NSAIDs, coxibs, CINOD and H2S-releasing NSAIDs: What lies beyond the horizon

Nonsteroidal anti-inflammatory drugs are widely prescribed for treatment of pain and inflammation, despite their association with gastrointestinal complications, including bleeding and perforation. Inhibition of cyclo-oxygenases, is the main mechanism of action of aspirin and nonsteroidal anti-inflammatory drugs. Non-selective nonsteroidal anti-inflammatory drugs inhibit cyclo-oxygenase-1 and cyclo-oxygenase-2. Inhibition of cyclo-oxygenase-1 derived prostanoids in the stomach represent the underlying mechanism involved in development of gastric and duodenal ulcers in patients taking nonsteroidal anti-inflammatory drugs. Selective cyclo-oxygenases-2 inhibitor (coxibs) spare cyclo-oxygenase-1 show enhanced safety profile in the gastrointestinal tract, but increase the risk of heart attack and stroke. Spurred by these findings, two coxibs, rofecoxib and valdecoxib, were withdrawn from the market. In addition to prostanoids, two gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H2S) exert protective effects in gastric mucosa. The inhibitory effects of NO on nonsteroidal anti-inflammatory drugs-induced leukocyte adherence have been exploited in the development of NO-releasing nonsteroidal anti-inflammatory drugs, also indicated as cyclo-oxygenase-inhibiting NO-donating drugs. Despite its non-selective profile versus cyclo-oxygenase isoenzymes, naprocyclo-oxygenase-inhibiting NO-donating drugs, the prototype of this class of anti-inflammatory agents, reduces systemic blood pressure and might have enhanced cardiovascular safety than coxibs, while causing less gastrointestinal damage than its parent drug, the naproxen. H2S-releasing nonsteroidal anti-inflammatory drugs derivatives have been recently developed, based on the observed ability of this gaseous mediator to cause vasodilation and to prevent leukocyte adherence. In pre-clinical settings, H2S-releasing nonsteroidal anti-inflammatory drugs produce less gastric damage as compared to the parent drugs. Cyclo-oxygenases-inhibiting NO-donating drugs and H2S-releasing nonsteroidal anti-inflammatory drugs 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.