Leukotrienes are pro-inflammatory mediators which may contribute to tissue, sputum, and blood eosinophilia seen in allergic and inflammatory diseases, including asthma. Montelukast is a cysteinyl leukotriene 1 (CysLT 1 ) receptor antagonist which improves asthma control; the aim of this study was to investigate its effect on induced sputum eosinophils.Montelukast 10 mg (n=19) or placebo (n=21) were administered orally once in the evening for 4 weeks to 40 chronic adult asthmatic patients, aged 19±64 yrs, in a double-blind, randomized, parallel group study. Patients were included if, at prestudy, they had >5% sputum eosinophils, symptomatic asthma with a forced expiratory volume in one second $65% of the predicted value and were being treated only with "as needed" inhaled b 2 -agonists. In addition to sputum eosinophils, blood eosinophils and clinical endpoints were also assessed.Four weeks of montelukast treatment decreased sputum eosinophils from 7.5% to 3.9% (3.6% decrease, 95% confidence interval (CI) -16.6±0.4). In contrast, placebo treatment was associated with an increase in sputum eosinophils from 14.5% to 17.9% (3.4% increase, 95% CI -3.5±9.8). The least squares mean difference between groups (-11.3%, 95% CI -21.1± -1.4) was significant (p=0.026). Compared with placebo, montelukast significantly reduced blood eosinophils (p=0.009), asthma symptoms (p=0.001) and b 2 -agonist use (p<0.001) while significantly increasing morning peak expiratory flow (p=0.001). Montelukast was generally well tolerated in this study, with a safety profile similar to the placebo.These results demonstrate that montelukast decreases airway eosinophilic inflammation in addition to improving clinical parameters. Its efficacy in the treatment of chronic asthma may be due, in part, to the effect on airway inflammation.

aaThe cysteinyl leukotrienes (LTC 4 , D 4 , E 4 ) are known to play an important role in the pathobiology of asthma. These compounds, derived from arachidonic acid via the 5-lipoxygenase pathway, are produced in cells of inflammation such as eosinophils, mast cells, monocytes, and basophils [1]. The leukotrienes have multiple effects that contribute to the airways obstruction and inflammation which characterize asthma, including constriction of small and large airways (effects up to a thousand-fold greater than histamine and methacholine) [2], and promotion of eosinophil migration into the airway mucosa [3]. In vitro studies with the cysteinyl leukotrienes have shown increased venous permeability [4], mucus secretion [5], and decreased activity of the respiratory cilia [6].Clinical studies of antileukotriene agents have provided direct evidence of the role of the cysteinyl leukotrienes in clinical asthma. Early clinical studies with MK-0571, a leukotriene receptor antagonist, demonstrated protection against both early-and late-phase bronchoconstriction due to inhaled allergens [7] and exercise-induced bronchoconstriction [8], while demonstrating rapid bronchodilation in other studies [9]. A six week course of therapy with zafirlukast, a leukotriene receptor antagonist, produced both an objective and subjective improvement of asthma [10], as did a three month course of zileuton, a 5-lipoxygenase inhibitor [11].Montelukast (MK-0476, SINGULAIR®) is a potent and specific CysLT 1 receptor antagonist [12]. When given once daily to patients with asthma, montelukast protects against LTD 4 -induced [13] and exercise-induced bronchoconstriction [14], 20-24 h after administration. Similarly, significant improvement in the signs and symptoms of chronic asthma have been observed after 6 weeks of double-blind treatment with montelukast dosed once daily between 10-200 mg [15].The similarity of the response between a daily dose of 10-200 mg suggested that the evaluation of doses <10 mg would be necessary to identify a dose-response relationship. Using a dose <10 mg, this multicentre study had the objective of investigating the dose-related tolerability and efficacy of montelukast. Materials and methods Study designThis double-blind, randomized, three-period, parallelgroup study comparing the clinical effect of three dosages After a two week placebo run-in period, chronic asthmatic patients with a forced expiratory volume in one second (FEV1) 40-80% predicted with Š15% increase (absolute value) after β 2 -agonist were randomly assigned to one of four treatment groups (placebo or montelukast 2, 10, or 50 mg once daily in the evening) for a three week, double-blind treatment period.For patient-reported end-points (daytime symptom score, use of as needed inhaled β 2 agonist, asthma-specific quality of life) and frequency of asthma exacerbations, montelukast 10 and 50 mg caused similar responses, superior to 2 mg and significantly (p<0.05; linear trend test) different from placebo. All three doses caused improvements in FEV1 and mor...

Both montelukast and inhaled corticosteroids were effective in controlling mild to moderate chronic asthma; the relative effectiveness of montelukast and beclomethasone were similar in open-label conditions. The hypothesis, that clinical practice conditions (e.g., adherence) may have a significant impact on the effectiveness of these therapies, should be tested in future clinical trials.

