Assessment of the safety of selective cyclo-oxygenase-2 inhibitors: where are we in 2003?

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide despite their well-documented adverse gastrointestinal (GI) effects. The risk of developing a severe GI event varies from patient to patient and NSAID to NSAID. Selective cyclo-oxygenase-2 inhibitors (coxibs) have been designed to have similar efficacy but less GI toxicity than traditional NSAIDs, and have been shown to have an improved GI tolerability and less adverse events across a range of different GI safety assessments. In clinical trials, particularly VIGOR and CLASS, rofecoxib and celecoxib, respectively, significantly reduce the risk of ulcers and ulcer complications than nonselective NSAID comparators with ulcer rates comparable to placebo. The real benefit of a coxib comes from the sparing of the thromboxane and hence preservation of normal platelet function. Thus, there is less risk of bleeding with selective inhibition of COX-2, which is the most common and serious complication of non-selective NSAIDs. Moreover, bleeding can occur anywhere in the GI tract. Although some concern has been raised about the cardiovascular safety of coxibs, when used in recommended doses, there is no convincing evidence that patients treated with a coxib have an increased risk of cardiovascular thrombotic events. Different approaches have been advocated to minimize NSAID-related GI toxicity. Choice of less harmful NSAIDs such as coxib has been one of the strategies promoted in guidelines. The introduction of coxibs with a higher benefit-risk ratio has dramatically changed the therapeutic scenario for anti-inflammatory treatment in the clinical practice.     

Assessment of the safety of selective cyclo-oxygenase-2 inhibitors: where are we in 2003?

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide despite their well-documented adverse gastrointestinal (GI) effects. The risk of developing a severe GI event varies from patient to patient and NSAID to NSAID. Selective cyclo-oxygenase-2 inhibitors (coxibs) have been designed to have similar efficacy but less GI toxicity than traditional NSAIDs, and have been shown to have an improved GI tolerability and less adverse events across a range of different GI safety assessments. In clinical trials, particularly VIGOR and CLASS, rofecoxib and celecoxib, respectively, significantly reduce the risk of ulcers and ulcer complications than nonselective NSAID comparators with ulcer rates comparable to placebo. The real benefit of a coxib comes from the sparing of the thromboxane and hence preservation of normal platelet function. Thus, there is less risk of bleeding with selective inhibition of COX-2, which is the most common and serious complication of non-selective NSAIDs. Moreover, bleeding can occur anywhere in the GI tract. Although some concern has been raised about the cardiovascular safety of coxibs, when used in recommended doses, there is no convincing evidence that patients treated with a coxib have an increased risk of cardiovascular thrombotic events. Different approaches have been advocated to minimize NSAID-related GI toxicity. Choice of less harmful NSAIDs such as coxib has been one of the strategies promoted in guidelines. The introduction of coxibs with a higher benefit-risk ratio has dramatically changed the therapeutic scenario for anti-inflammatory treatment in the clinical practice.     

Impact of COX-2 inhibitors in common clinical practice a gastroenterologist's perspective

Non-selective NSAIDs enhance the risk of serious ulcer complications (bleeding, perforation, obstruction), hospitalization and death about 3-10-fold. The gastrointestinal side effects of NSAIDs have a considerable economical burden, since they are responsible for 5-10 billion dollars in hospitalization charges and lost work time. NSAIDs cause gastrointestinal damage by both topical and systemic effects. COX-1-mediated inhibition of prostaglandin synthesis is probably the most relevant mechanism, but NSAIDs can cause gastrointestinal injury also by COX-independent pathways. COX-2-selective inhibitors (Coxibs) such as celecoxib, rofecoxib or valdecoxib have been developed to achieve an equal relief of pain and inflammation as classical NSAIDs but without their risk of gastrointestinal side effects. Within the first three months, celecoxib became the fastest selling drug in history. The gastrointestinal safety of classical NSAIDs and Coxibs has been compared in a variety of endoscopic investigations, meta-analyses and outcome studies. In conclusion, these studies have clearly shown, that Coxibs are associated with significantly less dyspeptic symptoms, erosions, ulcers and ulcer complications. In contrast, Coxibs seem to delay gastric ulcer healing to the same extent as traditional NSAIDs. Besides their effects on the upper gastrointestinal tract, NSAIDs can cause small intestinal inflammation, ulcers of the small and large intestine, ileal dysfunction, intestinal strictures, colitis and NSAID enteropathy. In addition, NSAIDs increase the risk of lower gastrointestinal complications including bleeding, perforation and obstruction. Current data suggest, that Coxibs are associated with a significantly lower risk of serious lower GI events than traditional NSAIDs. It is now under debate, who should receive COX-2-selective inhibitors instead of classical NSAIDs, since Coxibs are much more expensive. Data from cost-effectiveness studies suggest, that Coxibs should currently be used only in patients with high risks of GI complications.     

