Recategorization of Non-Aspirin Nonsteroidal Anti-inflammatory Drugs According to Clinical Relevance: Abandoning the Traditional NSAID Terminology

Non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat pain, fever, and inflammation. Historically, NSAIDs have been categorized as traditional NSAIDs and newer cyclooxygenase (COX)-2 inhibitors (coxibs). However, traditional NSAIDs also inhibit the COX-1 and COX-2 enzyme isoforms to a varying degree. This diversity of COX-1 and COX-2 selectivity within the class of traditional NSAIDs has proven clinically important, with evidence accumulating on the cardiovascular risks associated with selective COX-2 inhibition. Thus, the relative COX-2 selectivity of traditional NSAIDs correlates with their cardiovascular risk profile, being more favourable for non-selective NSAIDs, such as naproxen and low-dose ibuprofen, and less favourable for more COX-2 selective agents, such as diclofenac. To enhance clinically relevant terminology, we advocate categorizing all non-aspirin NSAIDs—including traditional NSAIDs—according to their relative COX-1 and COX-2 selectivity as either COX-1 inhibitors, non-selective NSAIDs, or COX-2 inhibitors. We further recommend subcategorizing COX-2 inhibitors as newer COX-2 inhibitors (coxibs) or older COX-2 inhibitors. Finally, we recommend examining the effects of the individual NSAIDs included in each of the proposed categories. Adhering to these recommendations will align future studies, advance interpretation of COX-specific adverse cardiovascular effects, and provide better guidance to clinicians prescribing NSAIDs.     

Nonsteroidal anti-inflammatory drugs in systemic lupus erythematosus

Up to 80% of patients with systemic lupus erythematosus (SLE) are treated with nonsteroidal anti-inflammatory drugs (NSAID) for musculoskeletal symptoms, serositis and headache. This survey reviews the literature on non-selective and selective inhibitors of cyclooxygenases, with an emphasis on the efficacy and safety profile reported in SLE patients. No lupus-specific data on gastro-intestinal side effects of NSAID exist. Both non-selective Cox inhibitors and selective Cox-2 inhibitors induce renal side effects, including sodium retention and reduction of the glomerular filtration rate. Lupus nephritis is a risk factor for NSAID-induced acute renal failure, but not for rare idiosyncratic toxic renal reactions to NSAID. In refractory nephrotic syndrome, NSAID have been used successfully. Cutaneous and allergic reactions to NSAID are increased in SLE patients as well as hepatotoxic effects, particularly with high dose aspirin. Whereas a variety of central nervous system side effects of NSAID are probably no more common in SLE patients than others, aseptic meningitis has been reported more frequently. Ovulation and pregnancy can be adversely affected by Cox inhibitors. The antiplatelet effect of aspirin and non-selective Cox inhibitors has a therapeutic potential in patients with antiphospholipid syndrome (APS). In summary, treatment of SLE with NSAID requires awareness for the increased frequency of some side effects and close monitoring of toxicity.     

Nonsteroidal anti-inflammatory drugs in systemic lupus erythematosus

Up to 80% of patients with systemic lupus erythematosus (SLE) are treated with nonsteroidal anti-inflammatory drugs (NSAID) for musculoskeletal symptoms, serositis and headache. This survey reviews the literature on non-selective and selective inhibitors of cyclooxygenases with an emphasis on the efficacy and safety profile reported in SLE patients. No lupus-specific data on gastro-intestinal side effects of NSAID exist. Both non-selective Cox-inhibitors and selective Cox-2 inhibitors induce renal side effects including sodium retention and reduction of the glomerular filtration rate. Lupus nephritis is a risk factor for NSAID-induced acute renal failure, but not for rare idiosyncratic toxic renal reactions to NSAID. In refractory nephrotic syndrome, NSAID have been used successfully. Cutaneous and allergic reactions to NSAID are increased in SLE patients as well as hepatotoxic effects, particularly with high dose aspirin. Whereas a variety of central nervous system side effects of NSAID are probably no more common in SLE patients than in others, aseptic meningitis has been reported more frequently. Ovulation and pregnancy can be adversely affected by Cox-inhibitors. The antiplatelet effect of aspirin and non-selective Cox-inhibitors has a therapeutic potential in patients with the antiphospholipid syndrome (APS). In summary, treatment of SLE with NSAID requires awareness for the increased frequency of some side effects and close monitoring of toxicity.     

