[Pharmacological profile and clinical effects of montelukast sodium (Singulair chewable tablet), an antiasthmatic agent]

[Article in Japanese]

Nishikibe M.

Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300-2611, Japan.

Montelukast (Singulair) is an antiasthmatic agent that has the chemical structure of a quinoline. Montelukast has a high affinity for the CysLT1 receptor and a potency that is not influenced by human serum protein. Montelukast antagonizes contractions of guinea-pig trachea induced by LTD4 in a competitive manner. Intravenous montelukast inhibited bronchoconstriction induced by LTD4 in guinea pigs. Oral montelukast inhibited increased airway resistance induced by antigen in squirrel monkeys. Montelukast also inhibited both inflammatory and immunologic responses induced by either LTD4 or antigen in guinea pigs and rats. Plasma concentrations of montelukast after oral administration of 10 mg in humans were shown to be over the effective level for at least 24 h. These lines of evidence support the effectiveness of a regimen of 10 mg/day for asthmatic symptoms in humans. In a number of clinical experiments, montelukast not only improved asthmatic symptoms and respiratory indices, but also inhibited airway inflammation and exercise-induced bronchoconstriction. These effects persisted during extended treatment. Montelukast produced an additive effect to basic therapy with an inhaled steroid. There were no differences in the incidence and magnitude of adverse effects between montelukast and placebo groups in clinical experiments. Montelukast is expected to serve as a first line of asthmatic therapy because of its consistent efficacy and good safety profile and it is associated with good compliance in patients because of its simple regimen of one 10 mg tablet/day.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12491810&dopt=Abstract montelukast, Singulair




Involvement of the cysteinyl-leukotrienes in allergen-induced airway eosinophilia and hyperresponsiveness in the mouse.

Martin JG.

Meakins-Christie Laboratories and Respiratory Division, Department of Medicine, McGill University, Montreal, Quebec, Canada.

The leukotriene modifiers are a novel generation of therapeutic agents in the treatment of allergic asthma. However, the mechanisms by which the cysteinyl (cys) leukotrienes (LTs) participate in allergen-induced airway eosinophilia and airway hyperresponsiveness (AHR) are still unclear. In the present study, we have investigated the role of cys-LTs in ovalbumin (OVA)-induced airway responses in a murine model of asthma. Montelukast (3 or 10 mg/kg), a selective cys-LT1 receptor antagonist, reduced airway eosinophilia and AHR after OVA challenge. The levels of interleukin (IL)-5 and eotaxin in the bronchoalveolar lavage fluid (BALF) from montelukast-treated (3 mg/kg) mice were unaffected, although a decrease in IL-5 was observed with a dose of 10 mg/kg. LTD4 (50 ng) instilled intranasally to immunized mice augmented macrophages in the BALF, but in conjunction with OVA challenge it caused BALF eosinophilia and neutrophilia when given before challenge and BALF neutrophilia but not eosinophilia when given 2 h after challenge. However, there were no increases of IL-5 or eotaxin in BALF following LTD4 treatment. Repeated instillations of LTD4 to immunized mice, mimicking allergen challenge, did not induce AHR but in conjunction with OVA challenge LTD4 enhanced AHR. These results indicate that allergen-induced eosinophilia and AHR are in part mediated by the cys-LT1 receptor, and that, although LTD4 alone has no effect on airway eosinophilia, in conjunction with antigenic stimulation it potentiates the degree of airway inflammation and AHR.

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Lipoxin A4 stimulates a cytosolic Ca2+ increase in human bronchial epithelium.

Urbach V.

INSERM U454, Department of Respiratory Disease, Centre Hospitalier Universitaire Arnaud de Villeneuve, 34295 Montpellier Cedex 05, France.

