To further define the role of platelet-activating factor (PAF) in endotoxin-induced lung dysfunction, we examined the effect of ABT-299, a specific and potent PAF-receptor antagonist, on the response to endotoxemia in six chronically instrumented awake sheep. We administered Escherichia coli endotoxin (0.5 μg/kg) intravenously with or without pretreatment with ABT-299 while monitoring mean pulmonary arterial pressure (Ppa), mean systemic arterial pressure (Psa), dynamic compliance of the lungs (Cdyn), and functional residual capacity (FRC). Endotoxin administration caused pulmonary hypertension, reduced Cdyn, leukopenia, and hypoxemia while having no significant effect on Psa or FRC. Administration of ABT-299 did not affect any of the measured variables at baseline. Pretreatment with ABT-299 attenuated the peak Ppa seen after endotoxin administration but had minimal effects on endotoxin-induced changes in Cdyn, white blood cell count, or alveolar-to-arterial oxygen difference. ABT-299 was shown to completely block the pulmonary hypertension and reduction in Cdyn seen after intravenous administration of exogenous PAF. We conclude that PAF does not play an essential role in the sheep’s response to endotoxin.

1997-07-01·Inflammation Research3区 · 医学

Ex vivo inhibition of β-thromboglobulin release following administration to man of ABT-299, a novel prodrug of a potent platelet activating factor antagonist

3区 · 医学

Article

作者: J. B. Summers ; A. E. Reyes ; D. W. Morgan ; H. D. Kleinert ; G. W. Carter ; D. H. Albert ; T. J. Magoc ; S. D. Menacherry ; E. Sun

OBJECTIVE AND DESIGNABT-299 is a prodrug that is converted by serum esterase to a potent platelet activating factor (PAF) antagonist (A-85783). In order to evaluate the pharmacological activity of this antagonist in man the effect of ABT-299 given to healthy volunteers on ex vivo PAF-induced beta-thromboglobulin (beta-TG) release in blood was assessed.SUBJECTS37 healthy male volunteers, age 18 to 40 (mean age of 23.6 years) and free of medication, participated in the study.TREATMENTSubjects were administered intravenously 0.8 mg, 2 mg, or 70 mg doses of ABT-299 (6-7 subjects per group) or placebo (9 subjects, pooled).METHODSPeripheral blood taken over 12 h after dosing was used for ex vivo beta-TG release and, in the case of the 70 mg dose, measurement of plasma drug concentration. Data were compared by Student's t-test.RESULTSAll three doses produced highly significant inhibition (p < 0.005 compared to predose values) of PAF-induced beta-TG release (units/ml plasma +/- SEM) 12 h after drug administration (54 +/- 14 vs. 405 +/- 51, n = 8; 79 +/- 23 vs. 480 +/- 127, n = 7; 21 +/- 10 vs. 327 +/- 72, n = 6, respectively) whereas there was no significant difference in beta-TG release in the placebo group (449 +/- 90 vs. 307 +/- 49, n = 9). Inhibition was associated with the rapid appearance in plasma of A-85783 and the pyridine N-oxide metabolite of A-85783. Within 2 h, the plasma concentration of the metabolite exceeded that of the parent drug. Both the parent drug and the metabolite exhibited potent in vitro inhibition of PAF-induced beta-TG release (A2 values of 4 and 1 nM respectively).CONCLUSIONSThese studies are the first to illustrate the utility of the beta-TG release assay for assessing ex vivo activity of PAF antagonists. These studies also demonstrate that the administration of ABT-299 to man results in potent, long lasting inhibition of PAF-mediated platelet activation, due in part to the pyridine-N-oxide metabolite, and support the potential therapeutic utility of this prodrug in treating PAF-mediated diseases.

1996-08-01·Shock2区 · 医学

ABT-299, A NOVEL PAF ANTAGONIST, ATTENUATES MULTIPLE EFFECTS OF ENDOTOXEMIA IN CONSCIOUS RATS

2区 · 医学

Article

作者: Luo, G ; Carter, G W ; Davidsen, S K ; Summers, J B ; Tapang, P ; Albert, D H ; Holms, J H ; Magoc, T J

ABT-299, a highly potent and selective platelet activating factor (PAF) antagonist, was found to be effective in rat models of endotoxic shock. ABT-299 inhibited and reversed LPS-induced hypotension (ED50 of .008 mg/kg, intraarterially). When given prior to LPS challenge, ABT-299 (.1 mg/kg, intravenously) completely inhibited LPS-induced intestinal damage for as long as 8 h after the administration of the antagonist. Pretreatment of rats with ABT-299 (5 mg/kg, intravenously over 4 h) prevented by 85-95% symptoms of disseminated intravascular coagulation (DIC) induced by LPS, including thrombocytopenia, prolongation of prothrombin and partial thromboplastin time, decreased serum fibrinogen, and elevation of serum fibrinogen/fibrin degradation products. A .1 mg/kg dose of ABT-299 administered orally or intravenously improved long-term survival to 80% and 90%, respectively, following a lethal dose (LD65) of LPS. ABT-299 (.1 mg/kg) was also effective in preventing hypotension and gastrointestinal damage induced by lipoteichoic acid (LTA), a putative causative agent of shock in Gram-positive infections. These results illustrate the impressive potency and duration of action of ABT-299 and support the putative role of PAF in acute models of endotoxic shock.

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