Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for treatment of pain and inflammation, despite their association with gastrointestinal complications, including bleeding and perforation. Inhibition of cyclooxygenases (COXs), is the main mechanism of action of aspirin and NSAIDs. Inhibition of COX-1 derived prostanoids in the stomach represent the underlying mechanism involved in development of gastric and duodenal ulcers in patients taking NSAIDs. Selective COX-2 inhibitors (coxibs) spare the gastrointestinal tract, but their use increases the risk of heart attack and stroke. In addition to prostanoids, two gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H2S) exert protective effects in the gastric mucosa. In rodent model administration of NO donors attenuates gastric injury caused by NSAIDs. This property has been exploited in the development of NO-releasing NSAIDs, also indicated as COX-inhibiting NO-donating drugs (CINODs). NaproCINOD, an NO releasing derivative of naproxen, is a non-selective COX inhibitor. Clinical studies have shown that this agent reduces systemic blood pressure and has better cardiovascular tolerability than coxibs, while causing less gastrointestinal damage than its parent drug. H2S-releasing NSAID derivatives have been recently developed, based on the observed ability of this gaseous mediator to cause vasodilation and to prevent leukocyte adherence. In preclinical settings, H2S-releasing NSAIDs produce less gastric damage as compared to the parent drugs. CINODs represent examples of new anti-inflammatory drugs created through the exploitation of the beneficial effects of endogenous gaseous mediators in the gastrointestinal and cardiovascular systems.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications in the world because of their demonstrated efficacy in reducing pain and inflammation. Musculoskeletal pain affects millions of people of all ages around the world, and it is estimated that each year health care providers write approximately 60 million prescriptions for various forms of NSAIDs in North America, many of which are for the treatment of osteoarthritis in the elderly. Acute or chronic pain limit physical and mental activity, have a major impact on quality of life, and may increase the risk of diseases different from those that cause pain. Treatment of pain is essential to medical clinical practice and should be considered a human right.
Although ancillary mechanisms have been demonstrated, the basic mode of action of aspirin and nonaspirin NSAIDs lies in the inhibition of COX, an enzyme involved in prostaglandin generation. Prostaglandins are produced by the gastric mucosa, exert a “cytoprotective function,” and mediate key mechanisms of what has been termed the “gastric mucosal barrier.” This includes the maintenance of gastric blood flow during exposure to a noxious substance, secretion of bicarbonate and mucus by the surface epithelial cells, and the rapid repair of superficial injury through the process of epithelial restitution.
The COX exists at least in two isoforms, COX-1 and COX-2, with prostaglandins mediating inflammation at the site of the injury generated by COX-2, whereas the prostaglandins involved in protecting the GI tract derive from COX-1. Traditional NSAIDs (tNSAIDs) nonspecifically inhibit both COX-1 and COX-2, and their adverse events in the GI tract are attributed to the inhibition of COX-1-derived prostaglandins.
Indeed, although effective at relieving pain and inflammation, nonselective NSAIDs (ns-NSAIDs) are associated with a significant risk of serious GI adverse events. Long-term NSAID therapy generates adverse GI complications ranging from stomach erosions and submucosal hemorrhages to life-threatening complications, such as bleeding and perforation. The average relative risk (RR) of developing a serious GI complication in patients exposed to NSAIDs, as a group, is five- to six-fold that of those not taking NSAIDs. NSAIDs are the leading cause of bleeding peptic ulcers; when sensitive biochemical assays are used, NSAIDs, including low-dose aspirin, may have been used in more than 90% of patients with bleeding ulcers. It is estimated that peptic ulcer bleeding and perforation occur with a frequency of 1% to 3% per 100-year patient treatment, with a mortality of 6% to 10%. Deaths related to NSAID-induced GI complications have been estimated to be as high as 16,500 per year in the United States. Recent observational data from the Spanish National Health System indicate a much lower frequency of 15.3 deaths per 100,000 NSAID users.
The growing public awareness of GI complications associated with the use of NSAIDs and aspirin has prompted a search for safer alternatives ( Table 1 ). These include adoption of cotherapies with the prostaglandin analog misoprostol or a proton pump inhibitor (PPI) and development of new NSAIDs that carry on a reduced risk of GI damage.
| Drug | Manufacturer | Stage |
|---|---|---|
| Coxibs | Various | On the market |
| Naproxcinod and CINOD | Nicox SA | Phase III |
| Dual COX-LOX inhibitors | Merckle | Phase III a |
| H 2 S-releasing NSAIDs | Antibe Therapeutics, CTG | Preclinical |
| Lipid-conjugated NSAIDs | Preclinical | |
| Coformulation of naproxen with PPI | Astra-Zeneca | Phase III |
In the last decade, several strategies have emerged as state-of-the-art approaches to improve the NSAID safety profile. These are (a) the development of selective inhibitors of the COX-2, the coxibs; (b) the development of new chemical agents obtained by the combination of NO-releasing moieties coupled with aspirins and ns-NSAIDs, the so-called NO-NSAIDs or CINOD; and (c) new formulations of tNSAIDs. The latter approach combines in a single pill a fixed dose of a tNSAID, mostly naproxen, with a fixed dose of a PPI (lansoprazole, omeprazole, and, more recently, esomeprazole).