Mechanisms of nonsteroidal anti-inflammatory drug-induced gastrointestinal injury and repair: a window of opportunity for cyclooxygenase-inhibiting nitric oxide donors.

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause damage in the upper gastrointestinal (GI) tract by impairing the ability of the mucosa to resist and respond to injury. Many of these effects of NSAIDs can be attributed to their ability to suppress mucosal prostaglandin synthesis. Selective inhibitors of cyclooxygenase (COX)-2 are less likely to disrupt mucosal defence and do not interfere with platelet aggregation. Thus, their use is associated with a reduced incidence of serious GI adverse events; however, a significant risk of such events still persists. At least in animal models, selective COX-2 inhibitors interfere with ulcer healing to the same extent as conventional NSAIDs. In contrast, COX-inhibiting nitric oxide donors (CINODs) produce anti-inflammatory and analgesic effects comparable or superior to those of NSAIDs, but with greatly reduced GI toxicity. Unlike NSAIDs and selective COX-2 inhibitors, CINODs do not interfere with ulcer healing. Moreover, because CINODs suppress the activity of both COX-1 and COX-2, they do not share with selective COX-2 inhibitors the lack of cardioprotection afforded by significant suppression of platelet aggregation. Because of their safety profile, CINODs may be particularly useful for long term prevention applications, such as for colon cancer, cardiovascular disease and Alzheimer's disease.     

The use and safety profile of non-steroidal antiinflammatory drugs among Turkish patients with osteoarthritis.

BACKGROUND/AIMS: To determine the use and safety profile of non-steroidal anti-inflammatory drugs (NSAIDs) among Turkish osteoarthritis patients. METHODS: Osteoarthritis patients were interviewed by 138 doctors from clinics in nine different cities. Doctors completed a questionnaire regarding non-steroidal anti-inflammatory drugs use and safety profile while interviewing the patients. RESULTS: Totally 3,755 patients (female/male: 3/1, mean age 59.0 +/- 12.2 years), 3,442 under non-steroidal anti-inflammatory drugs treatment, were included in the study. The use of meloxicam (5.5% vs. 14.4%) and specific cyclooxygenase-2 (COX-2) inhibitors (for celecoxib 3.3% vs. 12.2%; for rofecoxib 3.0% vs. 11.2%) increased more than that of other non-selective non-steroidal anti-inflammatory drugs. The most common side effects were epigastric burning (37%), other dyspeptic symptoms (25.3%), abdominal pain (17.0%), constipation (12.7%), nausea (10.6%) and diarrhea (3.0%). COX-2 selective and specific inhibitors had significantly lower incidence of dyspeptic complaints compared to non-selective non-steroidal anti-inflammatory drugs. No difference was found between the different non-steroidal anti-inflammatory drugs regarding the ratio of discontinuation of therapy due to inefficacy. The ratios of discontinuation due to side effects were lower in patients using COX-2 specific inhibitors compared to non-selective and selective non-steroidal anti-inflammatory drugs: celecoxib (7.7%), rofecoxib (10.3%), etodolac (12.4%), meloxicam (12.6%), tenoxicam (16.5%), diclofenac (16.8%), ibuprofen (19.4%), and naproxen (27.4%). Discontinuation of the non-steroidal anti-inflammatory drugs due to dyspeptic complaint was significantly less for specific COX-2 inhibitors than for non-selective and selective non-steroidal anti-inflammatory drugs: celecoxib (2.5%), rofecoxib (8.4%), meloxicam (9.5%), etodolac (13.4%), tenoxicam (14.0%), diclofenac (14.1%), ibuprofen (17.2%), and naproxen (24.4%). CONCLUSIONS: The use of meloxicam and specific COX-2 inhibitors seems to have increased more than that of other non-selective non-steroidal anti-inflammatory drugs, if previously used non-steroidal anti-inflammatory drugs are considered. Fewer dyspeptic complaints have been reported with specific COX-2 inhibitors.     

Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin?

