ratio [aRR], 0.9; 95% confidence interval [CI], 0.7-1.2), rofecoxib (aRR, 1.0; 95% CI, 0.8-1.4), naproxen (aRR, 1.0; 95% CI, 0.6-1.7), or nonnaproxen nonselective NSAIDs (aRR, 1.2; 95% CI, 0.9-1.4). The findings of this observational study suggest no increase in the short-term risk of AMI among users of selective cyclooxygenase 2 inhibitors as commonly used in clinical practice. Furthermore, the findings do not support a short-term reduced risk of AMI with naproxen.",2003.0,0,0
234,12620950,The difficulties of ambulatory interscalene and intra-articular infusions for rotator cuff surgery: a preliminary report.,Stephen M Klein; Susan M Steele; Karen C Nielsen; Ricardo Pietrobon; David S Warner; Aliki Martin; Roy A Greengrass,"Rotator cuff repair may result in severe postoperative pain. We compared a continuous intra-articular infusion to a continuous interscalene block with ropivacaine for patients undergoing outpatient rotator cuff repair. Seventeen patients were randomized to one of two groups: 1) interscalene block with 0.5% ropivacaine (40 mL) followed by a postoperative intra-articular infusion or; 2) interscalene block with 0.5% ropivacaine (40 mL) followed by a postoperative continuous interscalene infusion. Infusions were 0.2% ropivacaine at 10 mL x hr(-1) for both groups. Infusions were maintained for 48 hr. Patients were discharged on the day of surgery. Verbal analogue pain scores (VAS) and postoperative oxycodone consumption were measured for 48 hr. Eight patients (47%; four in each group) had side effects or logistical problems complicating care. The mean VAS scores at rest and with movement in the postanesthesia care unit and at 12 hr, 24 hr, and 48 hr were not different (P > 0.1). Inadequate analgesia was reported in 50-75% of all study patients. Time until first oxycodone use was similar between groups 829 min +/- 432 (interscalene) and 999 min +/- 823 (intra-articular; P = 0.6). Total oxycodone consumption was also similar 49 mg +/- 48 and 59 mg +/- 51 (P = 0.7), respectively. This study demonstrates the difficulties of ambulatory interscalene and intra-articular infusion for rotator cuff surgery. The high VAS scores and need for additional medical care suggest that intra-articular administration may not be reasonable for this magnitude of surgery. Further refinement of the perineural local anesthetic infusion is necessary to consistently provide analgesia after ambulatory rotator cuff surgery.",2003.0,0,0
235,12635906,Testing for interaction in studies of noninferiority.,Brian L Wiens; Joseph F Heyse,"We consider the role of interaction tests in the context of active-controlled clinical trials that aim to demonstrate the noninferiority of an experimental treatment compared to a standard (control) treatment. When the subjects can be grouped into strata (e.g., study sites, gender, race, etc.), there may be a desire to determine whether the experimental treatment is noninferior to the standard in each of the strata. We present five possible analysis strategies to test for heterogeneity of relative treatment effects among strata. These strategies are either identical to or straightforward modifications of strategies that can be used to test for interaction when the objective of the study is to show differences rather than noninferiority. The various analysis strategies implicitly depend on different definitions of interaction. Power of the various tests will be low, a phenomenon that often occurs when testing for interaction. We present simulation results to quantify the power and type I error rates under different scenarios and an example to demonstrate the proposed tests. None of the analysis strategies is best under every parameter configuration. The tests may be best used in a descriptive or exploratory manner. Extensions to two-sided equivalence testing are also discussed.",2003.0,0,0
236,12639178,Effect of cyclooxygenase-2 inhibitors on blood pressure.,Deanna L Johnson; Tina M Hisel; Beth Bryles Phillips,"To evaluate the effect of cyclooxygenase-2 selective inhibitors (CSIs) on blood pressure. Clinical literature accessed through MEDLINE (1966-May 2002). Key search terms included COX-2 selective inhibitors; anti-inflammatory agents, nonsteroidal; celecoxib; rofecoxib; and hypertension. Data from prospective studies on the effects of CSIs on blood pressure are conflicting. Several studies have reported increased blood pressure as an adverse effect of CSIs. Additional studies are needed to evaluate the effects of CSIs on blood pressure. CSIs should be used with caution in hypertensive patients and blood pressure monitored closely if a CSI is indicated.",2003.0,0,0
237,12641865,"The cost-effectiveness of acetaminophen, NSAIDs, and selective COX-2 inhibitors in the treatment of symptomatic knee osteoarthritis.",Celia C Kamath; Hilal Maradit Kremers; David J Vanness; W Michael O'Fallon; Rosa L Cabanela; Sherine E Gabriel,"The objective of this study was to conduct an economic evaluation of rofecoxib and celecoxib compared with high-dose acetaminophen or ibuprofen with and without misoprostol for patients with symptomatic knee osteoarthritis (OA). A decision analysis model was designed over 6 months using two measures of effectiveness: 1) number of upper gastrointestinal (GI) adverse events averted; and 2) number of patients who achieved perceptible pain relief. Separate analyses were conducted for all patients and for those who did not respond to acetaminophen. Outcome probabilities were obtained from a comprehensive review of randomized controlled trials and observational studies. Costs were derived from actual resource utilization of OA patients. In terms of averting GI events, acetaminophen dominates the other options for an average risk patient population. For patients who did not respond to acetaminophen, rofecoxib had the lowest incremental cost-effectiveness ratio (ICER) per GI event avoided (32,000 US dollars) relative to ibuprofen. In terms of pain control, ibuprofen had an ICER of 610.77 US dollars per additional patient achieving minimal perceptible clinical improvement (MPCI) relative to acetaminophen, while rofecoxib had an ICER of 12,000 US dollars relative to ibuprofen. For patients who did not respond to acetaminophen and who are at high risk of developing an adverse GI event, rofecoxib dominates ibuprofen as the preferred alternative for both measures of effectiveness. One-way, two-way, and probabilistic sensitivity analyses established that these results were generally robust. Our results suggest that for average-risk knee OA patients, acetaminophen dominates the other therapies in terms of cost per GI event averted. In terms of pain relief, cost-effectiveness acceptability curves indicate that if one values pain relief below 275 US dollars per patient achieving MPCI, acetaminophen is the therapy most likely to be optimal; between 275 US dollars and 14,150 US dollars, ibuprofen is most likely to be optimal; and above 14,150 US dollars, rofecoxib is most likely to be optimal.",2003.0,0,0
238,12653769,The selective cyclooxygenase-2 inhibitor rofecoxib may improve the treatment of chronic idiopathic urticaria.,W-H Boehncke; R J Ludwig; T M Zollner; F Ochsendorf; R Kaufmann; B F Gibbs,,2003.0,0,0
239,12655261,Effects of selective COX-2 inhibitors on the gastric permeability of sucrose: a controlled study with placebo and ibuprofen.,Meltem Ekenel; Erol Avşar; Neşe Imeryüz; Meral Yüksel; Goncagül Haklar; Ozan Kocakaya; Nurdan Tözün,"Acute and chronic use of non-steroidal anti-inflammatory drugs can increase gastrointestinal permeability. Celecoxib, which selectively inhibits the enzyme cyclooxygenase-2, is a novel anti-inflammatory drug with minimal gastrointestinal toxic effects while retaining anti-inflammatory efficacy. Our aim was to assess the potential effects of celecoxib on gastric permeability in comparison with placebo and ibuprofen. We conducted a prospective, double-blind, cross-over study. This study is carried out at Marmara University Hospital. Twenty-five healthy subjects entered the study but 19 subjects completed the treatment. Subjects were randomized to celecoxib 100 mg twice daily, ibuprofen 600 mg twice daily or placebo for 7 days in pre-defined sequences. Treatments were separated by a 7 day washout period. Gastric permeability was assessed by measuring urinary excretion of sucrose spectrophotometrically. Ibuprofen 600 mg twice daily produced greater increases in gastric permeability compared with placebo or celecoxib (geometric mean of urinary sucrose recovery was 59.15, 32.65 and 33.11 mg/h for ibuprofen, placebo and celecoxib, respectively) (P < 0.001). Celecoxib was generally better tolerated than ibuprofen. When compared with ibuprofen, celecoxib 100 mg twice daily has no significant effect on gastric mucosa in healthy subjects.",2003.0,0,0
240,12659372,Toxic epidermal necrolysis due to administration of celecoxib (Celebrex).,Pierre Giglio,,2003.0,0,0
241,12664317,Indomethacin versus meloxicam for prevention of heterotopic ossification after total hip arthroplasty.,Robert Legenstein; Peter Bösch; Alfred Ungersböck,"Heterotopic ossification (HO) is a recognized postsurgical complication after total hip arthroplasty. Brooker et al. [6] established a grading system to define the degree of HO. The results of several studies have shown that non-steroidal anti-inflammatory drugs (NSAID) and radiation therapy reliably reduce the occurrence of severe HO. The exact cause and mechanism of bone formation are not known. The efficacy of indomethacin versus meloxicam for the prevention of heterotopic periarticular ossification and clinical NSAID side-effects after primary, cementless total hip arthroplasty was evaluated. Probands underwent cementless total hip replacements at the Orthopaedic Department, Hospital Wiener Neustadt, from January 1997 to January 1998, did not take NSAID up to 4 weeks preoperatively and had no NSAID contraindications. Patients were separated into two groups by different hospitalisation floors. All patients selected for this study suffered from primary or secondary coxarthrosis. Data were collected as a prospective, randomised, parallel group study. Patients were given 50 mg indomethacin 2 times daily ( n=58) vs 7.5 mg meloxicam ( n=58) in a 12-day treatment course. A two-sided Cochran-Armitage trend test showed no statistically significant difference ( p<0.05) for one of the drugs regarding influence on ectopic bone formation according to the grading system of Brooker et al. Our study demonstrates that there is no statistically significant trend that indomethacin or meloxicam protects a hip arthroplasty better from heterotopic bone formation. We prefer indomethacin therapy because it is almost half the price of meloxicam therapy, and we recommend indomethacin in a 12-day treatment course given 50 mg 2 times daily as an effective, inexpensive and easily administered HO prophylaxis.",2003.0,0,0
242,12668898,Prevention and treatment of reactions to NSAIDs.,Ronald A Simon,"Avoidance of ASA and other NSAIDs prevents the reactions and careful attention to clinical history along with patient education are important. However, blanket advice to avoid all NSAIDs is no longer reasonable. Except for AERD and chronic urticaria, cross-reactivity with other NSAIDs does not occur. A physician can definitively prove this by giving the patient another NSAID in their office and observing no reaction. Furthermore, for patients with AERD and chronic urticaria, they can be given the new selective COX-2 inhibitors (rofecoxib and celecoxib) without any cross-reactivity. All AERD patients can be desensitized to ASA and treated with ASA indefinitely. However, ASA desensitization in chronic urticaria is not possible. Underlying mild and moderate AERD responds well to topical and systemic corticosteroids and leukotriene modifiers. However, the severe forms of the disease should be desensitized to ASA and treated with this drug on a long term basis. In the future, new drugs that prevent eosinophil activation and chemotaxis or enhance eosinophil apoptosis are likely to be useful. Specific blockers of the second cystLT receptor would also be useful. Ultimately as the genetics of these heterogeneous disorders are unraveled, gene substitution therapy may be the ultimate answer.",2003.0,0,0
243,12678570,Modelling therapeutic strategies in the treatment of osteoarthritis: an economic evaluation of meloxicam versus diclofenac and piroxicam.,Manouche Tavakoli,"To assess the economic efficiency of meloxicam, a cyclo-oxygenase (COX)-2 selective inhibitor, versus diclofenac and piroxicam in the UK for the treatment of patients with osteoarthritis and the impact on the NHS budget of substituting nonselective NSAIDs with meloxicam. Methods and perspective: A decision analytical model was used to compare the effects of 4 weeks' treatment of osteoarthritis with meloxicam (7.5 mg/day), diclofenac (100 mg/day) and piroxicam (20 mg/day). The decision tree was derived by combining best practice and clinical reality. Analysis was from the NHS perspective. The study considered only the direct costs. These included costs for drug acquisition and management of all adverse events, both serious gastrointestinal events requiring hospitalisation, and non-serious events that required maintenance. Resource use and treatment costs were obtained from local and published sources. A range of sensitivity analyses was carried out. Based on two 4-week large-scale trials, the Meloxicam Large-scale International Study Safety Assessment (MELISSA) and Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trials, and a decision analytical model, the findings suggested that meloxicam had the lowest cost per patient ( pound 30 versus pound 35 for piroxicam and pound 51 for diclofenac [costs presented as 1998 values except for drug costs which were in 2000 values]). The results of the Monte Carlo probabilistic sensitivity analysis, using 4000 samples, suggested that meloxicam was the optimal strategy in the drug treatment of patients with osteoarthritis compared with nonselective NSAIDs both individually and as a group. The cost savings were due to lower levels of serious adverse events accompanied by fewer days in intensive care units and shorter overall duration of hospital stay observed with meloxicam compared with diclofenac and piroxicam in the 4-week trials. Based on the 4-week trial period, meloxicam was predicted to be the lowest cost drug therapy, and thus the optimal drug therapy, in the management of patients with osteoarthritis compared with nonselective NSAIDs such as diclofenac and piroxicam. Applying the cost savings per patient derived from the model, switching patients from piroxicam and diclofenac to meloxicam would indicate a cost saving of over pound 25 million per annum. Models such as this can facilitate better clinical guidance and is a useful way of assessing treatment outcomes.",2003.0,0,0
244,12701989,"Chemoprevention of colorectal cancer: slow, steady progress.",Carol A Burke; William M Bauer; Bret Lashner,"In population-based observational studies, people had lower rates of colorectal cancer if they were taking various agents, including nonsteroidal anti-inflammatory drugs, calcium, and folate. In placebo-controlled trials in patients with familial adenomatous polyposis and in patients with sporadic colon adenomas, nonsteroidal anti-inflammatory drugs reduced the rates of adenomas, and there is a biologic rationale that they would be effective in reducing colorectal cancer as well. Randomized trials of chemopreventive agents are underway in the general population.",2003.0,0,0
245,12707572,Disease-modifying antirheumatic drug therapy for spondyloarthropathies: advances in treatment.,Philip J Mease,"The inflammatory arthritides included in the category of spondyloarthropathy (ankylosing spondylitis, psoriatic arthritis, reactive arthritis, undifferentiated spondyloarthropathy, and arthritis associated with inflammatory bowel disease) may cause significant, progressive morbidity. Therapy with nonsteroidal antiinflammatory drugs and traditionally used disease-modifying antirheumatic drugs, such as methotrexate, often fails in patients with more severe peripheral arthropathy and axial involvement, and alternative treatment options have been limited. With increased understanding of the pathologic processes involved in these disorders, new therapeutics have arisen and are being investigated in the various subtypes of spondyloarthropathy. This article reviews recent progress in disease-modifying therapy for spondyloarthropathy, including new biologic response modifiers, such as the tumor necrosis factor-alpha inhibitors etanercept and infliximab.",2003.0,0,0
246,12720115,The effect of postsurgical administration of a selective cyclo-oxygenase-2 inhibitor on the healing of intrabony defects following treatment with enamel matrix proteins.,Anton Sculean; Mohammad Berakdar; Nicolaos Donos; Thorsten M Auschill; Nicole B Arweiler,"Regenerative treatment with enamel matrix proteins (EMD) has been shown to promote regeneration in intrabony periodontal defects. However, up to now various postoperative regimens such as the routine administration of nonsteroidal anti-inflammatory drugs (NSAIDs) were often used in combination with enamel matrix proteins. Therefore, it cannot be excluded that the results might have been influenced by the effect of the postoperative medication. The aim of this randomized, controlled, blinded, clinical investigation was to determine the effect of postsurgical administration of a selective cyclo-oxygenase-2 inhibitor on the healing of intrabony periodontal defects following regenerative periodontal surgery with EMD. Twenty two patients, each of whom exhibited one deep intrabony defect, were randomly treated with either EMD plus a selective cyclo-oxygenase-2 (COX-2) inhibitor (test) or with EMD alone (control). The postoperative regimen consisted of oral administration of 12.5 mg rofecoxib twice daily for 14 days. The following parameters were recorded at baseline and at 6 months by the same calibrated and blinded investigator: plaque index (Pl), gingival index (GI), bleeding on probing (BOP), pocket depth (PD), gingival recession (GR), and clinical attachment level (CAL). Power analysis to determine superiority of the anti-inflammatory treatment showed that the available sample size would yield 70% power to detect a 1 mm difference. No statistical significant differences in any of the investigated parameters between the two groups were observed at baseline. The results show that, in the test group, mean PD decreased from 8.7+/-1.4 mm to 4.7+/-2.0 mm (P<0.001) and mean CAL from 9.7+/-2.0 mm to 6.5+/-2.1 mm (P<0.001). In the control group, mean PD decreased from 8.6+/-1.6 mm to 4.7+/-1.8 mm (P<0.001) and mean CAL from 9.5+/-1.6 mm to 6.5+/-2.2 mm (P<0.001). There were no significant differences between the two groups in any of the investigated parameters. Within the limits of the present study, it can be concluded that the systemic administration of a selective COX-2 inhibitor following regenerative periodontal surgery with EMD did not result in additional clinical improvements when compared to treatment with EMD alone.",2003.0,0,0
247,12734151,Prior ibuprofen exposure does not augment opioid drug potency or modify opioid requirements for pain inhibition in total hip surgery.,Marian L T Bugter; Ris Dirksen; Khem Jhamandas; Robert Slappendel; Eric W G Weber; Brian Milne,"In previous animal studies, a prior exposure to non-steroidal anti-inflammatory drugs (NSAID) augmented opioid drug potency. This study was designed to answer the question whether a similar effect can be attained in man. The objective was to use NSAID for preoperative pain reduction and at the same time use the NSAID exposure to reduce opioid requirements for pain inhibition in major orthopedic surgery. In this double-blind, randomized study, 50 patients scheduled for total hip surgery were included. Patients of Group I received a placebo drug three times a day two weeks before surgery, and those allocated to Group II received ibuprofen (600 mg) three times a day. For surgical anesthesia, all patients received intrathecal bupivacaine 20 mg plus 0.1 mg morphine in a total volume of 4 mL. The preoperative or postoperative visual analogue scale pain scores or the amount of iv morphine showed no differences between the two groups in the first 24 hr after surgery. The median total blood loss in the ibuprofen group was 1161 mL vs 796 mL in the placebo group (P < 0.01). Pretreatment with ibuprofen before major hip surgery does not improve the pain scores or reduce morphine requirement but significantly increases blood loss. Considering the presence of relevant adverse effects, pretreatment with a non-selective NSAID is not recommended.",2003.0,0,0
248,12737768,What is the best NSAID regimen for arthritis patients with bleeding ulcer?,Eric A Jackson,,2003.0,0,0
249,12740337,"Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre, randomised, double blind study.",C J Hawkey; L Laine; T Simon; H Quan; S Shingo; J Evans; Rofecoxib Rheumatoid Arthritis Endoscopy Study Group,"Previous studies in patients with osteoarthritis have suggested that the selective cyclooxygenase (COX)-2 inhibitor rofecoxib results in less gastrointestinal damage than non-selective non-steroidal antiinflammatory drugs (NSAIDs). This study compared the incidence of endoscopically detected gastroduodenal ulcers in rheumatoid arthritis patients treated with rofecoxib or a non-selective NSAID. In this multicentre, randomised, double blind, 12 week study, patients with rheumatoid arthritis were allocated to rofecoxib 50 mg once daily (n=219), naproxen 500 mg twice daily (n=220), or placebo (n=221). Endoscopy was performed at baseline and at six and 12 weeks. Lifetable analysis and log rank tests were used to analyse the incidence of gastroduodenal ulcers > or =3 mm. Gastric or duodenal ulcers > or =5 mm and erosions were also evaluated as secondary end points. Tolerability was assessed by adverse events. The cumulative incidence of ulcers > or =3 mm at 12 weeks was significantly higher in patients on naproxen (25.5%) than in patients receiving rofecoxib (6.8%; difference 18.7% (95% confidence interval (CI) 11.7%, 25.7%); p<0.001) or placebo (2.9%; difference 22.6% (95% CI 16.1%, 29.1%); p<0.001). The difference between rofecoxib (6.8%) and placebo (2.9%) did not reach statistical significance (p=0.066). Results were similar for ulcers > or =5 mm and for mean changes from baseline in the number of gastroduodenal erosions. The overall incidence of clinical adverse events was similar among treatment groups (61% of patients on placebo, 62% in patients on rofecoxib, and 66% in patients on naproxen). Rofecoxib 50 mg daily (twice the dose recommended for this patient population) resulted in a lower incidence of endoscopically detected gastroduodenal ulcers and erosions than treatment with naproxen 500 mg twice daily.",2003.0,1,1
250,12742818,NSAIDs and hypertension.,Paul S Aisen; Kimberly Schafer; Michael Grundman; Ronald Thomas; Leon J Thal,,2003.0,0,0
251,12747281,Rofecoxib exerts no effect on platelet plug formation in healthy volunteers.,M Homoncik; M Malec; C Marsik; T Sycha; S Anzenhofer; B Gustorff; B Jilma,"Although rofecoxib has very high selectivity for cyclo-oxygenase 2 (COX-2), supratherapeutic rofecoxib concentrations (> 1000 mg) inhibit purified human COX-1 in vitro and TXB2 formation in vivo. It is therefore possible that higher doses of rofecoxib may affect platelet function. This could be important if rofecoxib is given to thrombocytopenic patients. In these cases, already moderate inhibition of platelet function could precipitate bleeding complications. We therefore set out to investigate the influence of rofecoxib on platelet function in healthy volunteers. We set up a balanced-randomised, double-blind, placebo-controlled, two way cross-over study. Peripheral blood was withdrawn from 42 healthy volunteers before and 3 hours after intake of 50, 250, 500 mg of rofecoxib or placebo (n = 14 per group). Platelet function was assessed by a platelet function analyzer (PFA-100) which measures collagen-epinephrine induced closure time (CEPI-CT) under shear stress. CEPI-CT increased by 14% (p = 0.002) and 11% (p = 0.003) three hours after intake of placebo and rofecoxib at dosages of up to 500 mg, respectively. The increase in CEPI-CT versus baseline was not significantly different in the placebo period compared with the active treatment periods (n = 42, p > 0.05). Rofecoxib does not impair platelet function. Thus, rofecoxib appears to be a valuable analgetic and antipyretic agent in the therapy of patients at risk for bleeding.",2003.0,0,0
252,12749519,A model analysis of costs of blood pressure destabilization and edema associated with rofecoxib and celecoxib among older patients with osteoarthritis and hypertension in a Medicare Choice population.,Russell V Becker; Thomas A Burke; Mark A McCoy; Jeffrey P Trotter,"Economic analyses consider all costs relevant to the use of a particular treatment or treatments. Recently, head-to-head, randomized, controlled trials have shown a significantly higher incidence of blood pressure (BP) destabilization and clinically significant edema with rofecoxib than with celecoxib among older, hypertensive patients with osteoarthritis (OA). The objective of this analysis was to estimate the COX-2 specific inhibitor medication costs, in addition to the costs of drugs and physicians' fees, for BP destabilization and clinically significant edema associated with the use of rofecoxib 25 mg QD and celecoxib 200 mg QD in patients with OA and hypertension in a Medicare Choice population (aged > or = 65 years). A decision analysis model was constructed to determine the costs (from the payer's perspective) of treating patients in this population with either of the 2 regimens for 6 weeks. The analysis used pooled data from 2 recent, independently conducted, multicenter, double-blind, randomized, controlled trials of OA patients aged > or = 65 years with treated hypertension who received either celecoxib 200 mg QD or rofecoxib 25 mg QD for 6 weeks. In the individual trials, rofecoxib was associated with significantly higher rates of destabilized BP (P < 0.032 and P < 0.001) and edema (P < 0.01 and P = 0.045) than celecoxib. For a 100,000-member Medicare Choice population, an estimated 25,630 persons would have OA and hypertension (stages I-III), and an estimated 5126 of these patients would use celecoxib or rofecoxib. The estimated costs were 33,938 dollars (6.2%) higher if all hypertensive patients with OA were treated with rofecoxib rather than celecoxib for 6 weeks. The cost per day of use was 0.16 dollars less with celecoxib, and per-patient, per-month costs were 4.79 dollars lower. Celecoxib was a less costly treatment option than rofecoxib among OA patients with hypertension aged > or = 65 years, based on our model of the direct costs of COX-2 specific inhibitor therapy combined with those associated with physician monitoring and treatment of edema and BP destabilization.",2003.0,0,0
253,12750232,Point: From animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system.,Denis E Corpet; Fabrice Pierre,"The Apc(Min/+) mouse model and the azoxymethane (AOM) rat model are the main animal models used to study the effect of dietary agents on colorectal cancer. We reviewed recently the potency of chemopreventive agents in the AOM rat model (D. E. Corpet and S. Tache, Nutr. Cancer, 43: 1-21, 2002). Here we add the results of a systematic review of the effect of dietary and chemopreventive agents on the tumor yield in Min mice. The review is based on the results of 179 studies from 71 articles and is displayed also on the internet http://corpet.net/min.(2) We compared the efficacy of agents in the Min mouse model and the AOM rat model, and found that they were correlated (r = 0.66; P < 0.001), although some agents that afford strong protection in the AOM rat and the Min mouse small bowel increase the tumor yield in the large bowel of mutant mice. The agents included piroxicam, sulindac, celecoxib, difluoromethylornithine, and polyethylene glycol. The reason for this discrepancy is not known. We also compare the results of rodent studies with those of clinical intervention studies of polyp recurrence. We found that the effect of most of the agents tested was consistent across the animal and clinical models. Our point is thus: rodent models can provide guidance in the selection of prevention approaches to human colon cancer, in particular they suggest that polyethylene glycol, hesperidin, protease inhibitor, sphingomyelin, physical exercise, epidermal growth factor receptor kinase inhibitor, (+)-catechin, resveratrol, fish oil, curcumin, caffeate, and thiosulfonate are likely important preventive agents.",2003.0,0,0
254,12751271,"The COX-2 selective inhibitor, valdecoxib, does not impair platelet function in the elderly: results of a randomized controlled trial.",Philip T Leese; David P Recker; Jeffrey D Kent,"The effects of the new cyclooxygenase (COX)-2 selective inhibitor, valdecoxib (40 mg bid; n = 17), on platelet function were evaluated, along with ibuprofen (800 mg tid; n = 15) and placebo (n = 15), in healthy elderly subjects (65-85 years) in this 7.5-day, randomized, single-center, double-blind study. Platelet aggregation (to sodium arachidonate, collagen, and adenosine diphosphate), bleeding time, and serum thromboxane B2 (TxB2) concentrations were measured up to 8 hours postdose on Days 1 and 8. Valdecoxib had no platelet effects, while ibuprofen significantly decreased platelet aggregation, significantly increased bleeding time (2-4 h postdose on each day), and significantly decreased TxB2 levels at all time points. In conclusion, unlike ibuprofen, valdecoxib 40 mg bid spares platelet COX-1 function in healthy elderly subjects. Valdecoxib's lack of effect on platelet aggregation and bleeding time suggests that it will have an improved clinical profile over nonselective NSAIDs, particularly in patients for whom bleeding complications are a concern.",2003.0,0,0
