leukotriene-e4 and Neutropenia

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)

Topics: Administration, Inhalation; Administration, Oral; Airway Resistance; Bronchoconstriction; Dihydropyridines; Dose-Response Relationship, Drug; Double-Blind Method; Eicosanoids; Humans; Imidazoles; Leukocyte Count; Leukotriene E4; Male; Neutropenia; Neutrophils; Platelet Activating Factor; Thromboxane B2

The role of lipoxygenase metabolites as inflammatory mediators in endotoxic shock remains uncertain. In the present study, the effects of a selective leukotriene (LT) D4/LTE4 antagonist, LY171883, 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-YL)-butoxy]-phenyl ethanone], on endotoxin-induced sequelae in the rat were assessed. LY171883 was given as a bolus (30 mg/kg i.v.) 10 min before Salmonella enteritidis endotoxin (40 mg/kg) in ketamine-anesthetized (200 mg/kg i.m.) rats, followed by an infusion (10 mg/kg/hr) starting at 30 min postendotoxin. Carotid artery blood pressures were determined at 10 min before and at intervals up to 240 minutes postendotoxin administration. Compared to shocked vehicle controls LY171883 attenuated (analysis of variance, P less than .02) the initial (0-30 min), but not the later, endotoxin-induced hypotension. LY171883 prevented completely (analysis of variance, P less than .001) the neutropenia (0-180 min), but not the thrombocytopenia induced by endotoxin. Hemoconcentration resulting from endotoxemia was reduced by LY171883 compared to the vehicle control group (P less than .02). These data demonstrate that this LTD4/LTE4 antagonist has significant salutary actions in endotoxemia and suggest that LTs may contribute to some endotoxin-induced sequelae.

Topics: Acetophenones; Analysis of Variance; Animals; Azoles; Bacterial Toxins; Blood Pressure; Endotoxins; Enterotoxins; Hematocrit; Leukotriene E4; Male; Neutropenia; Platelet Count; Rats; Salmonella enteritidis; Shock, Septic; SRS-A; Tetrazoles; Thrombocytopenia