Aktiviertes Protein C hemmt die Entzündungsreaktion und verbessert das Überleben bei experimenteller akuter Pankreatitis

Abstract

Objective: To evaluate the effect of Drotrecogin alfa (activated) (DrotAA) in experimental acute pancreatitis (AP). Summary Background Data: DrotAA is the pharmacological form of activated protein C (APC) and is the first FDA-approved drug for treatment of severe sepsis. It has not been evaluated in acute pancreatitis. Methods: Safety of i. v. DrotAA was assessed in healthy animals with different dosages. Mild (iv cerulein) or severe (iv cerulein + intraductal glycodeoxycholic-acid) AP was induced in 72 rats and coagulation parameters were compared to 42 healthy and sham-operated animals. Rats with severe AP were randomized to treatment with 100 μg/kg/h DrotAA or saline. End-points included histologic scoring of pancreatic necrosis, inflammation of pancreas and lung (measured by myeloperoxidase (MPO)), coagulation parameters, and 24h survival. Results: Severe consumptive coagulopathy, disseminated intravascular coagulation (DIC), hemoconcentration, and leukocytosis were observed six hours after induction of severe AP, but not in mild AP. Treatment of AP with 100 μg/kg/h DrotAA did not worsen coagulation parameters. While the degree of pancreatic necrosis was comparable in treated and untreated animals with severe AP, APC significantly reduced MPO levels in pancreas (p = 0.009) and lungs (p = 0.03). 24 h survival in severe AP was markedly improved in animals treated with APC (86% vs. 38%, p < 0.05 ). Conclusion: Animals with severe AP suffer from severe consumptive coagulopathy and DIC, but administration of 100 μ/kg/h DrotAA does not worsen coagulation abnormalities. DrotAA treatment reduces inflammation in the pancreas and lungs and significantly improves survival. These results encourage clinical investigation of DrotAA in treatment of severe acute pancreatitis.