Comparison of reporting of Stevens-Johnson syndrome and toxic epidermal necrolysis in association with selective COX-2 inhibitors.

BACKGROUND: Stevens-Johnson syndrome and toxic epidermal necrolysis are closely related severe acute life-threatening, drug-induced skin disorders. The US FDA Adverse Events Reporting System (AERS) has received reports of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of the recently introduced selective cyclo-oxygenase (COX)-2 inhibitor NSAIDs, two of which are also sulfonamides. OBJECTIVE: The objective of this study is to review cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA associated with the use of the selective COX-2 inhibitor NSAIDs celecoxib, rofecoxib and valdecoxib, and to compare reporting rates of the two conditions associated with these drugs to each other, meloxicam (an oxicam NSAID that came on the US market at a similar time) and the background incidence rate. METHODS: We reviewed all US cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA AERS database associated with the use of celecoxib, rofecoxib, valdecoxib and meloxicam since these agents were first marketed. We utilised AERS and drug use data to calculate reporting rates for each drug after the first 2 years of marketing. We obtained the background rate from the medical literature. RESULTS: Up to the end of March 2004, there were 63 cases of Stevens-Johnson syndrome/toxic epidermal necrolysis reported with valdecoxib use, 43 with celecoxib, 17 with rofecoxib (the non-sulfonamide coxib) and none for meloxicam. In the first 2 years of marketing the reporting rate for Stevens-Johnson syndrome/toxic epidermal necrolysis with valdecoxib was 49 cases per million person-years of use, 6 cases per million person-years for celecoxib and 3 cases per million person-years for rofecoxib. The reporting rates for the sulfonamide coxibs were substantially higher than the background rate of 1.9 cases per million population per year, with the valdecoxib rate being 8-9 times that of celecoxib and approximately 25 times that of the background rate. CONCLUSION: There is a strong association between Stevens-Johnson syndrome/toxic epidermal necrolysis and the use of the sulfonamide COX-2 inhibitors, particularly valdecoxib. Physicians should be aware of the possibility of this serious life-threatening event when prescribing these drugs and advise patients to discontinue use at the earliest possible sign or symptom.     

Clinical implications of drug interactions with coxibs

Nonsteroidal antiinflammatory drugs (NSAIDs) often are prescribed to patients who are taking concomitant drugs. Cyclooxygenase (COX)-2 inhibitors (coxibs) rofecoxib and celecoxib are highly selective inhibitors of COX-2, differentiating them from nonselective NSAIDs, which substantially inhibit both COX-1 and COX-2. Like nonselective NSAIDs, coxibs are hepatically metabolized: rofecoxib primarily by reduction by cytosolic enzymes and celecoxib by the cytochrome P450 (CYP) enzyme system. Because rofecoxib is not significantly metabolized by CYP, it has fewer confirmed or potential drug interactions than celecoxib. However, potent inducers of CYP, such as rifampin, may decrease rofecoxib concentrations because of induction of general hepatic metabolic activity. Celecoxib is metabolized by CYP2C9 and may be increased or decreased by CYP2C9 modifiers. It also inhibits CYP2D6 and may affect concentrations of CYP2D6 substrates. Similar to NSAIDs, many pharmacodynamic interactions involving coxibs are related to inhibition of production of renal prostaglandins. However, coxibs have no antiplatelet activity and may be preferred to NSAIDs in patients receiving antithrombotic therapy. Nonetheless, when a potential for an interaction exists, standard monitoring is recommended when starting or discontinuing a coxib. Due to lack of data to support these interactions, which are primarily theoretical, additional studies are necessary to establish the drug interaction profiles of coxibs.     

Are rofecoxib and celecoxib safer NSAIDS?

