[Antileukotrienes in the prevention of postoperative recurrence of nasal polyposis in ASA syndrome]

[Article in Italian]

Cerqua N.

A.C.O. San Filippo Neri, Unita Operativa di Otorinolaringoiatria, Roma. ldirienzo tiscalinet.it

There is a high incidence of post-surgical recurrences of nasal polyps (NP) in patients suffering from the ASA Syndrome. The numerous theories as to the pathogenesis of the ASA Syndrome include an increase in lipoxygenase-mediated arachidonic acid metabolism, with the subsequent hyperproduction of leukotrienes (LT), and an inhibition of the cycloxygenase. Therefore, based on the information acquired on the immunobiological action mechanism of montelukast, a cysteinyl-LT receptor antagonist, it appeared worth testing the effectiveness of this substance in preventing post-surgical NP recurrences in a group of ASA Syndrome patients. After taking a case history, filling out a questionnaire scoring nasal symptoms, undergoing rhinoendoscopy and rhinomanometry, 40 patients suffering from ASA-Syndrome and NP (age range 30-72 years) were recruited for the study. They were uniformly classified according to Lund and Mackay using high resolution CT of the nose and paranasal sinuses performed after at least 1 month of nasal medical treatment. All the patients underwent microendoscopic anterior-posterior ethmoidectomy and bilateral maxillary antrostomy. After removing the nasal packing, the only treatment administered was 10 mg of montelukast/die for 6 months, with the drug suspended for 1 months after the first 3 months of treatment. The monthly follow-up included rhinoendoscopy, rhinomanometry and the questionnaire to score symptoms. After the seventh month a new CT was performed and compared with the pre-operative CT. In a control group of subjects, homogeneous with the test group, momethasone furoate nasal spray was administered at a dose of 100 mcg per nostril/die and loratadin tablets 10 mg/die. The results obtained in the patients treated with montelukast were analogous with those obtained in the second group, and during follow-up all patients showed total absence of any local recurrence, good nasal patency and no significant nasal symptom score on the questionnaire. In no case did the comparative CT, performed after the seventh month, show any signs of recurrence. The patients taking the montelukast reported a significant reduction in the use of steroids and bronchodilator inhalants during the course of the study than did the second group; indeed the number of asthmatic episodes dropped and they reported an improvement in the quality of life. Based on these results, the authors suggest that the use of montelukast in the treatment of post-surgical NP recurrences in ASA Syndrome is possible and advisable, even in synergetic association with the treatment administered to the second group. The positive results also support the hypothesis of altered arachidonic acid metabolism and call attention to the role of cysteinyl-LT in the pathogenesis of the ASA Syndrome.

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Correlation of airway obstruction and patient-reported endpoints in clinical studies.

Reiss TF.

Dept of Clinical Biostatistics, Merck Research Laboratories, Rahway, NJ 07065, USA.

To establish the correlation among asthma efficacy parameters over a long period, data from over 1,500 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" beta-agonist 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.

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[Pharma-clinics. Medication of the month. Montelukast (Singulair)]

[Article in French]

Louis R.

Service de Pneumologie, Universite de Liege.

Montelukast (Singulair, Merck Sharp & Dohme) is a leukotriene receptor antagonist (LTRA) recommended in asthma inadequately controlled by inhaled corticosteroids, or in exercise-induced asthma. The molecule combines bronchoprotective, bronchodilating and anti-inflammatory effects. The drug has to be taken by the oral route at the dosage of 10 mg/day in adults and 5 mg/day in children under 15 years. In asthmatics montelukast decreases diurnal and nocturnal symptoms, the use of short-acting bronchodilator and improves lung function. The beneficial effects of montelukast are observed whether inhaled corticosteroids are concomitantly used or not. The drug is generally well tolerated and does not require serum monitoring. Montelukast is a complementary to inhaled corticosteroids in controlling asthma.

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[The effect of montelukast on airway remodeling and the expression of interleukins and transforming growth factor-beta2 mRNA]

[Article in Chinese]

Wu HC.

Department of Respiratory Medicine, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China.

