Effects of montelukast (MK-0476), a new potent cysteinyl leukotriene (LTD 4) receptor antagonist, in patients with chronic asthma,☆☆,,★★

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Abstract

BACKGROUND: Cysteinyl leukotrienes mediate signs and symptoms of asthma. In a double-blind, placebo-controlled, crossover study, a new potent and specific cysteinyl leukotriene (LTD 4) receptor antagonist, montelukast (MK-0476), was evaluated for tolerability and clinical efficacy in patients with chronic asthma (receiving and not receiving inhaled corticosteroids). METHODS: Twenty-nine nonsmoking patients with asthma (15 treated concomitantly with inhaled corticosteroids) with FEV 1 percent predicted values between 50% to 80% received MK-0476, 200 mg, or placebo three times daily for 10 days (31 doses) in a random, crossover manner, after a 2-week, open, baseline period. Comparisons in FEV 1 (mean percent change from baseline after the first and last dose), mean daily daytime asthma and nocturnal awakening scores, and mean daily β-agonist use were made between treatment periods. RESULTS: Montelukast, compared with placebo, caused improvements in FEV 1 (mean percentage point difference of the percentage change from baseline) 3 and 4 hours after dosing on day 1 (hour 3, 9.0%; 95% confidence interval [CI] 0.53, 18.72; hour four, 10.9%; 95% CI −0.25, 20.20) and day 11 (hour 3, 14.0%; 95% CI 0.76, 31.43; hour 4, 13.4%; 95% CI 1.24, 28.83). Reductions were observed in mean daily β-agonist use (1.0 puff/day [95% CI −1.61, −0.26]), mean daytime symptom scores, and nocturnal awakenings over the 10 day treatment period. There were no important differences between the groups receiving and those not receiving inhaled corticosteroids. Montelukast was well tolerated with no serious clinical adverse events reported. CONCLUSIONS: In this study Montelukast, 200 mg, administered three times daily for 10 days, compared with placebo, was generally well tolerated and resulted in significant improvement in chronic asthma, irrespective of the presence of inhaled corticosteroids. (J ALLERGY CLIN IMMUNOL 1996;98:528-34.)

Section snippets

Patients

Nonsmoking (at least 1 year, having smoked no more than 5 pack-years) male and female (without childbearing potential) patients between 18 and 55 years of age (within 15% of ideal body weight) with a history of recurring symptoms associated with asthma including dyspnea, wheezing, or cough requiring treatment for at least 1 year were eligible for study participation. Patients admitted to the study were required to have reversible airway obstruction (defined as an FEV 1 between 50% and 80% of

Patient profile

Twenty-nine asthmatic (23 male and 6 female) patients were enrolled in the trial (Table I). Twenty-eight patients completed the first treatment period (one patient discontinued for personal reasons soon after the start of the period). Twenty-seven patients entered (one patient discontinued between treatment periods because of an upper respiratory tract infection) and 25 completed the second treatment period (two patients discontinued during the second treatment period because of a rash and an

DISCUSSION

This first multiple-dose trial of montelukast (200 mg three times daily for 10 days) in patients with chronic asthma demonstrates that this orally active, potent, and selective cysteinyl LT 1 receptor antagonist improves objective and subjective measurements of asthma; compared with placebo, significant improvements in FEV 1 and daytime asthma symptoms/activity scores and a decrease in as-needed β-agonist use were observed. The improvement in the nocturnal awakening score, which favored

Acknowledgements

We thank Ms. Susan Ruffalo for editorial assistance, Ms. Nancy Noonan for study monitoring and data review, and Ms. Judy Evans for typing the manuscript.

References (17)

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From aDepartments of Pulmonary/Immunology and Biostatistics, Merck Research Laboratories, Rahway; bAllergy and Infectious Diseases, Pacific Medical Center, Seattle; cAllergy and Asthma Center, North Dartmouth; dDepartment of Allergy and Immunology, Creighton University School of Medicine, Omaha; and eClinical Research of the Ozarks, Inc., Rolla.

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Supported by a grant from Merck Research Laboratories.

Reprint requests: Theodore F. Reiss, MD, Merck Research Laboratories, P.O. Box 2000, RY 33-648, Rahway, NJ 07065.

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