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PubMed1986

Immunomodulatory effects of treatment with naproxen in patients with rheumatic disease.

We evaluated the effects of a nonsteroidal antiinflammatory drug, naproxen, on phytohemagglutinin (PHA)-induced lymphocyte proliferation. When added in vitro to cultures of peripheral blood mononuclear cells, naproxen enhanced the proliferative response toward PHA of lymphocytes from rheumatoid arthritis (RA) patients but not from healthy volunteers, and it reduced prostaglandin E2 (PGE2) synthesis in the cultures. Oral treatment for 7 days with naproxen also resulted in a significant enhancement of the in vitro PHA-induced proliferation of lymphocytes from RA patients and from age-matched control patients with noninflammatory rheumatic diseases, but not from young healthy controls. This enhancement of PHA-induced lymphocyte proliferation after oral intake of naproxen was not accompanied by diminished in vitro PGE2 production in the cultures. It did occur when PGE2-producing monocytes were removed and when in vitro PGE2 synthesis was blocked with indomethacin. We conclude that oral treatment with naproxen has an immunomodulatory effect and improves in vitro PHA-induced proliferation of lymphocytes from rheumatic disease patients. This effect is not due to reduced PGE2 synthesis in the in vitro cultures, but reflects a more fundamental in vivo change in immunoregulation.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Single dose pharmacokinetics of ketoprofen, indomethacin, and naproxen taken alone or with sucralfate.

The effects of sucralfate on the rate and extent of absorption of ketoprofen, indomethacin, and naproxen were investigated in healthy volunteers. Six volunteers each received sucralfate (2 g) half an hour before a ketoprofen (50 mg) capsule, and, on another occasion, a ketoprofen (50 mg) capsule alone according to a 2 X 2 Latin square pattern of administration. The same design was used for studies with indomethacin (50 mg) capsules and naproxen (500 mg) tablets. Sucralfate decreased significantly (p less than 0.05) the maximum plasma concentrations (Cmax) of ketoprofen, indomethacin, and naproxen. Although the time necessary to attain Cmax (tmax) for the three drugs tended to increase, only for indomethacin was this increase significant. Sucralfate decreased significantly the rate of absorption (ka) of naproxen and indomethacin, but not that of ketoprofen; it had no significant effect on the elimination half-life and area under the plasma concentration as a function of time curves (AUC0----infinity) of the three drugs. Sucralfate thus decreases the Cmax and increases the tmax of ketoprofen, indomethacin, and naproxen without affecting their bioavailabilities.

Adult↗
PubMed1975

Naproxen: long-term study in rheumatoid arthritis and "placebo pulse".

Naproxen is by now a relatively well-known antirheumatic drug, and many short-term studies have shown its efficacy and relatively good tolerance. We have observed 64 patients with definite or classical rheumatoid disease, 27 of whom have been followed for well over two years on daily doses of naproxen to ascertain the persistence of drug efficacy and safety. In this part of our study, patients were subjected to complete clinical and biochemical evaluations at two-monthly intervals. Naproxen was well tolerated, and the few side effects reported were transient and mild in nature. Sequential laboratory studies revealed no significant anomaly. Clinical evaluation showed no pattern suggestive of decreasing antirheumatic activity. A question frequently encountered in the treatment of certain diseases such as rheumatoid arthritis is whether long-term improvement is due to efficacious suppressive therapy or spontaneous abatement of disease activity. We devised a double-blind placebo pulse phase in which 19 of our 28 long-term patients participated in a study within a study lasting four weeks. They were divided into two groups. The first group took their usual dose of naproxen during the first two weeks and a corresponding number of placebo tablets in the next two weeks. The procedure was reversed in the other group. We conclude that naproxen remains efficacious.

Adult↗
PubMed1992

[99mTc]diphosphonate uptake and hemodynamics in experimental arthritis: effect of naproxen in the canine carrageenan injection model.

