The effect of montelukast (Mg-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma

Background Cysteinyl leukotrienes are capable of inducing chemotaxis of eos inophils in vitro and within the airways of animals and humans in vivo. Objective We hypothesized that montelukast (MK-0476), a potent cysLT(1) rec eptor antagonist, would protect against allergen-induced early (EAR) and la te (LAR) asthmatic responses by virtue of anti-inflammatory properties. Hen ce, we studied the effect of pretreatment with oral montelukast on allergen -induced airway responses. As an exploratory endpoint, changes in inflammat ory cell differentials and eosinophil cationic protein (ECP) were evaluated in hypertonic saline-induced sputum. Methods Twelve asthmatic men (20-34 years, FEV1 79-109% predicted, histamin e PC20FEV1 <4 mg/mL) with dual responses to inhaled house dust mite extract participated in a two-period, double-blind, placebo-controlled, crossover study. Three oral doses of montelukast (10 mg) or matching placebo were adm inistered 36 and 12 h before, and 12 h post-allergen. The airway response t o allergen was measured by FEV1, and the EAR and LAR were expressed as the corresponding areas under the time-response curves (AUC(0-3 h) and AUC(3-8 h), respectively). During each study period, sputum was induced with 4.5% N aCl 24 h before and 24 h after a standardized allergen challenge. Processed whole sputum cytospins were stained with Giemsa, and cell counts expressed as percentage nonsquamous cells. ECP was measured by FEIA in sputum supern atants. Results All subjects completed the study. The changes in baseline FEV1 were not significantly different between the two pretreatments (P = 0.183). Mon telukast significantly inhibited the EAR and LAR, reducing the AUC(0-3 h) b y 75.4% (P < 0.001) and the AUC3-8h by 56.9% (P = 0.003) as compared with p lacebo. Sputa of nine subjects could be included in the analysis (<80% squa mous cells). Allergen challenge significantly increased sputum eosinophils after placebo (mean change +/- SD: 4.8 +/- 5.8%, P = 0.038), with a similar trend after montelukast (mean change +/- SD: 4.1 +/-. 5.4%; P = 0.056). Th e allergen-induced changes in sputum eosinophils and ECP, however, were not significantly different between the two pretreatments (P = 0.652 and P = 0 .506, respectively). Conclusion We conclude that oral montelukast protects against allergen-indu ced early and late airway responses in asthma. However, using the present d osing and sample size, this protection was not accompanied with changes in sputum eosinophil percentage or activity, which may require more prolonged pretreatment with cysLT(1) receptor antagonists.