Decreased inflammation and improved survival with recombinant human activated protein C treatment in experimental acute pancreatitis.
OBJECTIVE
Drotrecogin alfa (activated), the pharmacologic form of activated protein C and the first Food and Drug Administration-approved drug for treatment of severe sepsis, is beneficial in experimental acute pancreatitis (AP).


METHODS
Animal study.


METHODS
Laboratory.


METHODS
Male Sprague-Dawley rats.


METHODS
Mild (intravenous cerulein) or severe (intravenous cerulein plus intraductal glycodeoxycholic acid) AP was induced in 72 rats, and coagulation evaluated. Rats with severe AP were randomized to treatment with drotrecogin alfa (activated), 100 microg/kg per hour, or isotonic sodium chloride.


METHODS
Histologic scoring of pancreatic necrosis, inflammation of the pancreas and lung (measured by myeloperoxidase concentration), coagulation measures, and 24-hour survival.


RESULTS
Severe consumptive coagulopathy, hemoconcentration, and leukocytosis were observed 6 hours after induction of severe AP, but not in mild AP. Treatment of AP with drotrecogin did not worsen coagulation measures. Although the degree of pancreatic necrosis was comparable in treated and untreated animals with severe AP, drotrecogin significantly reduced myeloperoxidase levels in the pancreas (P = .009) and lungs (P = .03). The 24-hour survival in severe AP was markedly improved in animals treated with drotrecogin (86% vs 38%; P = .05).


CONCLUSIONS
Animals with severe AP have severe consumptive coagulopathy, but administration of drotrecogin alfa (activated), 100 microg/kg per hour, does not worsen coagulation abnormalities. Drotrecogin treatment reduces inflammation in the pancreas and lungs and significantly improves survival. These results encourage clinical investigation of drotrecogin in the treatment of severe AP.
Alsfasser
Guido
G
Department of Surgery and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Warshaw
Andrew L
AL
Thayer
Sarah P
SP
Antoniu
Bozena
B
Laposata
Michael
M
Lewandrowski
Kent B
KB
Fernández-del Castillo
Carlos
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002108:Ceruletide / Q000633:toxicity; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000188:drug therapy* / Q000401:mortality; D009195:Peroxidase / Q000378:metabolism; D011486:Protein C / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use; D012720:Severity of Illness Index; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011486:Protein C; D011994:Recombinant Proteins; D002108:Ceruletide; D009195:Peroxidase; C421124:drotrecogin alfa activated