The impact of naproxen treatment on juxta-articular hemodynamics and bone metabolism in experimental juvenile arthritis was studied in the articular carrageenan injection model. Unilateral gonarthritis was induced for 12 weeks in eight dogs receiving naproxen (dosage, 2 mg/kg) and eight controls. Regional blood flow was assessed by the microsphere method, plasma volume by the distribution space of [125I]fibrinogen, and bone metabolism by the 2-h uptake of [99mTc]diphosphonate ([99mTc]DPD). Synovial effusion was less prominent with naproxen treatment as judged by joint fluid volume and pressure. Naproxen reduced the arthritic capsular hyperemia, almost normalized a severe blood flow increase in patella and both juxta-articular epiphyses, ameliorated an expansion of plasma volume in the patella and the distal femoral epiphysis, and normalized an increased [99mTc]DPD uptake in subchondral femoral bone and the tibial cortex. Significantly increased arteriovenous shunting in the arthritic extremity was unaffected by naproxen. The study suggests that long-term cyclooxygenase inhibition offers protection against hemodynamic and metabolic changes in juxta-articular bone secondary to synovial inflammation.

Animals↗
PubMed1993

In vivo effects of naproxen on composition, proteoglycan metabolism, and matrix metalloproteinase activities in canine articular cartilage.

Naproxen is a nonsteroidal anti-inflammatory drug commonly used in the clinical treatment of joint disease. In this study, its effect in vivo on the biochemical composition, metabolic activities, and metalloproteinase activities of normal canine articular cartilage was analyzed. The articular cartilage from the knee joints of dogs who had been given naproxen for 4 weeks to maintain a serum level of 40-50 micrograms/ml was examined. Control animals were given a placebo. Treatment with naproxen was not found to change the composition (water, collagen, and proteoglycan) of the articular cartilage. The culture studies of cartilage explants indicated that proteoglycan synthesis rates were unaffected by the treatment with naproxen but that proteoglycan release from the tissue was suppressed. Analysis of the cartilage for matrix metalloproteinase activities showed reduced activity of neutral matrix metalloproteinase by 80%, of collagenase by 40%, and of gelatinase by 87%, with no change in activity of acid metalloproteinase or of tissue inhibitor for metalloproteinase. These findings indicate that in vivo treatment with naproxen has the capacity to modulate catabolic activities in articular cartilage.

Animals↗
PubMed1990

Endoscopic comparison of cimetidine and sucralfate for prevention of naproxen-induced acute gastroduodenal injury. Effect of scoring method.

Nonsteroidal antiinflammatory drug-induced gastroduodenal mucosal damage observed endoscopically is usually categorized as hemorrhages, erosions, or ulcerations. We undertook this study to determine whether the injury produced by a commonly prescribed NSAID, naproxen, could be reduced by cotherapy with sucralfate or cimetidine and to determine how dependent the differences in the degree of protection against mucosal injury measured were on the scoring system used. Four groups of 20 healthy volunteers with endoscopically normal gastric and duodenal mucosa received naproxen (500 mg twice a day) plus cimetidine (300 mg four times a day or 400 mg twice a day), sucralfate (1 g four times a day), or placebo for seven days. After seven days of therapy, a second endoscopy was performed. Separate scoring systems were used for the presence of hemorrhages, erosions, and a combination of both types of injury. There were significantly fewer mucosal hemorrhages present when naproxen and cimetidine were administered than when naproxen was administered with placebo or sucralfate (placebo vs 300 mg cimetidine, P = 0.04, and placebo vs 400 mg cimetidine, P = 0.006, placebo vs sucralfate, P = 0.26). Both cimetidine dosages resulted in significantly fewer hemorrhages than were present following cotherapy of naproxen and sucralfate (P less than 0.05). In contrast, there was no discernible difference in the mucosal injury between placebo and any drug or between any two active therapies when the injury was evaluated based on the presence of gastric erosions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Endoscopic evaluation of etodolac and naproxen, and their relative effects on gastric and duodenal prostaglandins.