In addition, we and other researchers have reported in 2007 on the generation of another class of NSAID derivatives, the hydrogen sulfide (H 2 S)-releasing NSAIDs, which exploits the protective effect of H 2 S in the gastric mucosa.
Additional approaches have also been described over the years and are listed in Table 1 .
The present and the future of coxibs
The development of coxibs was grounded on the hypothesis that COX-2 was the source of prostaglandins E 2 and I 2 , which mediate inflammation, and that COX-1 was the source of the same prostaglandins in gastric epithelium, where they afford cytoprotection. Three coxibs—celecoxib, rofecoxib, and valdecoxib—have been approved for use by the Food and Drug Administration (FDA); a fourth, etoricoxib, has been approved by the European regulatory authority, and a fifth, lumiracoxib, has been withdrawn from the market on August 11, 2007, by Australia’s Therapeutic Goods Administration (TGA, the Australian equivalent of the FDA and the European Medicines Agency) due to concerns that it may cause liver failure. According to the TGA, the agency had received eight reports of serious adverse liver reactions to the drug, including two deaths and two liver transplants (see on http://www.tga.gov.au/media/2007/070811-lumiracoxib.htm ). Coxibs are significantly better tolerated than NSAIDs in the GI tract. However, although coxibs produce severe GI complications less frequently than ns-NSAIDs, GI bleeding still develops in approximately 1% patient years. This “residual” damage may be a consequence of the fact that COX-2 is rapidly expressed in response to GI injury and contributes significantly to mucosal defense and repair by generating lipoxins, a lipid mediator involved in gastric adaptation.
Shortly after their introduction into the market, it was clear that coxibs might cause adverse effects in the renal and cardiovascular systems. Rofecoxib and celecoxib suppress the formation of prostacyclin (PGI 2 ) in healthy volunteers (see for a review). Prostaglandin I 2 had previously been shown to be the predominant COX product in endothelium, inhibiting platelet aggregation, causing vasodilatation, and preventing the proliferation of vascular smooth-muscle cells in vitro. Studies in mice and humans have shown that COX-2 is the dominant source of PGI 2 . The individual cardiovascular effects of PGI 2 in vitro contrast with those of thromboxane (TX)A 2 , the major COX-1 product of platelets, which causes platelet aggregation, vasoconstriction, and vascular proliferation. Whereas aspirin and tNSAIDs inhibit both TXA 2 and PGI 2 , the coxibs leave TXA 2 generation unaffected, reflecting the absence of COX-2 in platelets. Thus, a unique mechanism, that is, depression of PGI 2 formation, might predispose patients receiving coxibs to an exaggerated thrombotic response perhaps through the rupture of an atherosclerotic plaque.
Rofecoxib was then withdrawn from the market by Merck, following the premature cessation of the Adenomatous Polyp Prevention on Vioxx study, which was designed to determine the drug’s effect on benign sporadic colonic adenomas. This study demonstrated a significant increase by a factor of 3.9 in the incidence of serious thromboembolic adverse events in the group receiving 25 mg of rofecoxib per day compared with the placebo group. Blood pressure was elevated in patients in the rofecoxib group early in the course of the study, but the incidence of myocardial infarction and thrombotic stroke in the two groups began to diverge progressively after a year or more of treatment.
Celecoxib, rofecoxib, and valdecoxib were approved by the FDA on the basis of trials that typically lasted 3 to 6 months and in which the end point was a clinical surrogate—endoscopically visualized gastric ulceration. After the drugs were approved, the results of two studies of GI outcomes were reported: the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial and the Celecoxib Long-Term Arthritis Safety Study (CLASS) trial. In the VIGOR trial, the rate of serious GI events among those receiving rofecoxib was half that among those receiving a tNSAID, naproxen—2% compared with 4%. However, a significant increase by a factor of 5 in the incidence of myocardial infarction was observed. Although this increase was a source of concern, it was argued that the small number of events reflected the play of chance or that naproxen was actually cardioprotective. However, epidemiologic studies of the possible cardioprotection afforded by naproxen have proved inconclusive.