NSAIDs work by inhibiting the enzyme cyclo-oxygenase (COX), responsible for prostaglandin synthesis. This enzyme exists in two isoforms, COX-1 and COX-2. Inhibition of COX-1 is thought to be the main cause of the gastrointestinal unwanted effects of NSAIDs, whilst inhibition of COX-2 results in anti-inflammatory effects. [symbol: see text]Rofecoxib (Vioxx--MSD) and [symbol: see text]celecoxib (Celebrex--Searle) have been developed as selective inhibitors of COX-2. Rofecoxib is licensed for the symptomatic treatment of osteoarthritis, but not for rheumatoid arthritis. The manufacturer claims that "in clinical studies rofecoxib inhibits COX-2 but not COX-1", has "the power of high-dose NSAIDs--diclofenac and ibuprofen" and "superior GI safety profile compared to conventional NSAIDs". Celecoxib is licensed for symptom relief in osteoarthritis and rheumatoid arthritis. The manufacturer claims that celecoxib has "comparable efficacy and superior GI tolerability when compared to diclofenac or naproxen". Here, we review rofecoxib and celecoxib and consider whether they are safer than conventional NSAIDs.     

Clinical pharmacology of celecoxib, a COX-2 selective inhibitor

NSAIDs are extensively used worldwide; nonetheless, they are associated with adverse gastrointestinal (GI) effects. COX-2 inhibitors (coxibs) have been developed to reduce pain and inflammation without associated GI and bleeding risks. Celecoxib was the first COX-2 inhibitor introduced on the market, and it still remains so, whereas rofecoxib and valdecoxib were withdrawn due to excess cardiovascular (CV) risk. There is consequently a concern that CV toxicity reflects a class effect of all COX-2 inhibitors. Celecoxib possesses anti-inflammatory and analgesic properties, and the evidence for CV risk is rather small and comparable to that of other traditional NSAIDs in short-term treatments (of < 4 weeks). It could be suggested that the use of low doses of celecoxib (100 mg b.i.d.) in short-treatment, especially in patients with previous experience of GI events and the recommendation of avoiding use of celecoxib in patients with CV history or risk, contribute in the decision-making process of prescribing COX-2 or NSAIDs.     

Celecoxib and cardiovascular risks

In a very short time, COX-2 enzyme inhibitors have gone from the darlings to the pariahs of the pharmaceutical industry. These drugs were developed based on the hypothesis whereby selective inhibition of the COX enzyme would lead to reduction in pain and inflammation without associated gastrointestinal and bleeding risks. However, in September 2004, rofecoxib was voluntarily removed from the market for increased cardiovascular risk and in April 2005, valdecoxib was also withdrawn, at least in part, due to excess cardiovascular risk. Celecoxib was the first COX-2 inhibitor introduced and the only remaining one on the US market. There is consequently a justified concern that cardiovascular toxicity is a class effect of all COX-2 inhibitors. This article systematically reviews the evidence surrounding COX-2 inhibitors and cardiovascular risk. Although the evidence suggests a fairly consistent cardiovascular risk with rofecoxib, the evidence for cardiovascular risk with celecoxib is more equivocal. Although isolated studies have suggested some cardiovascular risk for celecoxib, the totality of the evidence suggests that any risk is likely to be small and comparable to traditional NSAIDs. The cardiovascular risks of COX-2 inhibitors appear heterogeneous, influenced not only by the drug class, but also individual drug, dosage and patient characteristics. Specific modifying factors of the cardiovascular risk of COX-2 inhibitors including dose, concomitant drugs, individual cardiac and genetic risk profiles, will require further study.     

