title: Inhibition of IgE-mediated leukotriene generation and bronchoconstriction in primates with a new 5-lipoxygenase inhibitor, E6080.
abstract: The inhibitory effects of a novel compound, 6-hydroxy-2-(4-sulfamoylbenzylamino)-4,5,7-trimethylbenzothiazo le hydrochloride (E6080) on IgE-mediated reactions in vitro and in vivo were determined in rhesus monkeys. E6080 inhibited both antigen- and anti-human IgE-induced leukotriene C4 generations from lung fragments at similar concentrations: the IC50s of E6080 were 1.11 and 0.96 microM, respectively. AA861 also inhibited both leukotriene C4 generations with IC50s of 0.79 and 0.76 microM, respectively. All 9 monkeys demonstrating positive cutaneous reactivity against Ascaris antigen at < 10(-7) g protein/0.1 ml showed reproducible bronchoconstriction upon aerosolized antigen challenge, but 5 monkeys demonstrating weak or no reactivity to the antigen at levels > 10(-5) g protein/0.1 ml showed no significant bronchoconstriction. The high responder monkeys showed a marked increase in lung resistance (RL 335.3 +/- 85.3%, n = 11) and a decrease in dynamic lung compliance (67.7 +/- 4.2%, n = 11) after antigen challenge following pretreatment with diphenhydramine. These pulmonary changes lasted for more than 30 min. E6080 at oral doses of 3 and 10 mg/kg showed dose-dependent inhibition of both pulmonary changes. Ten milligrams per kilogram of E6080, administered 1.5 h prior to antigen challenge, significantly inhibited the changes in both parameters, while 3 mg/kg showed significant inhibition of only the RL change. These results demonstrate that E6080 inhibited immunologically stimulated leukotriene production in the lung, resulting in inhibition of the antigen-induced airway response in primates.
authors.affiliation: Department of Pharmacology, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Katayama
authors.forename: Y
authors.initials: Y
authors.lastname: Sakuma
authors.forename: S
authors.initials: S
authors.lastname: Abe
authors.forename: H
authors.initials: H
authors.lastname: Tsunoda
authors.forename: I
authors.initials: I
authors.lastname: Yamatsu
authors.forename: K
authors.initials: K
authors.lastname: Katayama
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D017165:Ascaris suum / Q000276:immunology; D001249:Asthma / Q000188:drug therapy; D016084:Bronchoconstriction / Q000187:drug effects*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006967:Hypersensitivity / Q000188:drug therapy / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000276:immunology; D008253:Macaca mulatta; D013189:SRS-A / Q000096:biosynthesis*; D012882:Skin Tests; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000941:Antigens; D016859:Lipoxygenase Inhibitors; D013189:SRS-A; D013844:Thiazoles; C064507:E 6080; D007073:Immunoglobulin E