Cyclo-oxygenase-2 selective inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of acute cardiovascular events. Only aspirin offers primary and secondary cardiovascular prophylaxis, but trials have not answered directly whether low-dose aspirin is cardioprotective with COX-2 inhibitors. A large inception cohort study showed that concomitant use of aspirin reduced risk of cardiovascular events when given with rofecoxib, celecoxib, sulindac, meloxicam, and indometacin but not when given with ibuprofen. In large trials assessing gastrointestinal safety, there were fewer gastrointestinal events in patients using both COX-2 inhibitors and aspirin than in those using non-selective NSAIDs and aspirin; significantly fewer uncomplicated upper gastrointestinal events took place in the MEDAL trial. Analysis of VIGOR and two capsule endoscopy studies showed significantly less distal gastrointestinal blood loss with COX-2 inhibitors than with non-selective NSAIDs. Endoscopy trials showed that low-dose aspirin does not diminish the gastrointestinal benefits of COX-2 inibitors over non-selective NSAIDs. In an elderly epidemiological cohort receiving aspirin, both celecoxib and rofecoxib reduced risk of admission for gastrointestinal events. Comparison of the cardiovascular and gastrointestinal risks is difficult: likelihood and severity of cardiovascular events differ between individuals, agents, and exposure. Mortality associated with gastrointestinal events is less frequent than with cardiovascular events, but asymptomatic ulcers can result in severe complications. Data support the conclusion that COX-2 inhibitors are preferable to non-selective NSAIDs in patients with chronic pain and cardiovascular risk needing low-dose aspirin, but relative risks and benefits should be assessed individually for each patient.     

Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin?

Cyclo-oxygenase-2 selective inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of acute cardiovascular events. Only aspirin offers primary and secondary cardiovascular prophylaxis, but trials have not answered directly whether low-dose aspirin is cardioprotective with COX-2 inhibitors. A large inception cohort study showed that concomitant use of aspirin reduced risk of cardiovascular events when given with rofecoxib, celecoxib, sulindac, meloxicam, and indometacin but not when given with ibuprofen. In large trials assessing gastrointestinal safety, there were fewer gastrointestinal events in patients using both COX-2 inhibitors and aspirin than in those using non-selective NSAIDs and aspirin; significantly fewer uncomplicated upper gastrointestinal events took place in the MEDAL trial. Analysis of VIGOR and two capsule endoscopy studies showed significantly less distal gastrointestinal blood loss with COX-2 inhibitors than with non-selective NSAIDs. Endoscopy trials showed that low-dose aspirin does not diminish the gastrointestinal benefits of COX-2 inibitors over non-selective NSAIDs. In an elderly epidemiological cohort receiving aspirin, both celecoxib and rofecoxib reduced risk of admission for gastrointestinal events. Comparison of the cardiovascular and gastrointestinal risks is difficult: likelihood and severity of cardiovascular events differ between individuals, agents, and exposure. Mortality associated with gastrointestinal events is less frequent than with cardiovascular events, but asymptomatic ulcers can result in severe complications. Data support the conclusion that COX-2 inhibitors are preferable to non-selective NSAIDs in patients with chronic pain and cardiovascular risk needing low-dose aspirin, but relative risks and benefits should be assessed individually for each patient.     

Osteoarthritis therapy--are there still unmet needs?

Non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors are commonly used to control pain and inflammation in osteoarthritis. However, these agents have been associated with gastrointestinal, renal and cardiovascular adverse effects. Together, these complications indicate a clear unmet need in the safety of current treatment options for the management of osteoarthritis. NSAIDs are known to have adverse gastrointestinal effects, and more recently it has been suggested that some selective COX-2 inhibitors are also associated with serious gastrointestinal complications. Selective COX-2 inhibitors have a similar capacity to NSAIDs to delay ulcer healing, and may not significantly decrease the incidences of perforation, ulceration and bleeding (the most clinically relevant gastrointestinal endpoints) compared with NSAIDs. These effects may be due to overlapping roles of COX-1 and COX-2 in physiological and pathophysiological processes. Furthermore, as COX-2 is integrally involved in renal homeostasis, selective COX-2 inhibitors are associated with negative effects on kidney function similar to those seen with NSAIDs. Electrolyte disturbances, oedema and hypertension have been correlated with the use of both drug classes. Additionally, selective COX-2 inhibitors have the potential to increase cardiovascular events, although further research is required to clearly determine such a risk. With the current unmet needs in the treatment of osteoarthritis, the opportunity exists for the development of new therapies. Novel agents include the COX-inhibiting nitric oxide donors and the lipoxygenase (LOX)/COX inhibitor licofelone. Initial results suggest that these therapies may have tolerability advantages over the NSAIDs and selective COX-2 inhibitors.     