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.     

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.     

Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis

Celecoxib (Celebrex?) was the first cyclo-oxygenase (COX)-2 selective inhibitor (coxib) to be introduced into clinical practice. Coxibs were developed to provide anti-inflammatory/analgesic activity similar to that of nonselective NSAIDs, but without their upper gastrointestinal (GI) toxicity, which is thought to result largely from COX-1 inhibition. Celecoxib is indicated in the EU for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. This article reviews the clinical efficacy and tolerability of celecoxib in these EU-approved indications, as well as overviewing its pharmacological properties. In randomized controlled trials, celecoxib, at the recommended dosages of 200 or 400?mg/day, was significantly more effective than placebo, at least as effective as or more effective than paracetamol (acetaminophen) and as effective as nonselective NSAIDs and the coxibs etoricoxib and lumiracoxib for the symptomatic treatment of patients with active osteoarthritis, rheumatoid arthritis or ankylosing spondylitis. Celecoxib was generally well tolerated, with mild to moderate upper GI complaints being the most common body system adverse events. In meta-analyses and large safety studies, the incidence of upper GI ulcer complications with recommended dosages of celecoxib was significantly lower than that with nonselective NSAIDs and similar to that with paracetamol and other coxibs. However, concomitant administration of celecoxib with low-dose cardioprotective aspirin often appeared to negate the GI-sparing advantages of celecoxib over NSAIDs. Although one polyp prevention trial noted a dose-related increase in cardiovascular risk with celecoxib 400 and 800?mg/day, other trials have not found any significant difference in cardiovascular risk between celecoxib and placebo or nonselective NSAIDs. Meta-analyses and database-derived analyses are inconsistent regarding cardiovascular risk. At recommended dosages, the risks of increased thrombotic cardiovascular events, or renovascular, hepatic or hypersensitivity reactions with celecoxib would appear to be small and similar to those with NSAIDs. Celecoxib would appear to be a useful option for therapy in patients at high risk for NSAID-induced GI toxicity, or in those responding suboptimally to or intolerant of NSAIDs. To minimize any risk, particularly the cardiovascular risk, celecoxib, like all coxibs and NSAIDs, should be used at the lowest effective dosage for the shortest possible duration after a careful evaluation of the GI, cardiovascular and renal risks of the individual patient.     

Gastrointestinal safety of selective COX-2 inhibitors

It appears that selective Cox-2 inhibitors do not affect the gastro duodenal mucosa whilst having anti-inflammatory and analgesic efficacy similar to non-selective NSAIDs. Two broad categories of drugs are Cox-2 selective: coxibs and a number of pre-existing NSAIDs retrospectively found to have selectivity. Cox-2 inhibitors cause less dyspepsia than NSAIDs. They spare gastrointestinal mucosal generation of prostaglandins (PGs) and PG-dependent bicarbonate secretion. Coxibs cause no acute mucosal injury in endoscopic ulcers compared to NSAID comparators. In the VIGOR study all upper GI events were reduced from 4.5 per 100 patient years to 2.1 per 100 patient years with supra-therapeutic doses of rofecoxib compared with naproxen. In the CLASS study, over a period of 3 days to 6 months, incidence of ulcer complications was 0.76% with celecoxib and 1.45% for ibuprofen or diclofenac. The less substantial reduction in events in the CLASS study compared with the VIGOR may be due, at least in part, to the fact that 21% of the patients were also on low dose aspirin. However it is premature to say that the benefit of Cox-2 inhibitors is lost in patients taking aspirin. There is continuing debate on the role of Cox-2 inhibitors in patients who have other risk factors for complicated ulcer disease e.g. patients who are elderly, on aspirin or corticosteroids, have a previous ulcer or have H. pylori infection.     