Comment and reply on: Atorvastatin: safety and tolerability

In a very short time, COX-2 enzyme inhibitors have gone from the darlings to the pariahs of the pharmaceutical industry. These drugs were developed based on the hypothesis whereby selective inhibition of the COX enzyme would lead to reduction in pain and inflammation without associated gastrointestinal and bleeding risks. However, in September 2004, rofecoxib was voluntarily removed from the market for increased cardiovascular risk and in April 2005, valdecoxib was also withdrawn, at least in part, due to excess cardiovascular risk. Celecoxib was the first COX-2 inhibitor introduced and the only remaining one on the US market. There is consequently a justified concern that cardiovascular toxicity is a class effect of all COX-2 inhibitors. This article systematically reviews the evidence surrounding COX-2 inhibitors and cardiovascular risk. Although the evidence suggests a fairly consistent cardiovascular risk with rofecoxib, the evidence for cardiovascular risk with celecoxib is more equivocal. Although isolated studies have suggested some cardiovascular risk for celecoxib, the totality of the evidence suggests that any risk is likely to be small and comparable to traditional NSAIDs. The cardiovascular risks of COX-2 inhibitors appear heterogeneous, influenced not only by the drug class, but also individual drug, dosage and patient characteristics. Specific modifying factors of the cardiovascular risk of COX-2 inhibitors including dose, concomitant drugs, individual cardiac and genetic risk profiles, will require further study.     

Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis

The discovery of the two isoenzymes of cyclooxygenase (COX) has recently lead to the development and clinical introduction of specific inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib, onto the market. Celecoxib is an effective anti-inflammatory, analgesic and antipyretic agent therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. In addition, celecoxib has some novel therapeutic and pharmacological activities. Celecoxib inhibits anti-apoptotic kinase activation and is the first specific COX-2 inhibitor to be marketed for familial adenomatous polyposis, an inheritable predisposition for colorectal cancer. Celecoxib is not without gastrointestinal (GI) side effects but demonstrates markedly reduced GI ulceration in clinical trials when compared to traditional non-specific non-steroidal anti-inflammatory drugs (NSAIDs). The specific COX-2 inhibitors each have distinctive pharmacokinetic properties. Celecoxib can be given either once or twice daily. Racial differences in drug disposition, and pharmacokinetic changes in elderly patients, patients with chronic renal insufficiency and patients with mild to moderate hepatic impairment, are evident with celecoxib. Despite the specific action of these drugs, there remains the potential for significant drug interactions. Celecoxib has demonstrated interactions with fluconazole, lithium and warfarin. Increased clinical vigilance should be maintained when co-prescribing medications with celecoxib until further clinical experience is gained. Celecoxib represents a major therapeutic advance in terms of GI safety. However, long-term safety in other organ systems, safety with concomitant drug administration, and pharmacoeconomic benefits still remain to be proven.     

Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis

The discovery of the two isoenzymes of cyclooxygenase (COX) has recently lead to the development and clinical introduction of specific inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib, onto the market. Celecoxib is an effective anti-inflammatory, analgesic and antipyretic agent therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. In addition, celecoxib has some novel therapeutic and pharmacological activities. Celecoxib inhibits anti-apoptotic kinase activation and is the first specific COX-2 inhibitor to be marketed for familial adenomatous polyposis, an inheritable predisposition for colorectal cancer. Celecoxib is not without gastrointestinal (GI) side effects but demonstrates markedly reduced GI ulceration in clinical trials when compared to traditional non-specific non-steroidal anti-inflammatory drugs (NSAIDs). The specific COX-2 inhibitors each have distinctive pharmacokinetic properties. Celecoxib can be given either once or twice daily. Racial differences in drug disposition, and pharmacokinetic changes in elderly patients, patients with chronic renal insufficiency and patients with mild to moderate hepatic impairment, are evident with celecoxib. Despite the specific action of these drugs, there remains the potential for significant drug interactions. Celecoxib has demonstrated interactions with fluconazole, lithium and warfarin. Increased clinical vigilance should be maintained when co-prescribing medications with celecoxib until further clinical experience is gained. Celecoxib represents a major therapeutic advance in terms of GI safety. However, long-term safety in other organ systems, safety with concomitant drug administration, and pharmacoeconomic benefits still remain to be proven.     