Update on guidelines for the treatment of chronic musculoskeletal pain

Chronic musculoskeletal pain is a major—and growing—burden on today’s ageing populations. Professional organisations including the American College of Rheumatology (ACR), American Pain Society (APS) and European League Against Rheumatism (EULAR) have published treatment guidelines within the past 5 years to assist clinicians achieve effective pain management. Safety is a core concern in all these guidelines, especially for chronic conditions such as osteoarthritis that require long-term treatment. Hence, there is a consensus among recommendations that paracetamol should be the first-line analgesic agent due to its favourable side effect and safety profile, despite being somewhat less effective in pain relief than anti-inflammatory drugs. Cyclooxygenase-2 (COX-2)-selective anti-inflammatory drugs were developed with the goal of delivering effective pain relief without the serious gastrointestinal (GI) side effects linked with traditional non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Clinical trial evidence supported these benefits, and COX-2 inhibitors were widely adopted, both in clinical practice and in official guidelines. Recently, accumulating data have linked COX-2 inhibitors with serious cardiovascular and/or cardiorenal effects and/or serious cutaneous adverse reactions (SCARs), particularly at anti-inflammatory doses or when used long term. Regulatory authorities in both Europe and the USA have responded to these data with the withdrawal of rofecoxib and valdecoxib, and the strengthening of prescribing advice on all anti-inflammatory drugs. COX-2 inhibitors and non-selective NSAIDs should now be used with increased caution in patients at increased cardiovascular and/or cardiorenal risk, e.g., patients with congestive heart failure, hypertension, etc. Regulatory advice and good clinical practice are to use anti-inflammatory drugs at the lowest effective dose and for the shortest possible time. There are as yet no updated official guidelines that incorporate these new data and regulatory advice. An international multidisciplinary panel, the Working Group on Pain Management, has generated new recommendations for the treatment of moderate-to-severe musculoskeletal pain. These guidelines, formulated in response to recent developments concerning COX-2 inhibitors and other NSAIDs, focus on paracetamol as the baseline drug for chronic pain management; when greater analgesia is desired, the addition of weak opioids is recommended based on a preferable GI and cardiovascular profile, compared with non-steroidal anti-inflammatory drugs.     

Update on guidelines for the treatment of chronic musculoskeletal pain

Chronic musculoskeletal pain is a major - and growing - burden on today's ageing populations. Professional organisations including the American College of Rheumatology (ACR), American Pain Society (APS) and European League Against Rheumatism (EULAR) have published treatment guidelines within the past 5 years to assist clinicians achieve effective pain management. Safety is a core concern in all these guidelines, especially for chronic conditions such as osteoarthritis that require long-term treatment. Hence, there is a consensus among recommendations that paracetamol should be the first-line analgesic agent due to its favourable side effect and safety profile, despite being somewhat less effective in pain relief than anti-inflammatory drugs. Cyclooxygenase-2 (COX-2)-selective anti-inflammatory drugs were developed with the goal of delivering effective pain relief without the serious gastrointestinal (GI) side effects linked with traditional non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Clinical trial evidence supported these benefits, and COX-2 inhibitors were widely adopted, both in clinical practice and in official guidelines. Recently, accumulating data have linked COX-2 inhibitors with serious cardiovascular and/or cardiorenal effects and/or serious cutaneous adverse reactions (SCARs), particularly at anti-inflammatory doses or when used long term. Regulatory authorities in both Europe and the USA have responded to these data with the withdrawal of rofecoxib and valdecoxib, and the strengthening of prescribing advice on all anti-inflammatory drugs. COX-2 inhibitors and non-selective NSAIDs should now be used with increased caution in patients at increased cardiovascular and/or cardiorenal risk, e.g., patients with congestive heart failure, hypertension, etc. Regulatory advice and good clinical practice are to use anti-inflammatory drugs at the lowest effective dose and for the shortest possible time. There are as yet no updated official guidelines that incorporate these new data and regulatory advice. An international multidisciplinary panel, the Working Group on Pain Management, has generated new recommendations for the treatment of moderate-to-severe musculoskeletal pain. These guidelines, formulated in response to recent developments concerning COX-2 inhibitors and other NSAIDs, focus on paracetamol as the baseline drug for chronic pain management; when greater analgesia is desired, the addition of weak opioids is recommended based on a preferable GI and cardiovascular profile, compared with non-steroidal anti-inflammatory drugs.     

