Mucosal lesions induced in the rat intestinal tract by the anti-inflammatory drug, Wy-41,770, a weak inhibitor of prostaglandin synthesis, contrasted with those from the potent prostaglandin inhibitor, indomethacin

Abstract

The intestinal ulcerogenic activity of the weak prostaglandin synthesis inhibitor drug Wy-41,770 [5H-dibenzo(a,d)-cyclohepten-5-ylidine] was contrasted with the potent synthesis inhibitor, indomethacin, in rats to establish the relationship of inhibition of prostaglandin synthesis to the intestinal damage. Wy-41,770 induced superficial erosions only in the cecum 26 hr after a single oral dose of 250 or 500 mg/kg of the drug, progressing to ulcers after 5 days dosing with ultrastructural evidence of bacteria in the mucosa. Indomethacin (5 or 10 mg/kg po) induced mucosal erosions in the ileum, initially at 26 hr progressing to ulcers after 5 days. Fewer bacteria were seen in the ileal mucosa of indomethacin-treated rats. Both drugs reduced prostaglandin E in those regions of the intestine coincident with the known accumulation of these drugs at sites of mucosal injury. Site-specific intestinal damage from these 2 drugs is associated with inhibition of the synthesis of mucosal-protective prostanoids, followed by pronounced bacterial invasion through the damaged mucosae with consequent appearance of local immuno-inflammatory reactions.