PHARMACOLOGICAL STUDIES ON OXATOMIDE (KW-4354) .7. ANTAGONISTIC EFFECTS ON CHEMICAL MEDIATORS

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Abstract
The effects of oxatomide, an anti-allergic drug, on the actions of chemical mediators were investigated in guinea pigs, rats and cats; and the following results were obtained. Studies on the guinea pig ileum revealed oxatomide to be a potent antagonist of histamine with a dual type of action, being competitive at low doses and noncompetitive at higher doses. Oxatomide at concentrations of 0.1 .mu.M or higher inhibited the contractile responses evoked by crude SRS-A [slow reacting substance of anaphylaxis] from sensitized guinea pig lung. Oxatomide (0.1 to 10 .mu.M) did not inhibit the chronotropic effect of histamine in guinea pig atrium. In anesthetized guinea pigs, serotonin-induced bronchoconstriction was anatagonized by oxatomide (0.1 to 1 mg/kg, i.v.) as effectively as histamine-induced bronchoconstriction. Oxatomide (up to 1 mg/kg, i.v.) did not inhibt acetylcholine-induced or arachidonic acid-induced bronchoconstriction. Oxatomide orally 5-30 mg/kg markedly inhibited the increased vascular permeability by histamine, serotonin and bradykinin in rats. Oxatomide .gtoreq. 0.03 mg/kg i.v. also prevented the contraction of the nictitating membrane induced by serotonin in cats. Oxatomide (0.3 and 1 .mu.M) competitively inhibited the Ca2+-induced contracture of fully-depolarized taenia coli of guinea pigs. Oxatomide appears to have potent antagonistic activities on the actions of various chemical mediators. These properties of oxatomide may contribute to its anti-allergic activity.