DOSE-RELATED PROTECTION OF EXERCISE BRONCHOCONSTRICTION BY MONTELUKAST, A CYSTEINYL LEUKOTRIENE-RECEPTOR ANTAGONIST, AT THE END OF A ONCE-DAILY DOSING INTERVAL

The dose-related protective effects of montelukast, a potent and selec tive cysteinyl leukotriene-receptor antagonist, against exercise-induc ed bronchoconstriction were investigated in a five-period, randomized, incomplete-block, crossover study with montelukast (0.4, 2, 10, 50 mg ) and placebo. The study subjects were 27 nonsmoking, healthy stable p atients with asthma (mean forced expiratory volume in 1 second [FEV1], 82.0% predicted) who demonstrated a a greater than or equal to 20% de crease in FEV1 while beta-agonist was withheld for 6 hours before trea dmill exercise. The standard exercise challenge was performed 20 to 24 hours, and again 32 to 36 hours, after the second of two once-daily d oses. The effect of oral montelukast on exercise was measured by the a rea above the postexercise percentage decrease in FEV1 versus time cur ve from 0 to 60 minutes [AUC(0-60)], the maximal percentage decrease i n FEV1 after exercise, and time after maximal decrease to recovery of FEV1, to within 5% of the preexercise baseline. Twenty to 24 hours aft er administration, montelukast caused dose-related protection, while p roviding similar protection against exercise-induced bronchoconstricti on at the two highest doses. The AUC(0-60) values (mean +/-SD) were 63 7 +/- 898, 715 +/- 870, 988 +/- 1147, and 927 +/- 968 min % for 50, 10 , 2, and 0.4 mg montelukast, respectively, and 1193 +/- 1097 min % for placebo (p = 0.003). No important clinical effect was present 36 hour s after dosing. Montelukast was generally well tolerated at all dose l evels. In conclusion, montelukast caused dose-related protection again st exercise-induced bronchoconstriction at the end of a once-daily dos ing interval. Protection against exercise-induced bronchoconstriction can be used to determine appropriate dose selection.