Clinical pharmacology of novel selective COX-2 inhibitors

Novel coxibs (i.e. etoricoxib, valdecoxib, parecoxib and lumiracoxib) with enhanced biochemical cyclooxygenase (COX)-2 selectivity over that of rofecoxib and celecoxib have been recently developed. They have the potential advantage to spare COX-1 activity, thus reducing gastrointestinal toxicity, even when administered at high doses to improve efficacy. They are characterized by different pharmacodynamic and pharmacokinetics features. The higher biochemical selectivity of valdecoxib than celecoxib, evidenced in vitro, may be clinically relevant leading to an improved gastrointestinal safety. Interestingly, parecoxib, a pro-drug of valdecoxib, is the only injectable coxib. Etoricoxib shows only a slightly improved COX-2 selectivity than rofecoxib, a highly selective COX-2 inhibitor that has been reported to halve the incidence of serious gastrointestinal toxicity compared to nonselective nonsteroidal antiinflammatory drugs (NSAIDs). Lumiracoxib, the most selective COX-2 inhibitor in vitro, is the only acidic coxib. The hypothesis that this chemical property may lead to an increased and persistent drug accumulation in inflammatory sites and consequently to an improved clinical efficacy, however, remains to be verified. Several randomized clinical studies suggest that the novel coxibs have comparable efficacy to nonselective NSAIDs in the treatment of osteoarthritis, rheumatoid arthritis and acute pain, but they share similar renal side-effects. The apparent dose-dependence of renal toxicity may limit the use of higher doses of the novel coxibs for improved efficacy. Large-size randomized clinical trials are ongoing to define the gastrointestinal and cardiovascular safety of the novel coxibs.     

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.     

COX-2 inhibition, H. pylori infection and the risk of gastrointestinal complications

Current data on the gastric safety of cyclooxygenase-2 (COX-2) inhibitors in the presence of H. pylori infection are largely derived from animal experiments and indirect clinical evidence. In animal models of H. pylori gastritis, COX-2 inhibitors suppressed prostaglandin synthesis and aggravated mucosal damage. In the human stomach, COX-1 appears to be the predominant source of prostaglandins despite the fact that COX-2 is upregulated in H. pylori gastritis. There are conflicting data on whether H. pylori alters the risk of ulcer in patients receiving COX-2 inhibitors. Among patients with H. pylori infection, rofecoxib reduced the risk of complicated gastric but not duodenal ulcers as compared to naproxen. The advantage of rofecoxib over naproxen also disappeared in patients with H. pylori infection and prior upper gastrointestinal events. In contrast, pooled data suggested that H. pylori increases the risk of ulcer in patients receiving nonselective nonsteroidal anti-inflammatory drugs but not in patients receiving celecoxib. In rodent gastric ulcers, COX-2 was upregulated in the granulation tissue and ulcer margin. Inhibition of COX-2 delayed healing of experimental gastric ulcer. Limited data showed that COX-2 expression was also increased in human gastric ulcer regardless of the H. pylori status. The functional significance of COX-2 in human gastric ulcer is unknown.     

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.     

Taking stock of coxibs

Highly selective COX-2 inhibitors ('coxibs') were developed in an attempt to minimise severe gastrointestinal toxicity associated with conventional NSAIDs, without loss of anti-inflammatory efficacy. Five years ago, we concluded that the evidence then available indicated, at most, a small advantage for rofecoxib and celecoxib (the first coxibs to be marketed) over conventional NSAIDs in terms of reduced risk of severe gastrointestinal complications, such as bleeding or perforation of gastric or duodenal ulcers. In September 2004, newly released evidence about cardiovascular risk with rofecoxib led Merck Sharp & Dohme to voluntarily withdraw the drug worldwide. This has raised questions about the balance of benefit and risk with coxibs in general. Here we discuss the evidence relating to the gastrointestinal and cardiovascular safety of coxibs in patients with osteoarthritis (OA) or rheumatoid arthritis (RA).     

NSAID-associated adverse effects and acid control aids to prevent them: a review of current treatment options.

