mobic and rofecoxib

Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) from genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, as well as for other unknown reasons.Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain, reduce fever, and for their anti-inflammation properties. They are commonly used within paediatric pain management. Non-steroidal anti-inflammatory drugs are currently licensed for use in Western countries, however they are not approved for infants under three months old. The main adverse effects include renal impairment and gastrointestinal issues. Common side effects in children include diarrhoea, headache, nausea, constipation, rash, dizziness, and abdominal pain.. To assess the analgesic efficacy and adverse events of NSAIDs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, as well as online clinical trial registries.. Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing any NSAID with placebo or an active comparator.. Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE and created three 'Summary of findings' tables.. We included seven studies with a total of 1074 participants (aged 2 to 18 years) with chronic juvenile polyarthritis or chronic juvenile rheumatoid arthritis. All seven studies compared an NSAID with an active comparator. None of the studies were placebo controlled. No two studies investigated the same type of NSAID compared with another. We were unable to perform a meta-analysis.Risk of bias varied. For randomisation and allocation concealment, one study was low risk and six studies were unclear risk. For blinding of participants and personnel, three studies were low risk and four studies were unclear to high risk. For blinding of outcome assessors, all studies were unclear risk. For attrition, four studies were low risk and three studies were unclear risk. For selective reporting, four studies were low risk, two studies were unclear risk, and one study was high risk. For size, three studies were unclear risk and four studies were high risk. For other potential sources of bias, seven studies were low risk. Primary outcomesThree studies reported participant-reported pain relief of 30% or greater, showing no statistically significant difference in pain scores between meloxicam and naproxen, celecoxib and naproxen, or rofecoxib and naproxen (P > 0.05) (low-quality evidence).One study reported participant-reported pain relief of 50% or greater, showing no statistically significant difference in pain scores between low-dose meloxicam (0.125 mg/kg) and high-dose meloxicam (0.25 mg/kg) when compared to naproxen 10 mg/kg (P > 0.05) (low-quality evidence).One study reported Patient Global Impression of Change, showing 'very much improved' in 85% of ibuprofen and 90% of aspirin participants (low-quality evidence). Secondary outcomesAll seven studies reported adverse events. Participants reporting an adverse event (one or more per person) by drug were: aspirin 85/202; fenoprofen 28/49; ibuprofen 40/45; indomethacin 9/30; ketoprofen 9/30; meloxicam 18/47; naproxen 44/202; and rofecoxib 47/209 (very low-quality evidence).All seven studies reported withdrawals due to adverse events. Participants withdrawn due to an adverse event by drug were: aspirin 16/120; celecoxib 10/159; fenoprofen 0/49; ibuprofen 0/45; indomethacin 0/30; ketoprofen 0/30; meloxicam 10/147; naproxen 17/285; and rofecoxib 3/209 (very low-quality evidence).All seven studies reported serious adverse events. Participants experiencing a serious adverse event by drug were: aspirin 13/120; celecoxib 5/15. We identified only a small number of studies, with insufficient data for analysis.As we could undertake no meta-analysis, we are unable to comment about efficacy or harm from the use of NSAIDs to treat chronic non-cancer pain in children and adolescents. Similarly, we cannot comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.We know from adult randomised controlled trials that some NSAIDs, such as ibuprofen, naproxen, and aspirin, can be effective in certain chronic pain conditions.

Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Juvenile; Arthritis, Rheumatoid; Aspirin; Celecoxib; Child; Child, Preschool; Chronic Disease; Chronic Pain; Fenoprofen; Humans; Ibuprofen; Lactones; Meloxicam; Methoxsalen; Naproxen; Randomized Controlled Trials as Topic; Sulfones; Thiazines; Thiazoles

The association between hemorrhagic stroke and use of nonsteroidal anti-inflammatory drugs (NSAIDs) is not well established. We conducted a systematic review and meta-analysis of observation studies to further characterize this possible association.. Case-control and cohort studies that reported odds ratio, relative risk, hazard ratio, or standardized incidence ratio comparing risk of hemorrhagic stroke among NSAIDs users versus nonusers were systematically searched. Point estimates from each study were extracted. Pooled risk ratios (RR) and 95% confidence intervals (CI) for all NSAIDs and individual NSAIDs were calculated using random-effect, generic inverse variance method.. Ten studies were identified and included in our data analysis. As a single group, NSAIDs use was associated with a small but insignificant risk of hemorrhagic stroke with the pooled RR of 1.09 (95% CI, 0.98-1.22). Individual NSAIDs analysis revealed a significantly increased risk among diclofenac and meloxicam users (RR 1.27; 95% CI, 1.02-1.59 and RR 1.27; 95% CI, 1.08-1.50, respectively). The risk estimate for rofecoxib users was higher, but statistically nonsignificant (RR 1.35; 95% CI, 0.88-2.06).. Overall, the use of NSAIDs is not associated with an increased risk of hemorrhagic stroke, although this risk was modestly significantly elevated in diclofenac and meloxicam users.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cerebral Hemorrhage; Diclofenac; Humans; Ibuprofen; Incidence; Indomethacin; Lactones; Meloxicam; Naproxen; Observational Studies as Topic; Odds Ratio; Piroxicam; Proportional Hazards Models; Stroke; Sulfones; Thiazines; Thiazoles

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.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Etodolac; Gastrointestinal Agents; Gastrointestinal Diseases; Humans; Isoenzymes; Lactones; Meloxicam; Membrane Proteins; Practice Guidelines as Topic; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides; Sulfones; Thiazines; Thiazoles

Among the most widely prescribed drugs worldwide, non-steroidal anti-inflammatory drugs (NSAIDs) are effective for relieving pain, but they are also associated with a high incidence of gastrointestinal (GI) adverse events. Both the beneficial and harmful effects of NSAIDs result from inhibition of the cyclo-oxygenase (COX) enzyme. Recognition of the two distinct COX isoforms prompted development of drugs that selectively block the activity of COX-2, thus providing pain relief and reducing inflammation while sparing COX-1, the enzyme apparently responsible for most protective prostaglandin synthesis in the mucosa of the stomach and duodenum. The results of preclinical and clinical studies indicate that COX-2 inhibitors exhibit high selectivity in inhibiting COX-2, provide excellent pain relief, and cause significantly less GI toxicity than do conventional nonselective NSAIDs. Although they represent a significant advance over nonselective NSAIDs, selective COX-2 inhibitors are not without limitations. They do not completely eliminate GI toxicity or the renal side effects associated with use of conventional NSAIDs. Moreover, in cases of inflammation or ulceration in the GI tract, COX-2 inhibition may delay ulcer healing. Finally, case reports and the results of animal experiments suggest that COX-2 inhibitors may adversely affect ovulation and cause a tendency towards prothrombotic events.

Topics: Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase Inhibitors; Humans; Lactones; Meloxicam; Neoplasms; Pyrazoles; Sulfonamides; Sulfones; Thiazines; Thiazoles

Non-steroidal anti-inflammatory drugs (NSAIDs) account for more reports of drug related toxicity than any other class of drugs. Their most widely recognised adverse effects are on the gastrointestinal tract. They cause acute erosions and chronic ulcers that result in hospitalisation and death because of ulcer bleeding and perforation. Between them, aspirin and non-aspirin NSAIDs may account for more than half of all episodes of ulcer bleeding and perforation.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Gastroscopy; Humans; Isoenzymes; Kidney; Lactones; Meloxicam; Membrane Proteins; Myocardial Infarction; Prostaglandin-Endoperoxide Synthases; Proton Pump Inhibitors; Pyrazoles; Randomized Controlled Trials as Topic; Stomach Ulcer; Sulfonamides; Sulfones; Thiazines; Thiazoles

Topics: Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Humans; Isoenzymes; Lactones; Meloxicam; Membrane Proteins; Pain; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Randomized Controlled Trials as Topic; Sulfonamides; Sulfones; Thiazines; Thiazoles

Cyclooxygenase is key enzyme in the prostaglandin synthesis. It exists in two isoforms, which have distinct functions in the organism. Cyclooxygenase-2 (COX-2) participates in the pathophysiology of inflammation. Differences in the molecular structure of cyclooxygenases allowed to develop drug that selectively inhibit that isoform. Recently, selective inhibitors of COX-2 were introduced into therapy, providing new opportunities to the treatment of inflammation.