255,12752071,Menorrhagia: an update.,M K Oehler; M C P Rees,"Menorrhagia is defined as a 'complaint of heavy cyclical menstrual bleeding occurring over several consecutive cycles'. Objectively it is a total menstrual blood loss equal to or greater than 80 ml per menstruation. It is estimated that approximately 30% of women complain of menorrhagia. Excessive bleeding is the main presenting complaint in women referred to gynecologists and it accounts for two-thirds of all hysterectomies, and most of endoscopic endometrial destructive surgery. Thus, menorrhagia is an important healthcare problem. Its etiology, investigation, medical and surgical management are described. In approximately 50% of cases of menorrhagia no pathology is found at hysterectomy. Abnormal levels of prostaglandins or the fibrinolytic system in the endometrium have been implicated. Effective medical treatments suitable for long-term use include intrauterine progestogens, antifibrinolytic agents (tranexamic acid) and nonsteroidal anti-inflammatory agents (mefenamic acid). Over the past decade there has been increasing use of endometrial destructive techniques as an alternative to hysterectomy. Their further refinement and the advent of fibroid embolization has increased the options available to women.",2003.0,0,0
256,12755551,The cost-effectiveness of cyclooxygenase-2 selective inhibitors in the management of chronic arthritis.,Brennan M R Spiegel; Laura Targownik; Gareth S Dulai; Ian M Gralnek,"Rofecoxib and celecoxib (coxibs) effectively treat chronic arthritis pain and reduce ulcer complications by 50% compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). However, their absolute risk reduction is small and the cost-effectiveness of treatment is uncertain. To determine whether the degree of risk reduction in gastrointestinal complications by coxibs offsets their increased cost compared with a generic nonselective NSAID. Cost-utility analysis. Systematic review of MEDLINE and published abstracts. Patients with osteoarthritis or rheumatoid arthritis who are not taking aspirin and who require long-term NSAID therapy for moderate to severe arthritis pain. Third-party payer. Naproxen, 500 mg twice daily, and coxib, once daily. Patients intolerant of naproxen were switched to a coxib. Lifetime. Incremental cost per quality-adjusted life-year (QALY) gained. Using a coxib instead of a nonselective NSAID in average-risk patients cost an incremental 275 809 dollars per year to gain 1 additional QALY. The incremental cost per QALY gained decreased to 55 803 dollars when the analysis was limited to the subset of patients with a history of bleeding ulcers. The coxib strategy became dominant when the cost of coxibs was reduced by 90% of the current average wholesale price. In probabilistic sensitivity analysis, if a third-party payer was willing to pay 150 000 dollars per QALY gained, then 4.3% of average-risk patients would fall within the budget. The risk reduction seen with coxibs does not offset their increased costs compared with nonselective NSAIDs in the management of average-risk patients with chronic arthritis. However, coxibs may provide an acceptable incremental cost-effectiveness ratio in the subgroup of patients with a history of bleeding ulcers.",2003.0,0,0
257,12760986,The efficacy of celecoxib premedication on postoperative pain and recovery times after ambulatory surgery: a dose-ranging study.,Alejandro Recart; Tijani Issioui; Paul F White; Kevin Klein; Mehernoor F Watcha; Louis Stool; Mary Shah,"Recently, the Food and Drug Administration increased the celecoxib dosage recommendation from 200 mg to 400 mg for acute pain management. No studies have directly compared the analgesic efficacy of different doses of celecoxib for the prevention of postoperative pain. In this prospective, double-blinded, placebo-controlled study, we compared oral celecoxib 200 mg to 400 mg when administered for premedication of outpatients undergoing minor ear-nose-throat surgery. A total of 93 healthy outpatients were assigned to 1 of 3 study groups: control (placebo; n = 30), celecoxib 200 mg (n = 30), or celecoxib 400 mg (n = 33). The study drug was given orally 30-45 min before surgery, and all patients received a standardized general anesthetic technique. During the postoperative period, pain scores (0-10), recovery times, the need for rescue analgesics, quality of recovery (0-100), patient satisfaction with pain management (0-100), and side effects were recorded. Pain was assessed at 30-min intervals using a verbal rating scale, with 0 = no pain to 10 = worst pain imaginable, in the postanesthesia care unit and day surgery unit recovery areas and at 24 h after surgery. Celecoxib 400 mg was significantly more effective than 200 mg (and placebo) in reducing postoperative pain. Both celecoxib 200 mg and 400 mg were more effective than placebo in reducing the postoperative fentanyl requirement (74 +/- 67 micro g and 56 +/- 62 micro g versus 120 +/- 86 micro g, respectively). The larger dose of celecoxib significantly reduced the percentage of patients with severe pain at discharge (6% versus 37% and 30% in the celecoxib 200 mg and control groups, respectively). The median number of doses of oral analgesic medication after discharge was also significantly reduced in the celecoxib 400 mg group (0 versus 2 and 2 in the celecoxib 200 mg and control groups, respectively). However, no differences were found among the three study groups with respect to recovery times and secondary outcome variables (e.g., patient satisfaction and quality of recovery). We conclude that oral premedication with celecoxib 400 mg was more effective than 200 mg in reducing severe postoperative pain and the need for rescue analgesic medication in the postoperative period. Oral premedication with celecoxib 400 mg was more effective than 200 mg in reducing postoperative pain and the need for rescue analgesic medication in the early postoperative period. However, neither dose of celecoxib was more effective than a placebo in facilitating the recovery process after outpatient surgery.",2003.0,0,0
258,12765488,Nonsteroidal anti-inflammatory agents in neonates.,John L Morris; David A Rosen; Kathleen R Rosen,"The use of NSAIDs has become routine for adults and children in the management of pain. NSAIDs (other than aspirin [acetylsalicylic acid]) are also enjoying greater popularity as antipyretics since the recognition of Reye's syndrome's putative association with aspirin. In neonates, NSAIDs have been used for many years in an attempt to pharmacologically close the ductus arteriosus. This review examines the various NSAIDs and their potential and real applications in the neonatal population. For completeness, acetaminophen (paracetamol), which has weak NSAID activity and is a widely used analgesic and antipyretic in this patient group, was also included. The prostaglandin system is important for healthy development, and conversely there are unique risks posed by pharmacologic interference with this system in the neonatal period. The prostanoid system in neonates has the capacity to modulate nociception, but comes at the expense of interfering with nearly every organ system. Physiologic effects of inhibition of prostaglandin synthesis applicable to neonates include disruption of the sleep cycle, increased risk of pulmonary hypertension, alterations in cerebral blood flow, decreased renal function, disrupted thermoregulation, and alterations in hemostasis balance, among others. Prostaglandins are also important for the normal development of the central nervous, cardiovascular, and renal systems, and there is evidence that the proper genesis of these systems may be adversely effected by NSAID exposure in utero and in the neonatal period. Gastrointestinal adverse effects have provided the impetus for the development and marketing of selective cyclo-oxygenase type 2 (COX-2) inhibitors. These agents' reputation for safety in adults may not be applicable to neonates. COX-2 is involved in the development of several organ systems, and its inhibition may induce a prothrombotic state. The advent of parenteral formulations of cyclo-oxygenase inhibitors, including COX-2-selective agents, increases the therapeutic flexibility of NSAIDs. However, objective data on the safety of these agents have not kept pace with their clinical availability.",2003.0,0,0
259,12768466,Systematic review for evaluation of tolerability of nonsteroidal antiinflammatory drugs in osteoarthritis patients in Japan.,Shinichi Uemura; Takahiro Ochi; Kentaro Sugano; Robert W Makuch,"To evaluate the gastrointestinal tolerability of nonsteroidal antiinflammatory drugs (NSAIDs) in osteoarthritis patients in Japan, a systematic review of Japanese randomized controlled trials was performed. This study consisted of double-blind, randomized, controlled clinical trials with 4-week NSAID treatment of osteoarthritis patients in Japan. The analysis included 4725 patients from 25 trials. On average the cumulative incidences of patients who had experienced any adverse reaction and any adverse digestive reaction were 14.3% [95% confidence interval (CI) 13.3%-15.3%] and 10.4% (95% CI 9.4%-11.4%), respectively. The cumulative incidence for the upper gastrointestinal (GI) symptoms such as abdominal pain, nausea/vomiting, and dyspepsia was estimated to be approximately 10.9%. When the risk of upper GI symptoms was compared between males and females, the summary odds ratio was 1.71 (95% CI 1.11-2.65). Comparing the risk of upper GI symptoms between patients 59 years of age and younger and those 60+ years old, the summary odds ratio was 1.07 (95% CI 0.75-1.52). Despite the incidence of adverse reactions varying across the drugs being used, there was an obvious increased risk of GI symptoms.",2003.0,0,0
260,12772009,Motion--Cyclo-oxygenase-2 selective nonsteroidal anti-inflammatory drugs are as safe as placebo for the stomach: arguments against the motion.,Andreas Maetzel,"Cyclo-oxygenase (COX) exists in two isoforms, COX-1 and COX-2, that direct the synthesis of prostaglandins, prostacyclin and thromboxane. Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both isoenzymes, resulting in damage to the mucosa of the stomach and duodenum, but also in cardioprotection. Selective COX-2 inhibitors are less likely to damage the upper gastrointestinal tract, as has been shown by large, randomized, controlled trials. Specifically, the newer agents are superior to ibuprofen and naproxen in this regard, but celecoxib and diclofenac were not significantly different in patients who were not also taking low-dose acetylsalicylic acid. These studies did not include a placebo arm, however, and controlled comparisons of COX-2 inhibitors with placebo have not enlisted enough subjects to demonstrate conclusively that they are equally safe. Selectivity for the COX-2 isoform affords protection against upper gastrointestinal toxicity possibly at the expense of the cardioprotective effect of traditional NSAIDs. This might explain the higher rate of nonfatal myocardial infarction in patients who are given rofecoxib compared with naproxen. A traditional NSAID, combined with either misoprostol or a proton pump inhibitor, is still a suitable alternative to selective COX-2 inhibitors for the treatment of arthritis.",2003.0,0,0
261,12774242,Cyclo-oxygenase 2 inhibitors: emerging roles in the gut.,J K Grover; S Yadav; V Vats; Y K Joshi,"Discovery of an isoform of Cyclo-oxygenase (COX) 1, the inducible COX-2, has made it possible to avoid some side effects of non-specific COX inhibitors. The COX-2 gene is over-expressed in reflux oesophagitis, Barrett's oesophagus, gastric and colon cancer, familial adenomatous polyposis, pancreatic cancer, hepatocellular carcinoma, hepatotoxicity, cirrhosis, and inflammatory bowel disease, and specific COX-2 inhibitors have been tried experimentally and clinically and found effective. A Medline search was performed of English-language experimental studies and controlled clinical trials from January 1980 to January 2002, and relevant citations were noted. Review of available literature shows that sulindac and COX-2 inhibitors are effective in preventing as well as regressing familial adenomatous polyposis. However, they have not been shown to prevent cancer in these patients. Studies evaluating NSAIDs and COX-2 inhibitors in carcinogen-induced and genetically manipulated animal models of various cancers have been promising especially in conditions such as Barrett's oesophagus, oesophageal and hepatocellular carcinoma and pancreatic cancer. COX-2 inhibitors may be of value in the treatment of reflux oesophagitis, pancreatitis and hepatitis, although carefully planned randomized controlled clinical trials demonstrating their efficacy need to be conducted. At present NSAIDs and COX-2 inhibitors cannot be recommended for average-risk individuals or for those with sporadic colorectal neoplasia (or other forms of cancers) as chemo-preventive agents. COX-2 inhibitors may open up a new therapeutic era in which these drugs can be used for chemo-prophylaxis. However, COX-2 selective inhibitors retain renal adverse effects of the non-selective inhibitors and the concern regarding the pro-thrombotic potential of COX-2 inhibitors will limit their value as chemo-preventive agents.",2003.0,0,0
262,12777194,A trial of adjuvant therapy in colorectal cancer: the VICTOR trial.,Stuart Pendlebury; Francesca Duchesne; Katharine A Reed; Justine L Smith; David J Kerr,,2003.0,0,0
263,12783912,Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial.,Paul S Aisen; Kimberly A Schafer; Michael Grundman; Eric Pfeiffer; Mary Sano; Kenneth L Davis; Martin R Farlow; Shelia Jin; Ronald G Thomas; Leon J Thal; Alzheimer's Disease Cooperative Study,"Laboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence the course of the disease. To determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD. Multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications. Forty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium. Participants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled. Once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo. The primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death). The 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group. The results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.",2003.0,0,0
264,12786631,,,,,0,0
265,12794781,The cost effectiveness of rofecoxib and celecoxib in patients with osteoarthritis or rheumatoid arthritis.,Andreas Maetzel; Murray Krahn; Gary Naglie,"To evaluate the cost effectiveness of the cyclooxygenase 2 (COX-2) selective nonsteroidal antiinflammatory drug (NSAID) rofecoxib compared with naproxen and the COX-2 NSAID celecoxib compared with ibuprofen and diclofenac. Cost-effectiveness analysis based on a 5-year Markov model. Probability estimates were derived from detailed data of 2 randomized trials and a systematic search of the medical literature. Utility estimates were obtained from 60 randomly selected members of the general public. Cost estimates were obtained from Canadian provincial databases. Incremental cost-effectiveness ratios were calculated for patients at average risk of upper gastrointestinal (UGI) events and for high-risk patients with a prior history of a UGI event. Subjects were patients with osteoarthritis or rheumatoid arthritis (RA) where a decision has been made to treat with NSAIDs but who do not require low-dose aspirin. Main outcome measures were proportion of patients with clinical or complicated UGI events, quality-adjusted life expectancy, and life expectancy. Evaluation of rofecoxib versus naproxen in patients with RA at average risk resulted in costs per quality-adjusted life year (QALY) gained of $Can271,188. Celecoxib was dominated by diclofenac in average-risk patients. Both rofecoxib and celecoxib are cost-effective in high-risk patients. Analyses by age groups and assuming a threshold of Can$50,000 per QALY gained, suggest that rofecoxib or celecoxib would be cost-effective in patients aged over 76 and 81, respectively, without additional risk factors. Both rofecoxib and celecoxib are economically attractive in high risk and elderly patients. They are not economically attractive in patients at average risk. Coprescription of proton-pump inhibitors with COX-2 NSAIDs is not economically attractive for patients at high risk.",2003.0,0,0
266,12797647,"Evaluation of efficacy, safety and tolerability of valdecoxib in osteo-arthritis patients--an Indian study.",S A Jagtap; Satish Lahoti; K Anwaruddin; S Ram; Chetna Ballary; Anish Desai,"Valdecoxib, a COX-2 inhibitor, has been introduced as a new treatment for osteo-arthritis (OA). The present study was conducted to evaluate the efficacy, safety and tolerability of valdecoxib, in OA patients in an Indian setting. The present 4-week study was a prospective, non-comparative, assessor blind, single group, multicentric trial with OA patients treated with valdecoxib, 10 mg once a day. Efficacy was assessed by analysing the changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analogue scale (VAS), patient's and physician's global assessment of arthritis. The incidence of adverse events was monitored throughout the study. There was a clinical and statistical significant improvement in the mean pain score, stiffness score, physical function, composite WOMAC index score and VAS (p<0.05). Patient's and physician's global evaluation of valdecoxib treatment was very good to good in 84.1% and 83.6% of cases respectively. The present study has shown that valdecoxib, in a dose of 10 mg/day given over 4 weeks, is an effective and safe treatment for the signs and symptoms of OA of hip and knee joints.",2003.0,0,0
267,12798395,Carcinogenesis and cyclooxygenase: the potential role of COX-2 inhibition in upper aerodigestive tract cancer.,Sivani Mohan; Joel B Epstein,"Cyclooxygenase-2 (COX-2) is upregulated in a number of epithelial cancers, including in upper aerodigestive tract (UADT) premalignant and malignant lesions. The purpose of this review is to provide a comprehensive examination of the potential of COX-2 inhibition in prevention of UADT premalignant and malignant disease. A Medline and Cancerlit literature search was conducted for the period 1993-2002, and identified literature was reviewed. There is evidence from in vitro studies, as well as animal models, that inhibition of COX-2 may suppress carcinogenesis by affecting a number of pathways of carcinogenesis, promoting apoptosis and inhibiting angiogenesis. Preliminary studies of gastro-intestinal (GI) carcinogenesis suggest that COX-2 inhibitors may represent an approach to the chemoprevention of epithelial cancers. COX-2 inhibitors may have a potential role in chemoprevention of UADT cancer, and clinical trials appear warranted.",2003.0,0,0
268,12800464,Etoricoxib in the treatment of chronic pain.,M R Duncan; H A Capell,"For the many patients who suffer chronic pain, we seek the most effective anti-inflammatory drug with the least side-effect profile and the greatest long-term safety. Etoricoxib, a selective COX2 inhibitor, has been shown to be as effective as non-selective non-steroidal anti-inflammatory drugs in the management of chronic pain in rheumatoid arthritis and osteoarthritis, for periods of up to one year. Data on etoricoxib efficacy in chronic low back pain is beginning to emerge. The side-effect profile of etoricoxib suggests it is well tolerated with similar adverse effects to non-selective NSAIDs. Larger studies are awaited, to see whether superior gastrointestinal tolerability can be proven. Further work will be required to show that etoricoxib is safe in patients with pre-existing cardiovascular or gastrointestinal comorbidity, and the potentially confounding role of aspirin still needs to be elucidated. However, etoricoxib shows promise as a new and effective COX2 inhibitor in clinical practice.",2003.0,0,0
269,12809852,Over-the-counter nonsteroidal anti-inflammatory drugs and risk of gastrointestinal symptoms.,Simren Sangha; Jaime A Oviedo,,2003.0,0,0
270,12810935,Current concepts and new developments in the treatment of psoriatic arthritis.,N Pipitone; G H Kingsley; A Manzo; D L Scott; C Pitzalis,"Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis with psoriasis. Many agents have been proposed for the treatment of PsA, but their use is based more on clinical experience than on sound scientific evidence. We reviewed MedLine up to November 2002, searching for 'psoriatic arthritis', 'drug therapy, 'controlled trials' and 'outcomes' and all possible acronyms for these terms. All relevant papers were then examined in detail. PsA is a condition that runs a variable clinical course. Mild forms can usually be controlled by non-steroidal anti-inflammatory drugs (NSAIDs). Intra-articular glucocorticoid injections are indicated in patients with persistent mono- or oligoarthritis. Patients with severe and progressive articular disease not responsive to NSAIDs should be treated with disease-modifying anti-rheumatic drugs (DMARDs) to prevent joint damage and disability. Currently, methotrexate and sulphasalazine are considered the DMARDs of choice, but the evidence for the use of methotrexate in PsA is still largely empirical, while the clinical benefit induced by sulphasalazine appears to be modest. Other DMARDs proposed for the treatment of PsA include cyclosporin, gold salts and, more recently, leflunomide. However, none of the DMARDs available to date are effective in the treatment of psoriatic pelvispondylitis; in addition, a number of patients with severe peripheral arthritis fail to respond to standard DMARDs. Recently, tumour necrosis factor alpha inhibitors have proved effective in many PsA patients with pelvispondylitis or recalcitrant peripheral synovitis. None of the current treatments for PsA is curative, but significant clinical amelioration can be achieved in the vast majority of patients. Identification and prompt treatment of patients with severe articular disease is crucial for the achievement of a satisfactory clinical response and the improvement of the long-term outcome.",2003.0,0,0
271,12810937,Valdecoxib is as effective as diclofenac in the management of rheumatoid arthritis with a lower incidence of gastroduodenal ulcers: results of a 26-week trial.,K Pavelka; D P Recker; K M Verburg,"To compare the efficacy and upper gastrointestinal (GI) safety of valdecoxib 20 and 40 mg daily with those of diclofenac 75 mg slow release (SR) twice daily in treating rheumatoid arthritis (RA). Seven hundred and twenty-two patients with adult-onset RA were enrolled into this 26-week, randomized, multicentre, double-blind, parallel-group study (246 in the valdecoxib 20 mg daily arm, 237 in the valdecoxib 40 mg daily arm and 239 in the diclofenac 75 mg SR daily arm). Acetylsalicylic acid use (< or =325 mg per day) was similar across all groups: 5.4% in the diclofenac group, 5.7% in the valdecoxib 20 mg group and 5.9% in the valdecoxib 40 mg group. Efficacy was measured by the Patient's Assessment of Arthritis Pain [visual analogue scale (VAS)] and the modified Health Assessment Questionnaire (mHAQ) at baseline and at weeks 2, 6, 8, 12, 18 and 26 of treatment, or at early termination. Upper GI safety was evaluated by endoscopy at the end of treatment, which took place no more than 2 days after the last dose of study medication or at early termination. Valdecoxib 20 and 40 mg daily were comparable to diclofenac 75 mg SR twice daily in treating the signs and symptoms of RA. No significant differences were observed between treatment groups with respect to mean changes from baseline in the Patient's Assessment of Arthritis Pain (VAS) or mHAQ. The incidence of gastroduodenal ulcers in patients receiving valdecoxib 20 mg daily (6%) and valdecoxib 40 mg daily (4%) was significantly lower (P < 0.001) than in patients receiving diclofenac 75 mg SR twice daily (16%). Valdecoxib 20 mg daily was also associated with significantly improved GI tolerability (P = 0.035) compared with diclofenac. Single daily doses of valdecoxib 20 and 40 mg provided efficacy comparable to that of diclofenac, with a superior upper GI safety profile in the long-term treatment of RA patients.",2003.0,1,1
272,12812401,Postoperative recovery and discharge.,Brid McGrath; Frances Chung,"Ambulatory surgery provides quality care that is cost-effective. The use of innovative surgical and anesthetic techniques will allow larger numbers of patients to take advantage of the benefits of undergoing an elective operation on an ambulatory basis. Anesthesiologists will be faced with more complex surgery, which will require careful selection and assessment of patients to ensure continuity of the excellent safety record of ambulatory anesthesia. Minor adverse events, such as pain and PONV, are still common. The occurrence of these minor adverse advents is now the major area of quality assessment and an area where improvement could be targeted. Fast tracking facilitates earlier discharge, but we must ensure this has benefit to the patient as speedy discharge may mask the true incidence of adverse minor symptoms. This can lead to patient dissatisfaction and a poor impression of ambulatory surgery.",2003.0,0,0
273,12814405,Recent randomised trials in colorectal disease.,A Chopada; I Taylor,Progress in colorectal surgery over the last few years is evident by the growing number of randomised controlled trials reported. We have scrutinised such trials reported over the last year across the entire spectrum of colorectal disease and have presented the significant findings in this trials report.,2003.0,0,0
274,12814613,Response relationship of VAS and Likert scales in osteoarthritis efficacy measurement.,J A Bolognese; T J Schnitzer; E W Ehrich,"Efficacy in osteoarthritis (OA) is principally measured using subjective visual analogue (VAS) and/or Likert scale responses. The relationship between these two scales and their relative precision in discriminating active from placebo treatment in OA patients was determined. Patient overall pain assessment, and patient and investigator global assessments were each measured on a 100mm VAS and on a 0 to 4 point Likert scale in a 6-week OA study of rofecoxib vs placebo. The relationship between the VAS and Likert responses was examined graphically and via summary statistics. Analysis of variance was used to assess consistency of the VAS/Likert relationship over time and across the different endpoints. Precision was compared using effect size, and normality of VAS scale of measurement was assessed using the Shapiro-Wilk test. Mean VAS scores and changes from baseline at individual time points were generally highly correlated with corresponding Likert responses (r-values generally approximately 0.7-0.8). The magnitude of VAS values and changes varied depending on endpoint, on the associated magnitude of increment of Likert score, and on the Likert baseline value (i.e., where on the Likert scale the change was occurring). Precision of VAS and Likert responses to detect difference between treatments was generally similar with effect sizes approximately 1. Normality and homogeneity of variance of VAS scores was most closely approximated by actual changes in comparison to percent change or log-transformed measures. VAS and Likert responses are highly correlated and yield similar precision for discriminating treatments in OA patients. Since Likert responses are easier to administer and interpret, they may be preferable to measure OA response.",2003.0,0,0
275,12819642,Antiplatelet therapy in peripheral arterial disease. Consensus statement.,Peripheral Arterial Diseases Antiplatelet Consensus Group,"Antiplatelet agents are commonly prescribed to reduce the risk of myocardial infarction, stroke and graft occlusion in patients with peripheral arterial disease (PAD). The objective was to summarise current evidence and provide recommendations on the use of antiplatelet agents in PAD. A consensus group was assembled including 20 specialists from a variety of fields involved in the management of patients with PAD. Data was circulated in a systematic manner prior to a main consensus meeting held in November 2001. The document subsequently produced was circulated within the group to ensure agreement in the interpretation and presentation of its findings. Consensus recommendations are provided in 7 common or contentious scenarios in PAD. The recommendations are graded to reflect the evidence available and interpretations of the group. Although the document provides recommendations, it is stressed that they must be interpreted in the light of individual patient circumstances. Antiplatelet agents have an important role in the management of patient with PAD. Although this document provides consensus recommendations, the optimum treatment in many scenarios remains unclear due to a lack of focussed clinical trials in PAD.",2003.0,0,0