Non-steroidal anti-inflammatory agents with selective inhibitory activity on cyclooxygenase-2. Interest and future prospects

INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of primary prostanoids by blocking the access of arachidonic acid to the active site of the cyclooxygenases (COXs). Because the prostanoids produced by COX-1 appear to play a physiological role (protection of the gastric mucosa, platelet aggregation, vascular homeostasis, maintenance of renal sodium-water balance) while those produced by COX-2 seem mainly to intervene in the inflammatory response and in certain processes associated with cell proliferation, the hypothesis has been put forward that the NSAIDs that are selective COX-2 inhibitors should theoretically be capable of maintaining NSAID therapeutic properties but also have fewer adverse side effects due to the maintenance of prostaglandin production at normal physiological levels. CURRENT KNOWLEDGE AND KEY POINTS: The hypothesis of COX isoenzyme selectivity has led to a proposed classification for COX inhibitors: 1) COX-1 selective inhibitors (low-dosage aspirin); 2) COX non-selective inhibitors (the majority of classified NSAIDs, which when administered over the long term, e.g., in cases of rheumatoid arthritis, cause duodenal ulcers in 20% of cases and gastric hemorrhage in 1-4% of cases/year); 3) COX-2 preferential inhibitors (meloxicam and nimesulide, which have fewer gastric side effects than standard NSAIDs, but which are not risk-free at high doses); 4) COX-2 selective inhibitors (celecoxib and rofecoxib). Preliminary clinical studies have shown that COX-2 selective inhibitors are as efficient as standard NSAIDs and have fewer adverse digestive side effects, thereby confirming the interest of this proposed classification. In the UK, the aforementioned studies have led to the commercialization of rofecoxib for the treatment of pain and osteoarthritis, while celecoxib has been introduced in medical practice in the USA and other countries for the treatment of rheumatoid arthritis and osteoarthritis. FUTURE PROSPECTS AND PROJECTS: Various epidemiological and laboratory studies have indicated that NSAIDs may be able to reduce the risk of cancer (colorectal cancer in particular) and Alzheimer's disease due to their inhibitory activity on COXs, especially COX-2. The therapeutic contribution of COX-2 specific inhibitors has to be more fully evaluated, particularly as these agents could delay the healing of duodenal ulcers and interfere with several COX-2-induced physiological functions. It is therefore suggested that until further information becomes available, this new class of NSAIDs should be used with caution in certain patient populations.     

Do selective cyclo-oxygenase inhibitors eliminate the adverse events associated with nonsteroidal anti-inflammatory drug therapy?

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.     

COX-2-Specific Inhibitors – the Emergence of a New Class of Analgesic and Anti-inflammatory Drugs

The prostaglandin series of bioactive compounds is formed by the interaction of two distinct but related enzymes, cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2). COX-1 is a constitutive form which is present mainly in the gastric mucosa, kidney and platelets. COX-2 is mainly an inducible form, although also to some extent present constitutively in the CNS, the juxtaglomerular apparatus of the kidney and in the placenta during late gestation. Both isoforms contribute to the inflammatory process, but COX-2 is of considerable therapeutic interest as it is induced, resulting in an enhanced formation of prostaglandins, during acute as well as chronic inflammation. Conventional NSAIDs inhibit both isoforms to a similar extent and in an approximately equal dose and concentration range. The two recently developed and clinically available selective COX-2 inhibitors, celecoxib and rofecoxib, are about 100–1000 times more selective on the COX-2 than on the COX-1 isoform. In Europe rofecoxib is today indicated for the symptoms and signs of osteoarthritis, whereas celecoxib is indicated for both osteoarthritis and rheumatoid arthritis. The major clinical interest of these drugs has been related to the lower incidence of gastrointestinal bleeding which, with the conventional COX-1/COX-2 agents has been a source of hospitalisation, disablement and death, especially in the elderly. Clinical trials have convincingly demonstrated that celecoxib and rofecoxib in clinical use induce very few gastrointestinal complications compared to conventional and non-selective NSAIDs. However, the well known contraindications for NSAIDs, such as late pregnancy, aspirin-induced asthma, congestive heart failure and renal dysfunction, will so far apply also to the COX-2 inhibitors. Compared to the traditional and non-selective NSAIDs, COX-2 inhibitors may provide an insight into additional therapeutic areas, such as gastrointestinal cancer and dementia, where the potential relevance to COX-2 mechanisms are currently being explored and clinical trials being performed. With the rapid clinical acceptance of celecoxib and rofecoxib, knowledge about their clinical usefulness in various inflammatory disease states and pain disorders is increasing. For the many patients suffering from such conditions, the selective COX-2 inhibitors are likely to become a significant addition to the therapeutic arsenal of analgesic and anti-inflammatory drugs. Received: 15 December 1999 / Accepted: 4 April 2000     