Topics: Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Humans; Inflammation; Isoenzymes; Lactones; Meloxicam; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Protein Isoforms; Pyrazoles; Sulfonamides; Sulfones; Thiazines; Thiazoles

Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for substantial morbidity and mortality as a result of the complications associated with gastroduodenal ulcers, such as perforation and bleeding. The central mechanism leading to the gastroduodenal toxicity of NSAIDs is their ability to inhibit mucosal prostaglandin synthesis. Recent recognition that there are 2 isoforms of the enzyme cyclooxygenase (COX) responsible for prostaglandin synthesis has enabled the development of drugs capable of sparing the gastric mucosa. The inducible COX-2 enzyme is responsible for some aspects of pain and inflammation in arthritis while the constitutive COX-1 enzyme appears responsible for most of the gastro-protective prostaglandin synthesis in the stomach and duodenum. Drugs selective for COX-2 probably act by binding to a pocket in the enzyme that is present in COX-2 but not in COX-1. As a result, drugs that have little or no COX-1 activity across their therapeutic dosage range have been developed. Two drugs that are claimed to be highly selective or specific in their ability to inhibit COX-2, rofecoxib and celecoxib, are now available on prescription in the US and rofecoxib is available in Europe. Short term volunteer studies of 7 days' duration and patient studies of 6 months' duration have shown these drugs to have a level of gastroduodenal injury that is similar or equivalent to that seen with placebo, whereas high rates of damage and ulceration are seen with nonselective NSAIDs. In addition, there appear to have been fewer perforations, clinical ulcers and bleeds in the phase III clinical trials of these agents, compared with nonselective NSAIDS. However, more experience will be needed before this promise can be confirmed. In addition, COX-2 inhibitors share the adverse effects of NSAIDs outside the gastrointestinal tract that are dependent on COX-2 inhibition.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Etodolac; Humans; Lactones; Meloxicam; Pyrazoles; Sulfonamides; Sulfones; Thiazines; Thiazoles

Topics: Advertising; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Industry; Gastrointestinal Diseases; Humans; Isoenzymes; Lactones; Meloxicam; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Safety; Sulfonamides; Sulfones; Thiazines; Thiazoles

Nonsteroidal anti-inflammatory drugs (NSAIDs) can affect renal function in a variety of ways. The most important clinical effects are decreased sodium excretion, decreased potassium excretion, and declines in renal perfusion. Decreased sodium excretion can result in weight gain, peripheral edema, attenuation of the effects of antihypertensive agents, and rarely precipitation of chronic heart failure. Hyperkalemia can occur to a degree sufficient to cause cardiac arrhythmias. Renal function can decline sufficiently enough to cause acute renal failure. Risk factors for all of these effects have been identified, allowing prospective identification of patients at risk with institution of appropriate precautionary measure. All NSAIDs seem to share these adverse effects. Preliminary data from cyclooxygenase-2-selective inhibitors suggest that they also affect renal prostaglandins. Therefore, the same cautions should be exercised with their use as with traditional NSAIDs.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Butanones; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Humans; Isoenzymes; Kidney; Lactones; Meloxicam; Membrane Proteins; Nabumetone; Natriuresis; Nephritis, Interstitial; Potassium; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Renal Circulation; Sodium; Sulfonamides; Sulfones; Thiazines; Thiazoles

To determine the effect of 3 different cyclo-oxygenase (COX) inhibitors on primary dysmenorrheic pain.. Eleven female patients self-medicated with either placebo (sugar), 25 mg of the COX-2 specific inhibitor rofecoxib, 50 mg of the nonselective COX inhibitor diclofenac potassium, or 7.5 mg of the COX-2 selective inhibitor meloxicam, over 4 menstrual cycles. Pain was assessed using the McGill Pain Questionnaire and a visual analog scale.. The pain response index, present pain index, and visual analog scale were highly correlated as measures of intensity of pain (r=0.81 to 0.96, P<0.0001). Rofecoxib and diclofenac potassium both decreased the duration of dysmenorrheic pain compared with placebo (P<0.001) and with meloxicam (P<0.01), and were equally effective in improving pain, compared with placebo, after each capsule (P<0.001). When compared with placebo, both drugs also provided 50% or more pain relief, after each capsule (P<0.0048). Meloxicam, although superior to placebo, was not as effective as rofecoxib and diclofenac potassium in reducing pain, and when compared with placebo, was associated with providing 50% or more of pain relief only after the third and fourth capsules (P=0.016).. Rofecoxib and diclofenac potassium, when taken in recommended doses, were equally effective in alleviating pain associated with primary dysmenorrhea.

Topics: Adult; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Dose-Response Relationship, Drug; Dysmenorrhea; Female; Humans; Lactones; Meloxicam; Pain Measurement; Self Medication; Sulfones; Thiazines; Thiazoles

To compare the safety and efficacy of rofecoxib* to naproxen for the treatment of juvenile rheumatoid arthritis (JRA).. This was a 12-week, multicenter, randomized, double-blind, double-dummy, active comparator-controlled, non-inferiority study with a prespecified 52-week open-label active comparator-controlled extension. Children (ages 2-11 yrs) and adolescents (ages 12-17 yrs) received lower-dose (LD)-rofecoxib [0.3 mg/kg/day up to 12.5 mg/day (base study only)]; or higher-dose (HD)-rofecoxib (0.6 mg/kg/day up to 25 mg/day) or naproxen 15 mg/kg/day as oral suspensions. Adolescents received daily rofecoxib (LD) 12.5 (base study only) or (HD) 25 mg, or naproxen 15 mg/kg/day (maximum 1,000 mg/day) as tablets. The primary endpoint was the time-weighted average proportion of patients meeting the American College of Rheumatology Pediatric-30 (ACR Pedi 30) response criteria. A prespecified bound for the 95% confidence interval for the ratio of the percentage of ACR Pedi 30 responders was used to assess non-inferiority of treatment response between groups. Safety was assessed throughout the study.. A total of 310 patients ages 2-17 years (181 (3/4) age 11) were randomized to receive LD-rofecoxib (N=109), HD-rofecoxib (N=100), or naproxen (N=101). The ACR Pedi 30 response rates following 12 weeks of treatment were 46.2%, 54.5%, and 55.1%, respectively. The relative rates of response compared to naproxen were 0.81 (95% CI 0.61, 1.07) and 0.98 (95% CI 0.76, 1.26) for LD- and HD-rofecoxib, respectively. Both rofecoxib doses were not inferior to naproxen. Patients (N=227) entering the extension received HD-rofecoxib or naproxen with efficacy maintained during the extension. All treatments were generally well tolerated throughout the study.. Daily treatment of JRA patients with rofecoxib up to 12.5 or 25 mg was well tolerated, providing sustained clinical effectiveness comparable to naproxen 15 mg/kg. *On September 30, 2004, Merck & Co., Inc. announced the voluntary worldwide withdrawal of rofecoxib from the market.

