B. Dahlen et al., THE LEUKOTRIENE-RECEPTOR ANTAGONIST MK-0679 BLOCKS AIRWAY-OBSTRUCTIONINDUCED BY INHALED LYSINE-ASPIRIN IN ASPIRIN-SENSITIVE ASTHMATICS, The European respiratory journal, 6(7), 1993, pp. 1018-1026
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.