abt-299 and Shock--Septic

The role of platelet-activating factor (PAF) as a mediator of endotoxin-induced pathophysiology has been studied in several animal models with conflicting results. We evaluated the effect of a new, potent, and specific PAF receptor antagonist, ABT-299 (Abbott Laboratories) against endotoxin (lipopolysaccharide; LPS)-induced cardiopulmonary dysfunction in a porcine model. In initial experiments, the potency of ABT-299 was confirmed in vitro by its ability to inhibit PAF-induced porcine platelet aggregation at an IC50 of .047 +/- .01 microM, and in vivo by the ability of low doses (.12 mg/kg + .03 mg/kg/h) to block the cardiopulmonary pathologic response to exogenous PAF infusion. To evaluate the effect of ABT-299 administration during endotoxemia, pigs were randomly assigned to one of three groups: controls (n = 7), LPS (n = 9), or ABT-299 + LPS (n =7). ABT-299 was given at 1.0 mg/kg from -0.5 to 0 h plus .3 mg/kg/h from 0 to 6 h. LPS was given at .5 micrograms/kg/hr from 0 to 6 h. ABT-299 reduced the early LPS-induced fall in cardiac index and stroke volume, pulmonary hypertension and vasoconstriction, bronchoconstriction, and hypoxemia. Administration of LPS resulted in 44% mortality (before 6 h), which was blocked by ABT-299. Results with this antagonist indicate that PAF contributes to endotoxin-induced cardiopulmonary dysfunction in the pig, and is associated with mortality in this model.

Topics: Animals; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Lipopolysaccharides; Lung; Peroxidase; Platelet Activating Factor; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Prodrugs; Pyridinium Compounds; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Shock, Septic; Stroke Volume; Swine; Thiazoles; Thromboxane B2; Vascular Resistance

Topics: Animals; Binding, Competitive; Blood Pressure; Edema; Esterases; Humans; Hypotension; Indoles; Kinetics; Lipopolysaccharides; Mice; Molecular Structure; Platelet Activating Factor; Platelet Membrane Glycoproteins; Prodrugs; Pyridinium Compounds; Rats; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Shock, Septic; Thiazoles