Topics: Adolescent; Arthritis, Juvenile; Child; Child, Preschool; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Lactones; Longitudinal Studies; Male; Meloxicam; Naproxen; Sulfones; Thiazines; Thiazoles; Treatment Outcome

To investigate pain relieving efficacy of six agents which are used in postoperative pain management after otolaryngologic operations.. 120 adult patients (63 females, 57 males; mean age 36; range 18 to 76 years) were included in the study. The same intraoperative anesthesia was applied to all the patients. The following medications were randomly given to the patients who declared pain in the sixth hour after the operation: naproxen sodium, meloxicam, rofecoxib, paracetamol, dipyrone, and etodolac in proper dosage to form groups of 20 for each medication. Before and after the application of pain reliever tablets, visual analog scale (VAS) and numerical rating scale (NRS) were used to inquire whether the agents were effective in relieving pain. ANOVA (one way), paired t-test, Kruskal-Wallis, and Student's t-test were used as statistical methods. p values <0.05 were considered to indicate statistical significance.. All the groups had similar VAS values before medication (p>0.05). When VAS values of each group were assessed after medication, it was recorded that naproxen sodium (p=0.020) and meloxicam (p=0.001) were effective. When the difference of NRS values between "before medication" and "after medication" was compared among the groups, all the agents significantly changed NRS values, but no inter-group differences were found (p>0.05).. In terms of NRS scores, the effectiveness of six different analgesic agents which had been used to reduce postoperative pain was confirmed. Moreover, naproxen sodium and meloxicam were found to be more effective than the other agents when taken in the postoperative period for the adult patients according to VAS values.

Topics: Acetaminophen; Adolescent; Adult; Aged; Analgesics; Dipyrone; Etodolac; Female; Humans; Lactones; Male; Meloxicam; Middle Aged; Naproxen; Otorhinolaryngologic Surgical Procedures; Pain Measurement; Pain, Postoperative; Postoperative Period; Sulfones; Thiazines; Thiazoles; Treatment Outcome

Intolerance to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) is a crucial problem in clinical practice. There is, therefore, a need for safer NSAIDs in patients with analgesic intolerance.. To assess the safety of nimesulide, meloxicam, and rofecoxib, selective COX-2 inhibitors, in a group of ASA/NSAIDs-intolerant patients.. Tolerances to nimesulide, meloxicam, and rofecoxib were assessed by single-blind placebo-controlled oral challenges. One hundred twenty-seven subjects with history of adverse reaction to ASA/NSAIDs received oral challenges with nimesulide, 61 subjects were challenged with meloxicam, 51 subjects were challenged with rofecoxib, and 37 subjects were challenged with all three drugs. Placebos were given to all patients on the first day of the study. On the second day, one-fourth and three-fourths of the therapeutic doses of the active drugs (nimesulide 100 mg, meloxicam 7.5 mg, or rofecoxib 25 mg) were given at 60-minute intervals. There was at least a 3-day interval between challenge tests. Erythema, pruritus accompanied by erythema, urticaria/angioedema, rhinorrhea, nasal obstruction, sneezing, dyspnea, or cough associated with a decrease of at least 20% in the forced expiratory volume (FEV1) and hypotension were considered as positive reactions.. Positive reactions to the nimesulide, meloxicam, and rofecoxib challenges were observed in 18/127 (14.3%), 5/61 (8.1%), and 1/51 (2.0%) patients, respectively. In each group of nine patients, there were two patients with asthma and four who developed skin type reactions and asthmatic reactions, respectively, to the nimesulide challenge. Among five patients who reacted to the meloxicam challenge, asthmatic type reactions were detected in two asthmatics. Only one urticarial type reaction was observed with rofecoxib challenge in one patient who presented with anaphylaxis to ASA/NSAIDs. All patients with asthma tolerated rofecoxib without any adverse effects. None of the patients reacted to the placebo. Among 37 patients challenged with all three drugs, 11 reacted to nimesulide, and one patient reacted only to meloxicam. Three patients reacted to more than one of the drugs tested, and one of them reacted to all drugs.. This is the first placebo-controlled report comparing these three drugs. The results indicate that among these alternative drugs for ASA/NSAIDs-intolerant patients, rofecoxib seems to have the most favorable tolerability.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Cyclooxygenase Inhibitors; Drug Hypersensitivity; Female; Humans; Immunologic Tests; Lactones; Male; Meloxicam; Middle Aged; Single-Blind Method; Sulfonamides; Sulfones; Thiazines; Thiazoles; Treatment Outcome; Urticaria

Acute attacks of gouty arthritis are characterized by the rapid onset of severe pain, swelling, and erythema of the affected joint. Nonsteroidal anti-inflammatory drugs are considered the drugs of first choice for treating acute gout. Rofecoxib is a specific cyclooxygenase-2 inhibitor, which has demonstrated analgesic efficacy in the setting of acute pain. Whether it is effective in the treatment of acute gouty arthritis remains to be evaluated.. The aim of this study was to assess the efficacy and tolerability of rofecoxib compared with diclofenac sodium sustained release (SR) and meloxicam in the treatment of acute gouty arthritis.. In this single-blind, randomized, controlled, parallel-group study, patients aged > or =18 years with acute gout within 48 hours of onset were randomized to receive oral treatment with 2 tablets of rofecoxib (25 mg), diclofenac (75 mg), or meloxicam (7.5 mg) once daily for 7 days. The primary outcome measures were patients global assessment of response to therapy and investigator assessment of response to therapy on days 3 and 8. Other efficacy measurements included investigator assessment of total inflammatory scores on days 3 and 8 and patient assessment of pain intensity during the first 12 hours of treatment.. Sixty-two patients (53 men, 9 women; mean [SD] age, 51.1 [12.1] years) were assigned to receive rofexocib (n = 20), diclofenac (n = 21), or meloxicam (n = 21). For patient global response to therapy on days 3 and 8, rofecoxib was associated with analgesic efficacy in significantly more patients compared with meloxicam (84.2% vs 40.0% of patients [ P=0.005] and 94.7% vs 60.0% of patients [ P=0.02], respectively); no significant differences versus diclofenac were found. Similarly, for investigator global assessment of response to therapy, a greater percentage of responders was found in the rofecoxib group compared with the meloxicam group on day 3 (88.9% vs 40.0% of patients [ P=0.02 ]), but the difference was not significant on day 8. A greater percentage of responders was found in the rofecoxib group compared with the diclofenac group on day 3 (88.9% vs 47.3% [ P=0.007 ]), but the difference was not significant on day 8. Compared with baseline, all regimens showed significant improvement in total inflammatory scores on days 3 and 8 (all P<0.01 ). During the first 12 hours after dosing, pain intensity score was significantly reduced with rofecoxib starting at 0.5 hours ( P<0.05 ), but not with diclofenac or meloxicam. Clinical adverse events (AEs) were reported in 4 (20.0%), 7 (33.3%), and 6 (28.6%) patients in the rofecoxib, diclofenac, and meloxicam groups, respectively; the most common AEs reported were edema in 1 patient each in the rofecoxib (5.0%) and meloxicam (4.8%) groups and 2 patients (9.5%) in the diclofenac group and abdominal (1 [5.0%], 1 [4.8%], and 2 [9.5%], respectively). No significant differences in tolerability were found among the 3 treatment groups.. In this study of patients with acute gouty arthritis, rofecoxib 50 mg once daily provided more effective treatment than diclofenac sodium SR 150 mg and meloxicam 15 mg administered orally once daily for 7 days in > or = 1 efficacy assessment of overall analgesic effect on day 3 or day 8. Rofecoxib achieved a rapid onset of pain relief, demonstrating significant improvement 30 minutes after dosing. All of the regimens appeared well tolerated in the population studied.

Topics: Acute Disease; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Gouty; Diclofenac; Female; Humans; Lactones; Male; Meloxicam; Middle Aged; Single-Blind Method; Sulfones; Thiazines; Thiazoles

Patients with aspirin-sensitive respiratory and cutaneous diseases experience cross reactions to all nonsteroidal anti-inflammatory drugs (NSAIDs) which inhibit cyclo-oxigenase (COX) enzymes. As are now available drugs which selectively inhibit COX-2, questions are raised whether cross-reactivity occurs between aspirin and these COX 2 inhibitors.. The aim of this study was to evaluate the tolerability of three COX-2 inhibitors (meloxicam, celecoxib and rofecoxib) in subjects with previous pseudoallergic respiratory and cutaneous reactions to NSAIDs.. 76 subjects with documented previous cutaneous and respiratory pseudoallergic reactions to aspirin and/or other NSAIDs underwent a single blind challenge with celecoxib, meloxicam and rofecoxib.. All subjects with previous respiratory reactions tolerated all drugs. Three subjects with multiple-drug induced urticaria complained of a generalized reaction after challenge (Two due to celecoxib and one due to meloxicam). Among the group of patients with NSAIDs-induced urticaria five complained of a relapse of the disease due to rofecoxib (one subject), celecoxib (two subjects and meloxicam (two subjects).. According to these results the cross-reactivity between aspirin and these COX-2 inhibitors does not occur in subjects with previous respiratory pseudoallergic reactions. A good safety profile was also demonstrated in patients with cutaneous reactions, being few reactions observed. However for this reason a controlled oral challenge with these drugs is useful for the proper management of patients sensitive to classic NSAIDs.

