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 neut ropenia with rebound neutrophilia, and generates urinary production of the bronchoconstrictor eicosanoids, thromboxane (TX)A(2), and the cys teinyl leukotrienes. We examined the effects of an oral PAF antagonist UK,74505 on each of these responses to a single 36 mu g dose of inhal ed PAF. In a double-blind randomized placebo-controlled crossover stud y, 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 matche d 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 neutrop enia at 5 min and rebound neutrophilia at 2 h, and stimulated producti on of urinary eicosanoids. Bronchoconstriction was maximal at 5 min bu t had receded at 1 h; (AUC mean [95% CI]; 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 neu tropenia and rebound neutrophilia were abolished by both doses of drug ; neutropenia at 5 min (expressed as mean [95% CI] change from baselin e; -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] af ter P; -0.2 [-0.8, 0.5] after 25 mg; -0.1 [-0.8, 0.5] after 100 mg). S imilarly, urinary LTE(4) (1.97 ng/mg creatinine [0.52, 3.42] after P) was markedly reduced after both treatment doses (0.05 [-0.02, 0.12] af ter 25 mg; 0.12 [-0.04, 0.28] after 100 mg) (p < 0.0001). Urinary 2,3- dinor-TXB(2) levels also fell significantly after treatment (1.58 [1.1 2, 2.04] ng/mg creatinine after P; 0.90 [0.58, 1.12] after 25 mg; 0.83 [0.54, 1.12] after 100 mg) (p < 0.02). Thus UK,74505 is a potent inhi bitor of airway and neutrophil responses to PAF with a duration of act ion of up to 24 h at the higher dose. In addition it inhibits PAF-indu ced secondary eicosanoid generation, suggesting that specific PAF anta gonists may have therapeutic potential in allergic and inflammatory di seases.