PEPTIC ULCER: PATHOGENESIS, HEALING AND ANTI‐ULCER DRUGS

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Studies were performed in three models of acute gastric mucosal damage (induced by oral ethanol, aspirin and indomethacin) and a model of chronic gastritis (induced by 7 day treatment with iodoacetamide) in rats to establish the role of leukotrienes (LTs) in the pathogenesis of these lesions. The protective effects of highly selective 5-lipoxygenase (5-LO) inhibitors and leukotriene antagonists were thus examined in rats given these ulcerogens. Ethanol (1 mL, p.o.)-induced haemorrhagic lesions were significantly reduced by prior oral administration of the 5-LO inhibitor L-656224 (50 mg/kg), whereas lower doses of this drug were ineffective. Prior treatment with oral doses (5 and 10 mg/kg) of the 5-LO inhibitor L-655224 or the LT antagonists L-649923 or L-660711, failed to affect lesions induced by aspirin (100 mg/kg, p.o.) and indomethacin (400 mg/kg, s.c.), whereas higher doses of all three drugs (50 mg/kg) showed protective effects. Repeated prior dosing up to 5 h with the novel five lipoxygenase activating protein (FLAP) inhibitor, MK886 (50 and 100 mg/kg), reduced the lesions developed by indomethacin (30 mg/kg, s.c.). Twice daily dosing with the 5-LO inhibitor L-656224 (5 mg/kg) or the LT antagonist L-649923 (2 or 5 mg/kg) for 7 days significantly reduced the development of iodoacetamide-induced gastritis during the period of induction of this condition, but higher doses of these inhibitors were not protective. We conclude that 5-LO products partially mediate the production of gastric mucosal lesions induced by damaging agents, which varies according to the ulcer model employed; the limited protective effects of the respective 5-LO inhibitors and LT antagonists depend on their individual pharmacokinetics and their time of dosing.