NSAIDs are central to the clinical management of a wide range of conditions. However, NSAIDs in combination with gastric acid, which has been shown to play a central role in upper gastrointestinal (GI) events, can damage the gastroduodenal mucosa and result in dyspeptic symptoms and peptic lesions such as ulceration.NSAID-associated GI mucosal injury is an important clinical problem. Gastroduodenal ulcers or ulcer complications occur in up to 25% of patients receiving NSAIDs. However, these toxicities are often not preceded by indicative symptoms. Data obtained from the Arthritis, Rheumatism, and Aging Medical Information System have shown that 50-60% of NSAID-associated peptic ulcer cases can remain clinically silent and do not present until complications occur. Therefore, prophylactic treatment to prevent GI complications may be necessary in a substantial proportion of NSAID users, especially those in groups associated with a high risk of developing these complications.Use of cyclo-oxygenase (COX)-2 selective NSAIDs, also known as 'coxibs', substantially reduces the incidence of upper GI toxicities seen with non-selective NSAIDs. However, there are concerns regarding the cardiovascular safety of coxibs. For this reason, the US FDA recommends minimal use of coxibs and only when strictly necessary. Additionally, rofecoxib has been removed from the US market and sales of valdecoxib have been suspended. Furthermore, upper GI toxicities still occur in patients receiving coxibs. Therefore, cotherapies are required to prevent and/or heal upper GI effects associated with NSAID use. Effective prophylactic and treatment strategies include misoprostol, histamine H(2) receptor antagonists and proton pump inhibitors (PPIs). The key role that gastric acid plays in upper GI adverse events among NSAID users suggests that it is important to choose the most effective agent for acid control to alleviate symptoms, heal mucosal erosions and improve the reduced quality of life in this patient population. PPIs provide effective acid suppression, which is essential to avoid GI mucosal injury, and they are, therefore, capable of dramatically decreasing the morbidity and mortality associated with this disorder.Since many serious GI complications are not heralded by any previous symptoms, physicians need to be aware of risk factor profiles that predispose patients to serious GI problems. Physicians also need to initiate the appropriate preventative acid suppressive therapy to minimise the burden of NSAID-associated GI adverse effects.     

Lumiracoxib: the evidence of its clinical impact on the treatment of osteoarthritis

INTRODUCTION: The symptoms of osteoarthritis (OA) include joint pain, stiffness, and a reduced ability to perform normal daily activities, which result in decreased quality of life. There is currently no known cure or means of preventing the progression of joint damage due to OA. Therefore, treatment focuses on the control of symptoms, including the use of various agents [including nonselective and selective nonsteroidal antiinflammatory drugs (NSAIDs)] to provide pain relief and reduce inflammation. Lumiracoxib is a selective cyclooxygenase-2 (COX-2) inhibitor for the treatment of OA. AIMS: To review the evidence for the treatment of OA with lumiracoxib. EVIDENCE REVIEW: There is evidence that lumiracoxib reduces the pain and stiffness associated with OA, and is as effective as nonselective NSAIDs, and the COX-2 inhibitor celecoxib. There is some evidence that lumiracoxib treatment results in a lower incidence of upper gastrointestinal (GI) ulcer complications compared with nonselective NSAIDs. However, evidence suggests that there is no GI benefit in patients receiving concomitant aspirin medication. With the exception of GI ulcers, the evidence indicates that lumiracoxib has a tolerability profile similar to nonselective NSAIDs: low risk of cardiovascular (CV) events and a low incidence of edema. Changes in liver function occur in some patients, largely at doses >100 mg. The cost effectiveness of lumiracoxib compared with nonselective NSAIDs remains to be determined. CLINICAL VALUE: Lumiracoxib is an alternative treatment option for OA which provides effective pain relief without the GI complications associated with nonselective NSAIDs, and with a low risk of CV events. Lumiracoxib is contraindicated in patients with current, previous, or at risk of, hepatic impairment.     

Clinical pharmacology of lumiracoxib, a second-generation cyclooxygenase 2 selective inhibitor