276,12830070,Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery.,Elisabeth Ott; Nancy A Nussmeier; Peter C Duke; Robert O Feneck; R Peter Alston; Michael C Snabes; Richard C Hubbard; Ping H Hsu; Lawrence J Saidman; Dennis T Mangano; Multicenter Study of Perioperative Ischemia (McSPI) Research Group; Ischemia Research and Education Foundation (IREF) Investigators,"Inhibition of cyclooxygenase 2 provides analgesia in ambulatory patients. We prospectively evaluated the safety and efficacy of a newly introduced cyclooxygenase 2 inhibitor in patients undergoing coronary artery bypass grafting surgery through a median sternotomy in a randomized clinical trial. A total of 462 patients with New York Heart Association classes I to III who were less than 77 years of age and were from 58 institutions in the United States, Canada, Germany, and the United Kingdom participated in this multicenter, phase III, placebo-controlled, double-blind, randomized, parallel-group trial. Patients were allocated at a ratio of 2:1 to parecoxib/valdecoxib or standard care (control) groups, respectively. Intravenous study drug (40 mg) was administered within 30 minutes after extubation and every 12 hours for a minimum of 3 days. Subsequently, oral treatment at a dose of 40 mg every 12 hours was initiated and administered for a combined total of 14 days. Patient-controlled analgesia with morphine, oral opioids, or acetaminophen was available as required. Assessment of the analgesic efficacy of the study drug was primarily based on morphine and morphine equivalent use. Additional efficacy evaluations included daily pain intensity, patient and physician global evaluation of study medication, and pain effect on quality of life. Clinical adverse events were assessed by the principal investigator at each site from the time of the first dose through the 30-day postdosing period. Patients in the parecoxib/valdecoxib group received significantly less morphine or morphine equivalents than patients in the control group during the 0- to 24-hour (P =.009), 24- to 48-hour (P =.017), 72- to 96-hour (P =.002), 96- to 120-hour (P =.004), and 120- to 144-hour (P =.037) periods. Both patients (P <.001) and physicians (P <.001) evaluated the study medication as significantly better than control therapy. The modified Brief Pain Inventory questionnaire used in the oral dosing period detected significant improvements in the parecoxib/valdecoxib treatment group in 6 of 8 domains tested (eg, current pain, worst pain, and mood) beginning on day 4 and continuing for at least 4 days. Although there were no differences between the groups in overall adverse events, serious adverse events occurred twice as frequently in parecoxib/valdecoxib-treated patients (19.0%, 59/311 patients) than in control patients (9.9%, 15/151 patients; P =.015). Regarding individual serious adverse events, a greater incidence in sternal wound infection was found in the parecoxib/valdecoxib patients (10 [3.2%]) versus control patients (0 [0%]) (P =.035). The incidences of other individual serious adverse events, including cerebrovascular complications, myocardial infarction, and renal dysfunction, were proportionally greater but not significantly different between the groups. In patients undergoing coronary artery bypass grafting surgery, the cyclooxygenase 2 inhibitor combination, parecoxib/valdecoxib, was effective for postoperative analgesia. However, the 14-day treatment regimen also was associated with an increased incidence of serious adverse events overall and sternal wound infections in particular. Therefore our study raises important concerns requiring their comprehensive evaluation in a large-scale trial before these cyclooxygenase 2 inhibitors are used in patients undergoing coronary artery bypass grafting surgery.",2003.0,0,0
277,12838977,"Phase III clinical trials in oncology. 20-21 January 2003, London, UK.",Marc Buyse,,2003.0,0,0
278,12841921,Experience of rofecoxib in patients with osteoarthritis previously treated with traditional non-steroidal anti-inflammatory drugs in Spain: results of phase 2 of the VICOXX study.,Luis R Arboleya; Enrique de la Figuera; María Soledad García; Belén Aragón; VICOXX Study Group,"To compare patient and physician attitudes to osteoarthritis (OA) treatment with rofecoxib or traditional non-steroidal anti-inflammatory drugs (tNSAIDs). A 6-month prospective study involving 562 OA patients enrolled at 29 Spanish primary-care centres. Patients were continued on established tNSAID therapy for the first 3 months then switched to rofecoxib 12.5 or 25 mg/day. Both patients and physicians were significantly more likely to be satisfied with rofecoxib treatment than with tNSAIDs (p < 0.001) and assessments of overall health status improved significantly during rofecoxib therapy (p < 0.001). Adherence to therapy was significantly better with rofecoxib than during tNSAID treatment (p < 0.001). Use of rofecoxib was associated with a significant reduction in the proportion of discontinuations attributed to lack of effectiveness (p < 0.001) or gastrointestinal (GI) adverse events (p < 0.001 compared with tNSAIDs). Rofecoxib was also associated with a > 60% reduction in the proportion of patients experiencing a GI adverse event and a halving in the proportion of patients who received GI co-medications; concomitant analgesic use decreased by one-third during rofecoxib therapy. Use of rofecoxib was associated with marked improvements in several indices of treatment effectiveness and tolerability, and in patient and physician satisfaction and perception of general health status compared with tNSAIDs. Rofecoxib is a valuable additional medication for relieving the symptoms of OA and its use in place of tNSAIDs may lead to a reduction in the prescription of concomitant medications.",2003.0,0,0
279,12848634,"A comparison of the upper gastrointestinal mucosal effects of valdecoxib, naproxen and placebo in healthy elderly subjects.",J L Goldstein; A J Kivitz; K M Verburg; D P Recker; R C Palmer; J D Kent,"In long-term outcomes studies, cyclooxygenase COX-2 specific inhibitors spare COX-1 at supratherapeutic doses and therefore demonstrate improved gastrointestinal safety over nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs). However, in clinical practice, anti-inflammatory drugs are often used for short-term treatment of pain. To compare the short-term upper gastrointestinal mucosal effects of naproxen with the new COX-2 specific inhibitor, valdecoxib, or placebo, in elderly subjects. In this multicentre, double-blind, randomized, study, elderly subjects (65-76 years old), with a normal baseline esophagogastroduodenoscopy (EGD), received oral valdecoxib (a supratherapeutic 40 mg b.d. dosage, n = 62), naproxen (500 mg b.d., n = 62), or placebo (n = 62) for 6.5 days. Upper gastrointestinal mucosal injury was evaluated post-treatment by EGD (day 7). Subjects receiving naproxen (11/60, 18%) had significantly more gastroduodenal ulcers post-treatment than those receiving placebo (2/61, 3%; P < 0.01) or valdecoxib (0/60, 0%; P < 0.001). A similar significant finding was observed for gastric ulcer rates. All treatments had similar adverse event rates and clinical laboratory findings. Valdecoxib, even at supratherapeutic doses, was associated with an ulcer rate significantly lower than naproxen but similar to placebo in healthy elderly subjects, despite the short duration of therapy (6.5 days). Naproxen and valdecoxib were as well tolerated as placebo.",2003.0,0,0
280,12849425,The potential of anti-inflammatory drugs for the treatment of Alzheimer's disease.,Paul S Aisen,"Genetic evidence suggests that generation of amyloid beta peptide is the pivotal step in the pathophysiology of Alzheimer's disease (AD). The mechanism by which this peptide induces neurodegeneration may involve inflammatory processes. Pharmacological suppression of inflammation may therefore ameliorate the neuropathology. Basic research studies provide substantial evidence that inflammatory processes present in the brains of patients with AD are destructive, and that anti-inflammatory drugs can provide protection. Furthermore, epidemiological studies suggest that anti-inflammatory drugs reduce the risk of AD. However, there is not yet any strong evidence from completed randomised controlled trials that anti-inflammatory treatment is beneficial. Large trials of glucocorticoid therapy, hydroxychloroquine, and non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of AD have so far been disappointing. Several studies, including a large primary prevention trial with NSAIDs, are still in progress. Major issues of selection of patients, drug regimen, and duration of treatment remain unresolved.",2003.0,0,0
281,12861846,Scratch-patch and patch testing in drug allergy--an assessment of specificity.,K Hug; N Yawalkar; A Helbling; W J Pichler,"Adverse drug reactions occur frequently in daily practice, but the identification of the eliciting drugs is difficult due to a lack of standardized procedures. The aim of this study was to evaluate and compare scratch-patch and patch tests prospectively with frequently used drugs in persons exposed or not exposed to the drug in order to define a nonirritating concentration. Altogether, 23 different drugs, mainly antibiotics and analgesics, were evaluated. Any contraindications for patch tests were excluded by a questionnaire. Sixty-one healthy individuals were tested. They were divided into two groups: Group 1 consisted of individuals who hadn't been exposed to the drug; Group 2 was comprised of individuals who had been exposed to the drug, without side effects. Each individual was tested with 10-20 scratch-patch and patch tests. The tests were performed on the upper back. Freshly prepared drug solutions were applied, on one side after scarification of the epidermis, on the other side without. Scratch-patch tests were read at 24 and 48 h, patch tests after 48 and 72 h. In addition, we included 73 individuals with a drug allergy to illustrate that the chosen drug concentrations are able to elicit a positive reaction in truly sensitized individuals. A positive reaction in the non-exposed and nonallergic individuals was considered to be an irritant reaction (IR). In Group 1 (non-exposed individuals), 341 scratch-patch tests were performed, with 22 showing a reaction at the first reading, 3 at the second. Of the 341 patch tests performed in this group, 21 reactions were observed at the first reading, and 7 at the second. In Group 2 (exposed individuals), 141 scratch-patch tests were performed, with 5 IR at the first reading and 1 at the second. Of the 138 patch tests performed in this group, 6 individuals showed an IR at the first, 2 at the second reading. The majority of IR were four drugs, namely cefuroxim, acetylsalicylic acid, propyphenazone/drofenin-HCl, and celecoxib. Lowering the concentration did not reduce the unspecified irritant skin reaction, while a change of the solvent (petrolatum instead of PBS) did reduce the IR. Our data show concentrations of 23 drugs suitable for scratch-patch or patch tests, as they do not elicit IR. Fourteen of these test preparations elicited a positive reaction in truly sensitized individuals, demonstrating that the test preparation is suitable to identify sensitized persons. Scratch-patch tests are an interesting alternative to patch tests, as they do not elicit more IR than patch tests but can be evaluated earlier. Certain drugs solved in PBS are irritant over a wide dosage range and need to be applied in petrolatum.",2003.0,0,0
282,12861847,"Celecoxib, a highly selective COX-2 inhibitor, is safe in aspirin-induced asthma patients.",C Martín-García; M Hinojosa; P Berges; E Camacho; R García-Rodriguez; T Alfaya,"In 5-10% of adult patients with asthma, aspirin and most other nonsteroidal anti-inflammatory drugs (NSAIDs) precipitate acute asthmatic attacks. Therefore, choosing an alternative anti-inflammatory agent for patients who have suffered adverse reactions to a nonsteroidal anti-inflammatory agent is a common problem in clinical practice. The discoveries that cyclooxygenase COX-2 is an inducible form of COX involved in inflammation and COX-1 is the major isoform responsible for the production of prostaglandins have provided a reasonable basis for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents. The purpose of this study is to demonstrate that celecoxib, a specific inhibitor of COX-2, does not cause asthmatic attacks in patients with aspirin and/or other nonsteroidal anti-inflammatory drug-induced asthma. We studied 33 patients, all of whom suffered from asthma induced by at least two different NSAID drugs. They were challenged in a single-blind manner with different doses of celecoxib on three different days, until either the therapeutic dose of 200 mg or intolerance was reached. Each patient was rechallenged with 200 mg celecoxib seven days later if no evidence of intolerance was previously observed. Celecoxib 200 mg was proven to be well tolerated in all 30 three aspirin- and NSAID-induced asthma patients. Our study appears to demonstrate that celecoxib is a suitable NSAID in aspirin-induced and/or nonsteroidal anti-inflammatory drug-induced asthma patients.",2003.0,0,0
283,12861852,Chronic urticaria with multiple NSAID intolerance: is tramadol always a safe alternative analgesic?,Riccardo Asero,"Mechanisms underlying multiple intolerance to nonsteroidal anti-inflammatory drugs (NSAID) in patients with chronic urticaria (CU) are unclear. One hypothesis is that COX-1 inhibition may play a relevant pathogenic role. If so, drugs that are not active on COX-1 would be expected to be well tolerated by CU patients. This study aimed at assessing the tolerability of a central analgesic (tramadol) in a group of patients with CU and a history of intolerance to several NSAIDs, asking for a safe, alternative compound. Twenty-eight patients with CU exacerbated by several, distinct NSAIDs underwent single-blind, placebo-controlled, oral challenges with increasing doses of tramadol (50 mg total dose). Most of them underwent oral challenges with rofecoxib, paracetamol, and/or nimesulide as well. Twenty-three patients tolerated tramadol, whereas, surprisingly, in 5 (18%) patients tramadol induced urticaria, in one case with laryngeal edema. A similar proportion of CU patients did not tolerate rofecoxib, and higher proportions of patients did not tolerate acetaminophen and nimesulide. Mechanisms other than COX inhibition may also play a role in drug intolerance in patients with CU. In CU patients intolerant to NSAID, the tolerability of tramadol, as well as of other ""alternative"" drugs, should be assessed by oral challenge tests.",2003.0,0,0
284,12869082,Economic analysis of celecoxib versus diclofenac plus omeprazole for the treatment of arthritis in patients at risk of ulcer disease.,K K C Lee; J H S You; J T S Ho; B Y Suen; M Y Yung; W H Lau; V W Y Lee; J Y Sung; F K L Chan,"To evaluate the economic impact of celecoxib therapy vs. diclofenac plus omeprazole therapy for the treatment of arthritis in Chinese patients with a high risk of bleeding, from the perspective of a public health organization in Hong Kong. The medical records of 287 Chinese arthritic patients with a history of bleeding ulcers who had previously participated in a randomised study of celecoxib 200 mg twice daily and extended-release diclofenac 75 mg twice daily plus 20 mg of omeprazole daily for 6 months were reviewed. Compared to the diclofenac plus omeprazole group, the average total direct cost per patient in the celecoxib group showed a significant reduction of 11%, from HK 10,915 (range HK dollars 10,915-57,899) to HK dollars 9714 (range HK dollars 9714-89,770) (P<0.0001) (1 US dollars=7.8 HK dollars). The median direct medical cost for routine management in the celecoxib group was significantly lower (11%) than that for the diclofenac plus omeprazole group [HK dollars 10,915 (range 10,915-28,048) vs. HK dollars 9714 (range HK dollars 6946-26,179) (P<0.0001)]. In patients who experienced recurrent bleeding, the celecoxib group showed a significantly higher median cost of management of recurrent bleeding than the diclofenac plus omeprazole group [HK dollars 8466 (range 572-29,851) vs. HK dollars 23,210 (range HK dollars 12,318-65,823)] (P=0.036). Celecoxib therapy appears to cost less compared with diclofenac plus omeprazole for treatment of arthritis in Chinese patients with a high risk of bleeding.",2003.0,0,0
285,12877584,"Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.",Carmen Almansa; José Alfón; Alberto F de Arriba; Fernando L Cavalcanti; Ignasi Escamilla; Luis A Gómez; Agustí Miralles; Robert Soliva; Javier Bartrolí; Elena Carceller; Manuel Merlos; Julián García-Rafanell,"The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.",2003.0,0,0
286,12879280,Metronomic oral low-dose treosulfan chemotherapy combined with cyclooxygenase-2 inhibitor in pretreated advanced melanoma: a pilot study.,Konstanze Spieth; Roland Kaufmann; Jens Gille,"The safety and efficacy of oral metronomic low-dose treosulfan chemotherapy in combination with the cyclooxygenase-2 (COX-2) inhibitor rofecoxib as a compound with antiangiogenic potential, a therapeutic regimen optimally targeting endothelial cells instead of tumor cells, were assessed in pretreated advanced melanoma patients. Endothelial cells were analyzed for proliferation, apoptosis and cytotoxicity in response to increasing concentrations of treosulfan, either in the absence or presence of COX-2 inhibitor, to determine whether inhibition of COX-2 enhanced the effect of treosulfan on cell function. In a clinical pilot study, 12 consecutive patients with pretreated advanced melanoma, meeting the eligibility criteria were enrolled. Patients received combined daily treosulfan chemotherapy (500 mg) with rofecoxib (25 mg). Metastatic lesions were assessed every 12 weeks. Patients with responsive or stable disease were eligible for a further 12-week treatment period. Response criteria according to the WHO handbook for reporting results of cancer treatment were applied. Side effects were classified according to the National Cancer Institute's Common Toxicity Criteria v2.0. At noncytotoxic concentrations, treosulfan inhibited endothelial cell proliferation in a dose-dependent fashion. Simultaneous inhibition of COX-2 significantly increased the extent to which treosulfan suppressed cell proliferation, without inducing cytotoxicity. In the pilot study in which 12 patients were treated, toxicity was mild; only hematologic toxicity of grade II was seen. An objective response was noted in one patient, and four patients showed stabilization of their disease for 24 weeks (one) and 36 weeks (three). The patient who had a partial response subsequently showed stable disease for 48 weeks. The median survival time was 13 months. As increases in response rates following polychemo- or biochemotherapy have not been shown to correlate with prolongation in overall survival, more durable control of metastatic melanoma represents an attractive therapeutic goal. Thus, regimens scheduled to primarily target endothelial cells may potentially provide a palliative alternative that preserves quality of life in the absence of significant treatment-related toxicity.",2003.0,0,0
287,12885487,Non-steroidal anti-inflammatory drugs and molecular carcinogenesis of colorectal carcinomas.,G Huls; J J Koornstra; J H Kleibeuker,"Colorectal cancer is the second most common cause of cancer-related mortality in the west. The high incidence and mortality make effective prevention an important public-health and economic issue. Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit colorectal carcinogenesis and are among the few agents known to be chemopreventive. Randomised trials have shown that sulindac and celecoxib suppress the development of adenomatous polyps and cause regression of existing polyps in patients with familial adenomatous polyposis (FAP), who have a high risk for developing colorectal cancer. The mechanisms by which NSAIDs inhibit neoplastic growth are not fully known. Two recently reported randomised placebo-controlled trials show a chemopreventive effect of aspirin in populations other than those with FAP (Robert Sandler and colleagues, N Engl J Med 2003; 348: 883-90; John Baron and colleagues, N Engl J Med 2003; 348: 891-99). In the Sandler study 635 patients with colorectal cancer were randomised to receive 325 mg aspirin or placebo daily. After a follow-up of around 31 months, the mean number of adenomas was lower in the aspirin group than in the placebo group, corresponding to a relative risk of any recurrent adenoma in the aspirin group of 0.65. In the Baron study 1121 patients with colorectal adenomas were assigned to receive 81 or 325 mg aspirin or placebo daily. Follow-up colonoscopy, 32 months after the index endoscopy, showed an incidence of one or more adenomas of 38% in the 81 mg aspirin group, 45% in the 325 mg aspirin group, and 47% in the placebo group. Together, these studies indicate a moderate chemopreventive effect of aspirin in populations with an intermediate risk of developing colorectal cancer. WHERE NEXT? The anticancer properties of NSAIDs have been demonstrated in vitro and in animal studies, epidemiological reports, and intervention studies. Several mechanisms through which NSAIDs alter colonic carcinogenesis have been elucidated, including the induction of apoptosis in neoplastic cells, via mechanisms dependent and independent of cyclo-oxygenase. Some studies have suggested an important role for the cell-cycle regulating protein p21 in mediating the chemopreventive effect of sulindac. A decrease in p21 expression may be one of the main oncogenic events in the development of colorectal cancer. Thus p21 could be the molecular link in the chemopreventive effects of NSAIDs.",2003.0,0,0
288,12889553,Low frequency of upper gastrointestinal complications in a cohort of high-risk patients taking low-dose aspirin or NSAIDS and omeprazole.,A Lanas; L Rodrigo; J L Márquez; E Bajador; F Pérez-Roldan; J Cabrol; E Quintero; M Montoro; F Gomollón; S Santolaria; S Lorente; M Cucala; J Nuevo; EMPHASYS Study Group,"There is very little information available on the incidence of complications and on the best prevention therapy in high-risk patients taking non-steroidal anti-inflammatory drugs (NSAIDs) and/or aspirin. Randomized-controlled trials in such patients are rare for ethical reasons. We studied the incidence of gastrointestinal complications in high-risk patients taking long-term low-dose aspirin or non-aspirin-NSAIDs combined with omeprazole in a real-life clinical setting. This was a multicentre, prospective and observational study including 247 consecutive high-risk patients who had a clinical indication for long-term treatment with either low-dose aspirin or non-aspirin NSAIDs and omeprazole therapy. The occurrence of gastrointestinal complications was measured. In addition to a recent history of peptic ulcer bleeding, all patients had at least 1 other risk factor and 112 (45.3%) had 3 or more risk factors; 78.9% were taking low-dose aspirin and the remainder non-aspirin NSAIDs. Mean follow-up was 14.6 +/- 10.38 months. Three patients taking low-dose aspirin developed upper gastrointestinal bleeding (1.2%; 95% CI 0.3-3.5; 1.0 event/100 patients/year). This was similar to the rate observed in studies involving non-high-risk patients taking low-dose aspirin and higher than that observed in patients not taking low-dose aspirin. Two additional patients developed a lower gastrointestinal bleeding event (0.81% (0.04%-3.12%); 0.67 events/100 patients/year), which was within the range expected in NSAID users. The use of omeprazole in the high-risk patient taking low-dose aspirin or NSAIDs seems to be a safe therapeutic approach in this population and is associated with a low frequency of upper gastrointestinal complications.",2003.0,0,1
289,12891223,Celecoxib inhibits metabolism of cytochrome P450 2D6 substrate metoprolol in humans.,Ulrike Werner; Dierk Werner; Thomas Rau; Martin F Fromm; Burkhard Hinz; Kay Brune,"In vitro data have shown that celecoxib inhibits the metabolism of cytochrome P450 (CYP) 2D6 substrates. However, very limited data are available on the influence of cyclooxygenase 2 inhibitors on the disposition of CYP2D6 substrates in humans. Therefore the objective of this study was to examine the effect of celecoxib and rofecoxib on the pharmacokinetics of the clinically relevant CYP2D6 substrate metoprolol. An open, randomized, 3-period crossover study was performed in 12 healthy male volunteers. Metoprolol (50 mg) was given in all 3 periods without or after 7 days of pretreatment with celecoxib (200 mg twice daily) or rofecoxib (25 mg daily) to achieve steady-state conditions of cyclooxygenase 2 inhibitors in periods 2 and 3. Celecoxib significantly increased the area under the plasma concentration-time curve of metoprolol from 271 to 414 micro g. h/L (64% +/- 57%, P <.001) and by more than 200% in 1 volunteer. The extent of this drug interaction was more pronounced in volunteers with 2 fully functional alleles compared with volunteers with 1 fully functional allele (103% +/- 75% versus 36% +/- 23%, P <.05). After administration of celecoxib, the area under the plasma concentration-time curve from 0 to 24 hours of alpha-hydroxymetoprolol decreased significantly from 474 to 387 micro g. h/L (P <.01). Rofecoxib caused no significant effects on the pharmacokinetics of metoprolol. We conclude that celecoxib inhibits the metabolism of the CYP2D6 substrate metoprolol but that rofecoxib does not. Clinically relevant drug interaction may occur between celecoxib and CYP2D6 substrates, particularly those with a narrow therapeutic index.",2003.0,0,0
290,12895187,Assessment of non-steroidal anti-inflammatory drug (NSAID) damage in the human gastrointestinal tract.,Martin W James; Christopher J Hawkey,"Aspirin is widely prescribed and confers considerable benefit to patients by reducing cardiovascular and cerebrovascular morbidity and mortality. Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective analgesics, antipyretics and reduce the inflammatory component in conditions such as rheumatoid arthritis. However, both agents are associated with an increased risk of gastrointestinal symptoms and the potentially serious consequences of gastroduodenal ulceration, bleeding and perforation. The introduction of highly selective cyclo-oxygenase (COX)-2 inhibitors or the coprescription gastroprotective agents with nonselective NSAIDs have offered strategies to reduce the incidence of such events. This review article analyzes the quantitative techniques that can be employed by clinical pharmacologists and the clinical studies performed to assess NSAID damage in the gastrointestinal tract.",2003.0,0,1
291,12899497,,,,,0,0
292,12901032,Interaction of rofecoxib and celecoxib with warfarin.,Monica G Schaefer; Brian K Plowman; Anthony P Morreale; Melissa Egan,"The interaction of celecoxib and rofecoxib with warfarin was studied. Patients stable on warfarin therapy and concurrently taking a cyclooxygenase-2 (COX-2) inhibitor comparator (traditional nonsteroidal antiinflammatory medications, salsalate, or acetaminophen) randomly received celecoxib 200 mg/day or rofecoxib 25 mg/day for three weeks. After a one-week washout period, the patients were crossed over to treatment with the opposite COX-2 inhibitor for three more weeks. The International Normalized Ratio (INR) was measured at baseline and at weeks 1, 2, and 3 of therapy with each COX-2 inhibitor by testing blood samples obtained by finger stick. Data for 16 patients were analyzed. The INR increased by 13%, 6%, and 5% on average in patients taking celecoxib at weeks 1, 2, and 3, respectively, and by 5%, 9%, and 5% in patients taking rofecoxib. Changes in the INR were statistically significant at week 1 for celecoxib and at week 2 for rofecoxib. Of the 12 subjects who had a clinically significant > or = 15% change in the INR while receiving either COX-2 inhibitor, 4 showed this change for both agents. Adverse drug reactions were similar for each COX-2 inhibitor, but the rate of edema requiring medical intervention was higher in the rofecoxib group. Significant increases in the INR were observed in patients who were stable on warfarin therapy after the addition of therapy with rofecoxib or celecoxib.",2003.0,1,1
293,12912856,"Channelling bias and the incidence of gastrointestinal haemorrhage in users of meloxicam, coxibs, and older, non-specific non-steroidal anti-inflammatory drugs.",T M MacDonald; S V Morant; J L Goldstein; T A Burke; D Pettitt,"Although clinical trial results suggest that meloxicam has less gastrointestinal toxicity than most other non-steroidal anti-inflammatory drugs (NSAIDs), in practice it has been associated with a large number of yellow card reports of gastrointestinal complications. To estimate whether meloxicam and the coxibs, rofecoxib and celecoxib, have been channelled towards high risk patients, and to estimate the risk of hospitalisation for gastrointestinal haemorrhage associated with the use of these drugs, allowing for the effects of channelling. Using the UK General Practice Research Database, this study included 7.1 thousand patient years (tpy) exposure to meloxicam, 1.6 tpy exposure to coxibs, and 628 tpy exposure to older non-specific NSAIDs. Cohort study of patients who received a prescription for an NSAID between June 1987 and January 2001. Exposure to newer NSAIDs (meloxicam, rofecoxib, celecoxib) and to older non-specific NSAIDs was identified. Channelling was assessed on factors including: demographic variables; diagnosis of arthritis; history of NSAID use or gastrointestinal events, including gastrointestinal haemorrhage; and use of ulcer healing drugs. Most risk factors for gastrointestinal haemorrhage were more prevalent among patients prescribed the newer NSAIDs. Adjusting for these risk factors reduced the relative risks of gastrointestinal haemorrhage on meloxicam and coxibs versus older non-specific NSAIDs to 0.84 (95% confidence interval 0.60, 1.17) and 0.36 (0.14, 0.97), respectively. Channelling towards high risk gastrointestinal patients occurred in the prescribing of newer NSAIDs. After attempting to correct for channelling bias, coxib exposure, but not meloxicam exposure, was associated with a significantly lower risk of gastrointestinal haemorrhage than older non-specific NSAID exposure.",2003.0,0,1
294,12914871,Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib.,William B White; Gerald Faich; Jeffrey S Borer; Robert W Makuch,"To determine whether the cyclooxygenase-2 (COX-2) inhibitor celecoxib affects cardiovascular thrombotic risk, we analyzed the incidence of cardiovascular events for celecoxib, placebo, and nonsteroidal anti-inflammatory drugs (NSAIDs) in the entire controlled, arthritis clinical trial database for celecoxib. The primary analysis used the Antiplatelet Trialists' Collaboration end points, which include: (1) cardiovascular, hemorrhagic, and unknown deaths, (2) nonfatal myocardial infarction, and (3) nonfatal stroke. Other secondary thrombotic events were also examined. Separate analyses were performed for all patients and for those not taking aspirin. Data from all controlled, completed arthritis trials of > or =4 weeks duration, including 13 new drug application studies and 2 large post-marketing trials (CLASS and SUCCESS) were included for analyses. Patients were randomized to celecoxib at doses from 100 to 400 mg twice daily (18,942 patients; 5,668.2 patient-years of exposure), diclofenac 50 to 75 mg twice daily, ibuprofen 800 mg thrice daily, naproxen 500 mg twice daily (combined NSAID exposure of 11,143 patients; 3,612.2 patient-years), or placebo (1,794 subjects; 199.9 subject-years). Data from a long-term uncontrolled trial with 5,209 patients (6,950 patients-years) treated with celecoxib were included in a supplemental analysis. The entire 15-trial database was searched for possible serious thrombotic events as well as to identify all deaths. For these patients, detailed clinical data were obtained and reviewed by 2 of the investigators (WBW and JSB), who were independently and blinded to exposure, to classify the event as primary, secondary, or neither. All analyses were done using the intent-to-treat population, and time-to-event analyses were performed using per-patient data. To examine heterogeneity of results among studies, tests of interaction were performed using the Cox model. Incidences of the primary and secondary events were not significantly different between the celecoxib and placebo groups, nor for the celecoxib group compared with the NSAIDs group, regardless of aspirin use and NSAID type. The relative risks comparing celecoxib with the NSAIDs for the primary events were 1.06 (95% confidence interval 0.70 to 1.61, p = 0.79) for all patients, and 0.86 (95% confidence interval 0.48 to 1.56, p = 0.62) for the subgroup not taking aspirin. Similarly, for secondary cardiovascular end points, all relative risks were < or =1 for celecoxib compared with either placebo or NSAIDs. These comparative analyses demonstrate no evidence of increased risk of cardiovascular thrombotic events associated with celecoxib compared with either conventional NSAIDs or placebo.",2003.0,1,1