Etodolac has been shown to have a favorable safety profile in short-term and long-term studies in both osteoarthritis (OA) and rheumatoid arthritis (RA). Two studies were conducted to further assess the gastrointestinal (GI) safety profile of this drug. These studies were designed to compare the therapeutic efficacy and upper GI effects of etodolac (600 mg/day) and naproxen (1000 mg/day) administered over 4 weeks in patients with active rheumatoid arthritis. In addition, the relative effects of the drugs on prostaglandin levels in the stomach and duodenum were assayed in one study. Fifteen patients were included in each study and received either 300 mg b.i.d. of etodolac or 500 mg b.i.d. of naproxen. In both studies, endoscopic examinations were performed on day 1 of the study and again 4 weeks later. In the second study, at the time of each endoscopy, samples of gastric and duodenal mucosa were taken for histologic study and prostaglandin assay. Endoscopy results from the first study showed significant differences in favor of etodolac between the two treatment groups. In the second study more naproxen-treated patients had abnormal endoscopy results than did etodolac-treated patients. Results from prostaglandin assays in gastric and duodenal mucosa showed no overall suppression of gastric or duodenal prostaglandin levels for etodolac-treated patients in contrast to naproxen-treated patients, who showed suppression of PGE2 and PGI2. The results of these studies show that etodolac therapy caused less gastric and duodenal injury than naproxen and also support the theory that the GI safety of etodolac may be due to selective sparing of cytoprotective prostaglandins.

Adolescent↗
PubMedDate not supplied

In vivo plasma protein binding interaction between valproic acid and naproxen.

The effect of naproxen on the kinetics of free and total plasma valproic acid (VPA) was investigated in 6 normal volunteers by using a recently developed simple ultrafiltration technique associated with an immuno-enzymatic assay (Free Level System I, Syva). Each subject received a single oral dose of sodium valproate on two occasions: a) on a control day and b) during concurrent treatment with naproxen (500 mg b.i.d. for 5 consecutive days). Naproxen caused a slight but significant decrease in total plasma VPA levels but left free VPA levels essentially unchanged. The free VPA fraction increased with increasing total VPA concentrations: at equivalent values of total VPA, however, the free fraction was higher in the presence of naproxen. It is concluded that naproxen exerts a moderate displacing effect on protein bound VPA, thereby increasing the clearance of total drug but leaving essentially unchanged the clearance of free drug.

Adult↗
PubMed1986

Flurbiprofen versus naproxen in the treatment of rheumatoid arthritis.

The efficacy and safety of flurbiprofen (Ansaid, Upjohn), 100 mg twice daily, were compared with those of naproxen, 250 mg twice daily, in a six-week, double-blind, randomized study involving 133 patients with rheumatoid arthritis. Patients completing the six-week treatment phase were then treated with flurbiprofen, 100 mg twice daily, during a six-week open-label phase. In the double-blind phase, both treatment groups showed improvement from baseline and, in general, the arthritic condition of all patients was significantly less severe while receiving treatment. In the open-label phase, the patients in whom therapy was switched from naproxen to flurbiprofen reported greater improvement compared with baseline than they did at the end of the double-blind phase. Statistically significant differences between medication groups were few. At weeks four and six, grip strength for the naproxen group increased from baseline by a marginal amount compared with the flurbiprofen group. Global evaluations of disease improvement by patients and physicians and proximal interphalangeal joint size showed trends in favor of flurbiprofen. In the double-blind phase, 29.4 percent of flurbiprofen-treated patients (n = 20) and 23.1 percent of naproxen-treated patients (n = 15) experienced side effects, most of which were gastrointestinal in origin. In the open-label phase, 81.0 percent of the patients (n = 87) satisfactorily completed the six weeks of flurbiprofen treatment. Based on this study, 100 mg of flurbiprofen administered twice daily was as effective as 250 mg of naproxen twice daily in the treatment of rheumatoid arthritis.

Adolescent↗
PubMed1987

Single-blind comparative study of nabumetone (Relafen) versus naproxen in the treatment of rheumatoid arthritis.

