Montelukast inhibits interleukin-5 mRNA expression and cysteinyl leukotriene production in ragweed and mite-stimulated peripheral blood mononuclear cells from patients with asthma.

Wang YC.

Division of Allergy Immunology and Clinical Immunopathology, Department of Medicine and Pathology, Nassau University Medical Center, State University of New York at Stony Brook, Stony Brook, New York, USA.

Important in the pathogenesis of asthma is the secretion of interleukin (IL)-5 by allergen-specific TH2 cells, which augments eosinophil functions, as well as subsequent synthesis of cysteinyl leukotrienes (CysLTs). Montelukast is an inhibitor of CysLT and also has been shown to decrease eosinophil counts in peripheral blood and sputum of patients with asthma. This study was performed to investigate the in vitro effects of montelukast, a leukotriene receptor antagonist, on CysLTs and IL-5 production and expression by peripheral blood mononuclear cells (PBMCs) stimulated with ragweed (RW) and mite (M) allergens. In this study 18 patients with allergic asthma (nine women and nine men, aged 27-67 years) were evaluated. PBMCs from these patients were cultured for 24 hours in the presence of phytohemagglutinin (15 micrograms/mL), RW antigen E (0.39 U/mL), or M (16.8 micrograms/mL) allergens with (1, 10, 50 microM) and without montelukast. Enzyme-linked immunosorbent assay was used to measure the concentration of CysLTs, regulated upon activation, normal T-cell expressed and secreted (RANTES), and IL-5 in the culture supernatants and total RNA was extracted from the cultured PBMCs. Reverse transcription-polymerase chain reaction was performed on the RNA samples using beta-actin polymerase chain reaction primers for a control and IL-5 specific primers for detecting IL-5 mRNA expression in the cells. Elevated CysLT levels were noted in 8 of 18 patients with RW (range, 8-580 pg/mL) and in 13 of 18 patients with M (range, 7-1613 pg/mL). Inhibition of CysLTs by 10 microM of montelukast was noted in 5 patients with RW and in 10 patients with M. Levels of RANTES in some patients were increased by both allergens without consistent inhibitory effects of montelukast. IL-5 secretion measured by Enzyme-linked immunosorbent assay was detected in only 1 of 11 patients. However, in seven of nine patients tested, IL-5 mRNA was induced by both RW and M, and montelukast at 10 microM completely blocked IL-5 mRNA expression. Therefore, montelukast may be anti-inflammatory by inhibiting IL-5 mRNA expression and reducing CysLT secretion by PBMCs from asthmatic patients.

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[A leukotriene antagonist (montelukast) in the treatment of atopic dermatitis in pediatric patients]

[Article in Spanish]

Arroyave CM.

Facultad Medicina, Universidad Autonoma de Queretaro.

BACKGROUND: Leukotrienes participate in certain biological activities such as contraction of human airway muscle, increased vascular permeability, chemotaxis and allergen-induced early and late responses. OBJECTIVE: To evaluate the leukotriene antagonist montelukast in patients with atopic dermatitis unresponsive to traditional treatment. METHODS: Eighteen children with atopic dermatitis were treated with 5 mg of chewable montelukast every 24 hs during a period of 24 weeks. Patient's history was utilized as a control for each individual. On each visit, every child was assessed by a single observer and objectively scored for disease extent and severity. In addition every parent filled a similar evaluation. RESULTS: There was statistical improvement (p < 0.01) when values before and after treatment were analyzed, although no improvement was reported in five. No adverse reactions were reported. CONCLUSION: Findings suggest that leukotriene antagonists can be used as an adjunct treatment on patients with atopic dermatitis that are refractory to traditional management.

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[A study on the heterogeneous apoptosis of lymphocytes, eosinophils, and neutrophils from peripheral blood of asthmatic patients]

[Article in Chinese]

Wang ZL.

West China Hospital of Sichuan University, Sichuan Chengdu 610041, China.

