The leukotriene-receptor antagonist MK-0679 blocks airway obstruction induced by inhaled lysine-aspirin in aspirin-sensitive asthmatics

Drugs which block the action or formation of the cysteinyl-leukotrienes (LTC₄, LTD₄ and LTE₄) inhibit asthmatic responses evoked by allergen, exercise and cold dry air. The purpose of this study was to determine whether the specific leukotriene-receptor antagonist MK-0679 could block the airway obstruction induced by aspirin (acetylsalicylic acid (ASA)) in aspirin-intolerant asthmatics. Eight asthmatics (mean age 45 yrs), with an average history of asthma and ASA-sensitivity of about 10 yrs duration, were subjected to bronchial provocation with lysine-ASA. Baseline ASA-sensitivity was first determined in an open prestudy session by inhalation of cumulative doses of lysine-ASA to establish the dose of ASA decreasing forced expiratory volume in one second (FEV₁) by 20% (PD₂₀). Rechallenge with lysine-ASA was performed on two different occasions, 1 h after oral administration of placebo, or 750 mg of MK-0679, under double-blind conditions, in a randomized, cross-over design. Leukotriene formation was estimated by the measurement of urinary LTE₄. The lysine-ASA challenge was highly reproducible (geometric mean for group PD₂₀ being identical for the open prestudy and the placebo session), and was associated with a post-challenge increase in urinary LTE₄. In contrast, after MK-0679, there was a rightward shift in the dose response relationship for all eight subjects (median shift being 4.4 fold), with three of the subjects failing to produce a 20% decrease in FEV₁ despite inhalation of the highest dose of lysine-ASA feasible to deliver. In conclusion, the leukotriene-antagonist MK-0679 substantially inhibited the airway response to inhalation of lysine-ASA, providing direct evidence that leukotrienes are mediators of ASA-induced bronchoconstriction.