NSAID-Induced Gastrointestinal Damage and the Design of GI-Sparing NSAIDs

抄録

The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to cause ulceration and bleeding throughout the gastrointestinal (GI) tract is well established. The development of selective cyclooxygenase (COX)-2 inhibitors has not had the beneficial impact that was claimed. Moreover, drugs developed to reduce NSAID-gastropathy, such as proton pump inhibitors and histamine H-2 receptor antagonists, have beneficial effects in the upper GI tract, but markedly worsen NSAID-induced damage in the lower GI tract. The mechanisms underlying the latter detrimental effects are become well understood, and progress is being made in developing NSAIDs that are safer in the lower intestine.

One of the approaches to solving the NSAID-gastroenteropathy problem is to covalently link NSAIDs to a hydrogen sulfide (H2S)-releasing moiety. H2S is a naturally occurring gaseous mediator that contributes significantly to maintenance of GI mucosal integrity. Suppression of endogenous H2S production renders the GI mucosa more susceptible to injury, while administration of H2S donors has significant beneficial effects: improved ulcer healing and resolution of inflammation. H2S-NSAIDs, such as ATB-346 (an H2S-releasing derivative of naproxen) have been shown to exert potent anti-inflammatory effects without producing significant GI damage and bleeding. ATB-346 has now progressed to Phase 2 clinical trials. One trial has been completed that demonstrated markedly increased anti-inflammatory/analgesic potency as compared to naproxen. A second Phase 2 trial is in progress which is examining the relative GI safety of ATB-346 versus naproxen (endoscopic detection of GI damage and bleeding). Results of that trial will be available at the time of this presentation.