In the CLASS trial, celecoxib was compared with ibuprofen or diclofenac. In the original report, celecoxib appeared to have a more favorable GI -side-effect profile, and no increase in cardiovascular risk was revealed. However, this report contained only half the data (from only 6 months of a 1-year study): when the full data set became available, it was clear that celecoxib did not differ from the tNSAIDs in its effect on the predefined GI end points. Indeed, the most powerful evidence supporting claims of celecoxib’s superiority over tNSAIDs in terms of GI effects rests on a post hoc analysis of the CLASS data for patients who did not use aspirin. However, a similar retrospective approach to the data also reveals signs of increased cardiovascular risk. The Therapeutic Arthritis Research and Gastrointestinal Event Trial is a large GI -outcome study that compared lumiracoxib with naproxen or ibuprofen. The primary end point was the incidence of serious GI events, which was reduced significantly among patients receiving lumiracoxib. This difference was observed only in patients who were not taking aspirin. Although the trial, much like the CLASS trial, was not powered to detect a difference in the rates of cardiovascular events in nonaspirin users, more such events occurred in the lumiracoxib group than those in the other group (0.26 vs. 0.18 per 100 patient years; hazard ratio, 1.47), although the difference was not significant. Further, in a study of patients undergoing coronary-artery bypass grafting, treatment with parecoxib, a valdecoxib prodrug, was associated with a cluster of cardiovascular events, and the drug was rejected by the FDA. Finally, a series of epidemiologic analyses have also raised questions about the cardiovascular safety of the coxibs. Although the epidemiologic approach has commonly relied on databases of prescriptions and is particularly subject to bias due to the over-the-counter consumption of NSAIDs and aspirin, these studies broadened the context of the available evidence by relating risk to the dose of rofecoxib used.
Lower gastrointestinal safety of coxibs
Increased mucosal permeability and mucosal inflammation are often silent but occur with most tNSAIDs. Anemia, occult blood loss, GI bleeding and perforation, diverticulitis and strictures due to fibrous diaphragms may also occur, although the frequency of these events has not been well studied. Indirect data from outcome trials estimate that serious GI events from the lower GI tract may represent 25% to 50% of all GI complications associated with NSAIDs. Coxibs have a better safety profile in the lower GI tract when compared with that of tNSAIDs, although the data are still scarce. Compared with classic NSAIDs, coxibs do not increase mucosal permeability and inflammation or are linked to occult bleeding. Studies with video capsule endoscopy in healthy volunteers have shown that the incidence of small-bowel lesions with naproxen plus omeprazole is higher than that observed with either celecoxib alone. Data obtained from different studies have shown that celecoxib is associated with risk reduction and a lower proportion of anemia than tNSAIDs. A post hoc analysis of the VIGOR trial revealed a lower incidence of serious lower GI events with rofecoxib when compared with that with naproxen. Consistent results were reported from a meta-analysis of lower GI events favoring rofecoxib/etoricoxib over ns-NSAIDs (RR, 0.55; 95% CI, 0.36–0.84). No clinical trial has specifically evaluated the lower GI tract adverse effects with NSAIDs or coxibs.
Lower gastrointestinal safety of coxibs
Increased mucosal permeability and mucosal inflammation are often silent but occur with most tNSAIDs. Anemia, occult blood loss, GI bleeding and perforation, diverticulitis and strictures due to fibrous diaphragms may also occur, although the frequency of these events has not been well studied. Indirect data from outcome trials estimate that serious GI events from the lower GI tract may represent 25% to 50% of all GI complications associated with NSAIDs. Coxibs have a better safety profile in the lower GI tract when compared with that of tNSAIDs, although the data are still scarce. Compared with classic NSAIDs, coxibs do not increase mucosal permeability and inflammation or are linked to occult bleeding. Studies with video capsule endoscopy in healthy volunteers have shown that the incidence of small-bowel lesions with naproxen plus omeprazole is higher than that observed with either celecoxib alone. Data obtained from different studies have shown that celecoxib is associated with risk reduction and a lower proportion of anemia than tNSAIDs. A post hoc analysis of the VIGOR trial revealed a lower incidence of serious lower GI events with rofecoxib when compared with that with naproxen. Consistent results were reported from a meta-analysis of lower GI events favoring rofecoxib/etoricoxib over ns-NSAIDs (RR, 0.55; 95% CI, 0.36–0.84). No clinical trial has specifically evaluated the lower GI tract adverse effects with NSAIDs or coxibs.
Aspirin comedication
Both the CLASS and TARGET studies have demonstrated that coxibs lose their protective effects on the GI tract when administered to patients taking aspirin. We have shown that the cause of this detrimental interaction might be the suppression of the generation of a class of lipid mediators produced by the interaction of aspirin with the COX-2 isoenzyme and named the aspirin-triggered lipoxin (ATL). ATLs are generated in the gastric mucosa in response to aspirin and appear to be involved in gastric adaptation to aspirin. Inhibition of COX-2 activity by ns-NSAIDs and coxibs interferes with the adaptation of the gastric mucosa to aspirin and exacerbates the mucosal injury. A similar mechanism has been demonstrated to take part in the human stomach.