Cyclooxygenase-2 inhibitors: a painful lesson

Non-steroidal anti-inflammatory drugs (NSAIDs) represent a clinically important class of agents. NSAIDs are commonly used in treatment of conditions such as headache, fever, inflammation and joint pain. Complications often arise from chronic use of NSAIDs. Gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulcerations and GI bleeds limit usage of NSAIDs. These toxicities are thought to be due to cyclooxygenase (COX)-1 blockade. COX-1 generates cytoprotective prostanoids such as prostaglandin (PG) E2 and prostacyclin (PGI2). COX-2 inhibitors, commonly referred to as coxibs, were developed to inhibit inflammatory prostanoids without interfering with production of COX-1 prostanoids. Concerns over cardiovascular safety, however, have evolved based on the concept of inhibition of COX-2-derived endothelial prostanoids without inhibition of platelet thromboxane A2, leading to increased cardiovascular risk. The Celecoxib Long-Term Arthritis Safety Study (CLASS) trial did not show a significant increase in cardiovascular risk for celecoxib (Celebrex), but results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study showed an increased cardiovascular risk with long-term daily usage of rofecoxib in patients with rheumatoid arthritis. The Adenomatous Poly Prevention on Vioxx (APPROVe) trial further evaluated cardiovascular effects of rofecoxib and recently led to removal of this drug from the marketplace. Coxibs affect renal function via blockade of normal COX-2 functions. COX-2 expression increases in high renin states and in response to a high-sodium diet or water deprivation. PGI2 and PGE2 are the most important renal prostanoids. PGI2 inhibition results in hyperkalemia. PGE2 inhibition results in sodium retention, which leads to hypertension, peripheral edema and potentially exacerbation of heart failure. This review article discusses beneficial and deleterious effects associated with prostanoids produced by COX-1 and COX-2 in various organs and how blockade of these products translates into clinical medicine.     

Defects in mouse nephrogenesis induced by selective and non-selective cyclooxygenase-2 inhibitors

BACKGROUND AND PURPOSE

Deletion of the cyclooxygenase-2 (COX-2) gene causes impairment of kidney development, but the effect of selective inhibitors of COX-2 (coxibs) or the non-selective inhibitors of COX (the classical non-steroidal anti-inflammatory drugs; NSAIDs) on kidney development was less well described.

EXPERIMENTAL APPROACH

We assessed the effects of equipotent analgesic doses of celecoxib, rofecoxib, valdecoxib, etoricoxib and lumiracoxib and of the NSAIDs, diclofenac and naproxen, on postpartum kidney development in mice, from postnatal day 1 (P1) to P21.

KEY RESULTS

All the COX inhibitors, at the doses used, blocked COX-2 activity by more than 80% as assayed by PGE₂ synthesis in lipopolysaccharide-stimulated mouse blood samples. Rofecoxib, etoricoxib and lumiracoxib exerted the most marked impairment of postpartum kidney development, demonstrated by attenuation of kidney growth, reduction in size of glomeruli, increase in immature superficial glomeruli, thinning of subcapsular cortical mass and reduction in size of juxtamedullary glomeruli. These defects were less severe than those in kidneys from COX-2^−/− mice. Administration of diclofenac and naproxen revealed renal defects similar to those after coxib treatment, but both NSAIDs induced greater arrest of immature superficial glomeruli in the outer cortex and increased the number of undifferentiated proliferating cell nuclear antigen-positive cells. Treatment with celecoxib or valdecoxib caused only minimal changes in renal morphology.

CONCLUSIONS AND IMPLICATIONS

Classical NSAIDs cause similar or even stronger nephrodysgenesis than the coxibs. Also, the ranking of coxibs regarding adverse effects on renal development, using equi-analgesic doses, is rofecoxib = etoricoxib = lumiracoxib > valdecoxib > celecoxib.     

Benefit-risk assessment of rofecoxib in the treatment of osteoarthritis.

