montelukast and Pulmonary-Disease--Chronic-Obstructive

The prototype cysteinyl leukotriene receptor antagonist, montelukast, is generally considered to have a niche application in the therapy of exercise- and aspirin-induced asthma. It is also used as add-on therapy in patients whose asthma is poorly controlled with inhaled corticosteroid monotherapy, or with the combination of a long-acting beta(2)-agonist and an inhaled corticosteroid. Recently, however, montelukast has been reported to possess secondary anti-inflammatory properties, apparently unrelated to conventional antagonism of cysteinyl leukotriene receptors. These novel activities enable montelukast to target eosinophils, monocytes, and, in particular, the corticosteroid-insensitive neutrophil, suggesting that this agent may have a broader spectrum of anti-inflammatory activities than originally thought. If so, montelukast is potentially useful in the chemotherapy of intermittent asthma, chronic obstructive pulmonary disease, cystic fibrosis, and viral bronchiolitis, which, to a large extent, involve airway epithelial cell/neutrophil interactions. The primary objective of this mini-review is to present evidence for the cysteinyl leukotriene-independent mechanisms of action of montelukast and their potential clinical relevance.

Topics: Acetates; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Cyclopropanes; Humans; Leukotriene Antagonists; Neutrophils; Pulmonary Disease, Chronic Obstructive; Quinolines; Receptors, Leukotriene; Sulfides

New drugs and new approaches of the treatment of chronic obstructive pulmonary disease (COPD) are needed. Despite recent advances in medical therapeutics, treatment of patients with COPD remains largely symptomatic. Although inhaled corticosteroids are currently the drug of choice for anti-inflammatory therapy, the inflammatory process in COPD is essentially steroid resistant. By now, COPD has been increasingly recognized as an inflammatory disease characterized by sputum neutrophilia and, in some cases, eosinophilia. Moreover other cell types thought to play the predominant role in COPD, are cytotoxic T lymphocytes (CD8+ T) cells and macrophages. Leukotriene B4, (LTB 4), a neutrophil and T cell chemoattractant which is produced by macrophages, neurophils and epithelial cells, is a potent inflammatory mediator. Also cysteinyl leukotrienes (LTC4, LTD4 and LTE4) are known to induce mucus secretion, inflammatory cell infiltration, increase vascular permeability and tissue edema, damage ciliary clirens, and cause severe bronchoconstriction. These are derivatives of arachidonic acid, metabolized via 5-lypoxygenase (5-LO) pathway. There are several sites along this pathway that antileukotriene agents exert their action and at the end-organ receptors. They are classified into two major categories: receptor antagonists and synthesis inhibitors. Beneficial effects on therapy of patients with COPD have already derived from studies, while they seem well tolerated. More studies are underway.

Topics: 5-Lipoxygenase-Activating Proteins; Acetates; Arachidonate 5-Lipoxygenase; Bronchoconstriction; Capillary Permeability; Carrier Proteins; CD8-Positive T-Lymphocytes; Cell Movement; Chromones; Cyclopropanes; Eosinophils; Humans; Indoles; Leukotriene Antagonists; Leukotrienes; Membrane Proteins; Neutrophils; Phenylcarbamates; Pulmonary Disease, Chronic Obstructive; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds

To determine the effect of inhaled corticosteroid (ICS) therapy on glucose control in adults with type 2 diabetes mellitus and coexisting asthma or chronic obstructive pulmonary disease (COPD).. A prospective randomized, double-blind, double-dummy placebo-controlled, crossover investigation of inhaled steroids and oral leukotriene blockers.. A United States Department of Veterans Affairs Health Care System outpatient setting.. Adults with type 2 diabetes and asthma or COPD.. Subjects (n=12) were randomized to receive either inhaled fluticasone propionate (440 microg twice daily) and oral placebo, or inhaled placebo and oral montelukast (10 mg/day). After 6 weeks, subjects were switched to the opposite therapy for 6 weeks. The primary outcome measure was the change in the percentage of glycosylated hemoglobin (%HbA1c) at 6 weeks relative to the baseline value.. Ten patients completed the study. The difference between the mean within-subject changes in %HbA1c associated with 6-week periods of fluticasone and the mean changes associated with montelukast therapy was small but statistically significant (mean difference=0.25; P<0.025). Neither fluticasone nor oral montelukast therapy for 6 weeks led to a significantly different mean % HbA1c compared with the relevant baseline (mean differences=0.11 and -0.14, respectively).. The absence of a clinically significant within-subject difference in the changes in %HbA1c associated with fluticasone versus oral montelukast therapy, or between either therapy or baseline does not warrant recommending changes in therapy for asthma or diabetes in patients with these co-morbid conditions. However, we suggest that clinicians carefully monitor blood glucose control when diabetic patients initiate ICS, especially with higher dosages.