Forty-seven patients with active rheumatoid arthritis were entered into a single-blind study to compare the safety and efficacy of nabumetone with naproxen. Patients were randomly assigned to receive a daily dose of 2 g of nabumetone or 1 g of naproxen after a placebo-washout period of at least three days. In addition to the usual clinical and laboratory measurements of disease activity, thermographic assessment was carried out at each visit and the heat distribution index was calculated. In addition, the safety and tolerance were assessed. Patients had improvement in severity of pain, severity and duration of morning stiffness, and articular index, and there was no statistical difference between the two treatment groups. By the end of six months, 13 patients had withdrawn from treatment; five patients in the naproxen treatment group and five in the nabumetone group were withdrawn from the study due to lack of efficacy. In no patient from the nabumetone group did an adverse reaction develop. In one patient in the naproxen group, a severe decrease in white blood cell count developed, and a skin rash and swollen gums developed in another patient. We conclude that nabumetone is well tolerated and of equal efficacy to naproxen in the treatment of active rheumatoid arthritis.

Adolescent↗
PubMed1989

Effects of food and sucralfate on the pharmacokinetics of naproxen and ketoprofen in humans.

Compliance to nonsteroidal anti-inflammatory drug therapy can be compromised by gastrointestinal side effects. To overcome this problem, food, antacid, or sucralfate are often co-administered with nonsteroidal anti-inflammatory drugs. Three studies were conducted on three groups of 12 volunteers in order to determine the influence of food or sucralfate on the pharmacokinetics of naproxen and ketoprofen. In a crossover experimental design, the first group received a single dose (50 mg) of ketoprofen with and without sucralfate (2 g). The second group received single (100 mg) and multiple (100 mg twice daily for 5 days) doses of enteric-coated ketoprofen with and without food. The third group received single (500 mg) and multiple (500 mg twice daily) doses of naproxen with and without sucralfate. Multiple blood samples were drawn and analyzed by high-pressure liquid chromatography. Short- and long-term pharmacokinetic parameters were determined. Results in group 1 showed that neither ketoprofen bioavailability nor maximal plasma concentration and time to reach maximal concentration were affected by the administration of sucralfate. However, in group 2 absorption of ketoprofen was markedly affected by food. In the presence of food, maximal plasma concentration decreased from 10.7 to 6.3 micrograms/ml after single-dose administration and 12.1 to 8.0 micrograms/ml after multiple-dose administration. The time to reach maximal plasma concentration was also modified by food, increasing from 2.8 to 7.1 hours after single-dose and 2.8 to 7.6 hours after multiple-dose administration. Food caused a significant decrease in the bioavailability of ketoprofen (over 40 percent) following both single-dose (23.8 versus 13.1 micrograms.hour/ml) and multiple-dose (29.3 versus 16.8 micrograms.hour/ml) administration. Results obtained in group 3 showed that sucralfate reduced the absorption rate constant of naproxen, from 1.7 to 1.2 hours-1 and from 1.5 to 0.7 hour-1 following single- and multiple-dose administration, respectively. However, bioavailability of naproxen was not affected by sucralfate administration. Overall, these studies have shown that sucralfate does not alter the pharmacokinetics of naproxen and ketoprofen; the amount of drug absorbed remains constant. However, plasma concentrations of ketoprofen after single- and multiple-dose administration were greatly affected by food, with a decrease of greater than 40 percent in bioavailability.

Adolescent↗
PubMedDate not supplied

Effects of naproxen and nabumetone on serum cholesterol levels in patients with osteoarthritis.