Topics: Adolescent; Adult; Aged; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Celecoxib; Cross Reactions; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Hypersensitivity; Female; Forced Expiratory Volume; Hemodynamics; Humans; Isoenzymes; Lactones; Male; Meloxicam; Membrane Proteins; Middle Aged; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Recurrence; Rhinitis, Allergic, Perennial; Single-Blind Method; Sulfonamides; Sulfones; Thiazines; Thiazoles; Urticaria

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.

Topics: Adolescent; Adult; Bleeding Time; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Female; Humans; Ibuprofen; Isoenzymes; Lactones; Lipopolysaccharides; Meloxicam; Membrane Proteins; Middle Aged; Naproxen; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Sulfones; Thiazines; Thiazoles; Thromboxane B2

Inflammatory conditions increase cardiovascular (CV) risk. Some nonsteroidal anti-inflammatory drugs (NSAIDs) that are used to treat pain and inflammation are also associated with CV complications. Inflammation, but not NSAIDs, disrupts the balance of vasodilator and vasoconstrictor components of the renin-angiotensin system within the heart. Herein, we report the effect of both inflammation and NSAIDs (rofecoxib, celecoxib, and meloxicam) on the physiologically active cytochrome P450 metabolites of arachidonic acid (ArA) in the rat with adjuvant arthritis. After oral administration of 7 daily therapeutically equivalent doses of NSAIDs or vehicle, the anti-inflammatory response, as well as the ArA metabolites and drug concentrations in plasma, heart and kidneys were assessed. Inflammation in the form of adjuvant arthritis caused a significant tissue-dependent imbalance of ArA metabolites by elevating the ratio of cardiotoxic 20-hydroxyeicosatetraenoic acid over cardioprotective epoxyeicosatrienoic acids in the heart, and reducing the ratio in the kidney. The observed imbalance was augmented by cardiotoxic rofecoxib but not by other examined NSAIDs with known milder cardiotoxicity. The cardio-renal toxicity of NSAIDs with known severe CV side effects may be due to altered cytochrome P450-mediated ArA acid metabolism. The ArA metabolism profile may be a marker of NSAIDs safety and toxicity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arthritis, Experimental; Celecoxib; Cytochrome P-450 Enzyme System; Heart; Hydroxyeicosatetraenoic Acids; Inflammation; Kidney; Lactones; Male; Meloxicam; Rats; Rats, Sprague-Dawley; Sulfones; Thiazines; Thiazoles

Encouraged by the anti-inflammatory activity of hinokinin in vivo, which is also observed for the analogues dinitrohinokinin and diidrocubebin, herein we used in vitro and in silico methods to assess their selectivity profiles and predict their binding modes with Cyclooxygenases (COX-1 and 2). The in vitro assays demonstrated dinitrohinokinin is about 13 times more selective for COX-2 than for COX-1, a similar profile observed for the drugs celecoxib (selective index ≈9) and meloxicam (selective index ≈11). Predictions of the binding modes suggested dinitrohinokinin interacts with COX-2 very similarly to rofecoxib, exploring residues at the hydrophilic pocket of the enzyme that accessible to ligands only in this isoform. This lignan also interacts with COX-1 in a similar mode to meloxicam, blocking the access of the substrate to the catalytic cleft. Therefore, dinitrohinokinin is a promising lead for the design of selective COX-2 inhibitors.

Topics: 4-Butyrolactone; Benzodioxoles; Binding Sites; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Humans; Lactones; Lignans; Meloxicam; Molecular Docking Simulation; Protein Binding; Quantitative Structure-Activity Relationship; Substrate Specificity; Sulfones

We aimed to examine whether the current users of specific NSAIDs have an increased risk of venous thromboembolism (VTE) among knee OA patients.. We conducted a population-based case-control study using The Health Improvement Network, a database of patient records from general practices in the UK. For every VTE case, we identified five controls matched on age, sex and calendar year of study enrolment. We used conditional logistic regression to assess the association between current use of specific NSAIDs and risk of VTE relative to remote NSAID users.. Among knee OA patients with at least one NSAID prescription, we identified 4020 incident cases of VTE and 20 059 matched controls. Adjusted odd ratios (ORs) relative to the remote users were 1.38 (95% CI: 1.32, 1.44) for recent users and 1.43 (95% CI: 1.36, 1.49) for current users. Among the current NSAID users, the risk of VTE was increased with diclofenac [OR 1.63 (95% CI: 1.53, 1.74)], ibuprofen [OR = 1.49 (95% CI: 1.38, 1.62)], meloxicam [OR = 1.29 (95% CI: 1.11, 1.50)] and coxibs [celecoxib, OR = 1.30 (95% CI: 1.11, 1.51); rofecoxib, OR = 1.44 (95% CI: 1.18, 1.76)]; naproxen did not increase VTE risk [OR = 1.00 (95% CI: 0.89, 1.12)].. Compared with the remote users of NSAIDs, the risk of VTE increased for current users of diclofenac, ibuprofen, meloxicam, and coxibs, but not for naproxen, in the knee OA population. Clinicians should consider the risk profile for specific NSAIDs when recommending their use.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Cyclooxygenase 2 Inhibitors; Diclofenac; Female; Humans; Ibuprofen; Lactones; Logistic Models; Male; Meloxicam; Middle Aged; Naproxen; Odds Ratio; Osteoarthritis, Knee; Risk Factors; Sulfones; Thiazines; Thiazoles; Treatment Outcome; United Kingdom; Venous Thromboembolism

Over the last decade, actions following some adverse drug events received major publicity. This study investigated changes in usage patterns of medications in Australia following two examples - rofecoxib market withdrawal (2004) and warnings about jaw necrosis following bisphosphonates (2007).. Dispensing data for COX-2 inhibitors (2000-2008) and anti-osteoporosis medications (2003-2012) were obtained from the Australian Pharmaceutical Benefits Scheme database. For bisphosphonates, data on Australian marketing expenditures were purchased from Cegedim(R).. For COX-2 inhibitors, celecoxib dispensing halved after rofecoxib withdrawal, but meloxicam dispensing increased by 60 %. When lumiracoxib was introduced (2006) there was uptake of prescribing at a faster rate than meloxicam in 2002, its first year of use. For bisphosphonates, alendronate had highest use at the time of the warnings (8.3 DDD/1000/day), dropping to 4.9 DDD/1000/day by 2012. In contrast, risedronate use rose 2007-2012 from 4.1 to 4.9 DDD/1000/day. There was 49 % increase in reported annual expenditure on detailing for risedronate from 2007 to 2008 (to AUD$7.3 million) and only 29 % increase for alendronate (to AUD$3.1 million).. The rapid uptake of prescribing of lumiracoxib and increased use of meloxicam flagged a concern, especially after rofecoxib withdrawal due to safety issues. Bisphosphonates are useful drugs, however the dramatic rise in expenditure on detailing, followed by a rise in utilisation of risedronate could suggest that adverse publicity triggered a marketing response. These examples highlight the importance of tracking utilisation of medication classes in real time, using different data as needed, to ensure that due caution is exercised (and quick intervention provided if needed) for medications in the same class.

