Gastrointestinal safety and anti-inflammatory effects of a hydrogensulfide-releasing diclofenac derivative in the rat.

BACKGROUND & AIMS: Gastrointestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remains a significant clinical problem. Hydrogen makes an important contribution to mucosal defense, and NSAIDs can suppress its synthesis. In this study, we evaluated the gastrointestinal safety and anti-inflammatory effects of a novel "HS-NSAID" (ATB-337) that consists of diclofenac linked to a hydrogen sulfide-releasing moiety. METHODS: The gastrointestinal injury-inducing effects of single or repeated administration of diclofenac versus ATB-337 were compared in rats, as were their effects on prostaglandin synthesis and cyclooxygenase-1 and -2 activities. The ability of these drugs to reduce carrageenan-induced paw edema and to elicit leukocyte adherence to the vascular endothelium (intravital microscopy) were also examined in rats. RESULTS: Diclofenac (10-50 micromol/kg) dose-dependently damaged the stomach, while ATB-337 did not. Repeated administration of diclofenac caused extensive small intestinal damage and reduced hematocrit by 50%. ATB-337 induced >90% less intestinal damage and had no effect on hematocrit. Diclofenac, but not ATB-337, elevated gastric granulocyte infiltration and expression of tumor necrosis factor alpha, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1. ATB-337 inhibited cycloxygenase-1 and cyclooxygenase-2 activity as effectively as diclofenac. ATB-337 did not induce leukocyte adherence, whereas diclofenac did, and was more potent at reducing paw edema. CONCLUSIONS: An HS-NSAID spares the gastric mucosa of injury despite markedly suppressing prostaglandin synthesis. This effect may be related to hydrogen sulfide-mediated inhibition of tumor necrosis factor-alpha expression and of the leukocyte adherence to vascular endothelium normally induced by cyclooxygenase inhibitors.