OBJECTIVE: To study the relation between Interleukin-4 (IL-4), IL-5, IL-13, transforming growth factor-beta(2) (TGF-beta(2)) and airway remodeling and to investigate the effects of Montelukast (MK) on airway inflammation and airway remodeling of asthma. METHODS: Twenty female BALB/c mice were randomly divided into a remodeling group and a treatment group (MK group), with 10 BALB/c mice in each group. The mice were sensitized by ovalbumin (OVA), and only the MK group was treated with MK (15 mg/kg). The number of total cells and eosinophils in bronchoalveolar lavage fluid (BALF) were counted. Light and electronic microscope were used to detect the pathologic histology and morphologic change. In situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) were used to measure IL-4, L-5, IL-13, and TGF-beta(2) mRNAs in the lung. RESULTS: The numbers of total cells and eosinophils in BALF of the remodeling group were (5.4 +/- 1.1) x 10(5)/ml and 2.32 +/- 0.20, while those of the treatment group were (3.9 +/- 1.6) x 10(5)/ml and 1.64 +/- 0.32, respectively, the difference being significant (P < 0.01). Histological and electronic microscopic examination showed extensive airway inflammation, notably accumulation of significant numbers of eosinophils and lymphocytes in the remodeling group. Other features including prominent proliferation of airway epithelial cells protruded like fingers, increased thickness of smooth muscle, hyperplasia of connective tissue, goblet cell hyperplasia and a marked increase in airway mucus secretion with mucus plugging and extensive collagen deposition around the airways were also noted in the remodeling group. In the treatment group, the inflammation was significantly decreased, with decreased production of mucus, decreased collagen and granule of mucus around airway, less proliferation of airway epithelium, smooth muscle hypertrophy and airway spasm. In situ hybridization showed that the expression of IL-13 mRNA and TGF-beta(2) mRNA in the lung of the remodeling group were 24 +/- 7 and 17 +/- 5 respectively, while those of the treatment group were 17 +/- 4 and 10 +/- 3. RT-PCR results showed that the absorbance of IL-4 mRNA and IL-5 mRNA in the lung of the remodeling group were 0.91 and 0.96, while those of the treatment group were 0.22 and 0.35; the differences between the groups were all significant (all P < 0.01). CONCLUSION: MK could effectively inhibit airway remodeling, which suggests a possible role of cysteinyl leukotrienes in the pathogenesis of chronic allergic inflammation with fibrosis.

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Montelukast, a cysteinyl leukotriene receptor-1 antagonist, dose- and time-dependently protects against focal cerebral ischemia in mice.

Zhao MH.

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

Our previous studies showed that cysteinyl leukotriene receptor-1 (CysLT1) antagonist pranlukast has a neuroprotective effect on cerebral ischemia in rats and mice. However, whether the neuroprotective effect of pranlukast is its special action or a common action of CysLT1 receptor antagonists remains to be clarified. This study was performed to determine whether montelukast, another CysLT1 receptor antagonist, has the neuroprotective effect on focal cerebral ischemia in mice, and to observe its dose- and time-dependent properties. Permanent focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). Montelukast was injected intraperitoneally either as multiple doses (once a day for 3 days and 30 min before MCAO) or as a single dose (at 30 min before, 30 min after, or 1 h after MCAO), respectively, and pranlukast and edaravone were used as controls. The neurological deficits, infarct volumes, brain edema, neuron density, and Evans blue extravasation in the brain were determined 24 h after MCAO. Pretreatments with multiple doses or a single dose of montelukast (0.1 and 1.0 mg/kg) before MCAO significantly attenuated all the ischemic insults. Post-treatment with a single dose of montelukast (0.1 and 1.0 mg/kg) at 30 min after MCAO also significantly decreased brain edema and infarct volume, but not neurological deficits. However, post-treatment with a single dose of montelukast at 1 h after MCAO had no significant effect. Pranlukast showed the same effects as montelukast, but edaravone attenuated the ischemic insults only with multiple doses before MCAO. Thus, montelukast has a dose- and time-dependent neuroprotective effect on permanent focal cerebral ischemia in mice, with an effective dose range of 0.1-1.0 mg/kg and a therapeutic window of 30 min. These findings further support the therapeutic potential of CysLT1 receptor antagonists in the treatment of cerebral ischemia at earlier phases. 2005 S. Karger AG, Basel.

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