[Anti-asthma drugs]

[Article in French]

Devillier P.

Laboratoire de pharmacologie-toxicologie, Hopital Maison Blanche, Centre hospitalier universitaire de Reims 51092 Reims. pdevillier chu-reims.fr

With respect to their main mechanism of action, anti-asthma drugs are classified as bronchodilators or anti-inflammatory drugs. Inhaled beta 2-agonists are the most effective bronchodilators. The shorts acting beta 2-agonists are used for the relief of acute symptoms whereas long acting beta 2-agonists are used on a regular basis, concomitantly with inhaled corticoids, for long-term control of symptoms. The others bronchodilators (methylxanthines or anticholinergics) may be used in addition to the inhaled beta 2-agonists. The treatment of bronchial inflammation is required in mild to severe persistent asthma. Inhaled corticoids are the main anti-inflammatory drugs. They have a low risk of adverse events at usual dosages. Anti-leukotrienes belong to a new class of anti-inflammatory drugs represented by montelukast in France. This drug is orally administered, well tolerated and used in addition to inhaled corticoids. Cromones and ketotifen are used only in mild persistent asthma. Inhaled beta 2-agonists, anti-leukotrienes and cormones are also used for prevention of exercise-induced asthma.

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Pharmacological differences among CysLT(1) receptor antagonists with respect to LTC(4) and LTD(4) in human lung parenchyma.

Nicosia S.

Laboratory of Molecular Pharmacology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.

We have previously reported, by means of equilibrium binding studies, the existence of two distinct binding sites with receptor characteristics for LTC(4) and LTD(4) in human lung parenchyma (HLP) membranes using S-decyl-glutathione (S-decyl-GSH) to inhibit LTC(4) binding to a number of non-receptor sites. Recently, we have been able to avoid the use of S-decyl-GSH in kinetic experiments and to characterize a distinctive pharmacological profile for the LTC(4) high affinity binding sites which do not correlates with the ability of both LTD(4) and LTC(4) to contract isolated HLP strips through the CysLT(1) receptor. Here, we report that the most advanced CysLT(1) receptor antagonists, some of which are already in clinical use, displayed a different behavior toward LTC(4) and LTD(4) in HLP. Equilibrium and kinetic binding studies demonstrated the following rank order of potency for (3)H-LTD(4) receptor (CysLT(1)): zafirlukast = montelukast > LM-1507 = LM-1484 = pranlukast. In addition, LM-1507, LM-1484, pranlukast and montelukast but not zafirlukast are able to interact also with the high affinity site for (3)H-LTC(4) (LM-1507 = LM-1484 > pranlukast; montelukast not detectable in the presence of S-decyl-GSH). In this respect, the behavior of the LM antagonists closely resembles that of pranlukast although LM-1507 and LM-1484 display a higher affinity for (3)H-LTC(4) sites. Montelukast has an intermediate behavior, inasmuch as its interaction with (3)H-LTC(4) sites can be revealed only in kinetic studies, while zafirlukast is totally unable to inhibit (3)H-LTC(4) binding. It might be, therefore, most relevant for a complete understanding of the clinical efficacy, besides their nominal potency, of the most advanced CysLT(1) receptor antagonists to consider their pharmacological differences with respect not only to LTD(4)/LTE(4), but also to LTC(4).

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Effect of montelukast, a once-daily leukotriene receptor antagonist, on peak expiratory flow variability.

Reiss TF.

Department of Clinical Biostatistics, Merck Research Laboratories, Rahway, New Jersey 07065, USA. zhangj merck.com