OBJECTIVES: To observe different responsiveness of lymphocytes, eosinophils, and neutrophils from peripheral blood of asthmatic patients to dexamethasone and montelukast-induced apoptosis and to explore the roles of Fas antigen and caspase-3 in the heterogeneity of cell apoptosis. METHODS: Lymphocytes, eosinophils, and neutrophils were isolated from peripheral blood of 18 asthmatic patients. Cells were incubated in vitro and treated with dexamethasone and leukotriene receptor antagonist montelukast respectively. Cell apoptosis rates and Fas expression rates were examined by flowcytometry whereas caspase-3 levels in these cells were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: (1) Apoptosis rates: in vitro lymphocytes, eosinophils and neutrophils were compromised of spontaneous apoptosis at lower rates [(6.9 +/- 0.7)%, (31 +/- 11)% and (32 +/- 30)%, respectively]. With induction of dexamethasone, the apoptosis rates were (17.1 +/- 10.8)%, (44 +/- 22)% and (35 +/- 24)%. Montelukast markedly elevated the apoptosis rates of these three cells [(22.5 +/- 17.6)%, (50 +/- 27)% and (55 +/- 22)%, respectively] (compared to control, P < 0.01, < 0.05, > 0.05, respectively). (2) Fas expression: lymphocytes, eosinophils and neutrophils expressed low levels of Fas antigen at baseline [(1.50 +/- 0.07)%, (2.20 +/- 0.10)% and (1.21 +/- 0.09)%, respectively]. Dexamethasone induced Fas antigen expression levels of these cells of (6.58 +/- 2.10)%, (7.52 +/- 3.20)% and (3.24 +/- 2.34)%, and montelukast induced the expression levels of (5.06 +/- 1.66, 7.45 +/- 2.63, 3.03 +/- 2.47, P < 0.01, < 0.01, > 0.05, respectively). (3) caspase-3 levels: lymphocytes, eosinophils and neutrophils expressed constitutive caspase-3 levels of [(3.3 +/- 2.9) ng/L, (5 +/- 4) ng/L and (4.3 +/- 2.6) ng/L, respectively]. The dexamethasone induced caspase-3 levels were (6.7 +/- 3.1) ng/L, (6 +/- 3) ng/L and (3.1 +/- 1.8) ng/L. The montelukast induced levels were (5.2 +/- 3.7) ng/L, (8 +/- 4) ng/L, and (3.1 +/- 2.0) ng/L (compared to control, P < 0.01, < 0.01, > 0.05, respectively). It was demonstrated that dexamethasone and montelukast significantly induced apoptosis of lymphocytes and eosinophils which were assocreased with increased expression of Fas antigen and caspase-3. Dexamethasone was incapable of inducing neutrophils to apoptosis and had no significant effects on Fas expression and caspase-3 activity. Neutrophils underwent significant apoptosis after montelukast treatment, however, the induction was unlikely to be regulated by Fas and caspase-3 pathway. CONCLUSIONS: In asthmatic inflammatory modulating and effective cells, neutrophils is distinct from lymphocytes and eosinophils in profile of apoptosis induced by glucocorticoids and leukotriene receptor antagonist. The signal pathway contributing neutrophil apoptosis heterogeneity may involve deficient caspase cascade or Fas/FasL.

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Nasal cytokine modulation by montelukast in allergic children: a pilot study.

Ricca V.

Allergy-ENT Unit, Head Neck Dpt., San Martino Hospital, Genoa, Italy.

BACKGROUND: Allergic rhinitis and asthma are characterized by chronic inflammation due to a Th2 cytokine polarization. Leukotrienes receptor antagonists have been shown to be effective in both diseases. OBJECTIVE: Aim of the study was to evaluate the modulation by the antileukotriene montelukast on Th2 and Th1 cytokines in allergic rhinitis. METHODS: Fourteen school children affected by persistent allergic rhinitis (PAR) and exercise-induced asthma (EIA) underwent a nasal lavage before and after a two-week treatment with montelukast. A panel of cytokines, including IL4, IL13, and IFN gamma, was measured by immunoassay on nasal lavage samples. RESULTS: Montelukast treatment induced a significant decrease of IL4 and IL13 levels (p < 0.001, for both comparisons), and a significant increase of IFN gamma (p < 0.001). CONCLUSIONS: Montelukast treatment reversed a typical Th2 cytokine pattern (IL4 and IL13) toward a Th1 (IFN gamma) predominance in children with PAR and EIA. This effect could be considered relevant for long term allergic inflammation control and of interest when treating EIA with concomitant PAR.

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Effect of montelukast pretreatment on inducible nitric oxide synthase mRNA expression in the lungs of antigen-challenged allergic mice.

Kivity S.

Department of Pulmonary and Allergic Diseases, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. allergy tasmc.health.gov.il

BACKGROUND: Growing evidence suggests that inducible nitric oxide synthase (iNOS) is the main source of the high output of exhaled nitric oxide (NO) in asthma. Treatment of asthmatic patients with glucocorticoids reduces high levels of exhaled NO mainly by inhibiting the transcription of iNOS. A similar reduction in exhaled NO was recently observed in patients treated with the leukotriene receptor antagonists, but the exact interaction between these drugs and iNOS remains obscure. OBJECTIVE: The purpose of this study was to evaluate the effect of a leukotriene receptor antagonist, montelukast, on the expression and activity of iNOS in a murine model of allergic asthma. METHODS: Twenty-four BALB/c mice were sensitized to OVA and were equally divided into 3 groups (Groups 1-3). Eight additional mice were sham sensitized and served as a negative control group (Group 4). Group 1 received montelukast 1 mg/kg/day in their drinking water, Group 2 received dexamethasone 1 mg/kg/day in their drinking water and Groups 3 and 4 received plain tap water. After 1 week, the animals were challenged by inhalation of OVA and, 3 h later, they were killed and their lung cells were isolated by enzymatic tissue digestion. NO generation was measured by a Griess assay, and iNOS mRNA was studied by RT-PCR. RESULTS: A significant increase in iNOS mRNA expression and in NO generation was evident after allergen challenge compared with the controls. Pretreatment with montelukast mildly decreased NO production without producing a concomitant significant decrease in iNOS mRNA expression. CONCLUSION: Unlike pretreatment with glucocorticoids, we failed to find compelling evidence for a major role for montelukast treatment in the modulation of iNOS mRNA in a murine model of acute asthma.

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