The effect of montelukast (MK-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 eosinophils in vitro and within the airways of animals and humans in vivo.


OBJECTIVE
We hypothesized that montelukast (MK-0476), a potent cysLT1 receptor antagonist, would protect against allergen-induced early (EAR) and late (LAR) asthmatic responses by virtue of anti-inflammatory properties. Hence, we studied the effect of pretreatment with oral montelukast on allergen-induced airway responses. As an exploratory endpoint, changes in inflammatory 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, histamine 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 administered 36 and 12 h before, and 12 h post-allergen. The airway response to allergen was measured by FEV1, and the EAR and LAR were expressed as the corresponding areas under the time-response curves (AUC0-3 h and AUC3-8h, respectively). During each study period, sputum was induced with 4.5% NaCl 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 supernatants.


RESULTS
All subjects completed the study. The changes in baseline FEV1 were not significantly different between the two pretreatments (P = 0.183). Montelukast significantly inhibited the EAR and LAR, reducing the AUC0-3h by 75.4% (P<0.001) and the AUC3-8h by 56.9% (P = 0.003) as compared with placebo. Sputa of nine subjects could be included in the analysis (<80% squamous 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). The 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).


CONCLUSIONS
We conclude that oral montelukast protects against allergen-induced early and late airway responses in asthma. However, using the present dosing and sample size, this protection was not accompanied with changes in sputum eosinophil percentage or activity, which may require more prolonged pretreatment with cysLT1 receptor antagonists.
Department of Pulmonology, Leiden University Medical Center, The Netherlands.
Z
Z
Diamant
D C
DC
Grootendorst
M
M
Veselic-Charvat
M C
MC
Timmers
M
M
De Smet
J A
JA
Leff
B C
BC
Seidenberg
A H
AH
Zwinderman
I
I
Peszek
P J
PJ
Sterk
D000085:Acetates / Q000494:pharmacology*; D000328:Adult; D000485:Allergens / Q000008:administration & dosage / Q000009:adverse effects; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology*; D001798:Blood Proteins / Q000187:drug effects / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D002452:Cell Count / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004311:Double-Blind Method; D047091:Eosinophil Granule Proteins; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D006969:Hypersensitivity, Immediate / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D008297:Male; D010349:Patient Compliance; D011804:Quinolines / Q000494:pharmacology*; D012260:Ribonucleases; D013183:Sputum / Q000166:cytology / Q000187:drug effects*; D013440:Sulfides; D016896:Treatment Outcome
D000085:Acetates; D000485:Allergens; D018927:Anti-Asthmatic Agents; D001798:Blood Proteins; D003521:Cyclopropanes; D047091:Eosinophil Granule Proteins; D020024:Leukotriene Antagonists; D011804:Quinolines; D013440:Sulfides; D012260:Ribonucleases; C093875:montelukast