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The dose-related protective effects of montelukast, a potent and selective cysteinyl leukotriene-receptor antagonist, against exercise-induced 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 patients with asthma (mean forced expiratory volume in 1 second [FEV1], 82.0% predicted) who demonstrated a >=20% decrease in FEV1 while[beta]-agonist was withheld for 6 hours before treadmill exercise. The standard exercise challenge was performed 20 to 24 hours, and again 32 to 36 hours, after the second of two once-daily doses. The effect of oral montelukast on exercise was measured by the area above the postexercise percentage decrease in FEV1 versus time curve from 0 to 60 minutes[AUC(0-60)], the maximal percentage decrease in FEV1 after exercise, and time after maximal decrease to recovery of FEV1 to within 5% of the preexercise baseline. Twenty to 24 hours after administration, montelukast caused dose-related protection, while providing similar protection against exercise-induced bronchoconstriction at the two highest doses. The AUC(0-60) values (mean /- SD) were 637 /- 898, 715 /- 870, 988 /- 1147, and 927 /- 968 min [middle dot] % for 50, 10, 2, and 0.4 mg montelukast, respectively, and 1193 /- 1097 min[middle dot] % for placebo (p = 0.003). No important clinical effect was present 36 hours after dosing. Montelukast was generally well tolerated at all dose levels. In conclusion, montelukast caused dose-related protection against exercise-induced bronchoconstriction at the end of a once-daily dosing interval. Protection against exercise-induced bronchoconstriction can be used to determine appropriate dose selection. (Clin Pharmacol Ther 1997;62:556-61.)

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