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-sulfamoylbenzyl-amino)-4,5,7-trimethylbenzothiazole 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 E6080were 1.11 and 0.96 μM, respectively. AA861 also inhibited both leukotriene C₄ generations with IC₅₀s of 0.79 and 0.76 μM, 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 (R_L 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 R_L 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.

Experimental Monkey Model Sensitized with Mite Antigen

“…Since many mite-allergic patients react to Der f 2 allergens, the 4 monkeys positive for both rDer f 2 and mite extract should be a good model of house dust mite allergy in humans. Although sensitivity and reactivity to the sensitizing antigen in our monkeys were comparable with that of pollen-sensitized animals in several studies [8,27], monkeys showing a larger histamine release from basophils (60-80%) and a lower provocative concentration for skin reaction ( 0.1 µg/ ml of antigen) in response to Ascaris suum or Japanese cedar allergens were reported [28,29]. Additional immunization of our monkeys may achieve a stronger sensitization to mite antigens.…”