Prevention of Nonsteroidal Anti-Inflammatory Drug-Induced Ulcer: Looking to the Future

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.