NSAIDs are widely used to treat pain and inflammation in osteoarthritis. Their use in this indication is generally intermittent and fluctuates with the intensity of the disease. Nonetheless, success of the therapy is frequently limited by injury to the gastrointestinal mucosa and complications such as bleeding, ulceration and perforation. A careful and detailed evaluation of these aspects in regard to the newly introduced NSAIDs is of considerable clinical importance. This review focuses on the NSAID rofecoxib, one of the selective cyclo-oxygenase (COX)-2 inhibitors, which are claimed to be as effective as nonselective NSAIDs with better gastrointestinal tolerability. Indeed, phase II, phase III and epidemiological studies have revealed that the efficacy of rofecoxib is comparable to that of conventional NSAIDs but with lower gastrointestinal toxicity, although this advantage may not be demonstrable in every patient. In patients treated with low-dose aspirin (acetylsalicylic acid) for cardiovascular prophylaxis, celecoxib (another selective COX-2 inhibitor) seems to have no obvious advantages over conventional NSAIDs, and similar conclusions may be applied to rofecoxib. A comparison of NSAID therapy +/- concomitant low-dose aspirin was not a primary outcome in this trial with celecoxib and there is thus a need for further studies which compare the gastrointestinal risk of a selective COX-2 inhibitor plus aspirin versus a conventional NSAID. Recent debate has emerged regarding the cardiovascular safety of rofecoxib. Although there is evidence both for and against higher cardiovascular risk with rofecoxib, a retrospective cohort study recently published suggested that there is no increased risk of acute myocardial infarction in the short-term when compared with non-selective NSAIDs. The renal toxicity of rofecoxib has been thoroughly investigated. Clinical studies revealed renal effects of rofecoxib similar to those of conventional NSAIDs. Since adverse effects increase with the degree of renal impairment, monitoring of renal function should be carried out in patients at risk. Although there are still insufficient data concerning certain important adverse effects of rofecoxib, this drug is becoming an important alternative in the therapy of osteoarthritis, especially in high-risk patients. Clinicians need to weigh up the benefits and risks of rofecoxib on a case-by-base basis.     

COX-2 selective inhibitors in the treatment of arthritis: a rheumatologist perspective

COX-2 selective inhibitors were developed in order to provide similar efficacy to traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) but with improved upper gastrointestinal safety. This paper presents an overview of randomized clinical trials demonstrating the efficacy of COX-2 selective inhibitors for the treatment of patients with arthritis, particularly osteoarthritis and rheumatoid arthritis. In osteoarthritis and rheumatoid arthritis, COX-2 selective inhibitors have been shown to be more effective than placebo and similarly effective as standard doses of nonselective NSAIDs. There are currently few randomized clinical trials comparing the efficacy of the 2 first-generation COX-2 selective inhibitors, celecoxib and rofecoxib, in osteoarthritis. Of 4 head-to-head studies comparing the 2 agents, 3 indicated similar efficacy, while the other demonstrated superiority of rofecoxib at a dose of 25 mg qd compared with celecoxib at a dose of 200 mg qd. There are no clinical trials comparing the efficacy of different agents for treatment of patients with rheumatoid arthritis. Some studies have also demonstrated efficacy for COX-2 selective inhibitors in patients with ankylosing spondylitis and gout. In aggregate, these data show that COX-2 selective inhibitors provide effective relief of pain in patients with osteoarthritis and rheumatoid arthritis, with efficacy that is similar to traditional NSAIDs. Cost-effectiveness and cost-utility studies suggest, however, that their use should be limited to patients at high risk of serious upper gastrointestinal side effects, including complicated ulcers.     

Assessing the cost-effectiveness of COX-2 specific inhibitors for arthritis in the Veterans Health Administration