Nitric oxide, hydrogen sulfide and Nonsteroidal anti-inflammatory drugs
NO is now recognized as one of the most important of such mediators in the human body, mediating blood flow, neurotransmission, immune reactions, and muscle contraction ( Table 2 ). The importance of NO in this regard was recognized by the award of a Nobel Prize to Furchgott, Murad and Ignarro in 1998. H 2 S is the latest gas to be recognized as an important endogenous mediator. In the context of the digestive system, roles for H 2 S in the maintenance of mucosal integrity, regulation of blood flow, and modulation of inflammatory reactions are rapidly emerging. Since the early 1990s, a body of evidence supports the notion that acute gastric injury in animal models of NSAID gastropathy is a neutrophil-dependent process. Rats that had been immunodepleted of their circulating neutrophils develop very little gastric damage when given NSAIDs at doses that, in normal rats, caused widespread hemorrhagic lesions. Moreover, interfering with the adherence of neutrophils to the vascular endothelium, through the administration of monoclonal antibodies directed against leukocyte or endothelial adhesion molecules, also greatly reduced the severity of NSAID-induced gastric damage. We were the first in the middle of the 1990s to demonstrate that NSAIDs trigger leukocyte adherence to the vascular endothelium though a mechanism that requires the release of tumor necrosis factor alpha (TNF-α), and administration of TNF-α antagonists or inhibitors protects against the gastric toxicity induced by ns-NSAIDs. In the same period of time, NO was demonstrated to be an important modulator of adhesive interactions between leukocytes and the vascular endothelium (reviewed in 12 ). This raised the possibility that the protective effects of NO that had been observed in experimental models of gastric damage might be in part due to its ability to inhibit leukocyte-endothelial adhesion. This lead to the generation by Del Soldato of a new class of anti-inflammatory drugs, the CINOD, that exploit the functional role of NO in gastric protection.
| Prostaglandin E 2 | Nitric Oxide (NO) | Hydrogen Sulfide (H 2 S) | |
|---|---|---|---|
| Expression of key enzymes in the stomach | COX-1 and COX-2 a | eNOS and iNOS b | CSE and CBS c |
| Mucosal blood flow | Increased | Increased | Increased |
| Bicarbonate production | Increased | Increased | Unknown |
| Mucus secretion | Increased | Increased | Unknown |
| Cytoprotection | Yes | Yes | Yes |
| Regulation of mucosal barrier integrity | Yes | Unknown | Unknown |
| Epithelial cell proliferation | Yes | No | Yes |
b Endothelial NO synthase (eNOS) and inducible NO synthase (iNOS).
c Cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS).
COX-inhibiting NO-donating drug
Cox-inhibiting no-donating drugs (CINODs) ( Fig. 1 and Table 3 ) were developed exploiting the concept that NO and/or NO-derived compounds endorsed by NO biological activity, released in the body circulation and gastric mucosa, would enhance the mucosal blood flow and reduce leukocyte-endothelial cell adherence into the gastric microcirculation. Aspirin and several ns-NSAIDs, including naproxen, diclofenac, and flurbiprofen (see Table 3 ), have since then been coupled to a nitroxybutyl or a nitrosothiol moiety to generate new chemical entities that, while maintaining the COX-inhibiting activity of parental NSAID, release a discrete amount of NO. On the other hand, CINODs show a substantially different pharmacokinetic in comparison with parent NSAIDs, including a delayed peak of plasma concentration, which could be explained by lower permeability of biological barriers to these agents and/or slower dissolution of the CINOD formulation. The full pharmacokinetic of CINODs is not completely understood yet. It is still unclear whether CINODs are absorbed intact or are metabolized by GI fluids, the GI wall, or during their first pass through the liver. The site of NO formation is also only partially known. This is an important issue, since the exact amount and the site where NO is released are of relevance for the biological effects. Although, it is unlikely that the different kinetic explains the reduced GI toxicity of CINODs, it may account for the absent hypotensive effect of these compounds with respect to an equimolecular dose of NO donors.
| Drug | Company | Status |
|---|---|---|
| NO-aspirin (NCX-4016) | NicOx a | Program abandoned |
| NO-diclofenac | NicOx | Preclinical |
| NO-naproxen“NaproCINOD” | NicOx | Two phase III trials ongoing b |
| NO-ketoprofen | NicOx | Preclinical |
| NO-ibuprofen | NicOx | Preclinical |
| S-NO-diclofenac | Nitromed | Pre-clinical |
| Selective COX-2 inhibitors: NO-rofecoxib | Nitromed/Merck Sharp and Dohme | Phase II c |
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