CI-959, a new, potential antiallergic drug, inhibits mediator release from lung and contractions of human airways in vitro.
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 microM; leukotriene, 0.7 +/- 1.6 microM and thromboxane, 9.6 +/- 3.3 microM. Using human lung the IC50s were: 2.3 +/- 1.3 microM for histamine; 0.3 +/- 5.1 microM for leukotriene, and 0.3 +/- 2.6 microM 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 microM, respectively. Cromolyn, 10 microM, 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.
Adolphson
R L
RL
Department of Experimental Therapy, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Mich.
Schellenberg
R R
RR
Thueson
D O
DO
Conroy
M C
MC
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D015289:Leukotrienes / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D013931:Thromboxanes / Q000378:metabolism
D006633:Histamine Antagonists; D015289:Leukotrienes; D013777:Tetrazoles; D013876:Thiophenes; D013931:Thromboxanes; C061662:CI 959; D007073:Immunoglobulin E