295,12925248,Effect of celecoxib and dexamethasone on postoperative pain after lumbar disc surgery.,Matthias Karst; Tanja Kegel; Anne Lukas; Wolf Lüdemann; Samii Hussein; Siegfried Piepenbrock,"This study was designed to assess the efficacy of perioperative administration of celecoxib (Celebrex; Pharmacia GmbH, Erlangen, Germany) in reducing pain and opioid requirements after single-level lumbar microdiscectomy. We studied 34 patients (mean age, 44.26 yr; standard deviation [SD], 13.09 yr) allocated randomly to receive celecoxib 200 mg twice a day for 72 hours starting on the evening before surgery or placebo capsules in a double-blind study. Fourteen patients received 20 to 80 mg dexamethasone intravenously during surgery (mean, 40 mg; SD, 19.22 mg) because of visible signs of compression of the affected nerve root. After lumbar disc surgery, patients were monitored for visual analog scores for pain at rest and on movement, patient-controlled analgesia (PCA) piritramide requirements, and von Frey thresholds in the wound area. Pain scores decreased and wound von Frey thresholds increased continuously until discharge, with no intergroup differences. Mean 24-hour PCA piritramide requirements were 22.63 mg (SD, 23.72 mg) and 26.14 mg (SD, 22.57 mg) in the celecoxib and placebo groups, respectively (P = not significant). However, patients with intraoperative dexamethasone (n = 14) required only 10.29 mg (SD, 8.55 mg) 24-hour PCA piritramide, in contrast to the 34.25 mg (SD, 24.69 mg) needed in those who did not receive intraoperative dexamethasone (P = 0.001). In addition, 24 hours after the operation, pain scores on movement were significantly lower in the dexamethasone subgroup (P = 0.003). Celecoxib has no effect on postoperative pain scores and PCA piritramide requirements. The intraoperative use of 20 to 80 mg dexamethasone is able to significantly decrease postoperative piritramide consumption and pain scores on the first day after surgery.",2003.0,0,0
296,12934656,Second-line chemotherapy for non-small cell lung cancer.,Frances A Shepherd,"Several agents have been evaluated for the second-line treatment of patients with non-small cell lung cancer. The TAX 317 trial found that patients treated with docetaxel (Taxotere) 75 mg/m2 had significantly longer survival than those treated with best supportive care alone. In addition, symptom control was better for patients who received chemotherapy. The TAX 320 trial found that treatment with docetaxel 75 or 100 mg/m2 resulted in significantly higher response rates than treatment with vinorelbine (Navelbine) or ifosfamide (Mitoxana), and the 1-year survival rate was also significantly better for patients treated with docetaxel 75 mg/m2. A large randomized trial compared pemetrexed (LY-231514 or Alimta) 500 mg/m2 with docetaxel 75 mg/m2. Response and survival rates were similar in the two treatment arms, however, the toxicity profile of pemetrexed was superior to that of docetaxel with significantly less Grade 3/4 neutropenia and febrile neutropenia. Fewer patients in the pemetrexed arm required hospitalization. Topotecan (Hycamtin) 2.3 mg/m2/day orally for 5 days has been compared with docetaxel 75 mg/m2 in a large 800-patient study. The results of this trial are awaited. Gemcitabine (Gemzar) and irinotecan (Campto) have been evaluated both as single agents and in combination with each other and study results do not suggest that either of these drugs is superior to docetaxel or pemetrexed. The vinca alkaloid vinorelbine has proved to be inferior to docetaxel in a randomized trial. The epidermal growth factor receptor inhibitors gefitinib (ZD1839, Iressa) and erlotinib (CP-358774, OSI 774, Tarceva) have been evaluated in Phase II trials in the second- and third-line setting. Both drugs have demonstrated interesting response rates ranging from 10 to almost 20%. The results of placebo-controlled randomized trials of this family of drugs are awaited. In summary, several studies have now found a definite role for the second-line treatment of patients with non-small cell lung cancer.",2003.0,0,0
297,12943480,Cost-effectiveness of different postoperative analgesic treatments.,Milo Engoren,"Pain may produce metabolic changes after surgery, which may contribute to further morbidity. A variety of medicines and techniques can be used to successfully treat pain. It is postulated that improved analgesia leads to improved outcomes, although analgesics may also contribute to morbidity. This article reviews the literature evaluating the cost-effectiveness of providing different types of postoperative analgesics and finds that most studies are so poorly conducted that they prevent definitive conclusions being made. The author suggests that further studies be done using analgesics as just one part of a multimodal rehabilitation approach with careful attention to defining outcome, costs and achieving sufficient power to find or exclude meaningful differences.",2003.0,0,0
298,12945071,Cyclo-oxygenase 2 inhibition in colorectal cancer therapy.,R D Church; J W Fleshman; H L McLeod,"Cyclo-oxygenase inhibition for the treatment of colorectal neoplasia has been studied with renewed interest since the discovery of cyclo-oxygenase (Cox) 2 and the introduction of specific Cox-2 inhibitors. These drugs have implications for both the prevention of colorectal carcinoma and the potential treatment of the disease. A Medline database search was performed for articles using the keywords ""colonic, colon or rectal and neoplasia or cancer"" and ""cyclo-oxygenase or Cox-2."" Cross-references of relevant historical papers were also included. There is substantial evidence that Cox-2 plays a role in the development and progression of colorectal cancer. The specific inhibition of this enzyme has been shown to inhibit cancer growth in in vitro and in vivo models. The mechanisms of action for these effects are poorly understood and potential clinical applications at present remain under investigation. Cox-2 inhibitors have great promise as useful additions to current cancer treatments. There is a need for randomized clinical trials to define a role for these drugs in chemoprevention, recurrence prophylaxis, and adjuvant therapy for colorectal and other solid tumours.",2003.0,0,0
299,12946034,Non-steroidal anti-inflammatory drug use is associated with reduction in recurrence of advanced and non-advanced colorectal adenomas (United States).,Joseph A Tangrea; Paul S Albert; Elaine Lanza; Karen Woodson; Don Corle; Marsha Hasson; Randall Burt; Bette Caan; Electra Paskett; Frank Iber; J Walter Kikendall; Peter Lance; Moshe Shike; Joel Weissfeld; Arthur Schatzkin; Polyp Prevention Study Group,"To prospectively examine the association between non-steroidal anti-inflammatory drugs (NSAIDs) use (including dose and dosage schedule) and the recurrence of colorectal adenomas among individuals who were diagnosed with an adenoma at entry into a clinical trial. For this analysis, participants who completed the full follow-up (n = 1905) for the Polyp Prevention Trial (PPT) were evaluated. Information on current use and dose of NSAIDs and other drugs was obtained at baseline and at each subsequent study visit over the duration of the trial. The study endpoint was the recurrence of colorectal adenomas in the 3 years between the 1-year trial colonoscopy (T1) and the end of the trial colonoscopy (T4). There was a significant reduction in overall adenoma recurrence among NSAIDs users (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.63-0.95), with the greatest effect seen in advanced polyps (OR = 0.51; CI: 0.33-0.79). Among aspirin users, we observed a significant dose response for overall adenoma recurrence, with a 40% reduction in the OR association (OR = 0.56; 95% CI: 0.31-0.99) among those taking more than 325 mg per day. This prospective study provides further evidence that NSAIDs may play an important role in the chemoprevention of recurrent colorectal adenomas, even those with advanced features.",2003.0,0,0
300,12946236,Pass the tablet please.,Al Czap,,2003.0,0,0
301,12948345,Pharmacologic therapies for neck pain.,Ali Nemat; Steven M Richeimer,A variety of drug types are available for the treatment of pain. Significant relief of acute neck pain is usually achievable. Treatment of chronic neck pain requires a more comprehensive rehabilitation approach combined with judicious use of medications. Research on the development of analgesics that affect other neurotransmitter systems and that have fewer side effects is currently underway.,2003.0,0,0
302,12949718,The effect of the selective cyclooxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases.,Stephen W Fenwick; Giles J Toogood; J Peter A Lodge; Mark A Hull,"Cyclooxygenase-2 (COX-2) is a potential target for chemotherapy of colorectal cancer (CRC). We tested the antineoplastic activity of the selective COX-2 inhibitor rofecoxib on human CRC liver metastases by measuring surrogate markers of tumor growth and angiogenesis in a randomized, double-blind, placebo-controlled trial. Patients undergoing liver resection surgery for metastatic disease were randomized to receive rofecoxib 25 mg daily or placebo before surgery (duration, >14 days). The apoptosis index (AI; neocytokeratin 18), proliferation index (PI; Ki-67), and microvessel density (MVD; CD31) were measured in metastases by immunohistochemistry. The effect of rofecoxib on COX-2-positive HCA-7 human CRC cell PGE(2) synthesis, proliferation, and apoptosis in vitro was also investigated. Patients who received rofecoxib (n = 23) and placebo (n = 21) were well matched regarding clinical and metastasis characteristics. The mean (range) duration of rofecoxib therapy was 26 (14-46) days. Rofecoxib-treated metastases had a 29% decrease in MVD (mean, 25.1 [SEM, 2.7] per hpf) compared with placebo-treated tissue (32.5 [SEM, 4.5] per hpf; P = 0.15). There was little difference in AI (rofecoxib mean, 2.03% [SEM, 0.43%] vs. placebo 1.39% [SEM, 0.39%]) or PI (rofecoxib 54.7% [SEM, 5.1%] vs. placebo 52.6% [SEM, 5.6%]). Rofecoxib-induced growth arrest and apoptosis of HCA-7 cells occurred only at concentrations (>10 micromol/L), which were significantly higher than the IC(50) for COX-2 inhibition. Rofecoxib may negatively regulate angiogenesis in human CRC liver metastases. The absence of a significant, direct effect of rofecoxib on epithelial cells in liver metastases in vivo mirrors the lack of activity on human CRC cells at pharmacologically relevant concentrations in vitro.",2003.0,0,0
303,12960371,Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa.,Stefano Fiorucci; Luca Santucci; John L Wallace; Marco Sardina; Mario Romano; Piero del Soldato; Antonio Morelli,"In addition to inhibiting cyclooxygenase (COX)-1-derived prostanoid biosynthesis, aspirin acetylates COX-2, enabling the conversion of arachidonic acid to 15(R)-epi lipoxin A4, or aspirin-triggered lipoxin (ATL). Selective COX-2 inhibitors block ATL formation and exacerbate mucosal injury in rats treated with aspirin. In the present study, we have examined whether inhibition of COX-2 activity in healthy volunteers taking aspirin exacerbates gastric mucosal injury and if such an effect would be prevented by NCX-4016, a NO-releasing derivative of aspirin. Thirty-two volunteers were randomized to receive 2 wk of treatment with NCX-4016 (800 mg twice a day) or aspirin (100 mg once a day) alone or in combination with 200 mg of celecoxib twice a day. Mucosal damage was assessed by endoscopy. The mean mucosal injury score was 5.8 +/- 1.8 in subjects treated with aspirin and 2.4 +/- 0.7 (P < 0.01 vs. aspirin) in subjects treated with NCX-4016. Administration of celecoxib increased the injury score in volunteers treated with aspirin (9.9 +/- 1.9) but not in subjects taking NCX-4016 (1.5 +/- 0.8). Aspirin and NCX-4016 caused a comparable suppression of serum thromboxane B2 levels and increased urinary excretion of ATL. Celecoxib inhibited endotoxin-induced prostaglandin E2 generation in whole blood by approximately 80% and abolished ATL formation. These findings suggests that (i) aspirin and NCX-4016 trigger ATL formation in humans, (ii) celecoxib inhibits ATL formation and exacerbates the mucosal injury caused by low doses of aspirin, and (iii) the NO-donating moiety of NCX-4016 protects the gastric mucosa even in the presence of suppression of COX-1 and COX-2.",2003.0,0,0
304,12966478,Single doses of parecoxib sodium intravenously are as effective as ketorolac in reducing pain after oral surgery.,Donald R Mehlisch; Paul J Desjardins; Stephen Daniels; Richard C Hubbard,"Our goal was to compare the analgesic efficacy and safety of single doses of intravenous parecoxib sodium, a prodrug of the novel cyclooxygenase (COX)-2-selective inhibitor valdecoxib, with intravenous ketorolac and placebo in postoperative oral surgery patients. Eligible patients experiencing moderate to severe pain within 6 hours of surgery to extract 2 or more impacted third molars were randomized to receive a single dose of parecoxib sodium 1, 2, 5, 10, 20, 50, or 100 mg; ketorolac 30 mg; or placebo. Analgesic efficacy was assessed over a 24-hour treatment period or until rescue analgesia was required. Parecoxib sodium doses (particularly 50 and 100 mg) had a rapid onset of analgesia (within 11 minutes). The analgesic efficacy of parecoxib sodium 20 to 100 mg was similar to that of ketorolac 30 mg. Parecoxib sodium doses below 20 mg had suboptimal analgesic activity compared with placebo and ketorolac. A plateau of efficacy was observed at the parecoxib sodium 50-mg dose. Parecoxib sodium 50 and 100 mg had a significantly longer duration of analgesia than ketorolac 30 mg. All doses of parecoxib sodium were well tolerated. Parecoxib sodium, a novel parenteral prodrug of the COX-2-selective inhibitor valdecoxib, is as effective and longer acting at 50- and 100-mg intravenous doses than a standard dose of ketorolac 30 mg intravenously. Parecoxib sodium appears to be safe and well tolerated and, therefore, merits further evaluation in other models of postsurgical pain.",2003.0,0,0
305,12971029,"Valdecoxib, a COX-2-specific inhibitor, does not affect cardiac repolarization.",Nenad Sarapa; Margaret R Britto; Barbara Cotton; Steven R Cox; Steven F Francom; Na Jin; Emery D Polasek; Stephen M Sainati; Sharon L Crosby-Sessoms; Joseph C Fleishaker,"This double-blind, four-way crossover study assessed the effect of valdecoxib on the QTc interval duration in 25 male and 9 female healthy adults. Subjects received placebo or 40 mg, 80 mg, or 120 mg valdecoxib once daily for 5 days. Serial ECGs were obtained for 24 hours before the first treatment (baseline) and on the 5th day of each treatment. The study was statistically powered to detect a difference of > or = 5.6 ms in the average daily QTc change from baseline and a > or = 7.8-ms difference in the average maximal daily change from baseline. No QTc prolongation versus placebo (Fridericia's or Bazett's correction) was observed for any valdecoxib dose. A 22% greater than proportional increase in valdecoxib AUC0-24 was observed over the 40- to 120-mg dose range, supporting the conclusiveness of the negative QTc risk assessment even at supratherapeutic doses (up to three times the maximum recommended dose of 40 mg per day) and concentrations. In conclusion, repeated administration of doses up to 120 mg valdecoxib had no effect on cardiac repolarization in healthy volunteers, suggesting that chronic administration of valdecoxib to patients would not increase the risk from cardiac arrhythmia associated with QT prolongation.",2003.0,0,0
306,14506910,"A randomised, double-blind, clinical trial comparing the efficacy of nimesulide, celecoxib and rofecoxib in osteoarthritis of the knee.",M Bianchi; M Broggini,"Joint pain is the main complaint in patients affected by osteoarthritis (OA), and NSAIDs are commonly used to treat pain associated with OA. Over the past few years, cyclo-oxygenase (COX)-2-selective inhibitors have been proved to have certain advantages over non-selective NSAIDs and have been increasingly used for pain management in patients with OA. The main objective of this randomised, double-blind, within-patient study was to compare the analgesic efficacy of three COX-2 inhibitors in 30 patients affected by symptomatic OA of the knee. We evaluated the effects of oral nimesulide (100mg), celecoxib (200mg) and rofecoxib (25mg). Each drug was administered for 7 days. Analgesic efficacy was determined using the patient's assessment of pain on a visual analogue scale (VAS) and by total pain relief over 3 hours (TOPAR3) on the first and last days of treatment. In addition, the overall analgesic efficacy and tolerability were determined by a global assessment by the patient at the end of each week of treatment, using 5-point categorical scales. At the end of the study, each patient was asked about which of the three forms of treatment they would choose as a continuation of the pain therapy. Taking all the results into consideration, nimesulide proved to be significantly more effective in providing symptomatic relief than did celecoxib and rofecoxib. Furthermore, nimesulide provided more rapid relief of pain associated with walking than did the other two drugs tested. Patients expressed similar preference for nimesulide and rofecoxib, but a lesser preference for celecoxib treatment. No patient withdrew from the study because of adverse events and the three different forms of treatment were generally safe and well tolerated. The present data confirm our previous observations in patients with rheumatoid arthritis, further suggesting that nimesulide represents an effective agent for the treatment of joint pain, with particular reference to the rapid onset of its analgesic effect.",2003.0,1,1
307,14512494,Effect of NSAIDs on risk of Alzheimer's disease: confounding factors were not discussed.,Michael Robertson,,2003.0,0,0
308,14519710,Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial.,Matthias Karst; Kahlid Salim; Sumner Burstein; Ingomar Conrad; Ludwig Hoy; Udo Schneider,"1',1'dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid (CT-3), a potent analog of THC-11-oic acid, produces marked antiallodynic and analgesic effects in animals without evoking the typical effects described in models of cannabinoids. Therefore, CT-3 may be an effective analgesic for poorly controlled resistant neuropathic pain. To examine the analgesic efficacy and safety of CT-3 in chronic neuropathic pain in humans. Randomized, placebo-controlled, double-blind crossover trial conducted in Germany from May-September 2002. Twenty-one patients (8 women and 13 men) aged 29 to 65 years (mean, 51 years) who had a clinical presentation and examination consistent with chronic neuropathic pain (for at least 6 months) with hyperalgesia (n = 21) and allodynia (n = 7). Patients were randomized to two 7-day treatment orders in a crossover design. Two daily doses of CT-3 (four 10-mg capsules per day) or identical placebo capsules were given during the first 4 days and 8 capsules per day were given in 2 daily doses in the following 3 days. After a washout and baseline period of 1 week each, patients crossed over to the second 7-day treatment period. Visual analog scale (VAS) and verbal rating scale scores for pain; vital sign, hematologic and blood chemistry, and electrocardiogram measurements; scores on the Trail-Making Test and the Addiction Research Center Inventory-Marijuana scale; and adverse effects. The mean differences over time for the VAS values in the CT-3-placebo sequence measured 3 hours after intake of study drug differed significantly from those in the placebo-CT-3 sequence (mean [SD], -11.54 [14.16] vs 9.86 [21.43]; P =.02). Eight hours after intake of the drug, the pain scale differences between groups were less marked. No dose response was observed. Adverse effects, mainly transient dry mouth and tiredness, were reported significantly more often during CT-3 treatment (mean [SD] difference, -0.67 [0.50] for CT-3-placebo sequence vs 0.10 [0.74] for placebo-CT-3 sequence; P =.02). There were no significant differences with respect to vital signs, blood tests, electrocardiogram, Trail-Making Test, and Addiction Research Center Inventory-Marijuana scale. No carryover or period effects were observed except on the Trail-Making Test. In this preliminary study, CT-3 was effective in reducing chronic neuropathic pain compared with placebo. No major adverse effects were observed.",2003.0,0,0
309,14530224,"Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial.",Jeffrey R Lisse; Monica Perlman; Gunnar Johansson; James R Shoemaker; Joy Schechtman; Carol S Skalky; Mary E Dixon; Adam B Polis; Arthur J Mollen; Gregory P Geba; ADVANTAGE Study Group,"Gastrointestinal (GI) toxicity mediated by dual cyclooxygenase (COX)-1 and COX-2 inhibition of nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious alterations of mucosal integrity or, more commonly, intolerable GI symptoms that may necessitate discontinuation of therapy. Unlike NSAIDs, rofecoxib targets only the COX-2 isoform. To assess the tolerability of rofecoxib compared with naproxen for treatment of osteoarthritis. Randomized, controlled trial. 600 office and clinical research sites. 5557 patients (mean age, 63 years) with a baseline diagnosis of osteoarthritis of the knee, hip, hand, or spine. Rofecoxib, 25 mg/d, or naproxen, 500 mg twice daily. Use of routine medications, including aspirin, was permitted. Discontinuation due to GI adverse events (primary end point) and use of concomitant medication to treat GI symptoms (secondary end point). Efficacy was determined by patient-reported global assessment of disease status and the Australian/Canadian Osteoarthritis Hand Index, as well as discontinuations due to lack of efficacy. Patients were evaluated at baseline and at weeks 6 and 12. Rates of cumulative discontinuation due to GI adverse events were statistically significantly lower in the rofecoxib group than in the naproxen group (5.9% vs. 8.1%; relative risk, 0.74 [95% CI, 0.60 to 0.92]; P = 0.005), as were rates of cumulative use of medication to treat GI symptoms (9.1% vs. 11.2%; relative risk, 0.79 [CI, 0.66 to 0.96]; P = 0.014]). Subgroup analysis of patients who used low-dose aspirin (13%) and those who previously discontinued using arthritis medication because of GI symptoms (15%) demonstrated a relative risk similar to the overall sample for discontinuation due to GI adverse events (relative risk, 0.56 [CI, 0.31 to 1.01] and 0.53 [CI, 0.34 to 0.84], respectively). No statistically significant difference was observed between treatments for efficacy in treating osteoarthritis or for occurrence of other adverse events. In patients with osteoarthritis treated for 12 weeks, rofecoxib, 25 mg/d, was as effective as naproxen, 500 mg twice daily, but had statistically significantly superior GI tolerability and led to less use of concomitant GI medications. Benefits of rofecoxib in subgroup analyses were consistent with findings in the overall sample.",2003.0,1,1
310,14555862,Tolerability of rofecoxib in patients with adverse reactions to nonsteroidal anti-inflammatory drugs: a study of 216 patients and literature review.,Maria Rosaria Perrone; Maria Cristina Artesani; Marinella Viola; Francesco Gaeta; Mario Caringi; Donato Quaratino; Antonino Romano,"Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are frequent, particularly among patients with chronic urticaria or asthma. The identification of an alternative safe and reliable drug is a common problem in clinical practice. To assess the tolerability of rofecoxib, a new NSAID that selectively inhibits the inducible isoform of cyclooxygenase, in a large group of NSAID-sensitive patients. We studied 216 patients (164 females and 52 males) who had suffered adverse reactions to one or more NSAIDs; 98 subjects (45.4%) had experienced reactions to only one NSAID (single hypersensitivity) and 118 subjects (54.6%) had reacted to multiple NSAIDs (multiple hypersensitivity). Cutaneous reactions were reported by 79.6% of the subjects, respiratory symptoms by 10.7%, cutaneous and respiratory symptoms by 8.3%, anaphylaxis by 1.4%. All the subjects underwent a single-blind, placebo-controlled oral challenge with divided therapeutic doses of rofecoxib (6.25 mg +18.75 mg 1 h later = cumulative dose of 25 mg). No reactions to the placebo were observed; only 1 subject (0.46%) experienced an urticarial reaction, after the second dose of rofecoxib. Considering previous studies and our own data, rofecoxib was well tolerated by all of the 174 patients with exclusively NSAID-related respiratory symptoms. Rofecoxib also had a very low rate (1.6%) of cross-reactivity in the 600 patients with exclusively cutaneous reactions to NSAIDs.",2003.0,0,0
311,14564311,Selective COX-2 inhibition and cardiovascular effects: a review of the rofecoxib development program.,Matthew R Weir; Rhoda S Sperling; Alise Reicin; Barry J Gertz,"See related Editorials on pages 561 and 563. Cyclo-oxygenase-2 (COX-2) inhibitors appear to alter the balance of vasoactive eicosanoids (prostacyclin and thromboxane) and to suppress the inflammatory mediators implicated in the progression of atherogenesis and ischemic myocardial injury. Neutral, harmful, and beneficial cardiovascular (CV) effects have all been postulated to result from these changes. Investigations conducted with rofecoxib, a selective COX-2 inhibitor, have substantially contributed to our understanding of this scientific area. Rofecoxib had little or no effect on platelet aggregation or platelet-derived thromboxane synthesis but reduced systemic prostacyclin synthesis by 50% to 60%. These findings prompted extensive analyses of CV thrombotic events within the rofecoxib development program. Among 5435 osteoarthritis trial participants, similar rates of CV thrombotic events were reported with rofecoxib, placebo, and comparator, nonselective NSAIDs (ibuprofen, diclofenac, and nabumetone). In the VIGOR gastrointestinal outcomes trial of >8000 patients, naproxen (an NSAID with aspirin-like sustained antiplatelet effects throughout its dosing interval) was associated with a significantly lower risk of CV events than was rofecoxib. A subsequent pooled analysis from 23 studies (including VIGOR) encompassing multiple disease states and including more than 14,000 patient-years at risk also demonstrated that rofecoxib was not associated with excess CV thrombotic events compared with either placebo or nonnaproxen NSAIDs. Again, naproxen appeared to be the outlier, suggesting a cardioprotective benefit of naproxen. Finally, among the predominantly elderly, male population participating in Alzheimer trials, both rofecoxib- and placebo-treated patients had similar rates of CV thrombotic events. The totality of data is not consistent with an increased CV risk among patients taking rofecoxib.",2003.0,0,0
312,14568792,Postoperative hemorrhage with nonsteroidal anti-inflammatory drug use after tonsillectomy: a meta-analysis.,Srinivasan Krishna; Larry F Hughes; Sandra Y Lin,"To use standard meta-analysis techniques to determine the risk of postoperative hemorrhage associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) after tonsillectomy. The MEDLINE database (1966-2001) restricted to the English language was searched using the keywords tonsillectomy, hemorrhage, analgesics, and NSAID in various combinations. Additionally, published articles were cross-referenced. To ensure completeness, the search was rerun using the Science Citation Index database. Of the 110 articles identified, 7 were selected. Selected studies were prospective trials comparing the effects of an NSAID and a control drug on posttonsillectomy pain and hemorrhage in pediatric and/or adult patients. In all cases, the NSAID or control was administered through an enteric route in the postoperative period. Patients were monitored for early and delayed hemorrhage. Data were extracted independently by 2 investigators. A random effects model was used to compute a pooled odds ratio. For the 1368 patients included in analysis, the pooled odds ratio of posttonsillectomy hemorrhage with NSAIDs compared with controls was 1.29 and was not statistically significant (95% confidence interval, 0.85-1.73; P>/=.05). A subgroup analysis revealed an odds ratio of 0.93 (95% confidence interval, 0.44 -1.95; P>/=.05) for the nonaspirin NSAID group, while the aspirin group had a statistically significant odds ratio of 1.94 (95% confidence interval, 1.09-3.42; P =.02). There is an increased risk of posttonsillectomy hemorrhage with the use of aspirin after tonsillectomy; however, there appears to be no significant increased risk of bleeding for nonaspirin NSAIDs in this meta-analysis.",2003.0,0,0
