THE LEUKOTRIENE-ANTAGONIST ICI-204,219 INHIBITS THE EARLY AIRWAY REACTION TO CUMULATIVE BRONCHIAL CHALLENGE WITH ALLERGEN IN ATOPIC ASTHMATICS

The hypothesis that cysteinyl-leukotrienes (LTC(4), LTD(4) and LTE(4)) are mediators of allergen-induced airway obstruction in asthmatics wa s tested with the specific receptor antagonist ICI-204,219, in a doubl e-blind, placebo-controlled, randomized, cross-over bronchoprovocation study. On three occasions, cumulative bronchial challenge with specif ic allergen was performed in 10 males with mild allergic asthma. The f irst control session established the baseline provocative dose of alle rgen producing a decrease in forced expiratory volume in one second (F EV(1)) by 20% (PD(20)FEV(1)). The two rechallenges were performed 2 h after oral administration of placebo or 20 mg of ICI-204,219. The alle rgen dose-response relations were highly reproducible, producing PD20 values at the control session and after placebo treatment which varied by no more than 0.7-1.3 fold (95% confidence interval(95% CI)). After ICI-204,219, the median cumulated allergen dose was 5.5 fold higher, and the group geometric mean PD, was increased 2.5 times. Furthermore, the recovery time after the immediate bronchoconstriction was shorter (40 vs 60 min). The wheal and flare responses to intradermally inject ed LTD, were somewhat inhibited by ICI-204,219, whereas responses to h istamine were unaffected. However, the findings suggest that skin test ing with LTD, is unlikely to predict the degree of leukotriene-antagon ism in the airways. The findings confirm and extend the indications th at cysteinyl-leukotrienes are important mediators of allergen-induced airway obstruction, and that leukotriene-antagonists should be evaluat ed as a potential new therapy in allergic asthma.