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.
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