313,14575647,Cyclooxygenases in the skin: pharmacological and toxicological implications.,Juliette L Lee; Hasan Mukhtar; David R Bickers; Levy Kopelovich; Mohammad Athar,"Cyclooxygenase (COX), a prostaglandin-endoperoxide synthase (PTGS), catalyzes the formation of prostaglandins from arachidonic acid. Prostaglandins are lipid signaling mediators that play a central role in a broad range of diverse physiological and pathophysiological processes, including inflammation, reproduction, nocioception, and gastrointestinal protection. Inhibition of cyclooxygenase activity is the mechanism by which nonsteroidal antiinflammatory drugs (NSAIDS) exert their analgesic, antipyretic, antiinflammatory, and antithrombotic effects. COX is currently believed to exist in three isoforms. In this review, we provide a concise state-of-the-art description of the role of COX in pharmacology and toxicology of skin including its involvement in normal physiology, cutaneous inflammation, nociception, wound healing, and tumorigenesis. COX-dependent pathways influence keratinocyte differentiation, hair follicle development, and hair growth. The critical role of COX-2 in pathophysiology of skin is also addressed. COX-2 mediates inflammatory processes in skin, including inflammatory hyperalgesia and nociception, and administration of specific COX-2 inhibitors reduces edema, vascular permeability, and other markers of cutaneous inflammation. A number of studies in animal models and in humans show that COX-2 inhibitors possess cancer chemopreventive properties. Selective COX-2 inhibitors have a more favorable side-effect profile. Topical formulations of COX-2 inhibitors are being developed as a novel pharmacologic approach for the treatment of COX-2 mediated skin diseases.",2003.0,0,0
314,14576372,"Cyclooxygenase-2 inhibitors: are they really atherothrombotic, and if not, why not?",Graeme J Hankey; John W Eikelboom,"BACKGROUND AND SUMMARY: Selective cyclooxygenase (COX)-2 inhibitors are increasingly being used in place of ""conventional"" nonsteroidal anti-inflammatory drugs (NSAIDs). This is because they are just as effective as NSAIDs in relieving arthritic pain and yet less gastrotoxic. However, the cardiovascular safety of selective COX-2 inhibitors has been questioned because they selectively reduce prostacyclin production, thus disrupting the normal homeostatic balance and promoting a prothrombotic state. These theoretical concerns appear to be supported by the results of clinical trials demonstrating an increased risk of myocardial infarction with COX-2 inhibitors compared with a conventional NSAID, and indirect comparisons of the rates of myocardial infarction among patients treated with a selective COX-2 inhibitor compared with aspirin in different trials. However, emerging data from animal, experimental and clinical studies suggest that COX-2 is atherogenic and thrombogenic, and that selective COX-2 inhibitors may be cardioprotective. Meta-analyses of randomized trials of selective COX-2 inhibitors compared with placebo have demonstrated no excess of cardiovascular events among patients allocated COX-2 inhibitors, and preliminary data from a randomized controlled trial of the selective COX-2 inhibitor meloxicam, in patients with acute coronary syndrome who were treated with aspirin, demonstrated a reduction in cardiovascular events among patients allocated the COX-2 inhibitor. Continuing uncertainty regarding the direction and magnitude of any cardiovascular effects of selective COX-2 inhibitors, coupled with their widespread and increasing use, mandates prospective randomized evaluation of their efficacy and safety in patients at increased risk of future cardiovascular events.",2003.0,0,0
315,14576559,Cyclooxygenase-2 inhibitors in postoperative pain management: current evidence and future directions.,Ian Gilron; Brian Milne; Murray Hong,,2003.0,0,0
316,14594148,Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial.,John S Morley; John Bridson; Tim P Nash; John B Miles; Sarah White; Matthew K Makin,"The analgesic effectiveness and adverse effect incidence of a daily dose of 10 or 20 mg of oral methadone were evaluated in 18 patients with a diverse range of chronic neuropathic pain syndromes, who had all responded poorly to traditional analgesic regimens. Analgesia was seen after each dose of methadone. As compared with placebo, the 20 mg daily dose (given as 10 mg bd) resulted in statistically significant (P = 0.013-0.020) improvements in patient Visual Analogue Scale ratings of maximum pain intensity, average pain intensity and pain relief, recorded at the same time daily. The analgesic effects extended over 48 hours, as shown by statistically significant (P = 0.013-0.020) improvements in all three outcomes on the rest days instituted between each daily dose. Analgesic effects (lowered maximum pain intensity and increased pain relief, on the day of dosing only) were also seen when the lower daily dose of 10 mg methadone (given as 5 mg bd) was used, but these failed to reach statistical significance (P = 0.064 and 0.065, respectively). Interpatient analysis showed that the analgesic effects were not restricted to any particular type of neuropathic pain. Patient compliance was high throughout the trial. One patient withdrew during the 10 mg and six during the 20 mg methadone treatment periods. This is the first double-blind randomized controlled trial to demonstrate that methadone has an analgesic effect in neuropathic pain.",2003.0,0,0
317,14603582,Gastroprotection by coxibs: what do the Celecoxib Long-Term Arthritis Safety Study and the Vioxx Gastrointestinal Outcomes Research Trial tell us?,Jaime A Oviedo; M Michael Wolfe,Current evidence suggests that PPIs might be effective in maintaining patients in remission during continued NSAID use and that the combination of omeprazole plus diclofenac is as effective as treatment with celecoxib in preventing recurrent bleeding. Larger outcome studies comparing the combination of a PPI with other nonselective NSAIDs and a selective COX-2 inhibitor (and the combination of a selective COX-2 inhibitor with a PPI or misoprostol) are required to determine whether or not any regimen will further decrease or eliminate the risk of ulcer complications in high-risk individuals.,2003.0,0,0
318,14612477,Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement: a randomized controlled trial.,Asokumar Buvanendran; Jeffrey S Kroin; Kenneth J Tuman; Timothy R Lubenow; Dalia Elmofty; Mario Moric; Aaron G Rosenberg,"Controlling postoperative pain after knee replacement while reducing opioid-induced adverse effects and improving outcomes remains an important challenge. To assess the effect of combined preoperative and postoperative administration of a selective inhibitor of cyclooxygenase 2 on opioid consumption and outcomes after total knee arthroplasty (TKA). Randomized, placebo-controlled, double-blind trial conducted June 2001 through September 2002, enrolling 70 patients aged 40 to 77 years and undergoing TKA at a university hospital in the United States. Patients were randomly assigned to receive 50 mg of oral rofecoxib at 24 hours and at 1 to 2 hours before TKA, 50 mg daily for 5 days postoperatively, and 25 mg daily for another 8 days, or matching placebo at the same times. Postoperative outcomes including postsurgical analgesic consumption and pain scores achieved, nausea and vomiting, joint range of motion, sleep disturbance, patient satisfaction with analgesia, and hematologic and coagulation parameters. Total epidural analgesic consumption and in-hospital opioid consumption were less in the group receiving rofecoxib compared with the group receiving placebo (P<.05). Median pain score (visual analog scale [VAS], 0-10) achieved for the knee was lower in the rofecoxib group compared with the placebo group during hospital stay (2.2 [interquartile range [IQR], 1.4-3.2] vs 3.5 [IQR, 2.7-4.3], P<.001) and 1 week after discharge (2.6 [IQR, 1.4-3.5] vs 3.7 [IQR, 2.9-4.7], P =.03). There was less postoperative vomiting in the rofecoxib group (6%) compared with the placebo group (26%) (P =.047), as well as a decrease in sleep disturbance compared with the placebo group on the night of surgery (P =.006) and on the first (P =.047) and second (P<.001) days postoperatively. Knee flexion was increased in the rofecoxib group compared with the placebo group at discharge (active flexion: mean [SD], 84.2 degrees [11.1 degrees ] vs 73.2 degrees [13.6 degrees ], P =.03; passive flexion: 90.5 degrees [6.8 degrees ] vs 81.8 degrees [13.4 degrees ], P =.05) and at 1 month postoperatively (109.3 degrees [8.5 degrees ] vs 100.8 degrees [11.8 degrees ], P =.01), with shorter time in physical therapy to achieve effective joint range of motion. The rofecoxib group was more satisfied with analgesia and anesthesia at discharge compared with the placebo group (median satisfaction score, 4.3 [IQR, 3.0-4.7] vs 3.3 [IQR, 2.3-4.3], respectively; P =.03), and the differences persisted at 2-week and at 1-month follow-up. There was no intergroup difference in surgical blood loss (P>.05 for both intraoperative and postoperative blood loss). Perioperative use of an inhibitor of cyclooxygenase 2 is an effective component of multimodal analgesia that reduces opioid consumption, pain, vomiting, and sleep disturbance, with improved knee range of motion after TKA.",2003.0,0,0
319,14613263,Comparison of rheumatoid arthritis clinical trial outcome measures: a simulation study.,Jennifer J Anderson; James A Bolognese; David T Felson,"Isolated studies have suggested that continuous measures of response may be better than predefined, dichotomous definitions (e.g., the American College of Rheumatology 20% improvement criteria [ACR20]) for discriminating between rheumatoid arthritis (RA) treatments. Our goal was to determine the statistical power of predefined dichotomous outcome measures (termed ""a priori""), compared with that of continuous measures derived from trial data in which there was no predefined response threshold (termed ""data driven""), and to evaluate the sensitivity to change of these measures in the context of different treatments and early versus later-stage disease. In order to generalize beyond results from a single trial, we performed simulation studies. We obtained summary data from trials comparing disease-modifying antirheumatic drugs (DMARDs) and from comparative coxib-placebo trials to test the power of 2 a priori outcomes, the ACR20 and improvement of the Disease Activity Score (DDAS), as well as 2 data-driven outcomes. We studied patients with early RA and those with later-stage RA (duration of <4 years and 4-9 years, respectively). We performed simulation studies, using the interrelationship of ACR core set measures in the trials to generate multiple trial data sets consistent with the original data. The data-driven outcomes had greater power than did the a priori measures. The DMARD comparison was more powerful in early disease than in later-stage disease (the sample sizes needed to achieve 80% power for the most powerful test were 64 for early disease versus 100 for later disease), but the coxib-versus-placebo comparison was less powerful in early disease than in later disease (the sample sizes needed to achieve 80% power were 200 and 100, respectively). When the effects of treatment on core set items were small and/or inconsistent, power was reduced, particularly for a less broadly based outcome (e.g., DDAS) compared with the ACR20. The simulation studies demonstrate that data-driven outcome definitions can provide better sensitivity to change than does the ACR20 or DDAS. Using such methods would improve power, but at the expense of trial standardization. The studies also show how patient population and treatment characteristics affect the power of specific outcome measures in RA clinical trials, and provide quantification of those effects.",2003.0,0,0
320,14613272,"Comparing the efficacy of cyclooxygenase 2-specific inhibitors in treating osteoarthritis: appropriate trial design considerations and results of a randomized, placebo-controlled trial.",Allan Gibofsky; Gary W Williams; Frank McKenna; John G Fort,"To compare the efficacy of the cyclooxygenase 2 (COX-2)-specific inhibitors celecoxib and rofecoxib in treating the signs and symptoms of osteoarthritis (OA). In this randomized, placebo-controlled, double-blind, multicenter study, 475 patients with OA of the knee received either celecoxib 200 mg/day (n = 189), rofecoxib 25 mg/day (n = 190), or placebo (n = 96) for 6 weeks. Arthritis assessments were performed at baseline, week 3, and week 6 (or at the time of early termination). In primary measures of efficacy (OA pain score on a 100-mm visual analog scale [VAS] and total domain score on the Western Ontario and McMaster Universities Osteoarthritis Index), celecoxib 200 mg/day and rofecoxib 25 mg/day demonstrated similar efficacy. At week 6, celecoxib was associated with a 34-mm mean improvement on the VAS for OA pain, compared with 31.6 mm for rofecoxib and 21.2 mm for placebo. The difference between celecoxib and rofecoxib was -2.5 mm, with an upper limit of the 95% confidence interval of 2.7 mm and within the prespecified definition of noninferiority. Secondary measures of efficacy showed similar results. All differences in primary and secondary measures of efficacy between the 2 active treatments and placebo were statistically significant (P < 0.02), whereas all of the comparisons of efficacy between celecoxib and rofecoxib met the predefined criteria for noninferiority. All treatments were well tolerated throughout the study, with similar proportions of patients withdrawing due to adverse events. Celecoxib 200 mg/day and rofecoxib 25 mg/day are equally efficacious in treating the signs and symptoms of OA.",2003.0,1,1
321,14633532,Preincisional treatment to prevent pain after ambulatory hernia surgery.,D Janet Pavlin; Karen D Horvath; Edward G Pavlin; Kristien Sima,"We designed this study as a randomized comparison of postoperative pain after inguinal hernia repair in patients treated with triple preincisional analgesic therapy versus standard care. Triple therapy consisted of a nonsteroidal antiinflammatory, a local anesthetic field block, and an N-methyl-D-aspartate inhibitor before incision. The treatment group (n = 17) received rofecoxib, 50 mg PO, a field block with 0.25% bupivacaine/0.5% lidocaine, and ketamine 0.2 mg/kg IV before incision; controls (n = 17) received a placebo PO before surgery. The anesthetic protocol was standardized. Postoperative pain was treated by fentanyl IV and oxycodone 5 mg/acetaminophen 325 mg PO as required for pain. Pain scores (0-10) and analgesic were recorded for the first 7 days after surgery. Pain scores were 47% lower in the treatment group before discharge (3.1 +/- 0.6 versus 5.9 +/- 0.6, P = 0.0026) (mean +/- SE) and 18% less in the first 24 h after discharge (5.6 +/- 0.4 versus 6.8 +/- 0.5, P = 0.05); oral analgesic use was 34% less in the treatment group (4.6 +/- 0.8 doses versus 7.1 +/- 0.7 doses, P = 0.02) in the first 24 h after surgery. We conclude that triple preincisional therapy diminishes pain and analgesic use after outpatient hernia repair, and encourage further evaluation of this technique. Outpatients undergoing inguinal hernia repair under general anesthesia report moderate-to-severe pain after surgery. Triple preincisional therapy that included rofecoxib, 50 mg PO, ketamine, 0.2 mg/kg IV, and local anesthetic field block reduced pain scores and analgesic use in the first 24 h after discharge.",2003.0,0,0
322,14665354,A randomized double-blind prospective study evaluating patient tolerance of transrectal ultrasound-guided biopsy of the prostate using prebiopsy rofecoxib.,Alireza Moinzadeh; Arthur Mourtzinos; Veronica Triaca; Karim J Hamawy,"To assess the use of a prebiopsy outpatient analgesia using the nonsteroidal anti-inflammatory agent rofecoxib (Vioxx). Urologists perform approximately 500,000 transrectal ultrasound (TRUS)-guided biopsies of the prostate per year, commonly without analgesia. Recent reports, however, have determined that a significant proportion of patients undergoing TRUS-guided biopsies have pain. We performed a prospective randomized double-blind study of 56 men referred for TRUS biopsy of the prostate. They were randomly assigned to receive 50 mg of oral rofecoxib or placebo before TRUS biopsy. After the biopsies, the patients were asked to score the severity of pain by filling out a visual analog pain scale. At the end of 1 week, all patients were asked to mail in a questionnaire regarding the morbidity of the prostate biopsy, including dysuria, hematuria, urinary retention, postbiopsy fever, and rectal bleeding. Analysis was completed to assess whether rofecoxib decreased the patients' perception of pain. The postbiopsy morbidity of patients receiving placebo versus rofecoxib was compared. Thirty-seven percent of patients receiving placebo and 42% of patients receiving rofecoxib had significant pain (5 or greater on the visual analog pain scale). The median pain score of patients receiving rofecoxib (4.0) versus placebo (4.0) was not significantly different statistically (P = 0.3139) using a Wilcoxon rank sum analysis. The incidence of postbiopsy morbidity was not different. Our results confirm the findings of previous studies demonstrating that a significant proportion of patients undergoing prostate biopsies have pain. More importantly, we found that prebiopsy rofecoxib did not significantly decrease the patients' severity of discomfort. Finally, the morbidity after biopsy was not increased with the use of rofecoxib.",2003.0,0,0
323,7506144,"Double-blind study of nimesulide in divers with inflammatory disorders of the ear, nose and throat.",G Banchini; I Scaricabarozzi; U Montecorboli; A Ceccarelli; F Chiesa; L Ditri; G Mazzer; R Moroni; M Viola; F Roggia,"200 divers of either sex, aged 18 to 54 years, entered a double-blind study to compare the efficacy and tolerability of nimesulide 200 mg/day with those of seaprose S 60 mg/day in the treatment of nonbacterial inflammatory disorders of the ear, nose, and throat. At the end of the 1-week treatment period, both drugs were judged to be effective, with improvements and, in most cases, complete remission of all symptoms observed. Nimesulide showed greater clinical efficacy, and both drugs were well tolerated.",1993.0,0,0
324,7506146,Treatment of upper airways inflammation with nimesulide.,L Bellussi; D Passàli,"Nimesulide treatment for 7 to 10 days is shown to be effective in controlling the inflammatory process in upper airways disorders such as rhinitis, rhinosinusitis, rhinopharyngitis and tubaritis, and in middle ear disorder (secretory otitis media). A concomitant antibacterial is considered necessary in cases involving infection, in order to retain the improvements in mucociliary transport obtained with anti-inflammatory treatment. Nimesulide is also shown to be effective when given in combination with the mucolytic drug ambroxol.",1993.0,0,0
325,7506148,Efficacy and tolerability of nimesulide in asthmatic patients intolerant to aspirin.,S Bianco; M Robuschi; G Petrigni; M Scuri; M G Pieroni; R M Refini; A Vaghi; P S Sestini,"Inflammation of the airways accompanied by eosinophil infiltration appears to play a fundamental role in the pathogenesis of bronchial asthma. Therefore, anti-inflammatory agents (at present corticosteroids, cromoglycate and nedocromil) are the first-line treatment for this condition. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin (acetylsalicylic acid) and indomethacin, however, have never been used in this setting, mainly for fear of adverse effects (e.g. severe obstructive reactions); these can occur, in a consistent number of patients as a consequence (according to the most widely accepted theory) of inhibition of prostaglandin synthesis. In a double-blind crossover placebo-controlled study involving 20 aspirin-sensitive patients with asthma, we found that oral nimesulide 100mg was well tolerated both clinically and functionally (no significant changes in forced expiratory volume in 1 second and specific airway resistance after drug intake). In a more recent study, we observed a mild obstructive reaction (easily controlled with inhaled bronchodilators) after oral administration of nimesulide 400mg to 3 patients who had previously tolerated a 100mg dose. On the basis of clinical experience, nimesulide (unlike most other NSAIDs) in the recommended doses appears to be well tolerated in aspirin-sensitive asthmatic patients. Furthermore, this distinctive anti-inflammatory agent might provide a novel approach to the treatment of bronchial asthma.",1993.0,0,0
326,7506150,A comparison of nimesulide vs paracetamol in the treatment of pyrexia in the elderly.,E Cunietti; M Monti; A Viganò; E D'Aprile; A Saligari; E Scafuro; I Scaricabarozzi,"The efficacy and safety of rectally administered nimesulide 200mg and paracetamol 500mg were assessed in a double-blind study. The study was conducted in 39 elderly inpatients with infections of the upper or lower respiratory tract associated with fever; 18 patients received nimesulide and 21 received paracetamol. Both treatments were given for 2 consecutive days and provided adequate therapy for pyrexia, with significant reductions in body temperature being observed. Both drugs were well tolerated. Only 1 patient in the nimesulide-treated group could not complete the study because cutaneous erythema occurred with itching; this resolved spontaneously upon treatment withdrawal. It is concluded that nimesulide is as active and safe as paracetamol for the treatment of pyrexia in the elderly.",1993.0,0,0
327,7506155,Controlled clinical studies of nimesulide in the treatment of urogenital inflammation.,T Lotti; V Mirone; C Imbimbo; F Corrado; G Corrado; F Garofalo; I Scaricabarozzi,"Two double-blind, randomised studies were conducted to compare the efficacy and tolerability of nimesulide (200 mg/day) with those of placebo or bromeline (240 mg/day). Treatments were administered orally to patients of either sex (aged 19 to 70 years) with acute infection and inflammation of the urogenital tract, and were given concomitantly with antimicrobial therapy for approximately 9 days. In both studies, a clinically significant improvement in symptoms, leading to complete remission, was achieved in most patients treated with nimesulide. Furthermore, treatment with nimesulide resulted in a more rapid improvement in symptoms and complete remission in a greater number of patients than did treatment with bromeline. Both nimesulide and bromeline were well tolerated.",1993.0,0,0
328,7506156,Treatment of abacterial prostato-vesiculitis with nimesulide.,D Canale; P Turchi; P M Giorgi; I Scaricabarozzi; G F Menchini-Fabris,"The efficacy and tolerability of nimesulide were assessed in the treatment of patients with prostato-vesiculitis. In a noncomparative investigation, 30 patients received oral nimesulide 100mg twice daily for three 10-day cycles. Micturition-related symptoms were resolved in 20 patients and clear amelioration of inflammatory signs was observed with transrectal ultrasound in 16 patients. Abnormal sperm forms decreased from 57 to 49% (p < 0.001). In a comparative investigation, 40 patients received nimesulide 200mg twice daily or ketoprofen 100mg twice daily via the rectal route. Patients and physicians expressed an overall opinion on efficacy in favour of nimesulide. In a pharmacokinetic study of healthy volunteers who received oral nimesulide 100mg as a single dose, the mean maximum nimesulide concentration (0.58 +/- 0.13 mg/L) in seminal fluid was achieved after 2 hours while the maximum seminal fluid: blood plasma ratio 0.32 +/- 0.02 was observed after 4 hours. These data suggest that nimesulide is an effective NSAID in the treatment of abacterial prostato-vesiculitis and also demonstrate that this drug has a favourable disposition within the genital tract.",1993.0,0,0
329,7506159,Nimesulide in the treatment of advanced cancer pain. Double-blind comparison with naproxen.,F Toscani; M Gallucci; I Scaricabarozzi,The analgesic efficacy and tolerability of nimesulide and naproxen were compared in 68 patients with advanced cancer who needed to be treated with nonsteroidal anti-inflammatory drugs according to the first step of the pharmacological analgesic scale of the WHO. Patients received either nimesulide 200mg or naproxen 500mg twice daily. The analgesic efficacy and tolerability of the 2 drugs appeared to be similar. Both drugs were effective and were associated with a low incidence of adverse reactions.,1993.0,0,0
330,7506161,Controlled clinical investigation of acute analgesic activity of nimesulide in pain after oral surgery.,J P Ragot; T Monti; A Macciocchi,"A double-blind study was conducted to determine the dose-effect relationship of nimesulide and to compare the acute analgesic activity of this agent with that of placebo and niflumic acid. Patients undergoing extraction of an impacted third molar were randomised into 4 groups (nimesulide 100mg; nimesulide 200mg; niflumic acid 250mg and placebo). They were instructed to take their allocated treatment after the onset of pain, and to record the pain severity and relief during the following 6 hours. 134 patients were evaluated. There were significant differences between groups for each time of observation/efficacy parameter (Kruskal-Wallis test). Pairwise comparison (Duncan's test) showed that all 3 active medications were significantly different from the placebo. No substantial differences were found between any of the active treatments. Analogous results were obtained when the amount of rescue drug used (paracetamol) was compared. More positive judgements were reported by patients treated with an active compound than by those taking placebo.",1993.0,0,0
331,7506162,A double-blind comparison of nimesulide and ketoprofen in dental surgery.,P Pierleoni; P Tonelli; I Scaricabarozzi,"The efficacy and tolerability of nimesulide were compared with those of ketoprofen when administered rectally in a double-blind investigation of 46 patients scheduled for dental surgery. Nimesulide was more effective and more rapid than ketoprofen in ameliorating the painful inflammatory symptoms (pain at rest and upon mastication) and signs (swelling and hyperaemia) associated with the operation. These effects were accompanied by improved quality of sleep and recovery of masticatory and swallowing function, which was superior for nimesulide-treated patients.",1993.0,0,0
332,7506163,A controlled clinical study of the efficacy and tolerability of nimesulide vs naproxen in maxillo-facial surgery.,G Ferrari Parabita; U Zanetti; F Scalvini; D Rossi; I Scaricabarozzi,"The anti-inflammatory and analgesic efficacy of nimesulide was assessed and compared with that of naproxen in the postoperative treatment of inflammatory complications of maxillo-facial surgery in a double-blind study. A total of 60 patients were randomly assigned to treatment with nimesulide (100mg twice daily) or naproxen (250mg twice daily) for 6 to 14 days. Treatment with either drug prevented the development of, or ameliorated the signs and symptoms associated with, the inflammatory process (spontaneous pain, difficulty in chewing and swallowing, swelling, hyperaemia, muscle contracture, poor sleep quality). Indeed, most patients experienced complete resolution of their signs and symptoms. The efficacy of nimesulide was considered to be superior to that of naproxen, although both drugs were tolerated equally well.",1993.0,0,0
333,7506164,"A comparison of nimesulide and ketoprofen in the prevention and treatment of painful postoperative inflammatory complications of ear, nose and throat surgery.",S Coscarelli; I Scaricabarozzi; M L Nava; E Alajmo,"In a randomised double-blind clinical study, 76 patients undergoing major ear, nose or throat (ENT) surgery (including 45 for cancer) were treated with nimesulide (200mg twice daily) or ketoprofen (100mg twice daily) administered rectally for 5 days. Pain intensity was significantly and similarly reduced in both treatment groups compared with baseline (p = 0.0001). A significant reduction in oedema and hyperaemia was observed on the second day for nimesulide-treated patients and on the third day for those treated with ketoprofen, with complete relief being noted for almost all patients by the fifth day. Fever was resolved in all patients. Adverse events attributable to treatment were observed for 1 patient in each group. These results suggest that nimesulide provides a worthwhile alternative to other NSAIDs in the treatment of postoperative pain and inflammation associated with ENT surgery.",1993.0,0,0
334,7506168,A multicentre double-blind investigation comparing nimesulide and naproxen in the treatment of minor sport injuries.,A Calligaris; I Scaricabarozzi; L Vecchiet,"A total of 660 patients with minor traumatic sport-related lesions of soft tissues were recruited to a randomised double-blind 7-day study to evaluate the efficacy and the tolerability of oral nimesulide (300 mg/day) in comparison with naproxen (750 mg/day). Both drugs were similarly effective in reducing the degree of oedema and intensity of pain, with most patients experiencing remission, which allowed resumption of regular sporting activities. Both drugs were generally well tolerated, although gastrointestinal intolerance was more frequently associated with naproxen therapy.",1993.0,0,1
335,7506169,"Nimesulide in the treatment of osteoarthritis. Double-blind studies in comparison with piroxicam, ketoprofen and placebo.",R L Dreiser; D Riebenfeld,"The efficacy and tolerability profiles of nimesulide (a nonsteroidal anti-inflammatory drug) were assessed in 3 comparative double-blind clinical trials that each recruited 60 patients with osteoarthritis of the hip or knee. The duration of each investigation varied with the comparator agent chosen: 2 weeks for placebo; 3 weeks for piroxicam; 2 months for ketoprofen. Nimesulide and ketoprofen were each administered orally as a 100mg dose twice daily, while piroxicam was administered orally as a single daily 20mg dose. In each study the principal efficacy parameters were the improvement in spontaneous pain, assessed using a visual analogue scale, and the degree of functional impairment evaluated using the severity index of Lequesne; the final judgement of efficacy was made by the physician. In all studies, nimesulide improved these and other efficacy parameters with an activity significantly superior to that of placebo and comparable with that of reference drugs.",1993.0,0,1
