Inhibition of leukotriene D4-induced bronchoconstriction in normal subjects by the oral LTD4 receptor antagonist ICI 204,219.
The sulfidopeptide leukotrienes may play a role in the pathogenesis of asthma. Previous clinical trials with leukotriene antagonists have shown only minimal protection from subsequent challenge with inhaled LTD4. Using a double-blind, placebo-controlled crossover design, we tested the hypothesis that the LTD4 receptor antagonist, ICI 204,219, could inhibit LTD4-induced bronchoconstriction in normal subjects. On separate days, 3 to 7 days apart, a single oral 40-mg dose of ICI 204,219 or placebo was ingested. At 2 h (Group I), 12 h (Group II), or 24 h (Group III) after the dose, six subjects in each group underwent bronchoprovocation testing with aerosolized LTD4. The airway response was assessed by measuring specific airway conductance (SGaw) and the FEV1. ICI 204,219 had no effect on baseline pulmonary function. When given 2 h before the LTD4 challenge, ICI 204,219 increased by 117-fold the concentration of LTD4 required to reduce SGaw 35%: 34 +/- 10 versus 3,965 +/- 894 micrograms/ml (placebo versus ICI 204,219; p less than 0.05). When given 12 h before the LTD4 challenge, ICI 204,219 increased by ninefold the concentration of LTD4 required to reduce SGaw 35%: 33 +/- 11 versus 304 +/- 125 micrograms/ml (p less than 0.05). When given 24 h before the LTD4 challenge, a smaller effect was found: 12 +/- 3 versus 60 +/- 24 micrograms/ml (p less than 0.05). Plasma levels of ICI 204,219 correlated with efficacy across groups (r = 0.83, p less than 0.001), but imperfectly within groups. No adverse effects (symptoms or abnormal laboratory test results) were noted after ingesting the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
Smith
L J
LJ
Department of Medicine, Northwestern University, Chicago, IL 60611.
Geller
S
S
Ebright
L
L
Glass
M
M
Thyrum
P T
PT
D000293:Adolescent; D000328:Adult; D000403:Airway Resistance / Q000187:drug effects*; D001980:Bronchi / Q000187:drug effects*; D001985:Bronchial Provocation Tests; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007211:Indoles; D008297:Male; D048448:Phenylcarbamates; D011897:Random Allocation; D011971:Receptors, Immunologic / Q000187:drug effects*; D018077:Receptors, Leukotriene; D012129:Respiratory Function Tests; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*
D007211:Indoles; D048448:Phenylcarbamates; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D013449:Sulfonamides; D014105:Tosyl Compounds; C062735:zafirlukast