A new treatment for NSAID-associated gastrointestinal damage

DESCRIPTION provided by applicant Non steroidal anti inflammatory drugs NSAIDs are among the most widely consumed pharmaceuticals but their prolonged use causes gastric injury and damage to the small intestine Previous work has shown that anandamide an endogenous endocannabinoid substance produced in the gastrointestinal GI mucosa plays an important role in epithelial homeostasis and repair The biological actions of anandamide are terminated by the intracellular enzyme fatty acid amide hydrolase FAAH To explore the role of anandamide in peripheral tissues we have recently developed a novel class of small molecule FAAH inhibitors that suppress anandamide deactivation only in the periphery of the body Previous selectivity safety and pharmacokinetic studies have identified the prototype member of this class a compound called URB as a potential lead candidate for preclinical development We recently discovered that URB suppresses NSAID induced gastric damage in animal models by amplifying a protective feedback mechanism mediated by endogenously produced anandamide These results suggest that URB might offer a transformative approach to prevent and or treat gastric and intestinal damage associated with prolonged NSAID use Our proposal has two primary goals Determine the comparative efficacy of URB in a model of acute NSAID induced gastric damage We will investigate the effects of different oral dosages of URB and compare them to those of two gastroprotectant drugs currently employed in the clinic omeprazole and misoprostol in a standard preclinical model of acute NSAID induced gastropathy using the potent NSAID indomethacin Determine the efficacy of URB in the prevention of chronic NSAID induced gastric and intestinal damage We will examine whether URB can i prevent the gastropathy and enteropathy elicited by chronic indomethacin and ii prevent the gastropathy produced by chronic aspirin These models mimic two distinct settings where the GI protecting effects of URB might find clinical application healing of NSAID associated GI damage in patients continuing NSAID therapy and prevention of peptic ulcers in cardiovascular patients taking low dose aspirin Development of URB will be continued if the compound fulfills at least one of the following criteria i activiy in preventing GI damage produced by acute and chronic indomethacin or ii activity in preventing gastric damage produced by chronic aspirin If either or both of these criteria is met we will apply for STTR Phase funding to move URB to full preclinical development for NSAID gastroenteropathy

PUBLIC HEALTH RELEVANCE Non steroidal anti inflammatory drugs NSAIDs like aspirin and naproxen are among the most widely consumed pharmaceuticals but their prolonged use can produce serious injuries to the stomach and the small intestine Our previous work has shown that anandamide a naturally occurring substance also produced in the gastrointestinal tract may protect these organs from the damage caused by NSAIDs Here we propose to determine whether a highly innovative molecule developed by our lab which blocks anandamide degradation and boosts the actions of this messenger may prevent and or treat the gastrointestinal damage associated with NSAID use in animal models