Abstract
We have established a novel sepsis model with reproducible manifestations of multiple organ failure (MOF) and disseminated intravascular coagulation (DIC). In the present study, attempts were made to modify MOF and DIC by intravenous administration of synthetic protease inhibitors [gabexate mesilate (FOY) and its newly developed analogue (ONO-3307)]. Among abnormal hematological parameters seen in an untreated model such as decrease in platelet and leukocyte count and value of prothrombin and fibrinogen, and prolongation of APTT, only the decrease in platelet count was significantly (p<0.01) prevented by administration of ONO-3307 (1mg/kg/hr) or FOY (10mg/kg/hr). However, the parameters of liver and kidney failure (elevation of bilirubin and creatinine) was significantly improved by the administration of the respective inhibitor. The favorable results were also confirmed by the histological evaluation of liver.
From these observations, it was suggested that the ocurrence of organ failure in sepsis is mediated by proteases, the true nature of which has yet to be elucidated. And also the newly developed ONO-3307 is at least 10 times potent in terms of the prevention of organ failure in sepsis.
