Montelukast modulates lung CysLT(1) receptor expression and eosinophilic inflammation in asthmatic mice.

Wei EQ.

Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310031, China.

AIM: To determine the expressions of cysteinyl leukotriene receptors, CysLT1 and CysLT2, in airway eosinophilic inflammation of OVA-induced asthmatic mice and the modulation by montelukast, a CysLT1 receptor antagonist. METHODS: Asthma model was induced by chronic exposure to ovalbumin (OVA) in C57BL/6 mice. The eosinophils in bronchoalveolar lavage (BAL) fluid and lung tissues were counted, IL-5 level in BAL fluid was measured, and CysLT1 and CysLT2 receptor mRNA expressions were detected by semi-quantitative RT-PCR. Results: Montelukast (6 mg/kg, once per day for 20 d) significantly suppressed the increased eosinophils in BAL fluid and lung tissue, and increased IL-5 level in BAL fluid in OVA challenged mice. OVA challenge increased CysLT1 but decreased CysLT2 receptor mRNA expression. Montelukast inhibited the increased CysLT1 but not the reduced CysLT2 expression after OVA challenge. CONCLUSION: CysLT receptors are modulated immunologically, and montelukast inhibits up-regulation of CysLT1 receptor and airway eosinophilic inflammation in asthmatic mice. Copyright 2004 Acta Pharmacologica Sinica

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Comparison study between the mechanisms of allergic asthma amelioration by a cysteinyl-leukotriene type 1 receptor antagonist montelukast and methylprednisolone.

Tanaka K.

Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.

We investigated the effects of cysteinyl-leukotriene (cysLT) type 1 receptor antagonist montelukast (MK) and compared them with those of methylprednisolone (MP) in an allergic asthma model. Rats sensitized to ovalbumin (OVA) received repeated intratracheal exposure to OVA for up to 3 consecutive days. Pretreatment with MK or MP before OVA exposure inhibited late airway response (LAR) and reduced cellular infiltration into the bronchial submucosa after the triple OVA. The amount of N-acetyl-leukotriene E(4) in the bile was significantly reduced by pretreatment with MK or MP, suggesting that both drugs reduced the production of cysLTs in the lungs. In the in vitro study, when the fragments of lungs that had been repeatedly pretreated with MK or MP and exposed to OVA were removed and incubated with OVA, the coaddition of either drug significantly reduced cysLT production. In contrast, the cysLT production following the addition of OVA to the lung fragments that had not received in vivo pretreatment with either drug was inhibited by MK but not by MP. These results indicate that MK and MP inhibit LAR by suppressing the infiltration of inflammatory cells into the bronchial submucosa, thereby inhibiting the production of cysLTs in the lungs, and that MK but not MP may inhibit cysLT production directly. The different effects on cysLT production between the two drugs may provide a rationale for the use of combination therapy with cysLT(1) receptor antagonists and steroids for the treatment of asthma.

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Novel inhibitory effect on 5-lipoxygenase activity by the anti-asthma drug montelukast.

Macchia L.

Department of Allergology and Clinical Immunology, University of Bari, Bari 70124, Italy.

5-Lipoxygenase is the key enzyme in the biosynthesis of leukotrienes, powerful lipid mediators involved in inflammation, cell-cell communication, and other important physiological and pathological conditions. Particularly, cysteinyl-leukotrienes have been recognized as playing a significant role in the pathophysiology of asthma and potent and effective Cys-LT1 receptor antagonists have been developed for the treatment of this illness. Here we report that montelukast, a structural Cys-LT1 receptor antagonist, also exerts a substantial and apparently direct inhibitory effect on 5-lipoxygenase activity in vitro, at concentrations in the lower micromolar range, which are of potential therapeutic relevance. Thus, when human mast cells HMC-1 were stimulated with the Ca ionophore A23187 in the presence of montelukast (up to 100 microM) a substantial decline in 5-lipoxygenase biosynthesis was observed. Similar results were obtained in the rat mast cell-like RBL-1 cell model (IC50 congruent with 2.5 microM) and in human polymorphonuclear leukocytes. Moreover, montelukast directly inhibited human recombinant 5-lipoxygenase. Kinetic experiments revealed that the inhibition was of the non-competitive type, suggesting that montelukast binds a yet undefined allosteric site on 5-lipoxygenase. 5-Lipoxygenase inhibition by montelukast appears to be highly selective since the drug had no effects on other enzymes of the leukotriene cascade, viz. LTC4 synthase and LTA hydrolase.

