INCREASED URINARY-EXCRETION OF LTE4 AFTER EXERCISE AND ATTENUATION OFEXERCISE-INDUCED BRONCHOSPASM BY MONTELUKAST, A CYSTEINYL LEUKOTRIENERECEPTOR ANTAGONIST

Background - A study was undertaken to determine whether montelukast, a new potent cysteinyl leukotriene receptor antagonist, attenuates exe rcise-induced bronchoconstriction. The relationship between the urinar y excretion of LTE4 and exercise-induced bronchoconstriction was also investigated. Methods - Nineteen non-smoking asthmatic patients with a forced expiratory volume in one second (FEV1) of greater than or equa l to 65% of the predicted value and a reproducible fall in FEV1 after exercise of at least 20% were enrolled. Subjects received placebo and montelukast 100 mg once daily in the evening or 50 mg twice daily, eac h for two days, in a three-period, randomised, double blind, crossover design. In the evening, approximately 20-24 hours after the once dail y dose or 12 hours after the twice daily dose, a standardised exercise challenge was performed. Data from 14 patients were available for com plete analysis. Results - The mean (SD) maximal percentage decrease in FEV1 after exercise was 29.6 (16.0), 17.1 (8.2), and 14.0 (9.4) for p lacebo, once daily, and twice daily regimens, respectively. The mean ( 95% CI) percentage protection was 37 (15 to 59) for the group who rece ived 50 mg twice daily and 50 (31 to 69) for those who received 100 mg once daily. Active treatments were not different from each other. The mean (SD) plasma concentrations of montelukast were higher after the twice daily regimen (1.27 (0.81) mu g/ml) than after the once daily re gimen (0.12 (0.09) mu g/ml); there was no correlation between the perc entage protection against exercise-induced bronchoconstriction and pla sma concentrations. After exercise urinary excretion of LTE4 increased significantly during placebo treatment (from 34.3 to 73.7 pg/mg creat inine; p<0.05) but did not correlate with the extent of exercise-induc ed bronchoconstriction. Conclusions - Montelukast protects similarly a gainst exercise-induced bronchoconstriction between plasma concentrati ons of 0.12 and 1.27 mu g/ml. The increase in the urinary excretion of LTE4 after exercise and the protection from exercise-induced bronchoc onstriction with a cysteinyl leukotriene receptor antagonist provide f urther evidence of the role of leukotrienes in the pathogenesis of exe rcise-induced bronchoconstriction.