Topics: Acetates; Administration, Inhalation; Adrenal Cortex Hormones; Aged; Androstadienes; Anti-Asthmatic Agents; Bronchodilator Agents; Cross-Over Studies; Cyclopropanes; Diabetes Complications; Diabetes Mellitus, Type 2; Double-Blind Method; Fluticasone; Glucose; Glycated Hemoglobin; Humans; Male; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Quinolines; Sulfides; Treatment Outcome

This study aims to investigate the possibility of additional value of leukotriene receptor antagonist (LTA) on dyspnea score, arterial blood gases (ABG), pulmonary function tests (PFTs), and quality of life (St. George QoL) in chronic obstructive pulmonary disease (COPD) patients. In this randomized, prospective, single-blind, and controlled study, 117 non-reversible COPD patients defined by global initiative for chronic obstructive lung disease (GOLD) criteria were randomized to receive ipratropium bromide, formoterol and montelukast (n:58, montelukast group) or ipratropium bromide and formoterol (n:59, control group) after a 2-week run-in period. There was no significant demographic difference between the two groups (P>0.05). Baseline ABG, PFT, visual analoque scores (VAS), and QoL scores were obtained and at first month and second month, PFT, VAS, and QoL scores were repeated and ABG was obtained at second month and the values were compared with baseline values. As the result of the comparison, there was significant increase in vital capacity, FVC, FEV1, VAS, and PaO2 parameters (P<0.05), and a significant decrease in the QoL scores (P<0.05) in the montelukast group. These parameters did not show any difference in the control group (P>0.05). Sputum samples that could be obtained in 24 of the COPD patients were evaluated and in the montelukast group, there was a decrease in neutrophilic activity after treatment (n:13) (P:0.059). These results suggest that LTA that is used additionally in routine treatment protocol can produce additive improvement on PFT, dyspnea score and especially QoL in patients with stable COPD and for these reasons, LTA may be taken into account when there is need for an additional anti-inflammatory treatment in COPD patients.

Topics: Acetates; Aged; Cyclopropanes; Dyspnea; Female; Humans; Leukotriene Antagonists; Male; Middle Aged; Neutrophils; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolines; Respiratory Function Tests; Single-Blind Method; Sputum; Sulfides

This study assessed the effect of the leukotriene receptor antagonist montelukast on hypertonic saline-induced airway obstruction. A total of 29 patients with chronic obstructive pulmonary disease (forced expiratory volume in one second (FEV1), 42+/-4% predicted) received either 10 mg montelukast and 3 h later placebo via metered-dose inhaler (MDI) (M), or placebo and 3 h later 200 microg salbutamol (S), or two doses of placebo (P), in a randomised order. Patients inhaled salbutamol 1 h after MDI and the challenge was performed 15 min later (3% saline, 5 min). Data are given as per cent changes versus baseline. Compared to P, S caused significant bronchodilation in FEV1 (7.3%) and forced inspiratory volume in one second (FIV1) (4.5%), and M in FIV1 (1.5%). The saline-induced fall in FEV1 was lower after M (-5.8%), compared with S (-10.3%) and P (-13.1%). FEV1 (11.3%) and FIV1 (7.6%) was improved over baseline after recovery by M but not P and S. Recovery times regarding FEV1 (8.5 min) and FIV1 (15.2 min) were shortest after M, respective values for S being 16.8 and 20.4 min, and for P 15.9 and 21.2 min. Effects were strongest in patients with low baseline FEV1 and/or inhaled corticosteroids. Data from this study indicate beneficial effects of montelukast on hypertonic saline-induced airway responses in patients with chronic obstructive pulmonary disease, particularly those with severe disease. The major effect was an accelerated recovery leading to values above baseline.

Topics: Acetates; Administration, Inhalation; Administration, Oral; Aged; Airway Obstruction; Albuterol; Bronchodilator Agents; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Female; Humans; Leukotriene Antagonists; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolines; Recovery of Function; Respiratory Function Tests; Saline Solution, Hypertonic; Solutions; Sulfides; Treatment Outcome

