Protection against aspirin-induced human gastric mucosal injury by bosentan, a new endothelin-1 receptor antagonist

Background: Gastric ulceration induced by aspirin and by non-steroidal anti -inflammatory drugs (NSAIDs) is a major clinical problem, The mechanism of injury is unclear, There is evidence that NSAID-induced injury may cause en dothelin activation. Endothelin-induced vasoconstriction has been shown to be capable of causing gastric ulceration, Aim: To investigate whether acute gastroduodenal injury induced in humans b y aspirin can be prevented by the endothelin-1 antagonist, bosentan, Method s: Eighteen healthy volunteers each received 5 x 900 mg aspirin every 12 h on three separate occasions (with either placebo, bosentan 700 mg or misopr ostol 400 mg), Treatment order was randomized by Latin square design. Subje cts were endoscoped and erosions counted before and 90 min after the first and last dose of aspirin. Plasma concentrations of bosentan were measured u p to 5 h post-dose, Results: There was a significant reduction in the mean number of erosions i n the aspirin plus bosentan and aspirin plus misoprostol groups after the f irst dose of aspirin, compared with controls (aspirin plus placebo) (P < 0. 05). This was not sustained after the fifth dose of aspirin in the aspirin plus placebo and aspirin plus bosentan groups, but was still present in the aspirin plus misoprostol group, The mean plasma concentration of bosentan measured 3.5 h post-dose fell from 4510 (95% CI: 2791-6230) ng/mL after the Ist dose to 2508 (95% CI: 1733-3283) ng/mL after the 5th dose (P = 0.02). Conclusion: Endothelin receptor antagonism by bosentan can protect the gast ric mucosa against aspirin damage. After five doses, bosentan levels fell, possibly because of enzyme induction, and protection was no longer evident. Further investigation is needed to assess whether higher doses would be ef fective.