336,7506173,A double-blind comparison of nimesulide and mefenamic acid in the treatment of acute upper respiratory tract infections in children.,R Salzberg; S Giambonini; M Maurizio; D Roulet; J Zahn; T Monti,"The efficacy and safety of nimesulide suspension were evaluated in comparison with mefenamic acid in a double-blind multicentre study that recruited 100 children with acute respiratory tract infections. On entry, each child was randomly allocated to receive either nimesulide 5 mg/kg/day or mefenamic acid 5 mg/kg divided into 2 or 3 daily doses as an oral suspension, for a period of 3 to 10 days. Body temperature returned to normal on the third day for most of the nimesulide-treated patients, but only on the fifth day for the mefenamic acid group. There was a significant difference (p < 0.01) between the antipyretic activity of nimesulide and that of mefenamic acid. Furthermore, treatment with nimesulide was associated with clinically significant improvement in all inflammatory signs and symptoms observed (rhinorrhoea, nasal obstruction, pharyngeal redness, swelling of lymph nodes and cough). Adverse effects considered possibly related to treatment were recorded for 3 patients treated with nimesulide and 1 with mefenamic acid.",1993.0,0,0
337,7506175,Clinical and pharmacokinetic study of nimesulide in children.,A G Ugazio; S Guarnaccia; M Berardi; I Renzetti,"The pharmacokinetic profile and efficacy of nimesulide were assessed in 2 separate studies that recruited children with hypoglycaemia or upper respiratory tract infection and fever, respectively. A single dose of nimesulide 50mg (granules) administered orally to 14 hypoglycaemic children was rapidly absorbed. A mean maximum nimesulide plasma concentration of 3.5 mg/L was achieved within 2 hours of administration, which subsequently declined over the following 12 hours. Nimesulide was metabolised to its principal hydroxy metabolite, which was detectable in samples obtained 0.5 hours after giving the parent drug. Levels of this metabolite steadily increased, surpassing those of intact nimesulide at the 9-hour sampling point. In a randomised nonblind clinical investigation, 100 hospitalised children with acute upper respiratory infections and fever received nimesulide oral suspension (5 mg/kg/day) or paracetamol (26 mg/kg/day) for 3 to 9 days. The antipyretic and anti-inflammatory effects of nimesulide were superior to those observed with paracetamol (p < 0.01) and both drugs were equally well tolerated.",1993.0,0,0
338,7506181,An assessment of the efficacy and tolerability of nimesulide vs paracetamol in children after adenotonsillectomy.,G Pasquale; I Scaricabarozzi; R D'Agostino; G Taborelli; R Vallarino,"The efficacy and tolerability of nimesulide were assessed and compared with those of paracetamol in the treatment of 35 children with pain and inflammation following adenotonsillectomy. The antipyretic and analgesic efficacy of the 2 drugs was similar, although more patients had complete remission of pain after 4 days of treatment with nimesulide. Both drugs were well tolerated, even though occasional elevation of transaminase enzymes and alkaline phosphatase was noted in the nimesulide-treated group. It is postulated that this effect may have been attributable to the volatile anaesthetics used during surgery.",1993.0,0,0
339,7506186,Renal effects of nimesulide in furosemide-treated subjects.,F Steinhäuslin; A Munafo; T Buclin; A Macciocchi; J Biollaz,"In clinical settings where effective plasma volume is decreased, nonsteroidal anti-inflammatory drugs (NSAIDs) may induce acute renal failure. We have evaluated the effects of single and repeated doses of nimesulide on renal haemodynamics and electrolyte excretion in 8 healthy volunteers during a prolonged course of furosemide (frusemide). Under these study conditions, renal prostaglandin synthesis is expected to be elevated, with renal function being dependent upon increased levels of prostaglandins. Nimesulide induced an acute but transient decrease in indices of renal haemodynamics. Furosemide-induced increases in plasma renin activity and aldosterone levels were blunted, and urinary excretion of prostaglandin E2 was markedly reduced by nimesulide. The magnitude and time course of the natriuretic, kaliuretic and diuretic effects of furosemide were attenuated by nimesulide. Although the transient nature of the observed renal haemodynamic changes suggests that the risk of developing acute renal failure is small, the rise should be taken into account in patients with renal dysfunction. Sodium and potassium retention, and the blunting of the diuretic-induced electrolyte excretion, could be of clinical relevance. Nimesulide appears, therefore, to share the prostaglandin-dependent renal effects of other NSAIDs.",1993.0,0,0
340,7506190,Tolerability of nimesulide. Epidemiological data.,G Fusetti; E Magni; M C Armandola,"This review describes the tolerability profile of nimesulide as documented in a global assessment of the clinical data available to Helsinn for this drug. Data from 151 trials were considered and the relevant case report forms and study reports were used as source information. The analysis was conducted using between-treatment and within-treatment comparisons. The between-treatment comparison included data derived from placebo-controlled trials, while the within-treatment comparison included nimesulide data only. Of 4945 subjects treated with nimesulide, 349 (7.1%) experienced adverse events and 52 (1.1%) withdrew from treatment. The most frequently reported adverse events were those related to the digestive system, body as a whole, skin and nervous system. The incidence and nature of adverse events observed for nimesulide-treated patients were similar to those of the placebo group. Nimesulide was particularly well tolerated by the liver, lungs, kidneys and blood.",1993.0,0,0
341,7506200,A clinical assessment of the potential for pharmacological interaction between nimesulide and digoxin in patients with heart failure.,E Baggio; F Maraffi; C Montalto; M L Nava; L Torti; I Casciarri,"The potential interaction between nimesulide, a nonsteroidal anti-inflammatory drug, and digoxin was studied in 9 patients [6 males, 3 females; mean age 67 (range 57 to 70) years] with mild heart failure. All patients were receiving maintenance therapy with digoxin (0.25 mg/day, orally) and were treated with oral nimesulide 100mg twice daily for 7 days. Blood samples were collected at 8am and 6pm for 4 days before and throughout the nimesulide treatment period for determination of serum digoxin concentrations. Physical health, electrocardiographic recordings and blood and urine samples were also monitored. Mean serum digoxin concentrations remained within the normal therapeutic range throughout the study despite large interindividual variation. Furthermore, there were no significant differences between the morning and afternoon serum digoxin concentrations and there was no major change in the clinical condition of any patient. These results indicate that short term administration (7 days) of conventional therapeutic doses of nimesulide (100mg twice daily) does not modify the serum digoxin profile in patients with low class heart failure treated with a maintenance dose (0.25 mg/day) of this cardiac glycoside.",1993.0,0,0
342,7589049,Influence of meloxicam on furosemide pharmacokinetics and pharmacodynamics in healthy volunteers.,F O Müller; R Schall; A C de Vaal; G Groenewoud; H K Hundt; M V Middle,"Fifteen healthy male volunteers participated in an open, multiple-dose study to investigate a possible interaction between furosemide and meloxicam, a new non-steroidal anti-inflammatory agent (NSAID). The study comprised three treatment periods. First, furosemide (40 mg) was administered as a single oral daily dose for 3 days. A wash-out day was followed by the administration of meloxicam (15 mg) as a single oral daily dose for 10 days. Thereafter, meloxicam and furosemide were administered concomitantly at the same doses as described above, for 3 days. The effect of concomitant ingestion of meloxicam and furosemide on furosemide-induced diuresis, urine and serum electrolytes, and furosemide pharmacokinetics was determined, after both single and repeated administration of furosemide. Estimates of the ""(furosemide+meloxicam)/(furosemide alone)"" mean ratio of the variable AUC(0-infinity) for plasma furosemide and the cumulative sodium excretion (0-8 h) were 97.4% (90% confidence interval 89.7-106%) and 88% (90% confidence interval 82-94%), respectively. The study results indicate that meloxicam does not affect the pharmacokinetics of furosemide in healthy volunteers, nor does it affect furosemide-induced diuresis or serum electrolytes. The cumulative urinary electrolyte excretion after concomitant administration of meloxicam and furosemide is somewhat lower than after administration of furosemide alone, in particular for the period 0-8 h after administration of furosemide. This effect of meloxicam on furosemide dynamics is small, and is probably not clinically relevant in healthy volunteers under the dosing regime studied.",1995.0,0,0
343,7589053,"The effect of cholestyramine on the pharmacokinetics of meloxicam, a new non-steroidal anti-inflammatory drug (NSAID), in man.",U Busch; G Heinzel; H Narjes,"The influence of multiple oral doses of cholestyramine on the single dose pharmacokinetics of meloxicam has been studied in 12 healthy male volunteers. Each subject received on two occasions a single IV injection of meloxicam 30 mg. The cholestyramine group received the material suspended in water 3 times a day. Compared to controls, cholestyramine accelerated the elimination of meloxicam. The mean terminal phase elimination half-life was reduced from 19.5 h to 12.7 h due to an increase in clearance of the drug (0.426 vs 0.636 l.h-1). Also, as a consequence of increased clearance in the presence of cholestyramine, the mean residence time of the drug in the body was significantly decreased (39%) P < 0.01. However, the volume of distribution for meloxicam was largely unaffected by cholestyramine which suggests that meloxicam undergoes gut recirculation. These changes are of the same magnitude as those previously reported for the structurally related piroxicam and are much smaller than those observed for tenoxicam.",1995.0,0,0
344,7611589,"Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial.",F E Silverstein; D Y Graham; J R Senior; H W Davies; B J Struthers; R M Bittman; G S Geis,"To investigate whether concurrent administration of misoprostol reduces the occurrence of serious upper gastrointestinal complications, such as perforation, gastric outlet obstruction, or bleeding, in patients with rheumatoid arthritis who are receiving nonsteroidal anti-inflammatory drugs (NSAIDs). 6-month randomized, double-blind, placebo-controlled trial. 664 clinical practices of family medicine, internal medicine, or rheumatology in the United States and Canada. 8843 men and women (mean age, 68 years) receiving continuous therapy with any of 10 specified NSAIDs for control of symptoms of rheumatoid arthritis. Patients were enrolled between July 1991 and August 1993. Patients were randomly assigned to receive 200 micrograms of misoprostol or placebo four times a day. Development of serious upper gastrointestinal complications detected by clinical symptoms or findings (not by scheduled endoscopy). Serious upper gastrointestinal complications were reduced by 40% (odds ratio, 0.598 [95% CI, 0.364 to 0.982; P = 0.049]) among patients receiving misoprostol (25 of 4404 patients) compared with those receiving placebo (42 of 4439 patients). During the first month, more patients receiving misoprostol (20%) than placebo (15%) withdrew from the study, primarily because of diarrhea and related problems (P < 0.001). Risk factors for serious upper gastrointestinal complications were increasing age, history of peptic ulcer or bleeding, and cardiovascular disease. Patients with all four risk factors would have a 9% risk for a major complication in 6 months. In older patients with rheumatoid arthritis, misoprostol reduced serious NSAID-induced upper gastrointestinal complications by 40% compared with placebo.",1995.0,1,1
345,7618455,The effect of nimesulide and naproxen on the uterine and ovarian arterial blood flow velocity. A Doppler study.,J Pirhonen; M Pulkkinen,"To measure the effect of oral naproxen and nimesulide treatments on the uterine and ovarian arterial blood flow velocity in both eumenorrheic and dysmenorrheic women. The double-blind, placebo-controlled, study comprised six eumenorrheic women receiving either placebo or nimesulide (100 mg,  single oral dose) during two consecutive cycles. Six women with moderate to severe dysmenorrhea were treated with placebo, nimesulide or naproxen (500 mg, single oral dose) during three consecutive cycles. Uterine impedance (pulsatile index, PI) was measured during the cycle day 1 at four different levels of the uterus and in the ovarian branch of the uterine artery at 0, 30, 60, and 120-140 min, with a color Doppler ultrasonograph for orientation and with pulsatile Doppler for recording waveforms. In the eumenorrheic women no significant changes were found with any treatment. In dysmenorrheic patients, nimesulide relieved symptoms and caused a decrease in uterine artery PI earlier than naproxen. Both treatments reduced the elevated uterine impedance in dysmenorrhea close to the normal level. When analyzing the PIs of the uterine artery at 4 different levels, the most prominent changes were observed in the fundus. The ovarian branch remained unaffected. Color Doppler ultrasonography and pulsatile Doppler are good methods for investigating disease- or drug-induced changes in uterine and ovarian blood flow velocities. Nimesulide induced a slightly faster and more complete decrease of the elevated uterine vascular resistance in dysmenorrhea, towards normal eumenorrheic levels, than naproxen. The fundal part of the uterus appears to be an important site of the pathogenesis in primary dysmenorrhea.",1995.0,0,0
346,7888445,Gastroduodenal toxicity of different nonsteroidal antiinflammatory drugs.,G Traversa; A M Walker; F M Ippolito; B Caffari; L Capurso; A Dezi; M Koch; M Maggini; S S Alegiani; R Raschetti,"Although the etiologic relation between nonsteroidal antiinflammatory drug (NSAID) use and gastrointestinal lesions is well documented, newly introduced NSAIDs deserve a fresh examination for their risk/benefit ratio. To estimate the association between consumption of ketorolac and the occurrence of gastroduodenal lesions, we conducted a case-control study. The study population comprised 600 outpatients with a confirmed endoscopic diagnosis of ulcer and erosion in 1991 and 1992 and 6,000 community controls matched by age and sex. We retrieved the prescription history through a computerized prescription monitoring system. We defined exposure to each study drug as ""current"" (month of endoscopy and preceding month), ""recent"" (second or third month preceding endoscopy). and ""past"" (fourth to sixth month preceding endoscopy). Current users of NSAIDs showed a 30% increase in the incidence of gastroduodenal lesions [odds ratio (OR) = 1.3; 95% confidence interval (CI) = 0.98 - 1.8] after adjustment for recent or past use of any NSAID, recent or past gastrotoxic therapy, recent or past use of gastroprotective drugs, and recent or past use of any other drug. Among NSAIDs, ketorolac was the only one showing a distinctly elevated risk of gastroduodenal lesions (OR = 4.2; 95% CI = 1.9-9.4). Current use of any NSAID was associated with almost a doubling of risk for ulcer alone (OR = 1.9; 95% CI = 1.3-3.0); no elevation in risk was found for erosions. The adjusted relative risk for ulcer associated with current use of ketorolac was 9.8 (95% CI = 3.4-28.10. Recent and past use of NSAIDs does not increase the risk of ulcer.(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0
347,7991575,Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain.,K Seibert; Y Zhang; K Leahy; S Hauser; J Masferrer; W Perkins; L Lee; P Isakson,"Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of inflammatory diseases, but significant side effects such as gastrointestinal erosion and renal damage limit their use. NSAIDs inhibit the enzyme cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to prostaglandins (PGs) and thromboxane. Two forms of COX have been identified--COX-1, which is constitutively expressed in most tissues and organs, and the inducible enzyme, COX-2, which has been localized primarily to inflammatory cells and tissues. In an animal model of acute inflammation (injection of carrageenan into the footpad), edema was produced that was associated with marked accumulation of COX-2 mRNA and thromboxane. A selective inhibitor of COX-2 (SC-58125) inhibited edema at the inflammatory site and was analgesic but had no effect on PG production in the stomach and did not cause gastric toxicity. These data suggest that selective inhibition of COX-2 may produce superior antiinflammatory drugs with substantial safety advantages over existing NSAIDs.",1994.0,0,0
348,8037411,Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis.,A G Johnson; T V Nguyen; R O Day,"A meta-analysis of randomized trials studying the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on blood pressure. Eight databases were searched, yielding 38 randomized, placebo-controlled trials and 12 randomized but not placebo-controlled trials (comparing two or more NSAIDs). Pooled mean treatment effects were computed in each trial for blood pressure, weight, creatinine clearance, plasma renin activity, and daily urinary excretion of sodium and prostaglandins. Meta-analyses of these variables were done for all randomized, controlled trials; for all randomized, uncontrolled trials; and for several subgroups. When pooled, NSAIDs elevated supine mean blood pressure by 5.0 mm Hg (95% CI, 1.2 to 8.7 mm Hg) but had no effect on variables other than blood pressure. Nonsteroidal anti-inflammatory drugs antagonized the antihypertensive effect of beta-blockers (blood pressure elevation, 6.2 mm Hg; CI, 1.1 to 11.4 mm Hg) more than did vasodilators and diuretics. Among NSAIDs, piroxicam produced the most marked elevation in blood pressure (6.2 mm Hg; CI, 0.8 to 11.5 mm Hg), whereas sulindac and aspirin had the least hypertensive effect. Nonsteroidal anti-inflammatory drugs may elevate blood pressure and antagonize the blood pressure-lowering effect of antihypertensive medication to an extent that may potentially increase hypertension-related morbidity. Although certain NSAIDs and antihypertensive agents could be more likely to produce these effects, the underlying mechanisms require further study.",1994.0,0,0
349,8140262,"NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro.",N Futaki; S Takahashi; M Yokoyama; I Arai; S Higuchi; S Otomo,"NS-398 is a novel anti-inflammatory and analgesic agent which produces much fewer gastrointestinal lesions in rats. Recently, two forms of cyclooxygenase have been identified: a COX-1 first purified from ram seminal vesicles and a newly discovered mitogen-inducible form (COX-2). Effects of NS-398 on activities of these two distinct forms of COX were investigated. COX-1 purified from ram seminal vesicles and COX-2 isolated from sheep placenta (purity was 70%) were used. The COX-1 activity was completely unaffected by 10(-4) M NS-398, whereas the COX-2 activity was concentration-dependently inhibited, the IC50 value being 3.8 x 10(-6) M. Indomethacin inhibited both COX-1 and COX-2 activity to the same degree, the IC50 values being 7.4 x 10(-7) M and 9.7 x 10(-7) M, respectively. The anti-inflammatory and analgesic effects of NS-398 were almost as potent as indomethacin, the effective dose range being 0.3 approximately 5 mg/kg in rats. The gastrointestinal lesions related to NS-398 were not significant following a dose of 1000 mg/kg given orally. NS-398 is the first documented agent to have selective inhibition for COX-2, which may result in the less gastrointestinal toxicity.",1994.0,0,0
350,8285810,A study of manufacturer-supported trials of nonsteroidal anti-inflammatory drugs in the treatment of arthritis.,P A Rochon; J H Gurwitz; R W Simms; P R Fortin; D T Felson; K L Minaker; T C Chalmers,"To study the relation between reported drug performance in published trials and support of the trials by the manufacturer of the drug under evaluation, we studied a sample of trials of nonsteroidal anti-inflammatory drugs (NSAIDs) used in the treatment of arthritis. All randomized control trials of NSAIDs published between September 1987 and May 1990 identified by MEDLINE were reviewed. If an article met the following criteria (n = 61), it was selected: trials involving adult patients with osteoarthritis or rheumatoid arthritis (n = 180), use of nonsalicylate NSAIDs marketed in the United States (n = 101), randomized control trial (n = 81), duration of the trial 4 or more days (n = 78), and use of an efficacy outcome measure (n = 61). Reviewers, ""blinded"" to manufacturer status, evaluated the narrative interpretation of results and extracted numeric data on efficacy and toxicity. Manufacturer-associated trials were defined as those that acknowledged an association with a pharmaceutical manufacturer. Because of the scarcity of non-manufacturer-associated trials (n = 9), we report only on the manufacturer-associated articles. Fifty-two publications (85.2%) representing 56 trials were associated with a manufacturer. The manufacturer-associated drug was reported as comparable with (71.4%) or superior to (28.6%) the comparison drug in all 56 trials. These narrative claims of superiority were usually justified with trial data. Of the trials identifying one drug as less toxic (n = 22), the manufacturer-associated drug's safety was reported as superior to the comparison drug in 86.4% of cases. Justification for the narrative interpretation of the trial findings regarding less toxicity was provided in only 12 (54.5%) of 22 trials. The manufacturer-associated NSAID is almost always reported as being equal or superior in efficacy and toxicity to the comparison drug. These claims of superiority, especially in regard to side effect profiles, are often not supported by trial data. These data raise concerns about selective publication or biased interpretation of results in manufacturer-associated trials.",1994.0,0,0
351,8564518,"Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new non-steroidal anti-inflammatory agent with favourable gastrointestinal tolerance.",G Engelhardt; D Homma; K Schlegel; R Utzmann; C Schnitzler,"The anti-inflammatory, analgesic and antipyretic properties of the new non-steroidal anti-inflammatory agent, meloxicam, were investigated in a variety of animal models and compared with the properties of piroxicam, diclofenac, indomethacin and several other NSAIDs. With respect to the total effect of a single oral dose, the anti-exudative effect of meloxicam on carrageenan-induced oedema in the rat exceeded that of all the NSAIDs included in the comparison. Additionally, meloxicam showed the greatest potency of all the compounds examined with respect to adjuvant-induced arthritis in the rat, the granuloma pouch model and the cotton pellet test in the rat. Unlike indomethacin, in the carrageenan pleurisy model in the rat, meloxicam caused both a dose-dependent reduction in exudate volume and also inhibition of leucocyte migration. Meloxicam showed a strong and lasting effect on inflammatory pain in the rat. Like other NSAIDs, but unlike dipyrone, meloxicam had no effect in the hot plate and tail clamp tests, which are used to identify weak central analgesic effects. Unlike dipyrone and like indomethacin, meloxicam had no effect in a model of visceral distention pain. In common with other NSAIDs, meloxicam had no influence on the body temperature of normothermic rats in the anti-inflammatory dose range, but did reduce yeast-induced fever in the rat in a dose-dependent manner. Like piroxicam, meloxicam had a uricosuric effect on rats treated with oxonic acid. Low-dose meloxicam inhibited both bradykinin-induced and PAF-induced bronchospasm in the guinea-pig, but had no effect on acetylcholine-induced bronchospasm. Piroxicam had greater ulcerogenic effects in the rat stomach than meloxicam. The therapeutic range of meloxicam in the rat, with regard to inhibition of adjuvant arthritis, was several times greater than that of piroxicam, indomethacin, diclofenac and naproxen.",1995.0,0,0
352,8595088,Studies on the gastric tolerability of the new non-steroidal anti-inflammatory drug amtolmetin guacyl.,E Tubaro; L Belogi; C M Mezzadri; L Ruco; A Stopacciaro,"Unexpectedly high levels of gastric tolerance to the new non-steroidal anti-inflammatory drug (NSAID) amtolmetin guacyl (CAS 87344-06-7, MED15) were observed in clinical practice. Further investigation of the drug was, therefore, undertaken in order to evaluate its gastrointestinal side-effects in animals. This new agent, which possesses high anti-inflammatory, analgesic and antipyretic activity, was recently introduced into medical therapy. In rats, repeated administration of MED15, even at high dosages, failed to produce any adverse effects on the gastric mucosa, unlike the reference NSAIDs used; the effect on the gastric mucosa was evaluated macro- and microscopically with a staining technique. In immature rat isolated stomachs MED15 strongly down-regulated the HCl output evoked by histamine, acetylcholine and gastrin. An effective NSAID which presents the added advantage of antisecretory properties has not previously been described amongst the many currently available, and reverses the dogma of the inevitable correlation between NSAID assumption and gastrointestinal reactions.",1995.0,0,0
353,8630631,"A double-blind, three-week study to compare the efficacy and safety of meloxicam 7.5 mg and meloxicam 15 mg in patients with rheumatoid arthritis.",J Y Reginster; M Distel; E Bluhmki,"A multicentre, double-blind, randomized study was conducted in patients with rheumatoid arthritis (RA) in order to compare the efficacy and safety of two different doses of meloxicam, a new preferential cyclooxygenase-2 (COX-2) inhibitor. Four hundred and twenty-three patients were randomized to receive once-daily oral meloxicam 7.5 mg (n = 216) or meloxicam 15 mg (n = 207) for 3 weeks. The Ritchie joint index and pain in the morning were significantly improved versus baseline (P < 0.001) in both groups. There were no significant differences between the effects of each dose with respect to these measures nor with respect to final assessment of global efficacy by the patients. However, the 15 mg dose was associated with a significantly (P < 0.05) better effect on morning stiffness and grip strength. No differences between the doses were observed with regard to the other secondary efficacy parameter (pain at night, body weight and erythrocyte sedimentation rate). Both doses of meloxicam were well tolerated. There were no differences between the doses with respect to global tolerance as assessed by the patient and the patients, 'general condition'. In conclusion, meloxicam at a once-daily dose of either 7.5 or 15 mg is well tolerated and effective in the treatment of patients with RA.",1996.0,0,0
354,8630632,A six-month double-blind trial to compare the efficacy and safety of meloxicam 7.5 mg daily and naproxen 750 mg daily in patients with rheumatoid arthritis.,J A Wojtulewski; M Schattenkirchner; P Barceló; X Le Loët; P J Bevis; E Bluhmki; M Distel,"Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID) which preferentially inhibits cyclooxygenase-2 over cyclooxygenase-1. A double-blind parallel-group trial compared meloxicam 7.5 mg once daily (n = 199) with naproxen 750 mg (n = 180) in rheumatoid arthritis. There was no significant difference between the groups regarding the primary efficacy variables (global efficacy assessment by patient and investigator, number of painful/tender and swollen joints) and eight of the ten secondary efficacy endpoints. Only the swollen joint severity index and the number of discontinuations due to lack of efficacy favoured naproxen 750 mg significantly over meloxicam 7.5 mg. Meloxicam was better tolerated in the gastrointestinal (GI) tract, with fewer GI adverse events in the meloxicam-treated group (30.3%) than in the naproxen-treated group (44.7%), where two patients developed ulcers. No ulcers were seen in meloxicam patients. Significantly more patients discontinued due to GI adverse events in the naproxen group. Additionally, there was a significant decrease in haemoglobin and a significant increase in serum creatinine and urea in the naproxen group compared with the meloxicam group. In conclusion, meloxicam 7.5 mg once daily is a promising treatment in rheumatoid arthritis, with efficacy comparable to naproxen 750 mg. Meloxicam has the advantage of a significantly lower incidence of GI and renal side effects.",1996.0,1,1
355,8630634,A double-blind study to compare the efficacy and safety of meloxicam 15 mg with piroxicam 20 mg in patients with osteoarthritis of the hip.,B Lindén; M Distel; E Bluhmki,"Meloxicam 15 mg once daily (n = 128) was compared with piroxicam 20 mg (n = 127) in this 6 week, double-blind, parallel-group, randomized, multicentre study in out-patients with symptomatic osteoarthritis (OA) of the hip. Assessments of pain, global efficacy and global tolerance were made on a 10 cm horizontal visual analogue scale; severity of OA was evaluated by Lequesne's index. Efficacy results showed significant improvement compared with baseline, with no significant difference between meloxicam 15 mg and piroxicam 20 mg. The type and frequency of adverse events were comparable for the two drugs. The most frequent events reported were gastrointestinal (GI) disorders, occurring in 21 and 23% of meloxicam and piroxicam patients respectively. The global tolerance assessment by patients at the end of treatment favoured meloxicam. In conclusion, meloxicam at a dose of 15 mg/day is comparable in efficacy and safety to piroxicam 20 mg.",1996.0,1,1