Lipoxins are biologically active eicosanoids possessing anti-inflammatory properties. Using a calcium imaging system we investigated the effect of lipoxin A(4) (LXA(4)) on intracellular [Ca(2+)] ([Ca(2+)](i)) of human bronchial epithelial cell. Exposure of the cells to LXA(4) produced a dose-dependent increase in [Ca(2+)](i) followed by a recovery to basal values in primary culture and in 16HBE14o(-) cells. The LXA(4)-induced [Ca(2+)](i) increase was completely abolished after pre-treatment of the 16HBE14o(-) cells with pertussis toxin (G-protein inhibitor). The [Ca(2+)](i) response was not affected by the removal of external [Ca(2+)] but completely inhibited by thapsigargin (Ca(2+)-ATPase inhibitor) treatment. Pre-treatment of the bronchial epithelial cells with either MDL hydrochloride (adenylate cyclase inhibitor) or (R(p))-cAMP (cAMP-dependent protein kinase inhibitor) inhibited the Ca(2+) response to LXA(4). However, the response was not affected by chelerytrine chloride (protein kinase C inhibitor) or montelukast (cysteinyl leukotriene receptor antagonist). The LXA(4) receptor mRNA was detected, by RT-PCR, in primary culture of human bronchial epithelium and in immortalized 16HBE14o(-) cells. The functional consequences of the effect of LXA(4) on intracellular [Ca(2+)](i) have been investigated on Cl(-) secretion, measured using the short-circuit techniques on 16HBE14o(-) monolayers grown on permeable filters. LXA(4) produced a sustained stimulation of the Cl(-) secretion by 16HBE14o(-) monolayers, which was inhibited by BAPTA-AM, a chelator of intracellular calcium. Taken together our results provided evidence for the stimulation of a [Ca(2+)](i) increase by LXA(4) through a mechanism involving its specific receptor and protein kinase A activation and resulting in a subsequent Ca(2+)-dependent Cl(-) secretion by human airway epithelial cells.

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Asthma control and patient satisfaction among early pediatric users of montelukast.

Markson LE.

Outcomes Research & Management, Merck & Co., Inc., West Point, Pennsylvania 19486, USA. siva_narayanan merck.com

OBJECTIVE: To assess asthma control and patient satisfaction among pediatric users of montelukast in a clinical practice setting. STUDY DESIGN: A prospective study of 175 children with persistent asthma, 6 to 14 years of age, who initiated treatment with montelukast between Feb-1998 and Aug-1998, in primary care and pediatric offices across the United States. Data on asthma control and satisfaction with treatment was collected in physicians' offices after enrollment and by survey to the patients' homes at 1 month of treatment. RESULTS: Across the study population, improvements in mean scores for asthma control and parent satisfaction were observed at the 1-month follow-up compared with baseline. At 1 month, 57.7% of patients had none offour issues indicative of poor asthma control, compared with 19.4% at baseline. Similarly, after 1 month of treatment with montelukast, 2.7 times as many parents reported being very satisfied with asthma therapy (using montelukast) compared with the previous controller therapy regimen at baseline. During the 1-month follow-up period, montelukast was used as the only controller medication by 18.3% of patients, and in combination with another controller medication by 81.7%. CONCLUSIONS: Observations from this study over one month suggest that a significant percentage of pediatric patients successfully managed their asthma with montelukast and their parents were satisfied with their medication, compared to baseline.

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[Effectiveness and safety of montelukast versus budesonide at various doses on bronchial reactivity in subjects with mild persistent asthma]

[Article in Italian]

De Lorenzo A.

Unita di Nutrizione Umana, Dipartimento di Scienze Biomediche, Universita G. D'Annunzio, Chieti, Italia. griccioni hotmail.com

PURPOSE: Insufficient data exist to evaluate the comparative effects of inhaled corticosteroids versus leukotriene receptor antagonists on airway inflammation and remodelling. The aim of the study was to evaluate the effectiveness and safety of montelukast versus budesonide at different doses on bronchial reactivity in mild-asthmatic adult patients. PATIENTS AND METHODS: A total of 40 patients were randomly assigned to a different treatment and divided in 2 treatment groups (A, B) as follows: A-10 mg of montelukast daily; B-400 mg of budesonide twice a day. RESULTS: We studied 40 subjects (21 males, 19 females) divided in two groups of 20 subjects each: group A with mean age 25.16 +/- 7.68 years, group B with mean age 26.18 +/- 6.15 years. After 16 weeks of treatment in the group A the PC20 (provocative concentration of methacholine which cause a fall of FEV1 > or = 20%) was 620.12 +/- 140.54 micrograms/mL significantly highly compared to basal value of 315.75 +/- 100.16 micrograms/mL (p < 0.02). In the group B the PC20 was 795.67 +/- 312.76 micrograms/mL significantly highly compared to basal value of 342.87 +/- 132.38 micrograms/mL (p < 0.001). We not found differences in FEV1, FVC e PEF before and after the treatment. CONCLUSIONS: Montelukast may be considered a valid alternative in the treatment of mild-persistent asthma, both for the benefits on bronchial reactivity and for the great advantage of the once-daily dosage, which consistently improves the compliance with the chronic treatment of the disease.

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