OBJECTIVE: This study was designed to assess the cost-effectiveness of cyclooxygenase-2 specific (COX-2) inhibitors (rofecoxib and celecoxib) over nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in high-risk arthritis patients from the perspective of the Veterans Health Administration (VA). METHODS: This literature-based economic analysis (with data summarized from MEDLINE-indexed and other published sources, FDA reports, and data on file at VA San Diego Healthcare System) compared rofecoxib and celecoxib to NSAIDS in two arthritis patient populations considered at higher risk of developing clinically significant upper gastrointestinal events (CSUGIEs): (1) patients of any age with previous medical history of perforation/ulcer/bleed (PUB); and (2) patients 65 years and older (regardless of history of PUB). Two outcome measures were reported: (1) incremental cost per CSUGIE averted over 1 year; and (2) incremental cost per quality-adjusted life-year (QALY) gained, considering both the mortality and morbidity associated with gastrointestinal (including CSUGIEs) and cardiovascular-related adverse events. When possible, costs were modeled to reflect the VA perspective. Sensitivity analyses were conducted to test the robustness of the analysis. RESULTS: Compared to NSAIDS, rofecoxib and celecoxib increased costs but reduced the incidence of CSUGIE. Cost per CSUGIE avoided were $7476 and $16,379 (in patients with a PUB history) and $14,294 and $18,376 (in patients aged > or = 65 years) for celecoxib and rofecoxib, respectively. In both populations, celecoxib was associated with a cost per QALY less than $50,000. In contrast, rofecoxib was found to cost more and result in a net QALY loss, due in particular to the increase in the risk of cardiovascular complications, and was therefore considered cost-ineffective. Results were most dependent on assumptions about the incidence of cardiovascular events and CSUGIE and the COX-2 inhibitors' acquisition price. CONCLUSIONS: This analysis suggests that COX-2 inhibitors may be cost-effective from the perspective of the VA. However, cost-effectiveness appears to depend less on the specific characteristics of the high-risk target population considered but more on the agent evaluated. Celecoxib appears to be an alternative to traditional NSAIDs in the patient populations studied.     

Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition

By optimizing binding to a selected target protein, modern drug research strives to develop safe and efficacious agents for the treatment of disease. Selective drug action is intended to minimize undesirable side effects from scatter pharmacology. Celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx) are nonsteroidal antiinflammatory drugs (NSAIDs) due to selective inhibition of inducible cyclooxygenase COX-2 while sparing inhibition of constitutive COX-1. While rofecoxib contains a methyl sulfone constituent, celecoxib and valdecoxib possess an unsubstituted arylsulfonamide moiety. The latter group is common to many carbonic anhydrase (CA) inhibitors. Using enzyme kinetics and X-ray crystallography, we demonstrate an unexpected nanomolar affinity of the COX-2 specific arylsulfonamide-type celecoxib and valdecoxib for isoenzymes of the totally unrelated carbonic anhydrase (CA) family, such as CA I, II, IV, and IX, whereas the rofecoxib methyl sulfone-type has no effect. When administered orally to glaucomatous rabbits, celecoxib and valdecoxib lowered intraocular pressure, suggesting that these agents may have utility in the treatment of this disorder. The crystal structure of celecoxib in complex with CA II reveals part of this inhibition to be mediated via binding of the sulfonamide group to the catalytic zinc of CA II. To investigate the structural basis for cross-reactivity of these compounds between COX-2 and CA II, we compared the molecular recognition properties of both protein binding pockets in terms of local physicochemical similarities among binding site-exposed amino acids accommodating different portions of the drug molecules. Our approach Cavbase, implemented into Relibase, detects similarities between the sites, suggesting some potential to predict unexpected cross-reactivity of drugs among functionally unrelated target proteins. The observed cross-reactivity with CAs may also contribute to differences in the pharmacological profiles, in particular with respect to glaucoma and anticancer therapy and may suggest new opportunities of these COX-2 selective NSAIDs.     