Topics: Aged; Australia; Bone Density Conservation Agents; Celecoxib; Cyclooxygenase 2 Inhibitors; Diphosphonates; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Lactones; Medication Adherence; Meloxicam; Osteoporosis; Sulfones; Thiazines; Thiazoles

Cyclooxygenase isoenzyme is known to be expressed in different regions of brain, and is mainly used for the treatment of pain and inflammation. Recently, it is proposed that cyclooxygenase isoenzyme may also play a key role in the pathophysiology of various brain-related disorders. The present study was aimed to explore the protective effect of cyclooxygenase inhibitors on stress by using an animal model of chronic stress.. The animals were forced to swim individually for a period of 6 min every day for 15 d. Then, the behavior (locomotor activity, anxiety and memory) and biochemical (lipid peroxidation, nitrite level, reduced glutathione, and catalase) alterations were assessed.. Forced swimming for 15 d caused impaired locomotor activity, anxiety-like behavior and decreased percentage of memory retention, as compared to naive mice (without chronic fatigue treatment). Biochemical analysis revealed significant increases in lipid peroxidation and nitrite level, while levels of reduced glutathione and catalase activity were both decreased. Chronic treatment with naproxen (14 mg/kg, i.p.), rofecoxib (5 mg/kg, i.p.), meloxicam (5 mg/kg, i.p.), nimesulide (5 mg/kg, i.p.) and valdecoxib (10 mg/kg, i.p.) significantly attenuated these behavioral and biochemical (oxidative damage) alterations in chronic-stressed mice.. The cyclooxygenase inhibitors could be used in the management of chronic fatigue-like conditions.

Topics: Animals; Anxiety; Catalase; Chronic Disease; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Glutathione; Isoxazoles; Lactones; Lipid Peroxidation; Male; Meloxicam; Memory; Mice; Motor Activity; Naproxen; Nitrites; Random Allocation; Stress, Psychological; Sulfonamides; Sulfones; Thiazines; Thiazoles

To investigate the role of substance P (sP), nitric oxide (ON) and prostaglandins (PGs) in acrolein (ACR)-induced cystitis, we studied the changes induced by ACR on bladder inducible nitric oxide synthase (iNOS) and mieloperoxidase (MPO) activities, along with PGs and NO metabolites levels. Sprague-Dawley male rats received i.p. ACR (5 mg/Kg) plus one of the following treatments: Group 1: saline 0.10 mL/100g i.p.; Group 2: Win-51.708 (WIN) 25 mg/Kg i.p.; Group 3: S-metilisothiourea (MITU) 35 mg/Kg i.p.; Group 4: Rofecoxib(ROF) 20 mg/Kg o.p.; Group 5: Meloxicam(MEL) 25 mg/Kg i.p.; Group 6: combination MITU+MEL. ACR-induced mortality was partially prevented by WIN (NK1 antagonist) and MITU (iNOS inhibitor). Animals that survived after 24h of ACR exposure, had histological inflammatory changes in bladder along with increased MPO activity. There was augmentation of nitrates+nitrites and of PGs. WIN didn't prevent any of these effects. ROF and MEL (COX-2 inhibitors) partially protected against bladder inflammation; MITU pre-treatment was able to prevent these changes and those of NO metabolites levels. The MITU+MEL combination produced the highest protection against ACR-induced damage. These results suggest that NO produced via iNOS and PGs produced by COX-1/COX-2, have an important role in the pathogenesis of cystitis induced by ACR. ACR could stimulate iNOS and COX-1/COX-2, producing lymphocyte migration and increases of NO and PGs.

Topics: Acrolein; Androstanes; Animals; Benzimidazoles; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cystitis; Dinoprostone; Drug Evaluation, Preclinical; Lactones; Male; Meloxicam; Membrane Proteins; Neurokinin-1 Receptor Antagonists; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Prostaglandins; Rats; Rats, Sprague-Dawley; Sulfones; Thiazines; Thiazoles; Urinary Bladder

Chronic arthritis adversely affects glomerular function and nonsteroidal anti-inflammatory drugs (NSAIDs) reduce electrolyte urinary excretion. In addition, both acute and chronic inflammations may alter clearance of drugs. We studied (a) the effects of inflammation on the renal function and pharmacokinetics of rofecoxib and meloxicam; (b) whether inflammation could exacerbate reduced electrolytes excretion changes observed with NSAIDs; and (c) the influence of inflammation on distribution of these drugs into the kidney. Single oral doses of rofecoxib (10 mg kg(-1)), meloxicam (3 mg kg(-1)) or placebo were administered to normal or pre-adjuvant arthritic rats. Blood and urine samples were collected for the measurement of plasma nitrite, BUN and creatinine. The urinary excretion of sodium and potassium was also determined. Nitrite, BUN and plasma creatinine were increased starting on day 9 in the groups with inflammation. Sodium and potassium excretion rates were not affected by inflammation. Meloxicam did not alter the electrolyte excretion in any of the groups. Rofecoxib significantly decreased sodium and potassium excretion in normal rats and potassium excretion in inflamed rats. Inflammation significantly increased plasma concentrations of rofecoxib, but not meloxicam. The ratios of the kidney:plasma concentrations were not significantly altered by inflammation following either drug. Inflammation altered kidney function, demonstrated by increases in BUN and plasma creatinine. However, it did not influence the urinary electrolytes excretion. Since we have observed similar patterns of the effect of NSAIDs on kidney under healthy and inflammatory conditions, one may conclude that inflammation does not exacerbate the adverse effect.

Topics: Administration, Oral; Animals; Area Under Curve; Arthritis, Experimental; Arthritis, Rheumatoid; Cyclooxygenase 2 Inhibitors; Kidney; Kidney Function Tests; Lactones; Male; Meloxicam; Rats; Rats, Sprague-Dawley; Sulfones; Thiazines; Thiazoles

The objective of this study was to examine the effects of rofecoxib, meloxicam, both cyclooxygenase-2 (COX-2) inhibitors and aminoguanidine hydrochloride, an inducible nitric oxide synthase (iNOS) inhibitor and their combinations in neuropathic pain in rats.. Neuropathy was induced by chronic constriction injury (CCI) of right sciatic nerve under ketamine anesthesia in rats. Effect of ED(50) of aminoguanidine hydrochloride, rofecoxib and meloxicam administered orally was investigated using behavioral tests. Effect of combinations of aminoguanidine hydrochloride with rofecoxib and meloxicam was also investigated in neuropathic pain employing behavioral tests.. Behavioral tests, mechanical, thermal and cold stimuli confirmed the development of neuropathic pain after CCI. Aminoguanidine hydrochloride, rofecoxib and meloxicam when administered alone, produced significant increase in paw withdrawal threshold to mechanical stimuli at 6 h in ipsilateral hind paw after CCI. Co-administration of aminoguanidine hydrochloride (30 mg/kg) with rofecoxib (1.31 mg/kg) and meloxicam (1.34 mg/kg) was also found to produce significant increase in paw withdrawal latencies to mechanical stimuli at 6 h. Combined administration of aminoguanidine hydrochloride with meloxicam and rofecoxib produced significant rise in pain threshold for mechanical hyperalgesia in ipsilateral hind paw when compared with the groups treated with aminoguanidine hydrochloride, meloxicam and rofecoxib alone.. Co-administration of meloxicam and rofecoxib with aminoguanidine hydrochloride may be an alternative approach for the treatment of neuropathic pain.

