Cysteinyl leukotrienes promote human airway smooth muscle migration.

O'Byrne PM.

Asthma Research Group, Firestone Institute for Respiratory Health, St. Joseph's Healthcare, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Cysteinyl leukotrienes promote airway smooth muscle (ASM) contraction and proliferation. Little is known about their role in ASM migration. We investigated this using cultured human ASMs (between the second and fifth passages) obtained from the large airways of resected nonasthmatic lung. Platelet-derived growth factor-BB (1 ng/ml) promoted significant (3.5-fold) ASM migration of myocytes across collagen-coated 8- micro m polycarbonate membranes in Transwell culture plates. Leukotriene E(4) (10(-7), 10(-8), 10(-9) M) did not demonstrate a chemotactic effect; it did promote chemokinesis. Priming by leukotriene E(4) (10(-7) M) significantly augmented the directional migratory response to platelet-derived growth factor (1.5-fold, p < 0.05). This was blocked by montelukast (10(-6) M), demonstrating the effect to be mediated by the cysteinyl leukotriene receptor. The "priming effect" was also partially attenuated by prostaglandin E(2) (10(-7) M). Whereas both the chemokinetic and the chemotactic "primed" responses were equally attenuated by a p38 mitogen-activated protein kinase inhibitor (SB203580, 25 micro M) and by a Rho-kinase inhibitor (Y27632, 10 micro M), the chemotactic response showed greater inhibition than chemokinesis by a phosphatidylinositol-3 kinase inhibitor (LY294002, 50 micro M). These experiments suggest that cysteinyl leukotrienes play an augmentary role in human ASM migration. The phosphatidylinositol-3 kinase pathway is a key signaling mechanism in the chemotactic migration of ASM cells in response to cysteinyl leukotrienes.

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Fluticasone is associated with lower asthma-related costs than leukotriene modifiers in a real-world analysis.

Malone DC.

College of Pharmacy, University of Arizona, Tucson 85721, USA.

STUDY OBJECTIVE: To compare the impact of fluticasone propionate versus three leukotriene modifiers-montelukast, zafirlukast, and zileuton-on the cost of asthma within a managed care organization. DESIGN: Retrospective quasi-experimental comparison. SETTING: Managed care organization with approximately 350,000 enrollees. PATIENTS: Three hundred forty-seven patients with asthma who received at least two prescriptions for either fluticasone or a leukotriene modifier. Patients receiving both fluticasone and a leukotriene modifier were excluded. MEASUREMENTS AND MAIN RESULTS: Multivariate analysis was used to compare total asthma-related costs between treatment groups. A significant difference in total asthma-related costs was found between patients receiving fluticasone (adjusted mean cost $511) compared with those receiving a leukotriene modifier ($1,092; p=0.0001). Other significant predictors of postindex asthma-related costs were pre-index asthma-related costs, a severity adjustment score, and the diagnosis of chronic obstructive pulmonary disease. Patients taking a leukotriene modifier obtained more short-acting beta-agonists than patients receiving fluticasone (6.49 +/- 4.05 vs 4.30 +/- 3.41, p < 0.0001). A survival analysis of time to receive any additional controller therapy revealed that patients receiving fluticasone were significantly less likely to receive another controller than were those receiving a leukotriene modifier (p=0.0014). CONCLUSION: These results suggest that fluticasone is associated with lower asthma-related costs than leukotriene modifiers.

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[Potential gastroprotective effect of a CysLT1 receptor blocker sodium montelukast in aspirin-induced lesions of the rat stomach mucosa]

[Article in Russian]

Panchenko AV.

Valdman Institute of Pharmacology, Pavlov State Medical University, ul. L. Tolstogo 6/8, St. Petersburg, 197022 Russia.

Montelukast sodium, a specific leukotriene receptor (CysLT1) blocker administered orally in a dose of 40 mg/kg prevented the stomach mucosa in rats from acute erosive gastritis model induced by acetylsalicylic acid (150 mg/kg, p.o.) in male albino Wistar rats. The potential role of a "5-lipooxygenase shunting" of the arachidonic acid metabolism in the gastrointestinal toxicity of non-selective cyclooxygenase inhibitors is discussed.

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Application of pressurized liquid extraction technology to pharmaceutical solid dosage form analysis.

Di Maso M.

Department of Pharmaceutical Research and Development, Merck Frosst Canada & Co., Pointe Claire-Dorval, QC, Canada. thanh_hoang merck.com

The technique of pressurized liquid extraction has been evaluated for the extraction of active ingredients from pharmaceutical dosage forms using montelukast sodium oral chewable tablets as a model. The extraction method was optimized for the number of extraction cycles, extraction time, extraction solvent composition and temperature. Samples were extracted using two cycles of water for 2 min with a cell temperature of 40 degrees C and a pressure of 1.0 x 10(4) kPa, to disintegrate the tablet, followed by three cycles of methanol for 3 min at 70 degrees C and 1.0 x 10(4) kPa, to solubilize montelukast sodium. The method demonstrated an extraction efficiency of 98.2% of label claim and an RSD of 1.3% (n=10), as compared to 97.6% and an RSD of 0.9% obtained using a validated mechanical extraction method.

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Montelukast prevents antigen-induced mucociliary dysfunction in sheep.

Abraham WM.

Division of Pulmonary and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida 33140, USA.

The cysteinyl leukotrienes are potent proinflammatory mediators that, in addition to their bronchospastic actions, can also contribute to mucociliary dysfunction, a central component of the pathophysiology of asthma. In this study, we determined whether montelukast, a cysteinyl leukotriene 1 receptor antagonist, could prevent and/or reverse antigen-induced mucociliary dysfunction in allergic sheep. We measured tracheal mucus velocity, a marker of mucociliary clearance, before and for 8 hours after antigen challenge in six animals treated with montelukast (0.15 mg/kg, intravenously) 30 minutes before, 1 hour after, or 4 hours after antigen challenge. In the control trial, the sheep received 0.9% saline intravenously at each of the previously mentioned time points. The maximum decrease in tracheal mucus velocity seen in the control trial was 56 +/- 4% (mean +/- SE) of baseline at 8 hours. Pretreatment with montelukast significantly protected against this reduction. However, treatment at 1 and 4 hours neither protected against nor reversed the allergen-induced fall in tracheal mucus velocity. We conclude that the early release of cysteinyl leukotrienes may contribute to the fall in tracheal mucus velocity that follows acute antigen challenge and that pretreatment with montelukast reduces this impairment.

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