CI-959, A NEW, POTENTIAL ANTIALLERGIC DRUG, INHIBITS MEDIATOR RELEASE FROM LUNG AND CONTRACTIONS OF HUMAN AIRWAYS INVITRO

Many symptoms of the immediate allergic response can be attributed to the synthesis/release and subsequent actions of histamine and metabolic products of arachidonic acid oxidation. CI-959 [5-methoxy-3-(1-methylethoxy)-N-1H-tetrazole-5-yl-benzo(b)thiophene-2-carboxamide], a new, potential antiallergic drug, inhibited the release of histamine, immunoreactive sulfidopeptide leukotrienes C4, D4 and E4 and immunoreactive thromboxane B2 from immunologically activated guinea-pig and human lung cells in vitro. The IC50S of CI-959 using guinea-pig lung were: histamine, 0.8 +/- 1.4-mu-M; leukotriene, 0.7 +/- 1.6-mu-M and thromboxane, 9.6 +/- 3.3-mu-M. Using human lung the IC50S were: 2.3 +/- 1.3-mu-M for histamine; 0.3 +/- 5.1-mu-M for leukotriene, and 0.3 +/- 2.6-mu-M for thromboxane. CI-959 caused a concentration-dependent inhibition of anti-IgE-induced contractions of human bronchial muscle. Mean percent inhibitions were 45, 65 and 96 at 1, 3 and 10-mu-M, respectively. Cromolyn, 10-mu-M, inhibited bronchial contractions only 42%. The ability of CI-959 to inhibit these immunologically induced contractions indicates that the release of all mediators responsible for bronchoconstriction was effectively inhibited. These data suggest that CI-959 may be effective in preventing the development of symptoms directly related to inflammatory mediator release in a variety of allergic and inflammatory states.