The leukotriene-antagonist ICI-204,219 inhibits the early airway reaction to cumulative bronchial challenge with allergen in atopic asthmatics

Abstract

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.

Effect of azelastine, montelukast, and their combination on allergen-induced bronchoconstriction in asthma

“…Other studies found azelastine to attenuate bronchoconstriction by 24-37 % during EAR and by 36-100 % during LAR [10,11]. Similarly, montelukast, when given alone, is known to protect against allergen-induced responses in asthma [13][14][15][16]. For example, pre-treatment with 10 mg montelukast, given 36 and 12 hours before and 12 hours after provocation with house dust mite, significantly reduced EAR and LAR between 0-3 and 3-8 hours, respectively [16].…”

“…Similarly, anti-leukotrienes, such as zafirlukast and montelukast, afford protection against allergen-induced bronchoconstriction [13][14][15][16]. As the protection is not complete, ranging from 50 to 75%, the question is raised whether the combination with an anti-histamine can further attenuate allergen responses.…”

The allergen bronchoprovocation model: an important tool for the investigation of new asthma anti‐inflammatory therapies

“…However, when these agents are used prior to allergen challenge, it appears that all aspects of the challenge including the LAR-induced AHR and induced eosinophil infiltrate can be suppressed (97)(98)(99)(100). Comparative studies show that the suppression, while statistically and clinically significant, is not as great in magnitude as that achieved with ICSs (101,102).…”

Leukotriene receptor antagonists and biosynthesis inhibitors: potential breakthrough in asthma therapy

“…ICI 204,219 also inhibited airway hyperresponsiveness to histamine at 6 h after allergen challenge [86]. ICI 204,219 inhibited the airway response to cumulative allergen challenge by 5.5 fold increase in allergen dose, associated with a shorter recovery time [89]. When administered by inhalation, ICI 204,219 (1.6 mg) reduced the early but not the late asthmatic response [90].…”