THE LEUKOTRIENE-RECEPTOR ANTAGONIST MK-0679 BLOCKS AIRWAY-OBSTRUCTIONINDUCED BY INHALED LYSINE-ASPIRIN IN ASPIRIN-SENSITIVE ASTHMATICS

Drugs which block the action or formation of the cysteinyl-leukotriene s (LTC4, LTD4 and LTE4) inhibit asthmatic responses evoked by allergen , exercise and cold dry air. The purpose of this study was to determin e whether the specific leukotriene-receptor antagonist MK-0679 could b lock 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 1 0 yrs duration, were subjected to bronchial provocation with lysine-AS A. Baseline ASA-sensitivity was first determined in an open prestudy s ession by inhalation of cumulative doses of lysine-ASA to establish th e dose of ASA decreasing forced expiratory volume in one second (FEV1) by 20% (PD20). Rechallenge with lysine-ASA was performed on two diffe rent occasions, 1 h after oral administration of placebo, or 750 mg of MK-0679, under double-blind conditions, in a randomized, cross-over d esign. Leukotriene formation was estimated by the measurement of urina ry LTE4. The lysine-ASA challenge was highly reproducible (geometric m ean for group PD20 being identical for the open prestudy and the place bo session), and was associated with a post-challenge increase in urin ary LTE4. In contrast, after MK-0679, there was a rightward shift in t he dose response relationship for all eight subjects (median shift bei ng 4.4 fold), with three of the subjects failing to produce a 20% decr ease in FEV1 despite inhalation of the highest dose of lysine-ASA feas ible to deliver. In conclusion, the leukotriene-antagonist MK-0679 sub stantially inhibited the airway response to inhalation of lysine-ASA, providing direct evidence that leukotrienes are mediators of ASA-induc ed bronchoconstriction.