Celecoxib inhibits 5-lipoxygenase

Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used in the therapy of inflammatory and painful conditions. Various COX-2-independent pharmacological effects, such as a chemo-preventive and tumor-regressive activity have been suggested, but the respective non-COX-2 targets of celecoxib are still a matter of research. We now demonstrate that celecoxib inhibits 5-lipoxygenase (5-LO), a key enzyme in leukotriene (LT) biosynthesis. Celecoxib suppressed 5-LO product formation in ionophore A23187-activated human polymorphonuclear leukocytes (IC(50) approximately 8 microM). Similarly, celecoxib inhibited LTB(4) formation in human whole blood (IC(50) approximately 27.3 microM). Direct interference of 5-LO with celecoxib was visualized by inhibition of enzyme catalysis both in cell homogenates and with purified 5-LO (IC(50) approximately 23.4 and 24.9 microM, respectively). Related lipoxygenases (12-LO and 15-LO) were not affected by celecoxib. Other COX-2 inhibitors (etoricoxib and rofecoxib) or unselective NSAIDs (non-steroidal anti-inflammatory drugs, diclofenac) failed to inhibit 5-LO. In rats which received celecoxib (i.p.), the blood LTB(4) levels were dose-dependently reduced with an ED(50) value approximately 35.2 mg/kg. Together, celecoxib is a direct inhibitor of 5-LO in vitro and in vivo. These findings provide a potential molecular basis for some of the described COX-2-independent pharmacological effects of celecoxib.     

Cyclo-oxygenase-2 inhibitors and the kidney: a case for caution.

Cyclo-oxygenase (COX) is one of the key enzymes in the biosynthesis of prostaglandins. Two isoforms of this enzyme COX-1 and COX-2 are known to exist. Among other functions, prostaglandins play an important role in the protection of the gastric mucosa and maintenance of renal function in pathophysiological conditions which would otherwise threaten it. Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin synthesis, resulting in gastric mucosal injury and renal dysfunction in susceptible individuals. The recent introduction of selective COX-2 inhibitors, celecoxib and rofecoxib, appear to induce less gastrointestinal morbidity. Although conclusive data are still lacking, there is evidence to suggest that COX-2 antagonists may be capable of causing some of the same renal syndromes seen in association with the older, less selective NSAIDs.     

A comparison of adverse renovascular experiences among osteoarthritis patients treated with rofecoxib and comparator non-selective non-steroidal anti-inflammatory agents

BACKGROUND: Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclo-oxygenase (COX) isoenzymes, i.e. COX-1 and COX-2. Rofecoxib, an agent that selectively inhibits COX-2, has been shown to provide equivalent anti-inflammatory and analgesic efficacy to comparator non-selective NSAIDs in osteoarthritis (OA) and other pain models with a significant improvement in gastrointestinal (GI) safety and tolerability. Based on renal physiology studies, it was predicted that rofecoxib would have renovascular effects similar to those observed with non-selective NSAIDs--specifically edema, blood pressure elevation, attenuation of the effects of ACE inhibitors, and (in rare circumstances), acute renal failure might be manifest in a small percentage of patients. OBJECTIVE: To assess the renovascular safety profile of rofecoxib in OA patients compared to that of non-selective NSAID comparators. METHODS: Renovascular adverse experiences (AEs) in over 5,000 participants in Phase IIb/III OA clinical trials were reviewed and compared between rofecoxib and non-selective NSAID comparators (ibuprofen 800mg tid, diclofenac 50 mg tid, nabumetone 1,500 mg qd). RESULTS:The incidence of lower extremity edema (LEE) AEs was generally similar between rofecoxib 12.5 mg/day, rofecoxib 25 mg/day, and non-selective comparator NSAIDs. Treatment discontinuations due to LEE AEs and clinically significant weight gain (> or = 2 kg) associated with LEE AEs were infrequent and generally similar in all active treatment groups. Congestive heart failure (CHF) was rare in all treatment groups. The incidence of hypertension AEs was low in all active treatment groups. Discontinuations due to hypertension AEs and hypertension AEs requiring a change or adjustment in blood pressure medications were similar and uncommon in all treatment groups. There was only a single report of acute renal failure (in the ibuprofen treatment group). CONCLUSIONS: In the rofecoxib phase IIb/III OA database, the renal safety profile for rofecoxib, a selective inhibitor of COX-2, was generally similar to that of the comparator, non-selective NSAIDs which were studied.