Topics: Animals; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Guanidines; Hyperalgesia; Lactones; Male; Meloxicam; Neuralgia; Neurons, Afferent; Nitric Oxide; Nitric Oxide Synthase Type II; Nociceptors; Pain Threshold; Peripheral Nervous System Diseases; Physical Stimulation; Rats; Reaction Time; Sciatic Neuropathy; Sulfones; Thiazines; Thiazoles; Treatment Outcome

We have evaluated the effect of the short-term administration of low therapeutic doses of modern COX-2 inhibitors on the healing of fractures. A total of 40 adult male New Zealand rabbits were divided into five groups. A mid-diaphyseal osteotomy of the right ulna was performed and either normal saline, prednisolone, indometacin, meloxicam or rofecoxib was administered for five days. Radiological, biomechanical and histomorphometric evaluation was performed at six weeks. In the group in which the highly selective anti-COX-2 agent, rofecoxib, was used the incidence of radiologically-incomplete union was similar to that in the control group. All the biomechanical parameters were statistically significantly lower in both the prednisolone and indometacin (p = 0.01) and in the meloxicam (p = 0.04) groups compared with the control group. Only the fracture load values were found to be statistically significantly lower (p = 0.05) in the rofecoxib group. Histomorphometric parameters were adversely affected in all groups with the specimens of the rofecoxib group showing the least negative effect. Our findings indicated that the short-term administration of low therapeutic doses of a highly selective COX-2 inhibitor had a minor negative effect on bone healing.

Topics: Analysis of Variance; Animals; Bony Callus; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Fracture Healing; Fractures, Bone; Indomethacin; Lactones; Male; Meloxicam; Prednisolone; Rabbits; Sulfones; Thiazines; Thiazoles

It is widely believed that the potencies of nonsteroid anti-inflammatory drugs (NSAIDs) as inhibitors of cyclooxygenase (COX) are influenced by protein binding in the extracellular fluid, since NSAIDs are bound to circulating albumin by well over 95%. This is an important point because the protein concentrations in synovial fluid and the central nervous system, which are sites of NSAID action, are markedly different from those in plasma. Here we have used a modified whole-blood assay to compare the potencies of aspirin, celecoxib, diclofenac, indomethacin, lumiracoxib, meloxicam, naproxen, rofecoxib, sodium salicylate, and SC560 as inhibitors of COX-1 and COX-2 in the presence of differing concentrations of protein. The potencies of diclofenac, naproxen, rofecoxib, and salicylate, but not aspirin, celecoxib, indomethacin, lumiracoxib, meloxicam, or SC560, against COX-1 (human platelets) increased as protein concentrations were reduced. Varying protein concentrations did not affect the potencies of any of the drugs against COX-2, with the exception of sodium salicylate (A549 cells). Clearly, our findings show that the selectivity of inhibitors for COX-1 and COX-2, which are taken to be linked to their efficacy and side effects, may change in different extracellular fluid conditions. In particular, selectivity in one body compartment does not demonstrate selectivity in another. Thus, whole-body safety or toxicity cannot be linked to one definitive measure of COX selectivity.

Topics: Aspirin; Blood Platelets; Blood Proteins; Calcimycin; Calcium; Celecoxib; Cell Line; Cerebrospinal Fluid Proteins; Cyclooxygenase 1; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Humans; Indomethacin; Ionophores; Lactones; Meloxicam; Naproxen; Organ Specificity; Organic Chemicals; Protein Binding; Pyrazoles; Sodium Salicylate; Sulfonamides; Sulfones; Synovial Fluid; Thiazines; Thiazoles; Thromboxane A2

Using national data (2001-2003), this study explored the risk of acute myocardial infarction (AMI), angina, stroke and transient ischaemic attack (TIA) in long-term users of rofecoxib and celecoxib in Taiwan and compared this data with that for those using meloxicam.. Patients included in the study had used celecoxib, rofecoxib or meloxicam for at least 180 days. Data were taken from National Health Insurance database for the period from 2001 to 2003. Main outcome measurements were the occurrence of AMI, angina, stroke or TIA after the initiation of long-term continuous use of these drugs. Person-time exposures and hazard ratios (HRs) were calculated based on data from 9602 eligible patients.. In patients without a history of a cardiovascular event within the year before drug treatment began, the overall rates of AMI, angina, stroke and TIA were 1.1%, 0.6%, 2.0% and 0.6%, respectively. In those with cardiovascular events in the year before treatment began, the overall rates of AMI, angina, stroke and TIA were 5.0%, 4.8%, 6.6% and 5.8%, respectively. Compared with meloxicam users, celecoxib users had lower HRs for the development of AMI (HR 0.78, 95% CI 0.63, 0.96) and stroke (HR 0.81, 95% CI 0.70, 0.93). Rofecoxib users were at no higher risk of cardiovascular events than those receiving meloxicam. Regardless of treatment, having had a cardiovascular event in the year before treatment began played a significant role in the development of the same cardiovascular event during the prescription period; the HRs associated with having had the same cardiovascular event in the past year, versus not having had such an event, were 3.02 (95% CI 1.44, 6.32) for AMI, 5.82 (95% CI 3.19, 10.63) for angina, 2.44 (95% CI 1.79, 3.33) for stroke and 7.16 (95% CI 3.70, 13.87) for TIA.. Patients taking celecoxib had a lower risk of cardiovascular events than those taking meloxicam. Patients taking rofecoxib were not found to be at higher cardiovascular risk than those taking meloxicam. The most significant determinant of cardiovascular risk was a history of such cardiovascular disease in the year preceding treatment initiation. Patients with a history of other medical conditions also appeared to be at higher risk of adverse cardiovascular events.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Angina Pectoris; Cardiovascular Diseases; Celecoxib; Cyclooxygenase 2 Inhibitors; Databases, Factual; Female; Humans; Insurance, Pharmaceutical Services; Ischemic Attack, Transient; Lactones; Male; Meloxicam; Middle Aged; Myocardial Infarction; National Health Programs; Proportional Hazards Models; Pyrazoles; Risk Assessment; Stroke; Sulfonamides; Sulfones; Taiwan; Thiazines; Thiazoles; Time Factors

A simple and selective CE using surfactant with UV detection is described for the simultaneous determination of selective cyclooxygenase-2 inhibitors, celecoxib, meloxicam, and rofecoxib. The simultaneous analysis of celecoxib, meloxicam, and rofecoxib was performed in Tris buffer (10 mM; pH 11) with 60 mM sodium octane-sulfonate and 20% ACN as an anionic surfactant and organic modifier, respectively. Under this condition, good separation with high efficiency and the required short analysis time is achieved. The linear ranges of the method for the determination of celecoxib, meloxicam, and rofecoxib were over 5-100 microg/mL; the detection limits at 200 nm (S/N = 3; injection 3.45 kPa, 5 s) were 2, 1, and 1 microg/mL, respectively. The small amount of sample required and the expeditiousness of the procedure allow content uniformity to be determined in individual pharmaceutical products.

Topics: Celecoxib; Chemistry, Pharmaceutical; Cyclooxygenase 2 Inhibitors; Electrophoresis, Capillary; Humans; Hydrogen-Ion Concentration; Lactones; Meloxicam; Molecular Structure; Pyrazoles; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Sulfonamides; Sulfones; Surface-Active Agents; Thiazines; Thiazoles

Non-steroidal anti-inflammatory drugs (NSAIDs) cause renal side-effects. In the present study, we tested the hypothesis that the extent of the renal effects of cyclo-oxygenase (COX)-2-selective NSAIDs is linked to their pharmacokinetics. A single oral dose of rofecoxib (10 mg/kg), celecoxib (40 mg/kg), meloxicam (3 mg/kg) or placebo was administered to rats. Urinary excretion of electrolytes, a marker of renal effects, and plasma and kidney concentrations of NSAIDs were measured. Rofecoxib and celecoxib, but not meloxicam, significantly decreased urinary sodium and potassium excretion. There was a significant correlation between the area under the 24 h plasma concentration-time curve (AUC0-24) of rofecoxib and the change in sodium (r = -0.65; P < 0.02) and potassium (r = -0.82; P < 0.0006) excretion. The AUC0-24 of celecoxib was correlated with sodium (r = -0.80; P < 0.05) but not potassium excretion. The ratios of kidney to plasma drug concentrations were 1.72, 3.16 and 0.17 for rofecoxib, celecoxib and meloxicam, respectively. The renal effect of the COX-2-selective NSAIDs examined, marked by their ability to reduce the excretion of electrolytes, is influenced by systemic exposure to the drugs. The relatively higher distribution into the kidneys of rofecoxib and celecoxib compared with meloxicam suggests involvement of direct drug exposure in the kidneys in the adverse renal effect.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Celecoxib; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Kidney; Lactones; Male; Meloxicam; Placebos; Potassium; Pyrazoles; Rats; Rats, Sprague-Dawley; Sodium; Sulfonamides; Sulfones; Thiazines; Thiazoles