Cardiovascular risk,hypertension, and NSAIDs

During the past 2 years, a great deal of evaluation has been conducted on the cardiovascular (CV) effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors. This review focuses on the effects of the NSAIDs and COX-2 inhibitors on blood pressure and CV events. Clinical trial databases for NSAIDs and COX-2 inhibitors have shown varying levels of destabilization of blood pressure control in treated hypertensive patients as well as variable incident rates of the development of arrhythmias, congestive heart failure, myocardial infarction, and stroke. Nonselective and COX-2 selective NSAIDs can be used carefully in arthritis patients with hypertension and stable CV disorders (excluding congestive heart failure and moderate to severe kidney dysfunction) when the individual clinical benefit of anti-inflammatory therapy outweighs the CV and gastrointestinal risk.     

Cardiovascular effects of coxibs

A new class of drugs, the selective cyclooxygenase-2 (COX-2) inhibitors, or coxibs, have recently been marketed as an alternative to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) on the basis of a lower risk of gastrointestinal side effects. The recent withdrawal of rofecoxib, along with safety concerns about other COX-2 selective inhibitors raises important questions about the cardiovascular toxicity of these drugs. Recently some concerns arose even for a possible cardiotoxicity of nonselective nonsteroidal anti-inflammatory drugs. From data available so far, it seems that coxibs still remain a rational choice for patients with low cardiovascular risk and high gastrointestinal risk. Long-term studies with a cardiovascular endpoint involving both selective and nonselective anti-inflammatory drugs are warranted.     

非类固醇类抗炎药相关消化性溃疡的预防和治疗

非类固醇类抗炎药(NSAIDs)是消化性溃疡(PU)的主要病因.NSAIDs相关PU的发病率和并发症发生率较高.在应用NSAIDs时,可选用胃肠毒性较低的非选择性NSAIDs,并与质子泵抑制剂或米索前列醇合用;或单用选择性环氧合酶-2抑制剂(高危患者考虑加用质子泵抑制剂),可以降低NSAIDs相关PU的发病率.治疗NSAIDs相关PU最有效的方法是停用NSAIDs,然后应用组胺H2受体拮抗剂或质子泵抑制剂,以促进溃疡愈合;不能停用NSAIDs的患者,应同时应用质子泵抑制剂,以缓解症状、促进溃疡愈合和预防并发症发生.选择性环氧合酶-2抑制剂是否增加心、脑血管血栓形成的危险,有待进一步研究.新一代安全性较高的NSAIDs正在研制中.     

Nonsteroidal antiinflammatory drugs and the kidney

Nonsteroidal antiinflammatory drugs (NSAIDs) have potentially important renal adverse effects. With regard to renal adverse effects there is no indication of significant differences between conventional NSAIDs and selective COX-2 inhibitors. Their nephrotoxicity has been well documented. Many of the renal abnormalities that are encountered as a result of NSAIDs use can be attributed to the inhibition of prostaglandins synthesis. The release of prostaglandins is particulary importent in high-risk patients, including patients with severe heart disease, liver disease, preexisting renal disease, elderly and patients with volume depletion. The common complication of NSAID use is retention of sodium and edema formation due to increased reabsorption of sodium and water in the loop of Henle and hyperkalemie due to diminished renin secretion. Nonsteroidal antiiflammatory drugs can induce two different forms of acute renal failure. Decreased prostaglandin synthesis can lead to reversible renal ischemia and hemodynamically-mediated acute renal failure. Second form of acute renal failure is acute interstitial nephritis. This type of interstitial nephritis is often accompanied by nephrotic syndrome due to minimal change disease. Nephrotic syndrome after NSAIDs treatments may be also associated with membranous nephropathy. Another complication of NSAIDs treatment is modest rise of systemic blood pressure in some hypertensive patients due to increase in renal and systemic vascular resistence. In patients consuming excessive amount of NSAIDs over a prolonged period of years papillary necrosis can occur. Exposure to large quantities of NSAIDs can probably induce in some patients chronic renal insufficiency.     

NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe?

Selective cyclooxygenase-2 (COX-2) inhibitors have provided relief for patients suffering from chronic pain and other inflammatory conditions and have reduced adverse gastrointestinal effects. The documented reduction in gastric erosions, ulcerations, and perforations during the use of COX-2-selective inhibitors raises the question: would the kidney be similarly spared? Our understanding of these enzyme isoforms in the kidney is incomplete. However, kidney tissue seems to possess "constitutive" or homeostatic COX-2 enzyme, suggesting a role for prostaglandins produced by this isoform. In addition, studies evaluating the renal effects of the selective nonsteroidal anti-inflammatory drugs (NSAIDs) are inconclusive, and available data on the renal effects of COX-2-selective inhibitors are conflicting. Inadequate numbers, varied baseline patient characteristics, and different doses and lengths of drug treatment hampers comparison of the small number of clinical investigations available for review. Therefore, this article reviews the role of cyclooxygenase enzyme activity and associated prostaglandins in the kidney and the adverse renal effects of nonselective NSAIDs. We also touch on the COX-1/COX-2 selectivity of NSAIDs, the localization of COX enzymes in kidneys, and clinical studies examining the renal effects of selective COX-2 inhibitors.     

Preventing effects of COX-2 inhibitors on rheumatoid joint destruction

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX) -2 inhibitors with the potential to reduce the risk of gastrointestinal bleeding, have their crucial role in the control of inflammation. However, they have recently been shown to have a preventing effect against joint destruction by basic studies related to pathophysiology in rheumatoid arthritis. Here we summarize the current knowledge on anti-proliferative action due to apoptosis, suppression of angiogenesis, and suppression of osteoclastic bone resorption by NSAIDs. COX-2-dependent and/or -independent mechanisms for these actions have been suggested. Several NSAIDs including selective COX-2 inhibitors have been suggested to possess the in vivo preventing effects on joint destruction in animal models of rheumatoid arthritis. However, clinical evidence on the disease modifying effects of COX-2 inhibitors in patients with rheumatoid arthritis remains to be studied.     

Preferential COX-2 inhibition: its clinical relevance for gastrointestinal non-steroidal anti-inflammatory rheumatic drug toxicity

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of arthritis and pain. These drugs tend to cause significant side effects, however, including gastric and intestinal toxicity. The mechanism of action of NSAIDs is through their inhibition of the key enzyme of prostaglandin biosynthesis, the cyclooxygenase. Recently, two forms of cyclooxygenase have been found to exist: COX-1 and COX-2, the constitutive and inducible forms, respectively. COX-1 exists in the stomach, intestine, kidneys and platelets, while COX-2, the inducible form, is expressed during inflammation. The therapeutic effects of NSAIDs are largely the result of inhibition of the enzyme cyclooxygenase-2 (COX-2), whereas the toxic effects (e.g., gastrointestinal, renal and platelet effects) are primarily due to the inhibition of COX-1. Individual NSAIDs show different potencies against COX-1 compared with COX-2 and this explains the variations in the side effects of NSAIDs at their anti-inflammatory doses. Drugs with high potency against COX-2 and a better COX-2-/COX-1 activity ratio will have anti-inflammatory activity with fewer gastrointestinal side effects. In contrast piroxicam and indomethacin, which drugs have a much higher potency against COX-1 than against COX-2, are amongst those with the highest gastrointestinal toxicity. Based on these findings, COX-2 seems to be an ideal target for the development of new anti-inflammatory drugs. Several compounds with preferential or specific COX-2 inhibiting properties have been synthesized and evaluated in pre-clinical and clinical studies i.e. Meloxicam, Celecoxib, MK-966, Flusolid and L-745, 337. The COX-2 selectivity of these novel NSAIDs relate well to their favorable gastrointestinal tolerability profile. Clinical trials have shown meloxicam and celecoxib to be as effective as currently available NSAIDs, but with an improved gastrointestinal tolerability profile. Further clinical trials and large-scale postmarketing surveillance programs are needed, however, to confirm the potential therapeutic benefits of these novel preferential or specific COX-2 inhibitors.