356,8630635,"Meloxicam in osteoarthritis: a 6-month, double-blind comparison with diclofenac sodium.",J Hosie; M Distel; E Bluhmki,"A multicentre, double-blind, randomized study was conducted in patients with osteoarthritis (OA) of the hip or knee in order to compare the efficacy and safety of the new cyclooxygenase-2 (COX-2) inhibitor, meloxicam, with diclofenac sodium, a conventional treatment for this condition. Three hundred and thirty-six patients were treated with oral meloxicam 7.5 mg once daily or diclofenac 100 mg slow release once daily for 6 months. There were no significant differences between the treatment groups with respect to overall pain, pain on movement, global efficacy or quality of life scores at the end of treatment, all of which showed good levels of improvement. Sixty-six patients were withdrawn after the start of the double-blind phase due to adverse events (n = 21, meloxicam; n = 31, diclofenac) or to lack of efficacy (seven in each group). The median of dose paracetamol taken concomitantly was statistically significantly lower in the meloxicam group than in the diclofenac group (185 vs 245 mg/day; P = 0.0123) with a comparable proportion of patients taking concomitant paracetamol therapy in both groups. Both drugs were well tolerated, although severe adverse events, treatment withdrawal and clinically significant laboratory abnormalities were more common with diclofenac than with meloxicam. Thus, meloxicam 7.5 mg is a safe and effective treatment for OA of the hip and knee which demonstrates a trend towards an improved safety profile compared with diclofenac.",1996.0,1,1
357,8630638,Tolerability of multiple administration of intramuscular meloxicam: a comparison with intramuscular piroxicam in patients with rheumatoid arthritis or osteoarthritis.,P R Ghozlan; M Bernhardt; P Vélicitat; E Bluhmki,"This multicentre, randomized, open controlled study compared the local and overall tolerability of i.m. meloxicam with i.m. piroxicam in 211 patients with rheumatoid arthritis (RA) (n = 95) or osteoarthritis (OA) (n = 116). Of these, 210 patients were randomized (2:1) to receive meloxicam 15 mg (n = 144) or piroxicam 20 mg (n = 66) for 7 days. Local tolerability of meloxicam was significantly better than piroxicam with respect to occurrence of redness after the first injection (P = 0.03) and global assessment after the first and final injections (P < 0.05). No rise in creatinine phosphokinase levels (a marker of muscle fibre damage) was observed with meloxicam, in contrast to piroxicam (P = 0.0001). The overall tolerability of both treatments was good. Significant differences in favour of meloxicam were observed for global efficacy assessed by the patient in RA (P < 0.05) and for overall pain intensity in OA patients (P = 0.02). In conclusion, i.m. meloxicam is safe and effective for the treatment of acute rheumatic pain and shows some superiority over piroxicam.",1996.0,0,0
358,8630640,"A 4-week, double-blind, parallel-group study to compare the gastrointestinal effects of meloxicam 7.5 mg, meloxicam 15 mg, piroxicam 20 mg and placebo by means of faecal blood loss, endoscopy and symptom evaluation in healthy volunteers.",L Patoia; L Santucci; P Furno; M S Dionisi; S Dell'Orso; M Romagnoli; A Sattarinia; M G Marini,"Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID) which preferentially inhibits cyclooxygenase-2 (COX-2) over cyclooxygenase-1 (COX-1). Gastrointestinal (GI) tolerability of meloxicam 7.5 and 15 mg vs piroxicam 20 mg was evaluated in a 4-week, double-blind, parallel group, placebo-controlled study in 51 healthy male volunteers, using a combination of oesphago-gastro-duodenal endoscopy, faecal blood loss measurement and symptom evaluation. Analysis of covariance found no significant difference in faecal blood loss between the groups. However, significantly higher bleeding was found with piroxicam 20 mg compared with placebo using a Student's t-test on the weighted means. Endoscopy score were significantly higher with piroxicam than with meloxicam 7.5 mg or placebo (P < 0.01). A significant difference from baseline was observed in the meloxicam 15 mg and piroxicam groups (P < 0.05), but not in the meloxicam 7.5 mg and placebo groups. Six piroxicam-treated volunteers were withdrawn following a poor endoscopic score, but no such withdrawals occurred in the meloxicam and placebo groups (P < 0.01). Meloxicam 7.5 mg caused less GI damage compared with piroxicam 20 when administered to healthy young volunteers for 28 days; a possible dose dependency effect in GI tolerability was also suggested for meloxicam 7.5 and 15 mg, in relation to endoscopic findings.",1996.0,0,1
359,8665995,"Renal and endocrine effects of flosulide, after single and repeated administration to healthy volunteers.",P Brunel; A Hornych; T T Guyene; A Sioufi; M Turri; J Ménard,"Two double-blind, placebo-controlled, balanced cross-over studies were carried out successively in 8 male normotensive volunteers to investigate the acute and chronic effects of two doses of a novel non-steroidal anti-inflammatory drug flosulide (5 mg b.d. and 25 mg b.d.), on the renin-angiotensin-aldosterone system, linking this to changes in the urinary excretion of prostaglandins. Plasma renin and aldosterone were determined on Days 2 and 9, with the subject supine, after 1 h of rest in the sitting position following 1 h of walking, and 3 h after oral intake of 40 mg furosemide, also in the sitting position. Twenty-four hour urine samples were collected on Days 1 and 8 for the measurement of the electrolytes, aldosterone pH1 and the urinary prostaglandins PGE2, PGF2 alpha, 6-keto-PGF1 alpha and TxB2. After the first day of treatment with 25 mg b.d. flosulide, the increase in body weight was close to significance (0.86 vs -0.08 kg with placebo). A dose- and time-dependent decrease in both active and inactive plasma renin were observed, whereas the fall in plasma and urinary aldosterone was statistically significant only after the higher dose of flosulide. These changes in the renin-angiotensin-aldosterone system were observed in the absence of oedema. Two out of eight volunteers experienced a strong and immediate reduction in the excretion of prostaglandins but overall the two doses tested did not produce a statistically significant inhibition in renal prostaglandins, especially following repeated dosing. The inhibitory effect of flosulide on renal prostaglandin synthesis was found to be less pronounced after repeated treatment, as documented on Day 9 by the lower inhibition of 6-keto-PGF1 alpha and TxB2. These two studies in normal volunteers, in spite of some methodological limitations, were helpful in order to select doses of flosulide which should be effective and safe in patients during Phase II trials, by examining the inhibitory effect of the drug on renin synthesis and renal prostaglandin synthesis.",1995.0,0,0
360,8703654,The effect of meloxicam on the pharmacokinetics of beta-acetyl-digoxin.,F L Degner; G Heinzel; H Narjes; D Türck,"The influence of multiple-dose administration of meloxicam on the pharmacokinetics of oral beta-acetyl-digoxin was studied in 12 healthy male volunteers in a randomized double-blind two-way crossover study. The primary endpoint, Cminss, was within the accepted range for bioequivalence, as were Cmaxss and AUCss. The 90% confidence interval and the point estimator of 98.7 for Cminss were within the equivalence range of 0.8-1.25. MRT and tmax were also unchanged, while the elimination rate constant was decreased slightly by 12%, which is of no therapeutic relevance. It is concluded that co-treatment with meloxicam has no effect on the pharmacokinetics of oral digoxin.",1995.0,0,0
361,8750399,Comparison of the onset and intensity of action of intramuscular meloxicam and oral meloxicam in patients with acute sciatica.,B Auvinet; R Ziller; T Appelboom; P Velicitat,"In this randomized, double-blind, double-dummy trial, 113 patients with acute sciatica were treated with a single 15-mg dose of meloxicam given intramuscularly (n = 54) or orally (n = 59). There was a significant improvement in induced pain (as measured by using the straight-leg-raising test) in both treatment groups at 60 minutes (P < 0.005), and there was a significant difference in favor of the intramuscular formulation in terms of the time to maximum improvement of induced pain (P = 0.01). Changes in spontaneous pain were similar in both treatment groups and were significant versus baseline (P < 0.01) at 30 minutes after study drug administration. Global efficacy evaluations by both the patients and investigators confirmed that meloxicam 15 mg in an intramuscular or oral formulation was effective in relieving pain in patients with acute sciatica. Meloxicam was generally well tolerated, and the local tolerability of the intramuscular injection was found to be excellent on the basis of both clinical evaluation and assessment of creatine phosphokinase levels.",1995.0,0,0
362,8788439,Prostaglandins play a role in memory consolidation in the chick.,C Hölscher,"Previous studies showed that inhibitors of cyclooxygenases have amnesic effects in chicks in a passive avoidance task. The onset of amnesia has a delay of 2 h post-training. To investigate if this effect is due to the inhibition of induction of the enzyme during learning, the release of cyclooxygenase products into the extracellular fluid was measured at 1, 2 and 3 h post-training. A cyclooxygenase inhibitor, ibuprofen, inhibited the training-dependent increase of cyclooxygenase products only 2 h and 3 h after learning when injected pre-training, as did dexamethasone which prevents cyclooxygenase induction, and SC58125 (1,2-diarylcyclopentene), an inhibitor of inducible cyclooxygenase. Injections 30 min post-training showed the same effect with the exception of dexamethasone. Injecting SC58125, ibuprofen, indomethacin, or dexamethasone i.c. before training showed amnesic effects for training on a one-trial passive avoidance task at 2 h but not 1 h after training. Injections 30 min post-training produced the same effects with the exception of dexamethasone. I conclude that cyclooxygenases are induced during training and that cyclooxygenase products are of importance in memory formation of the chick.",1995.0,0,0
363,8806245,"Treatment of menorrhagia during menstruation: randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid.",J Bonnar; B L Sheppard,"To compare the efficacy and acceptability of ethamsylate, mefenamic acid, and tranexamic acid for treating menorrhagia. Randomised controlled trial. A university department of obstetrics and gynaecology. 76 women with dysfunctional uterine bleeding. Treatment for five days from day 1 of menses during three consecutive menstrual periods. 27 patients were randomised to take ethamsylate 500 mg six hourly, 23 patients to take mefenamic acid 500 mg eight hourly, and 26 patients to take tranexamic acid 1 g six hourly. Menstrual loss measured by the alkaline haematin method in three control menstrual periods and three menstrual periods during treatment; duration of bleeding; patient's estimation of blood loss; sanitary towel usage; the occurrence of dysmenorrhoea; and unwanted events. Ethamsylate did not reduce mean menstrual blood loss whereas mefenamic acid reduced blood loss by 20% (mean blood loss 186 ml before treatment, 148 ml during treatment) and tranexamic acid reduced blood loss by 54% (mean blood loss 164 ml before treatment, 75 ml during treatment). Sanitary towel usage was significantly reduced in patients treated with mefenamic acid and tranexamic acid. Tranexamic acid given during menstruation is a safe and highly effective treatment for excessive bleeding. Patients with dysfunctional uterine bleeding should be offered medical treatment with tranexamic acid before a decision is made about surgery.",1996.0,0,0
364,8829018,"Evaluation of the safety, tolerability, and efficacy of meloxicam tablets in patients with osteoarthritis.",P J Prouse; P J Bevis; E Bluhmki; M Distel,"This 12-week, open-label, multicenter study assessed the safety, tolerability, and efficacy of the tablet formulation of meloxicam 15 mg, a new, nonsteroidal antiinflammatory drug (NSAID), in patients with confirmed osteoarthritis (OA) of the hip or knee. Meloxicam differs from established NSAIDs in its preferential activity against cyclooxygenase type 2 compared with cyclooxygenase type 1. One hundred thirty-nine patients were given meloxicam tablets 15 mg once daily. Data were analyzed using an intent-to-treat analysis. Assessments of global tolerability at the end of the study showed meloxicam tablets to be well or very well tolerated by 83% of patients, with only 4% rating the tablets poorly. This finding was supported by the low incidence of adverse events. Only 11% of patients discontinued therapy due to gastrointestinal adverse events, and no serious gastrointestinal adverse events related to meloxicam 15-mg tablets occurred during treatment. Efficacy results showed significant improvement from baseline, with 41% of patients experiencing mild or no pain by the end of the study. In conclusion, the tablet formulation of meloxicam 15 mg is well tolerated and effective in patients with moderate-to-severe, clinical confirmed OA of the hip or knee.",1996.0,0,0
365,8838440,Pharmacokinetics and tolerability of meloxicam after i.m. administration.,H Narjes; D Türck; U Busch; G Heinzel; G Nehmiz,"1. The pharmacokinetics and tolerability of a new nonsteroidal anti-inflammatory drug (NSAID), meloxicam, administered i.m., were investigated in two studies conducted in healthy male volunteers. Study 1 was an open, placebo-controlled design in which 32 volunteers were randomized to a single ascending i.m. dose of meloxicam (5, 10, 20, and 30 mg) or placebo. Study 2 had an open, randomized two way crossover design in which 12 volunteers received single i.m. and i.v. doses of meloxicam (15 mg). 2. Meloxicam showed an excellent tolerability in both studies. No effect was seen on serum creatinphosphokinase (CK, the isoenzyme of the skeletal muscle enzyme, CK-MM, was determined). 3. Following i.m. administration meloxicam was rapidly and completely absorbed (mean absolute bioavailability 102%). Dose-proportionality was demonstrated with respect to Cmax (maximum plasma concentration) and AUC (extrapolated area under the plasma concentration-time curve from zero time to infinity) over a range of 5-30 mg. 4. Intravenous administration of meloxicam (15 mg) resulted in higher initial plasma concentrations (C3min, i.e. concentration in plasma 3 min after start of injection = 2.99 +/- 0.75 microgram.ml-1) than after i.m. injection (Cmax: 1.62 +/- 0.20 mg ml-1). All other pharmacokinetic parameters were similar for both routes of administration (apparent elimination half-life = 15-22 h; plasma clearance = 7-9 ml min-1). 5. In conclusion, the excellent tolerability of i.m. meloxicam together with its rapid and complete absorption may provide an alternative to oral administration of this drug.",1996.0,0,0
366,8872509,"Interaction between enoxacin, a new antimicrobial, and nimesulide, a new non-steroidal anti-inflammatory agent in mice.",Y Taniguchi; Y Deguchi; K Noda,"Convulsions induced by the combination of enoxacin, a new antimicrobial, and nonsteroidal anti-inflammatory drugs including nimesulide, ketoprofen, pranoprofen and loxoprofen sodium, were investigated in mice. The oral administration of nimesulide alone induced clonic convulsions at more than 300 mg/kg. The oral administration of ketoprofen, pranoprofen or loxoprofen sodium induced no convulsion up to 1000 mg/kg, 500 mg/kg and 600 mg/kg, respectively, and that of enoxacin induced no convulsion at more than 5000 mg/kg. The combination of nimesulide at 200 mg/kg and enoxacin at 400 mg/kg induced no convulsion. In contrast, the combination of enoxacin at 100 mg/kg and either ketoprofen at 125 mg/kg or pranoprofen at 500 mg/kg induced clonic convulsions, while that of enoxacin at 400 mg/kg and loxoprofen sodium at 600 mg/kg induced no convulsion. These results suggest that the combination of nimesulide and enoxacin may possibly induce few or less convulsions in the clinical setting.",1996.0,0,0
367,8932547,"Interaction of meloxicam with cimetidine, Maalox, or aspirin.",U Busch; G Heinzel; H Narjes; G Nehmiz,"Meloxicam is a new enol carboxamide nonsteroidal antiinflammatory drug (NSAID). Preclinical studies have indicated that it possesses a high antiinflammatory potency and a low ulcerogenic potency. This open, randomized, crossover study was conducted to examine the effects of aspirin, the antacid Maalox (Rhone-Poulenc Rorer, Cologne, Germany), and cimetidine on the pharmacokinetics and bioavailability of a single oral dose of meloxicam 30 mg in healthy male volunteers. Plasma concentrations of meloxicam were determined and subjected to noncompartmental pharmacokinetic analysis. Meloxicam was well tolerated, and concomitant treatment with cimetidine or Maalox had little or no effect on the plasma concentration-time curves, maximum plasma concentration (Cmax), or the area under the plasma concentration-time curve (AUC0-infinity) of meloxicam. Concurrent treatment with aspirin increased plasma concentrations of meloxicam, increasing Cmax by approximately 25% and AUC0-infinity by 10%. These differences were not considered to be clinically relevant, and no adjustments of meloxicam dose should be required with coadministration of aspirin, Maalox, or cimetidine.",1996.0,0,0
368,9002004,The acute phase and function in early rheumatoid arthritis. C-reactive protein levels correlate with functional outcome.,J Devlin; A Gough; A Huissoon; P Perkins; R Holder; R Reece; V Arthur; P Emery,"To discover whether normalization of C-reactive protein (CRP) in patients with rheumatoid arthritis (RA) results in stabilization of their functional state, and whether a measure of disease activity can be used as a predictor of functional outcome. To examine the relationship between change of CRP and Health Assessment Questionnaire (HAQ) over a 24 mo period to define the sensitivity of HAQ to change. A prospective study of 109 consecutive patients who fulfilled the American College of Rheumatology criteria for RA and had elevated CRP before steroid or 2nd line therapy. A full clinical assessment including HAQ was performed at presentation and at 3, 6, 12, and 24 mo. On the basis of the change in CRP at 6 mo, patients were divided into 3 groups: (1) CRP suppression to normal, (2) 50% reduction in CRP, and (3) less than 50% CRP change. The 3 groups were clinically and immunologically similar at onset. At 6 mo the median HAQ fell to 5 (lower to upper quartiles 7.5 to 19) in Group 1 (CRP normalized, n = 34), 6 (3.75 to 10) in Group 2 (CRP reduced by 50%, n = 30), and 12 (6 to 18) in Group 3 (less than 50% CRP change, n = 44), p < 0.005 for Groups 1 and 2 versus Group 3. At 12 and 24 mo HAQ remained significantly lower in Groups 1 and 2 compared with Group 3. In Group 1, patients either maintained a normal CRP (n = 28) or their CRP became elevated (n = 6). Only in those patients in whom a re-elevation of the CRP occurred was deterioration in HAQ subsequently seen. Suppression of elevated CRP in patients with active RA is associated with improvement in functional score, whereas persistent elevation of CRP is associated with functional deterioration. Once abnormal CRP is suppressed, no functional deterioration is likely to occur without re-elevation in CRP. Therefore, elevated CRP provides a convenient short term correlation with functional outcome and can be used as a guide for therapy. A HAQ score is a sensitive indicator of change in early disease.",1997.0,0,1
369,9002006,Individual relationship between progression of radiological damage and the acute phase response in early rheumatoid arthritis. Towards development of a decision support system.,M A van Leeuwen; M H van Rijswijk; W J Sluiter; P L van Riel; I H Kuper; L B van de Putte; M B Pepys; P C Limburg,"Evaluation of the individual relationship between C-reactive protein (CRP) production or erythrocyte sedimentation rate (ESR) and progression of radiologic damage in early rheumatoid arthritis (RA), to improve the predictive value of monitoring the acute phase response. The relationship was modeled mathematically using adjustments for discontinuity in the radiographic scoring system and for clustering in the occurrence of score points in the initial phase. The model was evaluated in a prospective study of 149 patients with early RA, monthly CRP assays, and 6-monthly Sharp scores of radiographs of the hands and feet. Time integrated CRP values correlated closely with radiologic progression in each patient, but there was considerable variation between individuals with similar radiographic scores. The theoretical model accommodated these results, and based on CRP measurements and radiographic scores over 6 months, it provided a k value for each patient that reflected the individual relationship between CRP and radiologic damage. Using this k value combined with actual CRP levels over 3 and 6 years, the model accurately predicted the extent of radiologic progression that was actually observed at these times. Best results were obtained using estimation of the k value from 6 or 12 month observational data. The model has been incorporated into a software program for routine clinical use that indicates the levels to which CRP should fall to prevent further joint damage. Similar results were obtained for ESR. A model has been established defining the individual relationship between time integrated CRP and ESR values, reflecting rheumatoid disease activity, and progression of radiologic damage. It accurately prediets outcome from 6 months after presentation and can be used as a practical decision support system.",1997.0,0,0
370,9032580,Gastroduodenal tolerability of highly specific cyclo-oxygenase-2 inhibitor.,J Hayllar; I Bjarnason,"Inhibition of constitutively expressed cyclo-oxygenase (COX-1) by NSAIDs is thought to play an important role is the gastrointestinal toxicity of NSAIDs. To minimise the intestinal toxicity of NSAIDS, highly selective COX-2 (induced at inflammatory sites) inhibitors have been developed. One such is flosulide. We assessed the gastroduodenal tolerability of flosulide (20 mg twice a day) in man and compared it with that of naproxen (500 mg twice a day) in a randomised, double blind crossover fashion in 19 patients with osteoarthrosis. Treatment period was 2 weeks with a 2-week washout period with endoscopy before and after each treatment. Gastroduodenal damage was assessed as by Lanza (Grades 0-4) and by the Gastroscopic Rating Scale (Grades 0-9). Flosulide was significantly better tolerated (p < 0.005, analyses of deviance) than naproxen. No stomach damage was seen in 13 (68%) patients following flosulide and 5 (37%) following naproxen (p < 0.001). Lanza scores following flosulide (0.58) were significantly better than that of naproxen (1.47) (p < 0.001). The duodenal damage was mild with both treatments. The selective COX-2 inhibitor, flosulide, is significantly better tolerated and causes less gastric mucosal damage than naproxen when given for two weeks.",1996.0,0,0
371,9034984,Efficacy and safety of meloxicam in patients with rheumatoid arthritis.,E M Lemmel; W Bolten; R Burgos-Vargas; P Platt; M Nissilä; D Sahlberg; O Björneboe; H Baumgartner; J P Valat; P Franchimont; E Bluhmki; G Hanft; M Distel,"To evaluate the efficacy and safety of meloxicam, a new acidic enolic nonsteroidal anti-inflammatory drug, at doses of 7.5 and 15 mg once daily in patients with rheumatoid arthritis (RA). Meloxicam 15 and 7.5 mg daily was administered for 21 days in this double blind, randomized, placebo controlled study. 159 patients received meloxicam 7.5 mg, 162 received meloxicam 15 mg, and 147 received placebo. Meloxicam 15 mg once daily was significantly superior (p < 0.05) to placebo in 3 of the 4 primary endpoints (disease activity assessed by the investigator, disease activity assessed by the patient, and reduction of the number of tender/painful joints). No difference was observed regarding number of swollen joints. The difference between meloxicam 7.5 mg once daily and placebo reached statistical significance in 2 of the 4 primary endpoints, disease activity assessed by the patient and number of tender/painful joints. A statistically significant difference between meloxicam 1.5 mg and 7.5 mg was not observed for any primary endpoint. The rating of global tolerance by investigators and patients at the end of the study was similar in the 3 treatment groups, indicating that meloxicam and placebo were generally similarly well tolerated. However, there was a slightly higher incidence of gastrointestinal (GI) disturbances reported by patients receiving meloxicam 15 mg. GI adverse events were reported by 11, 11, and 16% of patients in the placebo, meloxicam 7.5 mg, and meloxicam 15 mg groups, respectively. None were serious. Meloxicam in daily doses of 7.5 and 15 mg is effective in treating the signs and symptoms of RA.",1997.0,0,1
372,9049585,Lack of interaction between meloxicam and warfarin in healthy volunteers.,D Türck; C A Su; G Heinzel; U Busch; E Bluhmki; J Hoffmann,"The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCss values for the more potent S-enantiomer were 5.07 mg.h.l-1 (27.5%) for warfarin alone and 5.64 mg.h.l-1 (28.1%) during the interaction phase. Respective AUCss values for R-warfarin were 7.31 mg.h.l-1 (43.8%) and 7.58 mg.h.l-1 (39.1%). The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory.",1997.0,0,0
373,9051872,"A randomized, double-blind, crossover comparative endoscopy study on the gastroduodenal tolerability of a highly specific cyclooxygenase-2 inhibitor, flosulide, and naproxen.",I Bjarnason; A Macpherson; H Rotman; J Schupp; J Hayllar,"Inhibition of constitutively expressed cyclooxygenase (Cox-1) is thought to play an important role in the gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs (NSAID), while their therapeutic action may be due to inhibition of the enzyme Cox-2, which is specifically expressed at sites of inflammation. NSAIDs with high affinity and specifity for Cox-2 hold the promise of maintaining efficacy without the gastrointestinal side effects of conventional NSAIDs. We assessed the gastrointestinal tolerability of flosulide (20 mg twice a day), a highly selective Cox-2 inhibitor with that of naproxen (500 mg twice a day), which has equal affinity for Cox-1 and -2 in 19 patients with osteoarthrosis in a randomized, double blind, crossover endoscopy study. Subjects were treated for 2 weeks with a 2-week washout period. Gastroduodenal damage was primarily assessed as by Lanza (grades 0-4). No stomach damage was seen in 13 (68%) patients after flosulide and in 5 (37%) after naproxen (P < 0.001). Lanza scores were significantly lower after flosulide (0.58) than after naproxen (1.47) (P < 0.001; odds ratio, 84.4; 95% confidence interval, 1.45-4908). Flosulide was significantly better tolerated (P < 0.005) than naproxen. These results endorse the idea that highly selective Cox-2 inhibitors may be associated with lesser gastrointestinal side effects than conventional NSAIDs.",1997.0,0,0
374,9074838,Drug treatment of rheumatic diseases in the 1990s. Achievements and future developments.,E H Choy; D L Scott,"There have been several advances in the therapy of arthritis. These are based on better understanding of the pathogenesis of rheumatic diseases, re-evaluation of previous therapeutic concepts such as combination therapy, and developments within biotechnology. There are 4 main areas of development, mainly involving the treatment of inflammatory synovitis. The first is with anti-inflammatory drugs, where there has been a focus on reducing gastrointestinal toxicity through the use of combination preparations such as diclofenac-misoprostol, and the introduction of drugs with more selectivity for cyclo-oxygenase-2 inhibition such as meloxicam. An additional approach has been the development of anti-inflammatory drugs such as tenidap which also control cytokine metabolism. The second area is slow-acting antirheumatic drugs with the introduction of cyclosporin as a single agent or in combination with methotrexate, the development of immunomodulating drugs such as leflunomide, and the demonstration that some antibiotics such as minocycline have slow-acting effects. The third area is the use of corticosteroids including the development of deflazacort as a bone sparing agent, the greater use of intramuscular depot steroids and the validation of low-dose oral corticosteroids in early rheumatoid arthritis. Finally, there have been advances in the biotechnology area with the demonstration that cytokine immunotherapy such as antibodies to tumour necrosis factor can rapidly improve the symptoms of rheumatoid arthritis, and that T cell immunotherapy with antibodies to the CD4 receptor may be effective in reducing synovitis. Many of these agents have not yet been introduced into clinical practice but they show the diversity of drug development and suggest the likelihood of major therapeutic benefits in the next few years.",1997.0,0,0
375,9084574,Effects of meloxicam and indomethacin on cyclooxygenase pathways in healthy volunteers.,D O Stichtenoth; B Wagner; J C Frölich,"Meloxicam is a new NSAID with selectivity for the inducible cyclooxygenase (COX-2) in vitro. We compared the effects of therapeutically equivalent doses of meloxicam and indomethacin, a preferential inhibitor of the constitutive cyclooxygenase (COX-1), on platelet aggregation and platelet thromboxane formation, which are exclusively COX-1 dependent, physiological renal, and total body prostaglandin E2 (PGE2) production. In a randomized cross-over design, 14 healthy female volunteers received meloxicam 7.5 mg per day for 6 days or indomethacin 25 mg three times per day for 3 days; the wash-out period was 5 days, and drug intake was adapted to the menstrual cycle. On the day before treatment and on the last day of each treatment period the following parameters were evaluated: maximum platelet aggregation and thromboxane B2 (TXB2) formation in response to 1.0 mmol/L arachidonic acid; 24-hour urinary excretion of PGE2 and 7 alpha-hydroxy-5, 11-diketo-tetranor-prosta-1, 16-dionic acid (PGE-M), the index metabolites of renal and total body PGE2 synthesis, respectively, were assessed by gas chromatography/tandem mass spectrometry. Maximum platelet aggregation and TXB2 formation were almost completely inhibited by indomethacin (-87% and -99%, respectively; p < 0.001, each) as compared to control (100%), but remained unaffected by meloxicam (-1% and +4%, respectively). Meloxicam showed no significant effects on urinary PGE2 excretion (-13%) and only slight effects on PGE-M excretion (-22%; p < 0.05), whereas indomethacin reduced urinary PGE2 excretion (-43%; p < 0.05) as well as PGE-M excretion (-36%; p < 0.001). Our data show, that meloxicam 7.5 mg per day is COX-1 sparing in humans in vivo.",1997.0,0,0