Although highly selective cyclooxygenase (COX)-2 inhibitors have been shown to be less toxic to the gastrointestinal tract than conventional non-steroidal anti-inflammatory drugs (NSAIDs), their overall safety profile is questioned. Since different selective COX-2 inhibitors were found to be associated with increased cardiovascular thrombotic events, the thrombotic hazard may be a class effect. Furthermore, warnings have been issued regarding serious skin and hypersensitivity reactions associated with valdecoxib. Lumiracoxib is a novel COX-2 selective inhibitor (coxib) with improved biochemical selectivity over that of currently available coxibs. It is structurally distinct from other drugs in the class and has weakly acidic properties. Clinical studies support a once-daily dosing regimen, despite its relatively short plasma elimination half-life (3 - 6 h). In randomised, controlled clinical trials, lumiracoxib 100 - 200 mg/day has been shown to be superior to placebo in patients with symptomatic osteoarthritis, with clinical efficacy similar to diclofenac 150 mg/day, celecoxib 200 mg/day or rofecoxib 25 mg/day. Furthermore, lumiracoxib 200 - 400 mg/day appeared to be effective in patients with rheumatoid arthritis. In patients with acute pain related to primary dysmenorrhoea, dental or orthopaedic surgery, lumiracoxib 400 mg/day was found to be at least as effective as standard doses of traditional NSAIDs and other coxibs. Endoscopic studies have indicated that lumiracoxib is associated with a rate of gastroduodenal ulcer formation that is significantly lower than with ibuprofen and does not differ from celecoxib. In the Therapeutic Arthritis Research and Gastrointestinal Trial, which enrolled 18,325 patients with osteoarthritis, the cumulative 1-year incidence of ulcer complications (primary end point) was significantly reduced by approximately threefold on lumiracoxib 400 mg/day compared with naproxen 1000 mg/day or ibuprofen 2400 mg/day (0.32 versus 0.91%). Reduction in ulcer complications was more pronounced in the population not taking low-dose aspirin (0.2 versus 0.92%, respectively). Conversely, the gastrointestinal advantage of lumiracoxib was abrogated in patients receiving low-dose aspirin (0.69 versus 0.88%, respectively, p = 0.49). Regarding cardiovascular events contributing to the trialists' composite end point (myocardial infarction, stroke or cardiovascular death), there was no significant difference between lumiracoxib (0.65%) versus combined comparator NSAIDs (0.55%). Similarly, no significant difference was recorded in rates of myocardial infarction (clinical and silent) between the lumiracoxib (0.25%) and the combined NSAID (0.19%) treatment groups. Liver function test abnormalities were more frequent with lumiracoxib (2.57%) than with the comparator NSAIDs (0.63%). Whether or not this would result in an increased risk of clinical hepatitis in the real world setting is unforeseeable.     

COXIBs, CINODs and H₂S-releasing NSAIDs: current perspectives in the development of safer non steroidal anti-inflammatory drugs

Traditional nonsteroidal anti-inflammatory drugs, tNSAIDs, are effective medication for prevention of ischemic events and treatment of pain, fever and inflammation. However their use associates with a significant risk to develop gastrointestinal and cardiovascular complications. Low doses of acetyl salicylic acid (ASA) and effective doses of tNSAIDs associate with a 2-6 fold increase in the risk of gastrointestinal bleeding. ASA and tNSAIDs inhibit cyclooxygenases (COXs). The COX exists at least in two isoforms, COX-1 and COX-2. Selective inhibitors of COX-2, the coxibs, spares the gastrointestinal tract while exert anti-inflammatory and analgesic effects. However, coxibs increase the risk of thrombo-embolic events. Nitric oxide (NO) and hydrogen sulfide (H?S), are potent vasodilatory agents that maintain mucosal integrity in the gastrointestinal tract. Hybrid molecules generated by coupling a NO or H?S releasing moiety to ASA or tNSAIDs has resulted into new classes of NSAIDs. These agents, the NO-releasing NSAIDs, or CINOD, and the H?S releasing NSAIDs are currently investigated as a potential alternative to tNSAIDs and coxibs. Naproxcinod has been the first, and so far the only, CINOD investigated in clinical trials. These studies have shown a slightly improvement in gastrointestinal tolerability in comparison to naproxen in surrogate endpoints (number of gastric and duodenal ulcers) and a significant reduction in the risk of destabilization of blood pressure control in patients with osteoarthosis taking anti-hypertensive medications in comparison to either naproxen and rofecoxib. The lack of outcome studies, however, has precluded the approval of naproxcinod by the Food and Drug Administration leading to a voluntary withdrawn of an application to the EMEA in May 2011. NSAIDs that releases H?S as a mechanism supporting an intrinsic gastrointestinal and cardiovascular safety are being investigated in preclinical models. Either naproxen and diclofenac hybrids have been reported to cause less gastrointestinal injury than parent NSAIDs. These novel chemical entities exert a variety of beneficial effects in rodent models of cardiovascular and metabolic disorders through a mechanism that might involve the release of H?S and/or by exerting anti-oxidant effects. The beneficial role these mechanisms in clinical settings await a proof-of-concept study.