In a 12-week controlled clinical study of the effects of two nonsteroidal anti-inflammatory drug regimens on serum lipoproteins in patients with osteoarthritis, 54 patients were treated with naproxen, 500 mg twice daily, and 45 patients were treated with nabumetone, 1,000 mg once daily. In patients who received naproxen, the mean levels of total serum cholesterol decreased by 18.3 mg/dL (7.0%) from baseline to 12 weeks, high-density lipoprotein (HDL) cholesterol remained unchanged, and low-density lipoprotein (LDL) cholesterol decreased by 15.4 mg/dL (8.7%). In patients who received nabumetone, mean levels of total serum cholesterol increased 10.4 mg/dL (4.0%), HDL cholesterol remained unchanged, and LDL cholesterol increased 7.2 mg/dL (4.1%). Furthermore, serum triglyceride levels tended to increase in nabumetone-treated patients and decrease in naproxen-treated patients, with a statistically significant (P < 0.05) difference between treatments. The decreases in total cholesterol and LDL cholesterol levels in patients receiving naproxen were statistically significant (P < 0.01). These results confirm previous findings on naproxen's cholesterol-lowering effect.

Adult↗
PubMedDate not supplied

Safety profile of over-the-counter naproxen sodium.

The safety of naproxen sodium for over-the-counter use was evaluated based on 48 randomized, double-blind, placebo-controlled clinical trials that evaluated naproxen/naproxen sodium (NAP) for indications appropriate to, and under, conditions common to, nonprescription analgesics. Of the 48 studies, 27 were single-dose studies and 21 were multiple-dose studies of 1 to 10 days' duration; 19 studies included ibuprofen and 9 included acetaminophen. A total of 4138 patients received naproxen or naproxen sodium (3589 patients received naproxen 187.5 to 400 mg and 549 received naproxen sodium 220 to 440 mg), 2423 received placebo, 1574 received ibuprofen (200 or 400 mg), and 671 received acetaminophen (500 to 1000 mg). Adverse-event rates were examined in three sets of comparisons: NAP versus placebo (48 studies); NAP versus ibuprofen and placebo (19 studies); and NAP versus acetaminophen and placebo (9 studies). Across all 48 studies, 83% of both the NAP- and placebo-treated patients reported no adverse events. The incidence rates were similar between NAP and placebo, with headache (4.8% NAP, 6.4% placebo), nausea (3.4% NAP, 3.1% placebo), and somnolence (2.7% NAP, 1.9% placebo) the most commonly reported events. Rates of adverse events with NAP, ibuprofen, and acetaminophen were similar.

Acetaminophen↗
PubMed1988

The influence of anxiety and locus of control on adolescents' response to naproxen sodium for mild to moderate pain.

This study assessed the influence of internal health locus of control (IHLC) and anxiety on the adolescent's response to the treatment of mild and moderate pain. Fifty-four adolescents (ages 16-22 years) from two adolescent clinics presenting with mild to moderate pain caused by dysmenorrhea, muscle sprain or strain, headache, or backache were studied. Following a physical examination and a pretest assessment of pain, IHLC, and the Spielberger State-Trait Anxiety Inventory, subjects were randomly assigned in a double-blind fashion to groups receiving placebo (n = 16), 100 mg of naproxen sodium (n = 19), or 200 mg naproxen sodium (n = 19) and assessed at 1, 2, 3, and 4 hours. Based on a repeated-measure analysis of covariance test, there were no differences between groups in the pretest measurements. All treatment groups had a decrease in pain over the 4 hours (p less than 0.0001). Patients from one institution had more pain reduction than at the other (p less than 0.0001), and females had more pain reduction than males (p less than 0.034). Subjects receiving 200 mg of naproxen sodium had more pain relief (p less than 0.034) than subjects taking placebo at hour 2. Baseline anxiety was positively associated with pain after receiving placebo, but inversely associated with pain after taking naproxen sodium. The IHLC appeared to have a positive effect on the response to naproxen sodium, but no effect on the response to placebo.

Adolescent↗
PubMed1992

Simultaneous quantitative determination of naproxen, its metabolite 6-O-desmethylnaproxen and their five conjugates in plasma and urine samples by high-performance liquid chromatography on dynamically modified silica.

