title: Dose-related protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval.
abstract: 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 > or = 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. % 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 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.
authors.affiliation: AAAA Medical Research Group, Salt Lake City, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Bronsky
authors.forename: J P
authors.initials: JP
authors.lastname: Kemp
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Guerreiro
authors.forename: T F
authors.initials: TF
authors.lastname: Reiss
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology*; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D015444:Exercise; D006801:Humans; D008875:Middle Aged; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D018102:Receptors, Leukotriene B4 / Q000187:drug effects*; D013440:Sulfides
chemical_list: D000085:Acetates; D003521:Cyclopropanes; D011804:Quinolines; D018102:Receptors, Leukotriene B4; D013440:Sulfides; C093875:montelukast