BACKGROUND: Peak expiratory flow (PEF) is an important measure of airway functin in asthma. PEF variability (PEFvar) assessment is described in asthma treatment guidelines as another means of evaluating patient status and response to therapy. OBJECTIVE: The goal of this study was to determine the clinical effect of oral montelukast, a leukotriene receptor antagonist, on PEFvar in asthmatic patients and to assess the relationship of PEFvar with other clinical measures. METHODS: This was a retrospective analysis of data from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, details of which have been published previously. Eligible patients had chronic stable asthma, had a forced expiratory volume in 1 second (FEV1) that was 50% to 85% of the predicted value, used inhaled beta-agonists, had at least 15% improvement in absolute FEV1 after inhaled beta-agonist administration, and showed a minimal predefined level of daytime asthma symptoms. Treatment consisted of a 2-week, single-blind, placebo run-in period followed by a 12-week, double-blind treatment period (montelukast 10 mg or matching placebo once daily at bedtime). RESULTS: Six hundred eighty-one patients (age range, 15-79 years) were randomized to treatment at 50 centers. Baseline PEFvar was 11.44% +/- 6.55% and 10.62% +/- 6.48% in the montelukast and placebo groups, respectively. PEFvar decreased 20.1% and 7.5% from baseline in the montelukast and placebo groups, respectively. The between-group difference was significant (P < 0.001). PEFvar had low correlation with other clinical measures. CONCLUSIONS: Over 12 weeks of treatment, montelukast significantly reduced PEFvar compared with placebo, indicating improved asthma control. The relative reduction in PEFvar was similar in patients with different degrees of variability at baseline. PEFvar did not correlate highly with other outcome variables and may measure different aspects of the disease.

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Interleukin-2-induced increased airway responsiveness and lung Th2 cytokine expression occur after antigen challenge through the leukotriene pathway.

Renzi PM.

University of Montreal Hospital Center, Notre-Dame Hospital, Quebec, Canada.

Previous studies have shown that the allergic late airway response (LR) is dependent on the leukotriene (LT) pathway in Brown Norway (BN) rats. In this same model, interleukin-2 (IL-2) has been shown to increase allergic airway responses without increasing LT production. This study examined the relationship between the upregulation of cellular immunity with IL-2 and the LT pathway in ovalbumin-sensitized BN rats. Airway responsiveness to LTD(4) was significantly increased in BN rats pretreated with IL-2 (20,000 U twice a day for 4.5 days). Treatment with montelukast, a cysteinyl LT(1) receptor antagonist, blocked IL-2's induced increase of the LR to ovalbumin challenge. When cytokine expression was assessed either by semiquantitative polymerase chain reaction or in situ hybridization, we found that montelukast decreased the amount of IL-4 mRNA expression in the lungs while increasing the amount of interferon-gamma mRNA expression 8 hours after challenge. These results indicate that upregulation of cellular immunity with IL-2 can increase the sensitivity of the airways to LTD(4) and that inhibition of the LT pathway will block the LR and modulate cytokine expression after antigen challenge.

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The effect of cysteinyl leukotrienes on growth of eosinophil progenitors from peripheral blood and bone marrow of atopic subjects.

Gauvreau GM.

Asthma Research Group, Firestone Institute for Respiratory Health, St Joseph's Healthcare, and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

BACKGROUND: The accumulation of eosinophils into the peripheral blood and airways of asthmatic subjects is, in part, dependent on cysteinyl leukotrienes (cysLTs). However, the effect of cysLTs on peripheral blood and bone marrow eosinophil pro-genitor cells in allergic subjects is not known. OBJECTIVE: The purpose of this study was to evaluate the effects of leukotriene (LT) D(4) and LTE(4) and the cysLT(1) receptor antagonist montelukast on peripheral blood and bone marrow eosinophil-basophil progenitor growth and development in atopic subjects. METHODS: Semisolid methylcellulose cultures for peripheral blood and bone marrow eosinophil-basophil colonies were counted after incubation with or without addition of LTD(4), LTE(4), and montelukast in the presence of suboptimal concentrations of GM-CSF, IL-3, and IL-5. RESULTS: Peripheral blood eosinophil-basophil colony-forming unit cultures grown in the presence of GM-CSF and bone marrow eosinophil-basophil colony-forming units grown in the presence of IL-5 were significantly increased by the addition of LTD(4) (0.1 micromol/L). This increase was suppressed by montelukast (1 micromol/L). CONCLUSION: This study has demonstrated that the cysLT LTD(4) can stimulate proliferation of eosinophil hematopoietic progenitor cells in the presence of eosinophilopoietic cytokines. The suppressive effect by montelukast demonstrates that this is a cysLT(1) receptor-mediated effect.

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