The Protective Effect of Inhaled Leukotriene D4Receptor Antagonist ICI 204,219 against Exercise-induced Asthma

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Abstract
Leukotrienes are potent bronchoconstrictors, and they are present in the airways of asthmatic subjects. Leukotriene receptor antagonists given intravenously or orally prior to exercise attenuate the bronchoconstrictor response to exercise in asthma. We have determined the prophylactic effect of an inhaled leukotriene D4-receptor antagonist ICI 204,219 (400 µg) against exercise-induced bronchoconstriction in nine asthmatic subjects in a randomized, placebo-controlled, double-blind, cross-over study. Exercise challenge was performed on a cycle ergometer at a predetermined work load that was kept constant throughout the study. A “screening” and a “run-in” exercise test were performed to determine the reproducibility of the challenge. ICI 204,219 or matched placebo was given 30 min prior to exercise challenge, and bronchoconstriction after exercise was assessed as change in FEV1 over 30 min. There was no significant effect on baseline airway caliber at 20 min after inhalation of ICI 204,219. ICI 204,219 significantly inhibited the bronchoconstrictor response to exercise. The mean maximal percentage fall in FEV1 after exercise was 14.5% as compared with the placebo of 30.2% (p = 0.043), and the area under curve (AUC) for FEV1 during the first 30 min (AUC0–30) after exercise was significantly reduced (p = 0.043). The time for recovery of FEV1 to 5% of baseline was also significantly shorter with ICI 204,219 than with placebo (median, 20 versus 60 min; p = 0.018). The protection against exercise-induced bronchoconstriction provided by ICI 204,219 was variable, with almost complete inhibition of the response in three subjects, partial inhibition in another three subjects, and no protection in three subjects. The study demonstrates that the leukotriene D4-receptor antagonist ICI 204,219 is clinically effective in providing prophylaxis against exercise-induced asthma.