Trends in development of gi-safe anti-inflammatory drugs

Abstract

Despite the introduction of anti-inflammatory drugs that selectively inhibit cyclo-oxygenase-2 (COX-2), and potent inhibitors of gastric acid secretion, the gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs) remain a significant clinical problem. Combined use of antisecretory drugs and COX-2 inhibitors is helpful to limit the damage in the proximal gastrointestinal tract (stomach and duodenum), but it increases the risk of injury of small intestine and colon. It was proven that proton pump inhibitors and H2 receptor antagonists significantly worsen NSAID-induced small intestinal damage and microbiota balance. Nowadays, there is no proven effective preventative or curative treatment for NSAID-induced enteropathy. The new strategy of gastrointestinal protection is based on the discovery of endogenous cytoprotective molecules such as hydrogen sulfide (H₂S). H2S is a gaseous mediator that produces strong cytoprotective and antioxidant effect on the gastrointestinal tract. The role of H₂S in promoting mucosal integrity, healing of tissue injury and resolution of inflammation has been well documented. In addition, H₂S stimulates productions of other cytoprotective molecules including prostaglandins, carbon monoxide and nitric oxide. Nowadays, the new generation of H₂S-releasing non-steroidal anti-inflammatory drugs is developed and tested in clinical trials. H₂S-NSAIDs possess enhanced anti-inflammatory activity and high gastrointestinal safety.