Effects of the PAF antagonists bepafant and L‐659, 989 in endotoxic and septic shock

Abstract

AbstractMany of the pathophysiological effects of endotoxin (ETX) can be mimicked by the administration of platelet activating factor (PAF), and the latter has been implicated as a possible mediator of the derangements seen in endotoxic shock. In this investigation, two new potent PAF antagonists, bepafant (WEB‐2170) and L‐659,989, were studied for their effects in experimental endotoxic and septic shock in rats. Pretreatment with the PAF antagonists, 15 min prior to the iv administration of Escherichia coli endotoxin (ETX), was found to be highly effective in decreasing the mortality caused by the lipopolysaccharide. The antagonists were less effective in reducing mortality when given as post‐treatment 15 min after ETX, and were ineffective when post‐treatment was delayed until 30 min after ETX. Administration of ETX caused manifestations of disseminated intravascular coagulation (DIC), including thrombocytopenia, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT), hypofibrinogenemia, elevation of serum fibrin(ogen) degradation products (FDP), and gastrointestinal hemorrhage. With the exception of the thrombocytopenia, the PAF antagonists reduced or abolished all of the hematological manifestations of DIC caused by ETX. Septic shock was produced by ligation and puncture of the cecum in rats. The PAF antagonists, given as two iv doses (an initial 2.0 mg/kg dose administered 1.5 or 2.5 h after cecal puncture and a second dose given 5 h later), significantly reduced the cumulative 24‐h mortality. These results provide added evidence of the importance of PAF and DIC in the pathophysiology of ETX and suggest that PAF antagonists may be useful in the clinical management of septicemia/endotoxemia. © 1993 Wiley‐Liss, Inc.