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Effects of montelukast and salmeterol on physical performance and exercise economy in adult asthmatics with exercise-induced bronchoconstriction.

Bjermer L.

Department of Lung Medicine, Heart and Lung Institute, University Hospital of Trondheim, N-7006 Trondheim, Norway. sigurd.steinshamn medisin.ntnu.no

STUDY OBJECTIVES: To compare the effect of montelukast and the long-acting beta(2)-agonist salmeterol on cardiopulmonary exercise economy and physical performance in adult patients with asthma during exercise. DESIGN AND PATIENTS: Asthmatic patients (n = 18), aged 18 to 35 years with exercise-induced bronchoconstriction (EIB), using a double-blind, double-dummy cross-over design. Montelukast, 10 mg/d, was compared to inhaled salmeterol, 50 microg bid. The study medication was administered for at least 5 days prior to testing, with a washout period of at least 5 days. Treadmill exercise tests (5.3% inclination, -15 degrees C ambient temperature) were performed at work loads of 80% of maximal oxygen uptake (Vo(2)max) [6 min], rest (4 min), 60% of Vo(2)max (6 min), and finally step increments until exhaustion. MEASUREMENTS AND RESULTS: We investigated parameters of gas exchange, physical performance, and lung function. After montelukast, the oxygen pulse was higher than after salmeterol, at 80% of Vo(2)max (p = 0.035), and 6 min at 60% of Vo(2)max (p = 0.011). Lung function during exercise, running time to exhaustion, Borg score, lactate levels, Vo(2)max, carbon dioxide elimination, minute ventilation, ventilatory equivalents, respiratory exchange ratio, and heart rate were not significantly different between the two treatments. The maximal postexercise fall in FEV(1) from baseline occurred 2 min after run to exhaustion, and was greater after salmeterol than after montelukast: mean, 16.2% (SD, 11.0) vs 10.0% (SD, 12.2) [p < 0.001]. CONCLUSIONS: In adult asthmatics with EIB, montelukast may have a more favorable effect on the oxygen pulse, thus suggesting improved gas exchange during exercise.

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Comparative cutoff points for adenosine monophosphate and methacholine challenge testing.

Lipworth BJ.

Asthma and Allergy Research Group, Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland.

BACKGROUND: Current use of the PC20 (provocation concentration that causes a decrease in forced expiratory volume in 1 second of 20%) cutoff point for bronchial challenge precludes its use in patients with more severe airflow obstruction. OBJECTIVE: To evaluate the efficacy and safety of lower cutoff points for adenosine monophosphate (AMP) and methacholine (MCH) bronchial challenge tools to monitor response to treatment in chronic asthma. METHODS: We retrospectively examined data from 5 previously published studies (2 using AMP, 2 using MCH, and 1 with MCH and AMP arms) and recalculated 10% and 15% cutoff points for AMP and MCH. Data were analyzed for correlation of single results and doubling dose shifts after anti-inflammatory treatment intervention. RESULTS: A total of 175 individual MCH challenges and 152 AMP challenges were evaluated. Evaluating the doubling dose shift produced by the addition of anti-inflammatory treatment (inhaled corticosteroids or montelukast) produced the following Pearson correlation coefficients: MCH PD20 (provocation dose that causes a decrease in forced expiratory volume in 1 second of 20%) vs PD15, 0.80; MCH PD20 vs PD10, 0.65; AMP PC20 vs PC15, 0.96; and AMP PC20 vs PC10, 0.84 (P < .001 for all). Subgroup analysis of AMP for before and after inhaled corticosteroids only (n = 41) shows AMP PC20 vs PC15 of 0.92 and AMP PC20 vs PC10 of 0.84 (P < .001 for both). CONCLUSIONS: The 10% and 15% cutoff points strongly predict the 20% cutoff value for AMP and MCH, as do the doubling dose shifts after anti-inflammatory treatment. The lower thresholds are suitable for monitoring response to therapy, and they expose patients to significantly less provocation agent.

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