ABT-299, a novel PAF antagonist, attenuates multiple effects of endotoxemia in conscious rats.
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.
Albert
D H
DH
Immunoscience Research Area, Abbott Laboratories, Illinois 60064-3500, USA. Dan.H.Albert@abbott.com
Luo
G
G
Magoc
T J
TJ
Tapang
P
P
Holms
J H
JH
Davidsen
S K
SK
Summers
J B
JB
Carter
G W
GW
D000818:Animals; D003243:Consciousness; D004211:Disseminated Intravascular Coagulation / Q000209:etiology / Q000517:prevention & control; D019446:Endotoxemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D004731:Endotoxins / Q000633:toxicity; D006471:Gastrointestinal Hemorrhage / Q000209:etiology / Q000517:prevention & control; D007022:Hypotension / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011726:Pyridinium Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013682:Teichoic Acids / Q000633:toxicity; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
D004731:Endotoxins; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011726:Pyridinium Compounds; D013682:Teichoic Acids; D013844:Thiazoles; C009900:lipoteichoic acid; C044101:endotoxin, Escherichia coli; C093306:ABT 299