The glucuronides of the anti-inflammatory drug naproxen and its metabolite 6-O-desmethylnaproxen have been produced on a preparative scale by enzymatic synthesis. 6-O-Desmethylnaproxen, the glycine conjugate of naproxen and the O-sulphate of 6-O-desmethylnaproxen were prepared by chemical synthesis. Naproxen and the purified metabolite and conjugates were used as standards for the analytical investigation of the metabolic pattern of naproxen in humans. A reversed-phase high-performance liquid chromatographic method based on bare silica dynamically modified with cetyltrimethylammonium ions has been developed. The system was optimized to give a separation of naproxen, 6-O-desmethylnaproxen and five conjugates. Using this method it is also possible to deduce the relationship between the amount of the intact ether-glucuronide and acyl-glucuronide of 6-O-desmethylnaproxen.

Adult↗
PubMed1994

Enzyme-catalysed enantioselective hydrolysis of racemic naproxen nitrile.

The bacterial strain Rhodococcus butanica (ATCC 21197), which exhibits nitrilase and nitrile hydratase/amidase activities, catalyses the enantioselective hydrolysis of racemic naproxen nitrile (R/S)-1 to furnish a moderate enantiomeric excess of (S)-naproxen (S)-3. Racemic naproxen amide (R/S)-2 is not a good substrate for this strain. Resting cells of the newly selected bacterial strain Rhodococcus sp. C3II catalyse the enantioselective hydrolyses of racemic naproxen nitrile (R/S)-1 and naproxen amide (R/S)-2 as well, to give (S)-3 in excellent optical (99% e.e.) and good chemical yields in aqueous medium and in the biphasic system of phosphate buffer/hexane.

Aminohydrolases↗
PubMed2004

Effects of rofecoxib and naproxen on life expectancy among patients with rheumatoid arthritis: a decision analysis.

BACKGROUND: The VIOXX Gastrointestinal Outcomes Research (VIGOR) trial showed a 53% decrease in the risk of upper gastrointestinal toxicity and a fivefold increase in the risk of myocardial infarction for rofecoxib (a selective cyclooxygenase-2 inhibitor) compared with naproxen. We examined the effects of these competing adverse events on life expectancy in patients with rheumatoid arthritis. METHODS: We used decision analysis to compare the life expectancy of a cohort of rheumatoid arthritis patients taking naproxen versus a similar cohort taking rofecoxib, using data from the VIGOR trial. We incorporated the competing risks of upper gastrointestinal toxicity and myocardial infarction, as well as their long-term health consequences, on the basis of population-based studies. RESULTS: For 58-year-old women with rheumatoid arthritis (i.e., typical of participants in the VIGOR trial), naproxen was associated with a longer life expectancy than was rofecoxib (difference = 4.4 months). This difference was larger among 58-year-old men (7.8 months). The probability that naproxen is associated with a longer life expectancy than rofecoxib among 58-year-old patients was 92% for women and 98% for men. Life expectancy became the same between the two treatments when the risk of upper gastrointestinal toxicity was 70% higher or the risk of myocardial infarction was 40% lower than that of the base case among women, and when the risk of upper gastrointestinal toxicity was 4.4-fold higher or the risk of myocardial infarction was 70% lower among men. CONCLUSION: Our analysis suggests that the competing risks of upper gastrointestinal toxicity and myocardial infarction shown in the VIGOR trial would project a longer life expectancy with naproxen than rofecoxib among patients with rheumatoid arthritis, except in those at low risk of myocardial infarction or at high risk of upper gastrointestinal toxicity.

Aged↗
PubMed2006

Analgesic efficacy of the cyclooxygenase-inhibiting nitric oxide donor AZD3582 in postoperative dental pain: Comparison with naproxen and rofecoxib in two randomized, double-blind, placebo-controlled studies.

