Acute bronchodilation with an intravenously administered leukotriene D4 antagonist, MK-679.
Descriptive studies suggest an association between the release of the cysteinyl leukotrienes and clinical asthma. To help clarify this association, we tested the hypothesis that an intravenous infusion of a potent and specific investigational LTD4 receptor antagonist, MK-679, would cause rapid bronchodilation. In a three-period, randomized, double-blind, crossover study, single doses of MK-679, 125 and 500 mg, and placebo were given intravenously by bolus infusion to nine patients with moderate, stable asthma (FEV1 40 to 80% predicted) on individual study days separated by a week. Spirometry was preformed predose and at intervals for as long as 8 h postdosing; blood samples for MK-679 concentrations were drawn over this time. Fifteen minutes after the end of infusion, the FEV1 percent change from baseline increased a mean of 15.8 +/- 15.7 and 7.8 +/- 11.6% with the 500- and 125-mg doses, respectively, compared with a mean decrease of 2.6 +/- 6.2% with placebo (p = 0.01, overall; p = 0.003, 500 mg versus placebo). The mean end-of-infusion MK-679 plasma concentrations were 86.2 +/- 13.9 and 19.9 +/- 2.7 micrograms/ml for the 500- and 125-mg doses, respectively. MK-679 was well-tolerated, with no significant adverse experiences observed. We conclude that a single, intravenously administered, bolus infusion of MK-679 causes bronchodilation in patients with moderate, stable asthma.
Impens
N
N
Department of Pneumology, Academic Hospital, Brije Universiteit Brussel, Belgium.
Reiss
T F
TF
Teahan
J A
JA
Desmet
M
M
Rossing
T H
TH
Shingo
S
S
Zhang
J
J
Schandevyl
W
W
Verbesselt
R
R
Dupont
A G
AG
D000328:Adult; D000704:Analysis of Variance; D001249:Asthma / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology / Q000503:physiopathology; D001980:Bronchi / Q000187:drug effects* / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011422:Propionates / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018077:Receptors, Leukotriene
D001993:Bronchodilator Agents; D011422:Propionates; D011804:Quinolines; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; C059141:verlukast