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 (LTC4, LTD4 and LTE4) are mediators of allergen-induced airway obstruction in asthmatics was tested with the specific receptor antagonist ICI-204,219, in a double-blind, placebo-controlled, randomized, cross-over bronchoprovocation study. On three occasions, cumulative bronchial challenge with specific allergen was performed in 10 males with mild allergic asthma. The first control session established the baseline provocative dose of allergen producing a decrease in forced expiratory volume in one second (FEV1) by 20% (PD20FEV1). The two rechallenges were performed 2 h after oral administration of placebo or 20 mg of ICI-204,219. The allergen 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 PD20 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 injected LTD4 were somewhat inhibited by ICI-204,219, whereas responses to histamine were unaffected. However, the findings suggest that skin testing with LTD4 is unlikely to predict the degree of leukotriene-antagonism in the airways. The findings confirm and extend the indications that cysteinyl-leukotrienes are important mediators of allergen-induced airway obstruction, and that leukotriene-antagonists should be evaluated as a potential new therapy in allergic asthma.
Dahlén
B
B
Dept of Thoracic Medicine, Karolinska Hospital, Stockholm, Sweden.
Zetterström
O
O
Björck
T
T
Dahlén
S E
SE
D000328:Adult; D000485:Allergens; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D004311:Double-Blind Method; D005541:Forced Expiratory Volume; D006801:Humans; D007211:Indoles; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors*; D008297:Male; D048448:Phenylcarbamates; D015203:Reproducibility of Results; D012882:Skin Tests; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*
D000485:Allergens; D007211:Indoles; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds; D017998:Leukotriene D4; C062735:zafirlukast