Potent leukotriene D4 receptor antagonist ICI 204,219 given by the inhaled route inhibits the early but not the late phase of allergen-induced bronchoconstriction.
ICI 204,219 is a potent and specific leukotriene D4 receptor antagonist that blocks both the early and late responses to allergen challenge in humans when given orally at a dose of 40 mg. Here we report our findings with an inhaled formulation of ICI 204,219 against allergen-induced bronchoconstriction. A group of 10 atopic subjects (mean age 25.6 +/- 4.2; 6 females; FEV1 > 90% of predicted; on inhaled beta 2-agonists only) were studied on 2 separate days 2 to 3 wk apart. In a randomized placebo-controlled trial they inhaled eight puffs of a standard metered dose inhaler containing either ICI 204,219 (200 micrograms/puff, total dose 1,600 micrograms) or propellant alone. They underwent bronchial allergen challenge 30 min later using a single concentration of allergen previously shown to lower the FEV1 by > or = 15%. FEV1 was monitored hourly for 10 h, and urine was collected for LTE4 determination. Inhalation of ICI 204,219 was well tolerated, with no adverse clinical or biochemical effects. There was no significant effect of ICI 204,219 inhalation on basal airway caliber (change in FEV1 30 min after inhalation was -149 +/- 67 ml after placebo versus 3 +/- 38 ml after ICI 204,219; p = 0.08). The early response to allergen was significantly inhibited by ICI 204,219 (the maximum fall in FEV1 was -21.2 +/- 6.1% after ICI 204,219 compared with -38.8 +/- 6.5% on placebo; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)
O'Shaughnessy
K M
KM
Department of Clinical Pharmacology and Medicine, Royal Postgraduate Medical School, London, UK.
Taylor
I K
IK
O'Connor
B
B
O'Connell
F
F
Thomson
H
H
Dollery
C T
CT
D000280:Administration, Inhalation; D000328:Adult; D000485:Allergens; D000704:Analysis of Variance; D001249:Asthma / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects*; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D007211:Indoles; D017999:Leukotriene E4; D008297:Male; D048448:Phenylcarbamates; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000031:analogs & derivatives / Q000652:urine; D013449:Sulfonamides; D013997:Time Factors; D014105:Tosyl Compounds / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology
D000485:Allergens; D007211:Indoles; D048448:Phenylcarbamates; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D013449:Sulfonamides; D014105:Tosyl Compounds; D017999:Leukotriene E4; C062735:zafirlukast