Topics: Adverse Drug Reaction Reporting Systems; Anti-Inflammatory Agents, Non-Steroidal; Bias; Gastrointestinal Diseases; Humans; Lactones; Meloxicam; Sulfones; Thiazines; Thiazoles

Clinical investigations have demonstrated a link between use of the sulfone cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, and increased risk for atherothrombotic events. This increased risk was not observed for a sulfonamide COX-2 inhibitor (celecoxib), indicating a potential non-enzymatic mechanism for rofexocib. To test this hypothesis, we compared the independent effects of COX-2 inhibitors on human LDL oxidation, an important contributor to atherosclerotic cardiovascular disease. The results showed that rofecoxib (100 nM) significantly decreased (>40%, p<0.001) the lag time for LDL conjugated diene formation and increased levels of thiobarbituric-acid-reactive-substances (TBARS) in vitro. The pro-oxidant activity of rofecoxib was dose-dependent and attenuated by 70% (p<0.001) with the antioxidant, Trolox. Rofecoxib and etoricoxib (100 nM) also caused a marked increase (>35%, p<0.001) in non-enzymatic generation of isoprostanes, as measured by mass spectroscopy. Addition of rofecoxib to fresh human plasma reduced the oxygen radical antioxidant capacity (ORAC) by 34% (p<0.0001). By contrast, other selective (celecoxib, valdecoxib, meloxicam) and non-selective COX inhibitors (ibuprofen, naproxen, diclofenac) had no significant effect on LDL oxidation rates or plasma ORAC values, even at suprapharmacologic levels. X-ray diffraction analysis showed that sulfone COX-2 inhibitors interact differently with membrane phospholipids, suggesting a physico-chemical basis for the pro-oxidant activity. These results demonstrate that sulfone COX-2 inhibitors increase the susceptibility of biological lipids to oxidative modification through a non-enzymatic process. These findings may provide mechanistic insight into reported differences in cardiovascular risk for COX-2 inhibitors.

Topics: Animals; Antioxidants; Celecoxib; Cholesterol, LDL; Chromans; Cyclooxygenase Inhibitors; Diclofenac; Humans; Ibuprofen; Isoprostanes; Isoxazoles; Lactones; Meloxicam; Naproxen; Oxidation-Reduction; Pyrazoles; Sulfonamides; Sulfones; Thiazines; Thiazoles

and objectives. Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal (GI) toxicity. Rofecoxib and meloxicam are classified as cyclooxygenase (COX)-2 selective inhibitors. The Drug Safety Research Unit monitored the safety of these drugs immediately after their launch in England using the non-interventional observational cohort technique of prescription-event monitoring (PEM). Our objective was to investigate whether there is a clinically relevant difference in the incidence of reported symptomatic (acid/peptic) and complicated upper GI conditions (perforations/bleeding) between rofecoxib and meloxicam during use in general practice.. Patients were identified from dispensed prescriptions written by general practitioners (GPs) for meloxicam (between December 1996 and March 1997) and rofecoxib (between July and November 1999). Simple questionnaires requesting details of events occurring during/after treatment and potential risk factors (including age, sex, history of upper GI problems, and NSAIDS prescribed within 3 months of treatment) were posted to prescribing GPs approximately 9 months after the first prescription for each patient. Incidence rates of the first event were calculated, and crude and adjusted rate ratios were obtained using regression modelling.. For rofecoxib and meloxicam respectively, 1127 (7.4%) and 1376 (7.2%) patients had symptomatic (acid/peptic) upper GI events, whereas 57 (0.4%) and 67 (0.4%) had complicated upper GI conditions (perforations/bleeding). A past medical history of upper GI problems was an important risk factor only for symptomatic (acid/peptic) upper GI events for both drugs, despite a two-fold difference in the proportion reporting previous GI problems (48.4 and 25.1% for rofecoxib and meloxicam respectively). The adjusted rate ratio of symptomatic (acid/peptic) upper GI events or complicated upper GI conditions (perforations/bleeding) for rofecoxib compared with meloxicam was 0.71 (95% confidence interval 0.65, 0.79) and 0.91 (95% confidence interval 0.59, 1.42) respectively.. This study reports a relative reduction (29%) in the incidence rate of symptomatic (acid/peptic) GI events, and no difference in the incidence rate of complicated upper GI conditions (perforations/bleeding) for rofecoxib compared with meloxicam.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Age Factors; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Prescriptions; England; Family Practice; Female; Gastrointestinal Diseases; Humans; Incidence; Isoenzymes; Lactones; Male; Meloxicam; Membrane Proteins; Middle Aged; Prostaglandin-Endoperoxide Synthases; Sex Factors; Sulfones; Thiazines; Thiazoles

Rofecoxib and meloxicam are classified as cyclo-oxygenase (COX)-2 selective inhibitors. The Drug Safety Research Unit (DSRU) monitored the post-marketing safety of these drugs in England using the non-interventional observational cohort technique of prescription-event monitoring (PEM).. To compare the incidence rates of selected thromboembolic (TE)(cardiovascular, cerebrovascular and peripheral venous thrombotic) events reported for patients prescribed rofecoxib and meloxicam in general practice.. Patients were identified from dispensed prescriptions written by general practitioners (GPs) for meloxicam (December 1996 to March 1997) and rofecoxib (July to November 1999). Simple questionnaires requesting details of events recorded during/after treatment, indication and potential risk factors (including age, sex and NSAIDs prescribed within 3 months of treatment) were posted to prescribing GPs approximately 9 months after the first prescription for each patient. Incidence rates of the first event within each TE group were calculated; crude and age- and sex-adjusted rate ratios (RR) obtained using regression modelling.. During the 9 months after starting treatment, 21 (0.14%) and 19 (0.10%) patients were reported to have cardiovascular TE events, and 74 (0.48%) and 52 (0.27%) cerebrovascular TE events, and 6 (0.05%) and 20 (0.10%) were reported to have peripheral venous thrombotic events for rofecoxib and meloxicam, respectively. Regarding time to first event, there was a persistent divergence between the two drugs from the start of treatment for both the cerebrovascular TE event group (log rank test P = 0.0063) and the peripheral venous thrombotic event group (log rank test P = 0.0264). Indication and use of a NSAID within 3 months prior to starting treatment had no statistically significant effect on the relative risk estimates of the event groups and was excluded from subsequent analyses. Adjusting for the two identified risk factors of age (age2) and sex, for rofecoxib the adjusted cerebrovascular TE event group rate was higher than for meloxicam [RR 1.68 (95% CI 1.15, 2.46)]; lower than meloxicam for the peripheral venous thrombotic event group [RR 0.29 (95% CI 0.11, 0.78)], and not different for the cardiovascular TE event group [RR 1.38 (95% CI 0.71, 2.67)].. This study reports a relative increase in the rate of cerebrovascular TE events and a relative reduction in peripheral venous thrombotic events in users of rofecoxib compared with meloxicam. There was no difference in the rate of cardiovascular thromboembolic events. The incidence of these three groups of events reported in each of these two drug cohorts was low (less than 0.5%), therefore the relevance of our findings needs to be taken into consideration with other clinical and pharmacoepidemiological studies.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Chi-Square Distribution; Cohort Studies; Cyclooxygenase Inhibitors; England; Family Practice; Female; Humans; Incidence; Lactones; Male; Meloxicam; Middle Aged; Osteoarthritis; Risk Factors; Sulfones; Survival Analysis; Thiazines; Thiazoles; Thromboembolism

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.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Bias; Celecoxib; Cohort Studies; Databases, Factual; Family Practice; Female; Gastrointestinal Hemorrhage; Humans; Lactones; Male; Meloxicam; Middle Aged; Pyrazoles; Risk Factors; Sulfonamides; Sulfones; Thiazines; Thiazoles

