Am. J. Respir. Crit. Care Med., Vol 150, No. 1, Jul 1994, 35-40.
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
BJ O'Connor, S Uden, TJ Carty, JD Eskra, PJ Barnes and KF Chung
Department of Thoracic Medicine, National Heart and Lung Institute, Royal Brompton Hospital, London, United Kingdom.
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)