376,9105543,Clinical pharmacokinetics of meloxicam.,D Türck; U Busch; G Heinzel; H Narjes,"Meloxicam (CAS 71125-38-7, UH-AC 62 XX) is a new non-steroidal anti-inflammatory drug (NSAID) which was developed for the treatment of osteoarthritis and rheumatoid arthritis. The basic clinical pharmacokinetics of meloxicam (7.5-30 mg) have been investigated in 78 healthy male volunteers after single and multiple dosing via oral, intravenous and rectal routes. Plasma concentrations of meloxicam were determined by validated high performance liquid chromatography (HPLC) methods. The pharmaco-kinetic profile of meloxicam is characterized by almost complete absorption over a prolonged phase-avoiding high initial drug concentrations- and is bound to plasma proteins by more than 99.5%. Meloxicam is metabolized to four biologically inactive metabolites and excreted in urine and faeces with an elimination half-life (t1/2) of around 20 h. This is reflected in a total plasma clearance of 7 to 8 ml/min. Steady state is achieved within 3 to 5 days. In addition, the pharmacokinetic parameters are linear over the entire dose range, there are no changes with multiple dosing and bioequivalence was shown for a number of different formulations. The results indicate that meloxicam is suitable for once-daily administration and that a switch from one formulation to another is easily possible if necessary or convenient for the patient.",1997.0,0,0
377,9146764,Emergency admissions for upper gastrointestinal disease and their relation to NSAID use.,A L Blower; A Brooks; G C Fenn; A Hill; M Y Pearce; S Morant; K D Bardhan,"There are considerable variations in estimates of the number of emergency upper gastrointestinal admissions per annum which are attributable to nonsteroidal anti-inflammatory drug (NSAID) use. To obtain a more accurate estimate of the number of these emergency admissions per annum in UK. A retrospective survey of the case notes of all emergency admissions for upper gastrointestinal disease ('Cases') to two English District General Hospitals with a combined catchment population of 550,000. Records of all community deaths attributed to upper gastrointestinal diagnoses (with the same ICD codes) were also surveyed. Matched controls were identified from emergency admissions not caused by upper gastrointestinal diagnoses. The proportions of patients taking NSAIDs on admission to hospital (or at the time of death at home) and the outcome following admission to hospital were analysed. 620 emergency upper gastrointestinal admissions were identified and matched with 460 controls. Cases were more likely to be NSAID users than Controls (31% vs. 16%, OR 2.4, 95% CI: 1.8, 3.3: P < 0.001). Case NSAID use was higher in females and with increasing age. As severity of mode of presentation worsened, the probability of NSAID use increased (e.g. OR relative to controls for peptic pain 1.9, for perforation 5.9). Blood transfusion requirements were significantly higher (P < 0.0001) in Cases taking NSAIDs, although NSAID use did not influence mortality. Extrapolation from these data indicate that there are 65,000 emergency upper gastrointestinal admissions per annum in UK; 12,000 of these admissions (including 2230 deaths) are attributable to NSAID use. A further 330 attributable deaths occur in the community. There is a strong association between NSAID use and propensity for upper gastrointestinal emergency admission; NSAID use is associated with significant morbidity and mortality each year in UK.",1997.0,0,0
378,9171202,A unique metabolite of nimesulide.,P Sarkar; J M McIntosh; R Leavitt; H Gouthro,Nimesulide is a nonsteroidal anti-inflammatory drug recently detected in equine blood and urine samples taken at the race track. The detection of the drug in a blood sample led to the identification of an unknown thin-layer chromatographic (TLC) spot in track urine samples as a metabolite of nimesulide. Characterization of the unknown TLC spot and comparison with the synthesized compound shows that the unknown TLC spot is a previously unreported equine metabolite of nimesulide. The metabolite was identified as resulting from the reduction of the nitro group on nimesulide to an amino group. This reduced nitro metabolite (4-amino-2-phenoxy-methanesulfonanilide) is a major metabolite of nimesulide in the equine.,1997.0,0,0
379,9219316,Meloxicam: selective COX-2 inhibition in clinical practice.,D E Furst,"Nonsteroidal antiinflammatory drugs (NSAIDs) exert their actions by inhibiting cyclooxygenase (COX). It has recently been postulated that NSAIDs' antiinflammatory efficacy arises from inhibition of the COX-2 isoform of cyclooxygenase, whereas inhibition of the COX-1 isoform produces the troublesome and sometimes serious gastric and renal side effects of NSAIDs. A relatively selective COX-2 inhibitor, such as meloxicam, may combine antiinflammatory efficacy with improved tolerability. In volunteers, indomethacin 75 mg, but not meloxicam 7.5 mg, inhibited renal prostaglandin E2 excretion and platelet aggregation (COX-1 mediated effects). Double-blind, randomized trials in osteoarthritis and rheumatoid arthritis patients have shown equivalent antiinflammatory efficacy among meloxicam 7.5 mg or 15 mg and diclofenac 100 mg, naproxen 750 mg, and piroxicam 20 mg. In a double-blind, placebo-controlled trial, meloxicam (7.5 or 15 mg) caused less endoscopically detected gastrointestinal (GI) damage (Lanza scale) than piroxicam 20 mg. The MELISSA study, a double-blind, randomized, 28-day trial in over 9,000 patients showed that meloxicam 7.5 mg caused statistically less total GI toxicity, dyspepsia, abdominal pain, nausea and vomiting, and diarrhea than diclofenac 100 mg, despite equivalent reductions in pain on movement for each treatment. A global safety analysis of clinical trials, representing over 5,600 patients and comprising 170 and 1,100 patient-years of exposure for meloxicam 7.5 mg and 15 mg, respectively, showed that meloxicam caused less GI toxicity and fewer peptic ulcers and GI bleeds than naproxen, diclofenac, or piroxicam. The renal safety profile and incidence of liver function abnormalities with meloxicam is equivalent to other NSAIDs available for clinical use. In conclusion, relatively selective COX-2 inhibition exemplified by meloxicam may offer effective symptom relief with an improved GI tolerability profile.",1997.0,0,1
380,9243303,"Analgesic activity of the novel COX-2 preferring NSAID, meloxicam in mono-arthritic rats: central and peripheral components.",J M Laird; J F Herrero; P García de la Rubia; F Cervero,"To study the characteristics and site of the analgesic action of meloxicam. Adult female Wistar rats. Monoarthritis was induced (for behavioural studies) by injection of complete Freund's adjuvant into the ankle. Meloxicam was given for 5 days (0.1-4 mg/kg/ day i.p.). Inflammation of the knee or paw (for electrophysiology) was induced with carrageenan. Meloxicam was given i.v. (4-64 mg/kg). Rats were tested daily for joint hyperalgesia, and hindlimb posture (behaviour). At post-mortem, joint stiffness, oedema and gastric lesions were assessed. In anaesthetised rats, nociceptive reflex responses to stimulation of the paw were compared (electrophysiology). Statistics were performed using one-way analysis of variance. Meloxicam reduced swelling and stiffness of the inflamed joint, joint hyperalgesia (ID50 = 0.4 +/- 0.4 mg/kg/ day) and spontaneous pain-related behaviour. It also inhibited peripherally mediated reflex responses to stimulation of inflamed tissue (ID50 = 7.6 +/- 0.8 mg/kg.i.v.) without affecting centrally mediated reflexes. Systemic meloxicam produces analgesia largely via peripheral mechanisms. The rapidity of its actions indicates a direct effect on sensitised nociceptors.",1997.0,0,0
381,9309800,"Evaluation of pharmacological profile of meloxicam as an anti-inflammatory agent, with particular reference to its relative selectivity for cyclooxygenase-2 over cyclooxygenase-1.",K Ogino; K Hatanaka; M Kawamura; M Katori; Y Harada,"We studied the anti-inflammatory activity of meloxicam on rat carrageenin-induced pleurisy and its toxicity for rat gastric mucosa, relative to its in vitro inhibitory potency against partially purified cyclooxygenase (COX)-1 and COX-2 preparations in order to clarify the pharmacological profile of the compound as an anti-inflammatory agent. In rat carrageenin-induced pleurisy, the plasma exudation rate peaked at 5 h, at which time COX-2 was detectable in cells from the pleural exudate. Meloxicam and piroxicam (1 and 3 mg/kg) and NS-398 (3 mg/kg) showed almost equal anti-inflammatory potency against 5-hour pleurisy. A single oral administration of the compounds caused a dose-dependent increase in the number of rats with gastric mucosal erosion. The ED50 value for meloxicam (5.92 mg/kg) was significantly higher than that for piroxicam (1.76 mg/kg), indicating that meloxicam is safer. Indometacin showed intermediate safety (2.59 mg/kg). In in vitro experiments, indometacin inhibited COX-1 about 1.7 times more potently than COX-2. NS-398 inhibited COX-2 with an IC50 of 0.32 microM, but never affected COX-1 activity, even at 100 microM. In the same assay system, meloxicam inhibited COX-2 about 12 times more selectively than COX-1. Piroxicam, however, inhibited both isoforms almost equally. These results indicate that meloxicam is a potent anti-inflammatory agent with low gastric toxicity. One reason for its in vivo pharmacological profile may be related to its relative selectivity for COX-2 over COX-1. Thus, meloxicam may belong to a group of COX-2 selective anti-inflammatory agents with a better safety profile than conventional COX-1 and COX-2 nonselective anti-inflammatory agents.",1997.0,0,0
382,9354315,An evaluation of the interaction of meloxicam with frusemide in patients with compensated chronic cardiac failure.,F O Müller; M V Middle; R Schall; J Terblanché; H K Hundt; G Groenewoud,"To evaluate the interaction of meloxicam with frusemide in patients with compensated cardiac failure. Nineteen patients with Grade II or III compensated chronic cardiac failure completed this randomized, double-blind, cross-over study. The patients received 40 mg frusemide day(-1) for 7 days. Thereafter, patients received either 15 mg meloxicam plus 40 mg frusemide day(-1), or one placebo tablet plus 40 mg frusemide day(-1) for 7 days. After a washout period of 7 days during which patients received 40 mg frusemide day(-1) for 7 days, the patients were crossed over to the alternate treatment. The effect of concomitant ingestion of meloxicam and frusemide on frusemide-induced diuresis, urine and serum electrolytes, urinary frusemide excretion, and plasma frusemide pharmacokinetics was also determined. The estimate (90% confidence interval) of the '(frusemide + meloxicam)/(frusemide alone)' mean ratio of the variables Cmax, AUC(SS) and Cmax/AUC(SS) for plasma frusemide were 121% (101% to 145%), 106% (96.4% to 117%), and 114% (98.3% to 132%), respectively. Similarly, the estimate (90% confidence interval) of the '(frusemide + meloxicam)/(frusemide alone)' of the mean ratio of the variable cumulative urinary frusemide excretion after multiple doses of frusemide were 123% (101% to 150%) for the period 0-8 h, and 122% (105% to 142%) for the period 0-24 h after drug administration on day 7. The estimate (90% confidence interval) of the '(frusemide + meloxicam)/(frusemide alone)' mean ratio of the pharmacodynamic variables cumulative sodium excretion was 105% (95.2% to 116%) for the period 0-8 h and 108% (96.5% to 121%) for the period 0-24 h after drug administration on day 7. Meloxicam may lead to slightly increased maximum concentrations of frusemide in plasma, as well as to slightly increased urinary excretion of frusemide, without affecting the pharmacodynamics of frusemide. Thus there is no clinically significant pharmacokinetic or pharmacodynamic interaction of meloxicam with frusemide following repeated co-administration of meloxicam and frusemide to patients with compensated chronic cardiac failure.",1997.0,0,0
383,9404473,"A double-blind, randomized trial to compare meloxicam 15 mg with diclofenac 100 mg in the treatment of osteoarthritis of the knee.",H S Goei Thè; B Lund; M R Distel; E Bluhmki,"Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID), which, in animal tests, displays a high potency for anti-inflammatory and analgesic action. The aim of this study was to investigate the efficacy and tolerability of 15 mg meloxicam in comparison with 100 mg slow-release diclofenac in patients with osteoarthritis of the knee. Two hundred and fifty-eight patients were included in the intent-to-treat analysis; these were randomized into two groups to receive either 15 mg meloxicam (N = 128) or 100 mg diclofenac (N = 130) for a period of 6 weeks. The results with respect to efficacy showed a trend in favor of meloxicam regarding pain on movement, global efficacy and paracetamol consumption, although these differences did not reach statistical significance. The most frequently-occurring adverse events in both groups were of a gastrointestinal (GI) nature. However, there was a higher incidence (26 vs 16%) of GI adverse events in the diclofenac group compared with the meloxicam group. Both drugs were well tolerated when assessed by the patients on a visual analog scale (VAS). Thus, 15 mg meloxicam is an effective and well-tolerated therapy for osteoarthritis and compares favorably with diclofenac 100 mg, a well-established treatment for this indication.",1997.0,1,1
384,9506875,,,,,0,1
385,9535022,Selective cyclo-oxygenase-2 inhibitors and their influence on the protective effect of a mild irritant in the rat stomach.,B Gretzer; K Ehrlich; N Maricic; N Lambrecht; M Respondek; B M Peskar,"1. The effects of the non-selective cyclo-oxygenase (COX) inhibitor indomethacin and the selective COX-2 inhibitors, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulphonamide (NS-398), 5-methanesulphonamido-6-(2,4-difluorothio-phenyl)-1-indan one (L-745,337) and 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanone (DFU), on the protection induced by the mild irritant 20% ethanol were investigated in the rat stomach. 2. Instillation of 20% ethanol (1 ml, p.o.) effectively protected against gastric mucosal injury induced by subsequent instillation of 70% or 96% ethanol (1 ml, p.o.). 3. Oral administration of indomethacin (1.25-20 mg kg[-1]) dose-dependently counteracted the protective effect of 20% ethanol (ID50: 3.5 mg kg[-1]). 4. Likewise, NS-398 (0.1-1 mg kg[-1]), L-745,337 (0.2-2 mg kg[-1]) and DFU (0.02-0.2 mg kg[-1]) inhibited the protective effect of 20% ethanol in a dose-dependent manner with ID50 values of 0.3 mg kg(-1), 0.4 mg kg(-1) and 0.06 mg kg(-1), respectively. 5. Inhibition of mild irritant-induced protection was also found when NS-398 (1 mg kg[-1]) was administered s.c. or when 96% ethanol was used to damage the mucosa. 6. Pretreatment with 16,16-dimethyl-prostaglandin (PG)E2 at 4 ng kg(-1), a dose that did not protect against ethanol (70%)-induced mucosal damage when given alone, completely reversed the effect of the selective COX-2 inhibitors on the mild irritant-induced protection. 7. Pretreatment with dexamethasone (3 mg kg(-1), 24 and 2 h before instillation of 20% ethanol) did not affect the protective activity of the mild irritant, indicating that enzyme induction is not involved. 8. Indomethacin (20 mg kg(-1), p.o.) did not prevent the protection conferred by sodium salicylate (100 mg kg[-1]), dimercaprol (30 microg kg[-1]), iodoacetamide (50 mg kg[-1]) and lithium (20 mg kg[-1]). Likewise, the protective effect of these agents was not counteracted by NS-398 (1 mg kg(-1), p.o.). 9. Whereas indomethacin (20 mg kg(-1), p.o.) near-maximally inhibited gastric mucosal formation of PGE2, 6-keto-PGF1alpha and thromboxane (TX) B2 as well as platelet TXB2 release, the selective COX-2 inhibitors were ineffective. 10. The findings show that selective COX-2 inhibitors, although lacking in ulcerogenic activity, prevent the protection conferred by a mild irritant. Prostaglandis generated by a constitutive COX-2 could thus contribute to physiological functions involved in gastric homeostasis, although at present a non-COX-2-related mechanism underlying the effect of the selective COX-2 inhibitors tested on mild irritant-induced protection cannot be completely excluded.",1998.0,0,0
386,9684433,Comparative efficacy and safety of the non-steroidal anti-inflammatory drugs nimesulide and diclofenac in patients with acute subdeltoid bursitis and bicipital tendinitis.,W Wober; V W Rahlfs; N Büchl; A Grässle; A Macciocchi,"The efficacy and tolerability of nimesulide, a non-steroidal anti-inflammatory drug (NSAID) 100 mg twice daily were compared with diclofenac 75 mg b.i.d. in short term treatment of acute shoulder (acute subdeltoid bursitis and bicipital tendinitis) in adult patients. In this double-blind (double-dummy), randomised, parallel group study over two weeks, 122 patients were included. The Mann-Whitney statistics revealed therapeutic equivalence of both treatments with a slight superiority for nimesulide. The tolerability of nimesulide, judged by investigators and patients and analysed statistically, was superior to that of diclofenac. Thus, the benefit-risk relationship was better for the test drug than for the reference drug.",1998.0,0,1
387,9705013,Oral anti-inflammatory and anti-ulcerogenic activities of a hydroalcoholic extract and partitioned fractions of Turnera ulmifolia (Turneraceae).,M A Antônio; A R Souza Brito,"Anti-inflammatory studies were conducted on rats or mice using a crude hydroalcoholic extract of the aerial parts of Turnera ulmifolia and it's partitioned fractions, i.e. the aqueous, ethyl acetate and ethanolic fractions. The hydroalcoholic extract and it's fractions (aqueous and ethanolic) inhibited carrageenan-induced edema. However, only the ethanolic fraction was used in the other experiments due to it's yield. The extract also inhibited the cotton pellet granuloma and the increase of vascular permeability induced by histamine, 5-hydroxytryptamine and prostaglandin E2, but not that produced by bradykinin. The extract or the fraction did not present analgesic activity in the writhing test using acetic acid and did not reduce croton oil-induced ear edema in mice. When the ethanolic fraction and LPS were administered i.p. to Balb/C mice 72 h before blood or peritoneal fluid collection, no changes were observed in the white or total blood cell counts in the peripheral blood. On the other hand, changes were observed in both total and differential cell counts in the peritoneal exudate since all doses of the fraction reduced the number of total leukocytes (mainly lymphocytes) obtained from the peritoneal exudate. In contrast to nonsteroidal anti-inflammatory drugs, the administration of the hydroalcoholic extract or the ethanolic fraction alone did not potentiate gastric mucosal lesions induced by aspirin. The extract and the fraction inhibited the appearance of gastric lesions induced by indomethacin, ethanol and pylorus ligature, but not those induced by stress. As also observed with carbenoxolone, the ethanolic fraction increased the wall mucus in hypothermical-restraint stress-induced gastric lesions. The anti-ulcerogenic effect of the extract and of the ethanolic fraction may be related to an increase of mucosal defensive factors, such as prostaglandin and mucus. The anti-inflammatory actions of the extract and the fraction may be due to an inhibitory effect on histamine and cyclooxygenase II, but not on cyclooxygenase I, because the extract and it's fraction present both anti-inflammatory and anti-ulcerogenic effects. The major substances present in the ethanolic fraction are flavonoids which will be isolated and identified.",1998.0,0,0
388,9723821,Gastrointestinal tolerability of meloxicam and piroxicam: a double-blind placebo-controlled study.,G R Lipscomb; N Wallis; G Armstrong; W D Rees,"The aim of the study was to compare the effects of meloxicam and piroxicam on the gastroduodenal mucosa in healthy adults. Forty-four healthy volunteers were given a 28 day course of either meloxicam 15 mg, piroxicam 20 mg or placebo. Damage to the oesophageal, gastric and duodenal mucosa was assessed, mucosal blood flow (MBF) measured at endoscopy and biopsies taken for prostaglandin content and microscopic assessment of damage before NSAID administration and during days 1, 7 and 28 of continued intake. Maximal macroscopic gastric mucosal damage (median grade+IQR) occurred within 24 h of piroxicam administration, the damage score increasing from 0 to 2.5 (0-3) (P=0.02) at day 1 before falling to 2.0 (0-2) at day 7 and 0 (0-1) at day 28 with resolution of damage observed in six out of the seven subjects who sustained acute injury. No significant macroscopic gastric damage occurred in either of the two other groups although some minor damage was observed in seven subjects taking placebo and five taking meloxicam. There was a trend towards piroxicam causing more acute gastric damage than meloxicam (P=0.06). Baseline antral, body and duodenal MBF were similar in all three groups. No significant changes occurred in any of the groups on any of the visits. There were also no changes in gastric mucosal prostaglandin content in any group. These observations suggest that meloxicam causes little acute damage to the upper gastrointestinal tract and piroxicam causes some acute gastric injury but such damage resolves in most subjects by 28 days.",1998.0,0,0
389,9737091,Effect of selective inhibition of the inducible cyclooxygenase on renin release in healthy volunteers.,D O Stichtenoth; B Wagner; J C Frölich,"Nonsteroidal anti-inflammatory drugs (NSAIDs) can block renin release via inhibition of cyclooxygenase (COX). The responsible COX-isoenzyme in man is unknown. Therefore, we assessed the effects of meloxicam, a selective inhibitor of COX-2, and indomethacin, an unselective inhibitor of COX-1 and COX-2, on furosemide stimulated plasma renin activity (PRA). In a randomized cross-over design 15 healthy female volunteers received no NSAID or meloxicam 7.5 mg/d for 6 days or indomethacin 25 mg tid for 2 days and 25 mg on the 3rd day. On the control day and on the last day of each treatment the following parameters were evaluated before and after furosemide 20 mg i.v.: PRA measured by RIA, urinary excretion of prostaglandin E2 (PGE2) assessed by gas chromatography-tandem mass spectrometry, urine volume and urinary excretion of sodium, potassium, and creatinine, and serum concentrations of sodium, potassium, and creatinine. Furosemide led to a more than two-fold rise of PRA. Indomethacin as well as meloxicam had no significant effect on basal PRA but inhibited the furosemide-stimulated PRA increase. PGE2 excretion on the control day rose two-fold after furosemide. Meloxicam had no effect on basal PGE2 excretion, whereas indomethacin reduced this parameter by 30%. Both drugs inhibited the increase of urinary PGE2 after furosemide. No drug effects on urine flow nor on electrolytes and creatinine in serum and urine could be observed. Meloxicam inhibited furosemide stimulated renin release, suggesting that in man COX-2 is responsible for prostaglandin synthesis mediating renin release.",1998.0,0,0
390,9751091,"Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects.",L S Simon; F L Lanza; P E Lipsky; R C Hubbard; S Talwalker; B D Schwartz; P C Isakson; G S Geis,"To investigate the efficacy and safety of SC-58635 (celecoxib), an antiinflammatory and analgesic agent that acts by selective cyclooxygenase 2 (COX-2) inhibition and is not expected to cause the typical gastrointestinal (GI), renal, and platelet-related side effects associated with inhibition of the COX-1 enzyme. Four phase II trials were performed: a 2-week osteoarthritis efficacy trial, a 4-week rheumatoid arthritis efficacy trial, a 1-week endoscopic study of GI mucosal effects, and a 1-week study of effects on platelet function. The 2 arthritis trials identified SC-58635 dosage levels that were consistently effective in treating the signs and symptoms of arthritis and were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, 19% of subjects receiving naproxen (6 of 32) developed gastric ulcers, whereas no ulcers occurred in subjects receiving SC-58635 or placebo. The study of platelet effects revealed no meaningful effect of SC-58635 on platelet aggregation or thromboxane B2 levels, whereas aspirin caused significant decreases in 2 of 3 platelet aggregation measures and thromboxane B2 levels. In all 4 trials, SC-58635 was well tolerated, with a safety profile similar to that of placebo. SC-58635 achieves analgesic and antiinflammatory efficacy in arthritis through selective COX-2 inhibition, without showing any evidence of 2 of the toxic effects of COX-1 inhibition associated with nonsteroidal antiinflammatory drugs.",1998.0,0,1
391,9783757,Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety Assessment.,C Hawkey; A Kahan; K Steinbrück; C Alegre; E Baumelou; B Bégaud; J Dequeker; H Isomäki; G Littlejohn; J Mau; S Papazoglou,"Although widely used, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a high incidence of gastrointestinal (GI) side-effects. Inhibition of the cyclooxygenase (COX) enzyme is the basis for both the efficacy and toxicity of NSAIDs. The discovery of two COX isoforms, constitutive COX-1 and inducible COX-2, has led to the hypothesis that selective inhibition of COX-2 will minimize the potential for GI toxicity without compromising efficacy. The Meloxicam Large-scale International Study Safety Assessment (MELISSA) trial reported here was therefore set up to investigate the tolerability of meloxicam, a preferential inhibitor of COX-2, compared to diclofenac. MELISSA was a large-scale, double-blind, randomized, international, prospective trial, conducted over 28 days in patients with symptomatic osteoarthritis. Patients received either meloxicam 7.5 mg or diclofenac 100 mg slow release, the recommended doses for the treatment of osteoarthritis. Evaluation of the profile of adverse events was the main aim of the trial, together with assessment of efficacy. A total of 9323 patients received treatment (4635 and 4688 in the meloxicam and diclofenac groups, respectively). Significantly fewer adverse events were reported by patients receiving meloxicam. This was attributable to fewer GI adverse events (13%) compared to diclofenac (19%; P < 0.001). Of the most common GI adverse events, there was significantly less dyspepsia (P < 0.001), nausea and vomiting (P < 0.05), abdominal pain (P < 0.001) and diarrhoea (P < 0.001) with meloxicam compared to diclofenac. Five patients on meloxicam experienced a perforation, ulcer or bleed vs seven on diclofenac (not significant). No endoscopically verified ulcer complication was detected in the meloxicam group compared to four with diclofenac. There were five patient days of hospitalization in patients on meloxicam compared to 121 with diclofenac. Adverse events caused withdrawal from the study in 254 patients receiving meloxicam (5.48%) compared to 373 (7.96%) on diclofenac (P < 0.001). These differences were attributable to differences in reported GI adverse events (3.02% on meloxicam vs 6.14% on diclofenac; P < 0.001). Differences in efficacy, as assessed by visual analogue scales, consistently favoured diclofenac. In all instances, 95% confidence intervals did not cross zero, suggesting a statistically significant effect. However, differences were small (4.5-9.01% difference) and did not reach pre-determined levels of clinical significance. Nevertheless, significantly more patients discontinued meloxicam because of lack of efficacy (80 out of 4635 vs 49 out of 4688; P < 0.01). The MELISSA trial confirms earlier studies suggesting that meloxicam has a significantly improved GI tolerability profile in comparison with other NSAIDs, including diclofenac. These results may in part reflect the preferential COX-2 selectivity of meloxicam, although the dose and other aspects of tolerability may be important. These results may provide support for the hypothesis that selective inhibition of COX-2 relative to COX-1 might be an effective approach towards improved NSAID therapy.",1998.0,1,1
392,9783758,"Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trial in osteoarthritis.",J Dequeker; C Hawkey; A Kahan; K Steinbrück; C Alegre; E Baumelou; B Bégaud; H Isomäki; G Littlejohn; J Mau; S Papazoglou,"SELECT is a large-scale, prospective, international, multicentre, double-blind, double-dummy, randomized, parallel-group trial. Patients with exacerbation of osteoarthritis were treated with the recommended dose of meloxicam (7.5 mg) or piroxicam (20 mg) once daily for 28 days; 4320 patients were administered meloxicam and 4336 piroxicam. The incidence of adverse events was significantly lower in the meloxicam group (22.5%) compared with the piroxicam group (27.9%; P < 0.001), mainly due to the significantly lower incidence of gastrointestinal (GI) adverse events in the meloxicam than in the piroxicam group (10.3% vs 15.4%,; P < 0.001), while the efficacy of both drugs was equivalent. Individual GI events occurred significantly less often with meloxicam than piroxicam: dyspepsia (3.4% vs 5.8%; P < 0.001), nausea/vomiting (2.5% vs 3.4%; P < 0.05) and abdominal pain (2.1% vs 3.6%; P < 0.001). There were 16 patients with perforations, ulcerations or bleeding (PUBs) of the upper GI tract in the piroxicam group compared with seven in the meloxicam group (relative risk piroxicam:meloxicam = 1.4). Four PUBs were complicated (perforations or bleedings); none of these occurred in the meloxicam group (relative risk piroxicam:meloxicam = 1.9). The outcome of SELECT is consistent with that of the large-scale clinical trial of similar design and size which compared 7.5 mg meloxicam with 100 mg diclofenac in patients with osteoarthritis, and with a previous global analysis of the safety of meloxicam. It adds further data to the proposed relationship between selective inhibition of cyclooxygenase-2 and improved GI tolerability of non-steroidal anti-inflammatory drugs.",1998.0,1,1
393,9874808,,,,,0,0