Airway inflammation in chronic obstructive pulmonary disease (COPD) is refractory to corticosteroids and hence COPD treatment is hindered and insufficient. This study assessed the effects of oral treatment with Montelukast (10 and 30 mg/kg) or dexamethasone (20 mg/kg) for 20 days on COPD model induced by chronic exposure to lipopolysaccharide (LPS). Six groups of male guinea pigs were studied. Group 1: naïve group, group 2: exposed to saline nebulization. Groups 3, 4, 5, and 6: exposed to 9 nebulizations of LPS (30 μg/ml) for 1 hour, 48 hours apart with or without treatment with Montelukast or dexamethasone. Airway hyperreactivity (AHR) to methacholine (MCh), histopathological study and bronchoalveolar lavage fluid (BALF) as well as lung tissue analyses were performed 48 hours after the final exposure to LPS (day 20). LPS-induced pulmonary dysfunction was associated with increased neutrophil count, leukotriene (LT) B4, and tumor necrosis factor (TNF)-α in BALF. Moreover, there was an increase in malondialdehyde (MDA) level and a decrease in histone deacetylases(HDAC) activity in the lung tissue. Both Montelukast (10 or 30 mg /kg) and dexamethasone significantly reduced neutrophil count in BALF and inflammatory cells in lung parenchyma as well as TNF-α, and MDA levels. However, dexamethasone was more effective (p < 0.05). Montelukast, at a dose of 30 mg /kg, significantly reduced specific airway resistance after the 9th LPS exposure, attenuated AHR to MCh, decreased LTB4 and increased HDAC activity in comparison to dexamethasone. These results suggest that treatment with Montelukast can be useful in chronic airway inflammatory diseases including COPD poorly responsive to glucocorticoids.

Topics: Acetates; Animals; Bronchoalveolar Lavage Fluid; Chronic Disease; Cyclopropanes; Dexamethasone; Disease Models, Animal; Glucocorticoids; Guinea Pigs; Histone Deacetylases; Inflammation; Leukocyte Count; Leukotriene Antagonists; Leukotriene B4; Lipopolysaccharides; Lung; Male; Malondialdehyde; Neutrophils; Pulmonary Disease, Chronic Obstructive; Quinolines; Respiratory Hypersensitivity; Sulfides; Tumor Necrosis Factor-alpha

The purpose of this retrospective study was to determine the effects of long-term treatment with montelukast on chronic obstructive pulmonary disease (COPD) control in a cohort of patients with moderate to severe COPD. The medical records of 20 consecutive male patients (18 African-Americans) aged 71.2 +/- 10.7 years diagnosed with moderate to severe COPD at the VA Chicago Health Care System, Chicago, Illinois, USA, and treated with oral montelukast, 10 mg every night, for 23.6 +/- 7.3 months were reviewed. Information on demographics and COPD control was extracted from each record. In each patient, a comparable follow-up period in the clinic before and after initiating montelukast therapy was reviewed and tabulated so each patient served as his own control. There was a significant improvement in complaints of shortness of breath, sputum production wheezing and nocturnal symptoms during the observation period (P < 0.05). There was a significant reduction in the use of oral and inhaled corticosteroids, inhaled bronchodilators and supplemental oxygen (P < 0.05). In addition, there was a significant reduction in the number of visits to the emergency department, number of hospitalizations and duration of hospitalizations for acute exacerbations of COPD (P < 0.05). No significant changes in FEV1 (% predicted), FEV1/FVC ratio (% predicted) and peak expiratory flow rate were recorded during this time. No side effects where reported during the observation period and no patient discontinued the medication. Collectively, these data suggest that long-term treatment with montelukast is safe and improves COPD control in elderly patients with moderate to severe COPD.

Topics: Acetates; Aged; Cyclopropanes; Forced Expiratory Volume; Humans; Leukotriene Antagonists; Long-Term Care; Male; Pulmonary Disease, Chronic Obstructive; Quinolines; Retrospective Studies; Sulfides; Vital Capacity

Five horses with moderate to severe chronic obstructive pulmonary disease (COPD) were treated with 0.11 (0.01) mg/kg bodyweight of montelukast, a cysteinyl leukotriene receptor antagonist, once a day for 26 days. The horses were evaluated clinically and endoscopically and subjected to arterial blood gas analysis and lung function tests before and after the period of treatment, and the plasma concentrations of montelukast were determined by high-performance liquid chromatography with fluorescence detection. The treatment did not result in statistically significant differences in the total scores of clinical and endoscopical signs, or in the difference in the arterioalveolar partial pressure of oxygen, maximal changes in pleural pressure, pulmonary resistance or dynamic compliance. The mean (sd) peak plasma concentration (C(max0) of montelukast was 12 (4) ng/ml and was reached 66 (13) minutes (t(max)) after its oral administration. The dose of montelukast per kg bodyweight was approximately the same as that for human beings, but the C(max) in the horses was 28 times lower and the t(max) was reached in one-fifth of the time, suggesting that its oral bioavailability may be lower.

Topics: Acetates; Animals; Cyclopropanes; Female; Horse Diseases; Horses; Leukotriene Antagonists; Male; Pulmonary Disease, Chronic Obstructive; Quinolines; Respiration; Severity of Illness Index; Sulfides; Treatment Outcome