To establish the correlation among asthma efficacy parameters over a long period, data from over 1500 patients in two one-year asthma clinical trials with montelukast, a Cys-LT1 antagonist, were analysed. Airway obstruction measurements, forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF), were measured at clinic visits. Patients recorded daytime symptom score, "as-needed" bagonist use, and PEF on a daily basis.Relationships among these parameters at baseline and during the one-year treatment period were established by correlation analyses. Multiple correlations between the airway obstruction (FEV1 and PEF) and patient-reported measurements were evaluated by canonical correlation analysis.Pairwise correlations of the efficacy parameters over a one-year time period were stable. Canonical correlation between the airway obstruction and patient-reported asthma efficacy endpoints was low, indicating that each category of endpoints measures a distinctively different aspect of the disease.It appears that at least one endpoint from each category should be used in asthma clinical studies. Eur Respir J 2001; 17: 220-224. Asthma is a variable and multifaceted disease. Many efficacy endpoints are measured and reported in asthma clinical trials. Cross-sectional correlations among the most commonly used asthma-related endpoints such as forced expired volume in one second (FEV1), peak expiratory flow (PEF), "as-needed" b-agonist use, and daytime and night-time symptoms have been explored, mostly in a small group of patients over short periods of time, and mild to moderate correlations have been observed [1 -3]. This paper investigates the relationship (over a oneyear period) among the endpoints of FEV1, PEF, "asneeded" b-agonist use, and daytime symptoms, and the relationship between the pulmonary function measurements (FEV1, PEF) and patient-reported efficacy measurement endpoints (daytime symptom, "asneeded" b-agonist use). The relationships were investigated based on a large data set collected over a one-year period, from 1576 patients who entered two large clinical trials, which were conducted as multi-centre, double-blind, placebo-controlled studies to determine the safety, tolerability, and efficacy of one-year continuous treatment of montelukast, a Cys-LT1 antagonist [4,5]. The relationships among these endpoints will provide more information about this multifaceted disease and establish the multi-dimensionality of these endpoints. Methods Study designStudy 1 was a multi-centre, double-blind, parallelgroup, placebo-controlled study comparing montelukast (MNT), inhaled beclomethasone (ICS) and placebo (table 1). The study consisted of a 2-week single-blind placebo run-in period (I), a 12-week, double-blind, active treatment period (II) and a 3-week, double-blind washout period (III). Patients taking concomitant oral theophylline (limited to approximately 25% of patients) were allowed to continue this medication at a constant dose. At the end of Period II, a prespecified subset of patien...

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The measurement characteristics of two asthma symptom diary scales developed for use as health outcome measures in clinical trials of asthma therapy were investigated. A daytime diary scale was designed to capture the frequency and inconvenience of daytime asthma symptoms and their effects on activities, and a nocturnal asthma symptom diary scale was designed to capture awakenings with asthma symptoms. The internal consistency, reliability, validity and responsiveness of both asthma diary scales were assessed in 346 adult asthma patients in two placebo-controlled clinical trials of an investigational asthma therapy, a leukotriene biosynthesis inhibitor. The daytime symptom scale showed sufficient internal consistency (0.90-0.92), and the daytime and nocturnal symptom scales showed sufficient test retest reliability (0.69-0.87). Construct validity was demonstrated by generally moderate-to-strong correlations for changes in the diary scales with changes in other measures of asthma status, such as forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), and puffs of beta-agonist inhaler. Both scales demonstrated significant responsiveness to change in asthma due to therapy in one of the clinical trials. Based on these results, the daytime and nocturnal asthma symptom diary scales show measurement characteristics appropriate for use as asthma outcome measures in clinical trials of asthma therapy.

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Our fax numbers: 617-739-9864 and 617-734-4457Our e-mail address: letters@nejm.orgWe cannot acknowledge receipt of your letter, but we will notify you when we have made a decision about publication. We are unable to provide prepublication proofs. Please enclose a stamped, self-addressed envelope if you want unpublished material returned to you. Financial associations or other possible conflicts of interest must be disclosed. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal' s various editions (print, data base, and optical disk) and in anthologies, revisions, and any other form or medium. 1. Nelson JA, Strauss L, Skowronski M, Ciufo R , Novak R , McFadden ER Jr. Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med 1998;339:141-6. 2. Strauss RH, McFadden ER Jr, Ingram RH Jr, Jaeger JJ. Enhancement of exercise-induced asthma by cold air. N Engl J Med 1977;297:743-7. 3. Simons FE, Gerstner TV, Cheang MS. Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment. Pediatrics 1997;99:655-9. 4. Ramage L, Lipworth BJ, Ingram CG, Cree IA, Dhillon DP. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol.