Oral leukotriene inhibitor (MK-886) blocks allergen-induced airway responses.
To elucidate the role of leukotrienes (LT) in allergic asthma in humans the effect of MK-886, an LT biosynthesis inhibitor, was evaluated on antigen-induced early (EAR) and late (LAR) asthmatic reactions and bronchial responsiveness to histamine. Eight atopic men participated in a two-part, double-blind, placebo-controlled, crossover trial. MK-886 was administered in two oral doses of 500 mg and 250 mg, 1 h before and 2 h after allergen inhalation, respectively. Biochemical effects of MK-886 were evaluated by the inhibition of urinary LTE4 excretion and calcium ionophore-stimulated LTB4 biosynthesis in whole blood ex vivo. MK-886 significantly inhibited the EAR by 58.4% (AUC0-3 h) and the LAR by 43.6% (AUC3-7 h) when compared with placebo (p < 0.01). There was no difference in PC20 histamine 30 h post allergen challenge between MK-886 and placebo (0.33 and 0.27 doubling doses, p > 0.1). MK-886 inhibited calcium ionophore-stimulated LTB4 production in whole blood (54.2 +/- 25.6%) for up to 6 h post allergen challenge. LTE4 excretion in urine was inhibited by 51.5% during the EAR by as much as 80% during the LAR. This indicates that LT play a role in allergen-induced asthmatic reactions in humans in vivo and that LT synthesis inhibitors such as MK-886 should be further explored for the treatment of asthma.
Clinical Pharmacology Department, Merck Research Laboratories, Rahway, NJ 07065.
B S
BS
Friedman
E H
EH
Bel
A
A
Buntinx
W
W
Tanaka
Y H
YH
Han
S
S
Shingo
R
R
Spector
P
P
Sterk
D000284:Administration, Oral; D000328:Adult; D000485:Allergens; D001249:Asthma / Q000378:metabolism / Q000503:physiopathology*; D001985:Bronchial Provocation Tests; D004311:Double-Blind Method; D004341:Drug Evaluation; D006632:Histamine; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D020024:Leukotriene Antagonists; D017999:Leukotriene E4; D008297:Male; D013189:SRS-A / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000097:blood; D002722:Chlorobenzenes
D000485:Allergens; D006632:Histamine; D007211:Indoles; D020024:Leukotriene Antagonists; D017999:Leukotriene E4; D013189:SRS-A; C060893:MK-886; D002722:Chlorobenzenes