This study examined the solubility enhancement of 4 cox-2 inhibitors, celecoxib, rofecoxib, meloxicam, and nimesulide, using a series of pure solvents and solvent mixtures. Water, alcohols, glycols, glycerol, and polyethylene glycol 400 (PEG 400) were used as solvents and water-ethanol, glycerol-ethanol, and polyethylene glycol-ethanol were used as mixed-solvent systems. A pH-solubility profile of drugs was obtained in the pH range 7.0 to 10.9 using 0.05 M glycine-sodium hydroxide buffer solutions. Lower alcohols, higher glycols, and PEG 400 were found to be good solvents for these drugs. The aqueous solubility of celecoxib, rofecoxib, and nimesulide could be enhanced significantly by using ethanol as the second solvent. Among the mixed-solvent systems, PEG 400- ethanol system had highest solubilization potential. In the case of meloxicam and nimesulide, solubility increased significantly with increase in pH value. Physico-chemical properties of the solvent such as polarity, intermolecular interactions, and the ability of the solvent to form a hydrogen bond with the drug molecules were found to be the major factors involved in the dissolution of drugs by pure solvents. The greater the difference in the polarity of the 2 solvents in a given mixed solvent, the greater was the solubilization power. However, in a given mixed-solvent system, the solubilization power could not be related to the polarity of the drugs. Significance of the solubility data in relation to the development of formulations has also been discussed in this study.

Topics: Celecoxib; Chemistry, Pharmaceutical; Cyclooxygenase 2; Enzyme Inhibitors; Hydrogen-Ion Concentration; Isoenzymes; Lactones; Meloxicam; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Solubility; Solvents; Sulfonamides; Sulfones; Thiazines; Thiazoles

Prostaglandins (PG) derived from COX-1 are essential for the maintenance of mucosal integrity but COX-2 isoform synthesizes PG at a site of inflammation. Recently, COX-2 mRNA expression was demonstrated at the ulcer edge during healing of chronic gastric ulcers but the role for expression of COX-2 and its products such as PGE(2) and cytokines including interleukin (IL-1beta) and tumor necrosis factor alpha (TNFalpha) in ulcer healing remains unknown. In this study, Wistar rats with gastric ulcers produced by serosal application of acetic acid (ulcer area 28 mm(2)) received daily treatment either with: (1) vehicle (saline); (2) NS-398 (10 mg/kg-d i.g.) and Vioxx (5 mg/kg-d i.g.), both, highly specific COX-2 inhibitors; (3) meloxicam (5 mg/kg-d i.g.), a preferential inhibitor of COX-2; (4) resveratrol (10 mg/kg-d i.g.), a specific COX-1 inhibitor; (5) indomethacin (5 mg/kg-d i.g); and (6) aspirin (ASA; 50 mg/kg-d i.g.), non-selective inhibitors of both COX-1 and COX-2. At day 3, 7, and 14 after ulcer induction, the animals were sacrificed and the area of gastric ulcers was determined by planimetry and histology, gastric blood flow (GBF) at ulcer base and margin was measured by H(2) clearance technique, and blood was withdrawn for measurement of plasma IL-1beta and TNFalpha levels. The mucosal biopsy samples were taken for the determination of PGE(2) generation by RIA and expression of COX-1, COX-2, IL-1beta, and TNFalpha mRNA by RT-PCR. In vehicle-treated rats, gastric ulcers healed progressively and at day 14 the healing was completed, accompanied by a significant rise in the GBF at ulcer margin. The IL-1beta, TNFalpha, and COX-1 mRNA were detected in intact and ulcerated gastric mucosa, whereas COX-2 mRNA were upregulated only in ulcerated mucosa with peak observed at day 3 after ulcer induction. The plasma IL-1beta level was significantly increased at day 3 and 7 but then declined at day 14 to that measured in vehicle-controls. Indomethacin and ASA, which suppressed PGE(2) generation both in the non-ulcerated and ulcerated gastric mucosa, significantly delayed the rate of ulcer healing and this was accompanied by the fall in GBF at ulcer margin and further elevation of plasma IL-1beta and TNFalpha levels, which was sustained up to the end of the study. Treatment with NS-398 and Vioxx, which caused only a moderate decrease in the PGE(2) generation in the non-ulcerated gastric mucosa, delayed ulcer healing and attenuated significantly the GBF at ulcer marg

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Chronic Disease; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Gastric Mucosa; Gastrins; Indomethacin; Interleukin-1; Isoenzymes; Lactones; Male; Meloxicam; Membrane Proteins; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Radioimmunoassay; Rats; Rats, Wistar; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Stomach Ulcer; Sulfonamides; Sulfones; Thiazines; Thiazoles; Tumor Necrosis Factor-alpha

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cost-Benefit Analysis; Cyclooxygenase Inhibitors; Drug Therapy, Combination; Gastritis; Humans; Lactones; Meloxicam; Netherlands; Pyrazoles; Sulfonamides; Sulfones; Thiazines; Thiazoles

The development of a COX-2 inhibitor rofecoxib (MK 966, Vioxx) is described. It is essentially equipotent to indomethacin both in vitro and in vivo but without the ulcerogenic side effect due to COX-1 inhibition.

Topics: Administration, Oral; Animals; Biological Availability; CHO Cells; Cricetinae; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Humans; Indomethacin; Inhibitory Concentration 50; Isoenzymes; Lactones; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Rats; Sulfones

Topics: Anti-Inflammatory Agents, Non-Steroidal; Butanones; Celecoxib; Clinical Trials as Topic; Confounding Factors, Epidemiologic; Cyclooxygenase Inhibitors; Drug Therapy, Combination; Humans; Lactones; Meloxicam; Nabumetone; Pyrazoles; Stomach Diseases; Sulfonamides; Sulfones; Thiazines; Thiazoles

In this study, ischemia-reperfusion produced in rats by clamping the celiac artery for 0.5 h followed by 1 h of reperfusion was used to develop a new model of superficial gastric erosions progressing to deeper ulcers. Ischemia alone resulted in an immediate fall in gastric blood flow but no gross mucosal lesions were observed. When ischemia was followed by reperfusion, gastric erosive lesions occurred, reached a maximum at 12 h and then declined after 24 h. These acute erosions progressed into deeper lesions 24 h after ischemia-reperfusion and reached a peak after 3 days. Gastric blood flow and the mucosal generation of prostaglandin E(2) were significantly suppressed immediately following ischemia-reperfusion, but with the healing of deeper gastric ulcers, both gastric blood flow and prostaglandin E(2) generation were gradually restored. Cyclooxygenase-1 mRNA was detected by reverse transcription-polymerase chain reaction in intact gastric mucosa and throughout the recovery of the mucosa from acute ischemia-reperfusion lesions, whereas cyclooxygenase-2 mRNA, was recorded only after ischemia-reperfusion. NS-398 and rofecoxib, selective inhibitors of cyclooxyganase-2, failed to affect prostaglandin E(2) generation in the non-ulcerated gastric mucosa but inhibited it significantly in the ulcer area. The two cyclooxygenase-2 inhibitors as well as resveratrol, a specific cyclooxygenase-1 inhibitor and indomethacin and meloxicam, non-specific inhibitors of cyclooxygenase, augmented acute gastric erosions induced by ischemia-reperfusion and delayed significantly the progression of these lesions into deeper ulcers at each time interval after ischemia-reperfusion. We conclude that prostaglandins generated by both cyclooxygenase-1 and cyclooxygenase-2 contribute to the healing of gastric lesions induced by ischemia-reperfusion.

Topics: Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Gastric Mucosa; Gastrins; Gene Expression Regulation, Enzymologic; Indomethacin; Interleukin-1; Isoenzymes; Lactones; Meloxicam; Membrane Proteins; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Regional Blood Flow; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Stomach Ulcer; Sulfonamides; Sulfones; Thiazines; Thiazoles; Time Factors