verlukast and Airway-Obstruction

To evaluate the effect of a potent experimental leukotriene receptor antagonist, MK-571, on airway responses to inhaled allergen.. Randomized, double-blind, placebo-controlled, crossover trial.. Clinical research center.. Eight male volunteers with allergic asthma.. An intravenous loading dose was followed by an 8-hour infusion of MK-571 or placebo, with a 7- to 14-day washout between treatments. Allergen challenge was performed after the loading dose and a histamine challenge was performed before and 24 hours after allergen.. Forced expiratory volume in 1 second was measured serially. MK-571 provided about 50% protection during maximum early and late responses compared with placebo (p=0.005), but airway obstruction persisted 8-24 hours after allergen on both treatment days. Airway responsiveness to histamine was not significantly attenuated at 24 hours.. Blocking Cys LT1 receptors for 8 hours attenuated the early and late responses but did not interrupt the cascade of events leading to subsequent allergen-induced airway obstruction and hyperreactivity.

Topics: Adult; Airway Obstruction; Allergens; Bronchial Hyperreactivity; Cross-Over Studies; Cysteine; Double-Blind Method; Forced Expiratory Volume; Humans; Leukotriene Antagonists; Leukotrienes; Male; Propionates; Quinolines

The cysteinyl leukotrienes (LTC4, LTD4, and LTE4) have been shown to mediate airway obstruction evoked by several factors which trigger asthmatic reactions--for example, allergen and exercise. Accordingly, drugs which block the action or formation of these leukotrienes are being evaluated as a new treatment of asthma. Elevated production of leukotrienes has been reported in asthmatic subjects who are intolerant to aspirin and related nonsteroidal anti-inflammatory drugs. In this study the influence of the specific leukotriene receptor antagonist MK-0679 was tested on basal airway function in asthmatic patients with documented aspirin intolerance.. The eight subjects in the study had a mean baseline FEV1 of 78% predicted (range 58-99%) and six required treatment with inhaled glucocorticosteroids (400-1200 micrograms budesonide/beclomethasone daily). On two separate days the subjects received either 825 mg MK-0679 or placebo, orally in a double blind, randomised, crossover design.. The leukotriene antagonist MK-0679 caused bronchodilation which lasted for at least nine hours. The average peak improvement in FEV1 was 18% above the predrug baseline, but the bronchodilator response varied between 34% and 5% and was found to correlate strongly with the severity of asthma and aspirin sensitivity.. The findings indicate that ongoing leukotriene production may be one cause of persistent airway obstruction in aspirin sensitive asthmatic subjects and that they may benefit from treatment with a leukotriene receptor antagonist.

Topics: Adult; Airway Obstruction; Aspirin; Asthma; Bronchi; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Propionates; Quinolines; SRS-A

The sulfidopeptide leukotrienes LTC4, LTD4, and LTE4 can cause airway smooth muscle contraction and have been implicated in the pathophysiology of asthma. MK-571 is a selective, potent LTD4 receptor antagonist that could attenuate airway obstruction in asthma by inhibiting the actions of sulfidopeptides at the LTD4 receptor site. The objectives of this study were to investigate the potential for MK-571 to cause bronchodilation in asthma patients with existing airway obstruction and to evaluate its effect on the bronchodilation response to an inhaled beta 2-agonist (albuterol). Twelve male patients (ages 19 to 42 yr) with asthma (baseline FEV1 50 to 80% predicted) participated in this placebo-controlled, randomized, two-period, cross-over study. On separate treatment days, each patient received either MK-571 or placebo intravenously for 6 h; inhaled albuterol was administered at the fifth and sixth hour of MK-571/placebo treatment to achieve maximal bronchodilation on that study day. Spirometry (forced expiratory volume in 1 s, FEV1) was monitored at intervals throughout each study period. MK-571 caused clinically significant bronchodilation; the increase in FEV1 above baseline, 20 min after the start of the MK-571 infusion, was 22 +/- 3.9% compared with 1.3 +/- 2.3% for placebo (mean +/- SE, p < 0.01). This degree of bronchodilation was maintained throughout the MK-571 infusion. In addition, bronchodilation from inhaled albuterol appeared additive with MK-571. Finally, baseline airway obstruction correlated with the degree of bronchodilation achieved with MK-571 (r = -0.73; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Airway Obstruction; Albuterol; Analysis of Variance; Asthma; Double-Blind Method; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Propionates; Quinolines; SRS-A