OBJECTIVE: This study assessed the analgesic efficacy of single doses of 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate (AZD3582) in acute postoperative dental pain after the removal of an impacted mandibular third molar (ie, wisdom tooth). METHODS: Two randomized, placebo-controlled, double-blind studies were performed. In a dose-finding study, 242 patients were randomized to AZD3582 375, 750, 1500, or 2250 mg (n = 41, 37, 42, and 41, respectively); naproxen 500 mg (n = 39); or placebo (n = 42). In a comparator study, 282 patients were randomized to AZD3582 500 mg (n = 78) or 750 mg (n = 83), rofecoxib 50 mg (n = 80), or placebo (n = 41). Primary outcomes included time to rescue medication, time to pain relief, and mean pain intensity difference (MPID), as well as safety profile. Pain was rated on a visual analog scale. RESULTS: In the dose-finding study, 52% (126/242) were women; the mean (SD) age was 25.1 (4) years, mean weight was 69.0 kg, and the mean (SD) body mass index (BMI) was 23.7 (3) kg/m2. In the comparator study, 58% (164/282) were women; the mean (SD) age was 27 (6.4) years, mean weight was 71 kg, and mean (SD) BMI was 24.2 (3) kg/m2. In the dose-finding study, the AZD3582 750-, 1500-, and 2250-mg groups were superior to placebo in the primary variables "time to rescue medication (0-8 hours)" (hazard ratios [HRs] [95% CIs], 0.17 [0.07-0.42], P < 0.003; 0.23 [0.11-0.50], P < 0.001; and 0.15 [0.06-0.36], P < 0.001, respectively), "time to meaningful pain relief" (HRs [95% CIs], 3.42 [1.87-6.25], P < 0.003; 2.49 [1.37-4.50], P < 0.003; and 3.07 [1.70-5.55], P < 0.001, respectively), and MPID (analysis of covariance [ANCOVA] least squares mean [LSM] differences [95% CIs], 25.8 [17.3-34.4], P < 0.003; 20.4 [12.1-28.7], P < 0.003; and 29.3 [20.9-37.6], P < 0.001, respectively). AZD3582 and naproxen did not show any statistically significant differences for the 3 primary variables, except that naproxen was superior to the AZD3582 375-mg dose for the variables time to meaningful pain relief (HR difference, 0.48 [95% CI, 0.29-0.78], P < 0.004) and MPID (difference in ANCOVA LSM, -10.2, [95% CI, -18.2 to -2.2], P < 0.012). The median times to meaningful pain relief were 115 minutes for AZD3582 375 mg, 66 minutes for 750 mg, 85 minutes for 1500 mg, 81 minutes for 2250 mg, and 162 minutes for placebo (P = NS, P = 0.003, P < 0.003, and P < 0.001, respectively). The median time to first rescue medication was 144 minutes for placebo, and <50% of the subjects on any of the AZD3582 doses or naproxen took rescue medication within 8 hours after dosing. In the comparator study, AZD3582 750 mg was superior to placebo in "time to rescue medication (0-24 hours)" (HR [95% CI], 0.4 [0.3-0.6], P < 0.001), "time to confirmed perceptible pain relief" (2.1 [1.1-3.8], P = 0.02), and MPID (11.9 [4.2-19.5], P = 0.002). However, inferiority of AZD3582 to rofecoxib for MPID could not be excluded (tolerance limit of 10 mm; P = NS for noninferiority testing). The median times to confirmed perceptible pain relief were 45 minutes for AZD3582 500 mg, 40 minutes for 750 mg, and 37 minutes for rofecoxib. The median times to first rescue medication were 218 minutes for AZD3582 500 mg, 365 minutes for 750 mg, 635 minutes for rofecoxib, and 90 minutes for placebo. Overall, AZD3582 was well tolerated. However, an effect on orthostatic blood pressure could not be excluded because there seemed to be more subjects with dizziness and orthostatic blood pressure reduction who were administered AZD3582 > or =750 mg. The proportions of patients with vertigo and decreased orthostatic blood pressure each group were as follows: AZD3582 500 mg, 6%; AZD3582 750 mg, 12%; rofecoxib, 3%; and placebo, 5%. CONCLUSIONS: AZD3582 750 mg had similar analgesic efficacy as equimolar doses of naproxen, but noninferiority to rofecoxib was not demonstrated.

Adolescent↗