abt-299 and Hypotension

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.

Topics: Animals; Consciousness; Disseminated Intravascular Coagulation; Endotoxemia; Endotoxins; Gastrointestinal Hemorrhage; Hypotension; Lipopolysaccharides; Male; Platelet Activating Factor; Platelet Aggregation Inhibitors; Pyridinium Compounds; Rats; Rats, Sprague-Dawley; Teichoic Acids; Thiazoles

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