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.(ABSTRACT TRUNCATED AT 250 WORDS)
Dept of Thoracic Medicine, Karolinska Hospital, Stockholm, Sweden.
B
B
Dahlén
M
M
Kumlin
D J
DJ
Margolskee
C
C
Larsson
H
H
Blomqvist
V C
VC
Williams
O
O
Zetterström
S E
SE
Dahlén
D001241:Aspirin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D001249:Asthma / Q000175:diagnosis / Q000503:physiopathology*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000502:physiology; D008239:Lysine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D011422:Propionates / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018077:Receptors, Leukotriene
D001993:Bronchodilator Agents; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011422:Propionates; D011804:Quinolines; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; C059141:verlukast; D008239:Lysine; D001241:Aspirin; C010395:acetylsalicylic acid lysinate