Effects of a potent platelet-activating factor antagonist, SR27417A, on allergen-induced asthmatic responses.
Platelet-activating factor (PAF) is a lipid-derived mediator that has been implicated in the pathophysiology of airway inflammation in asthma. Its actions include chemotaxis and activation of inflammatory cells, particularly eosinophils. Inhaled PAF causes bronchoconstriction and increased airway responsiveness in human subjects. However, PAF antagonists have so far failed to show benefits in allergen challenge or in the treatment of chronic asthma. SR27417A is a novel PAF antagonist with increased potency compared with previously tested compounds. Twelve asthmatic subjects received treatment with either SR27417A or placebo for 1 wk in a double-blind crossover study. After treatment each subject underwent allergen challenge. Effects were assessed in terms of early and late asthmatic responses and allergen-induced effects on airway responsiveness. Baseline lung function and airway responsiveness were also examined. Treatment with SR27417A significantly attenuated the late asthmatic response (AUC LAR4-10h: 107 +/- 24 after placebo, 79 +/- 17 after SR27417A, p < 0.05; mean maximal percent fall in FEV1 LAR: 29 +/- 6% after placebo, 23.5 +/- 5.4% after SR27417A, p < 0.05). There were no effects on early asthmatic responses, allergen-induced airway responsiveness, or baseline lung measurements. SR27417A is the most potent PAF antagonist to date, and it has a modest inhibitory effect on the late asthmatic response. This suggests that PAF has a small role in allergic inflammation.
Evans
D J
DJ
Clinical Studies Unit, Royal Brompton Hospital, London, United Kingdom.
Barnes
P J
PJ
Cluzel
M
M
O'Connor
B J
BJ
D000328:Adult; D000485:Allergens / Q000009:adverse effects; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
D000485:Allergens; D010972:Platelet Activating Factor; D013844:Thiazoles; C071317:Foropafant