Inhibitory effect of UK,74505, a potent and specific oral platelet activating factor (PAF) receptor antagonist, on airway and systemic responses to inhaled PAF in humans.
Inhaled PAF provokes bronchoconstriction, causes peripheral blood neutropenia with rebound neutrophilia, and generates urinary production of the bronchoconstrictor eicosanoids, thromboxane (TX)A2, and the cysteinyl leukotrienes. We examined the effects of an oral PAF antagonist UK,74505 on each of these responses to a single 36 micrograms dose of inhaled PAF. In a double-blind randomized placebo-controlled crossover study, 12 normal male subjects inhaled PAF on two consecutive days, 3 and 24 h after intake of two doses of UK,74505 25 mg and 100 mg, or matched placebo (P). After P, inhalation of PAF provoked bronchoconstriction, measured at regular time points for 60 min as a change in sGaw from baseline and computed as area under the curve (AUC), induced a neutropenia at 5 min and rebound neutrophilia at 2 h, and stimulated production of urinary eicosanoids. Bronchoconstriction was maximal at 5 min but had receded at 1 h; (AUC mean [95% Cl]; 20.0 [13.2, 26.8] at 3 h; 11.0 [5.3, 16.6] at 24 h) and was completely abolished by both doses of UK,74505 at 3 h and by the higher 100 mg dose at 24 h. PAF-induced neutropenia and rebound neutrophilia were abolished by both doses of drug; neutropenia at 5 min (expressed as mean [95% Cl] change from baseline; -2.5 x 10(9)/L [-2.9, -2.1] after P; -0.3 [-0.7, 0.1] after 25 mg; 0.1 [-0.3, 0.4] after 100 mg), neutrophilia at 2 h (2.0 [-1.3, 2.6] after P; -0.2 [-0.8, 0.5] after 25 mg; -0.1 [-0.8, 0.5] after 100 mg).(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Thoracic Medicine, National Heart and Lung Institute, Royal Brompton Hospital, London, United Kingdom.
B J
BJ
O'Connor
S
S
Uden
T J
TJ
Carty
J D
JD
Eskra
P J
PJ
Barnes
K F
KF
Chung
D000280:Administration, Inhalation; D000284:Administration, Oral; D000403:Airway Resistance / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects*; D004095:Dihydropyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015777:Eicosanoids / Q000652:urine*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007958:Leukocyte Count / Q000187:drug effects; D017999:Leukotriene E4 / Q000652:urine; D008297:Male; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils / Q000187:drug effects*; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine
D004095:Dihydropyridines; D015777:Eicosanoids; D007093:Imidazoles; D010972:Platelet Activating Factor; C073027:modipafant; D013929:Thromboxane B2; C028965:2,3-dinor-thromboxane B2; D017999:Leukotriene E4