Administration of human recombinant activated protein C is not associated with pancreatic parenchymal haemorrhage in L-arginine-induced experimental acute pancreatitis.
BACKGROUND
Microvascular thrombosis is a critical event in severe acute pancreatitis. Human recombinant activated protein C (Xigris®, Eli Lilly, Indianapolis, IN, USA) modulates the interplay between pro-inflammatory and pro-coagulant pathways and maintains microvascular patency. However, the anticoagulant properties of Xigris® may precipitate bleeding from the inflamed pancreas.


OBJECTIVE
This study tests the hypothesis that Xigris® can ameliorate experimental acute pancreatitis without causing pancreatic haemorrhage.


METHODS
Sprague Dawley rats were allocated as follows: Group 1: control (n=7); Group 2: acute pancreatitis (n=6); Group 3: administration of Xigris® 500 µg/kg body weight before induction of acute pancreatitis (n=6); and Group 4: Administration of Xigris® 500 µg/kg body weight 30 minutes after induction of acute pancreatitis (n=6). Acute pancreatitis was induced by intraperitoneal administration of L-arginine 300 mg/100 g body weight. Animals were sacrificed at 48 hours and biochemical, haematological, and histological markers of pancreatic haemorrhage and inflammation assessed.


RESULTS
Median lipase in animals with acute pancreatitis was 10 U/mL (range: 7-16 U/mL) compared to 5.5 (range: 3-8 U/mL) in controls (P=0.028). Lipase was also elevated in animals given Xigris® both before (12 U/mL, range: 8-22 U/mL; P=0.031 vs. control group) and after (46 U/mL, range: 9-71 U/mL; P=0.015 vs. control group) induction of acute pancreatitis). Haemoglobin levels were similar among all groups (P=0.323). There was no histological evidence of pancreatic haemorrhage in animals treated with Xigris®. Pre-treatment with Xigris® was associated with a significant reduction in pancreatic injury. This effect was absent when Xigris® was administered after induction of acute pancreatitis.


CONCLUSIONS
Xigris® did not lead to pancreatic haemorrhage in experimental acute pancreatitis. Administration of Xigris® prior to induction of acute pancreatitis was associated with amelioration of injury. This effect was not seen with administration of Xigris® after induction of acute pancreatitis.
Academic Hepatobiliary Unit, University of Manchester. Manchester, United Kingdom. ajith.siriwardena@cmft.nhs.uk.
Saurabh
S
Jamdar
Benoy I
BI
Babu
Mahesh
M
Nirmalan
Maria
M
Jeziorska
Raymond F T
RF
McMahon
Ajith K
AK
Siriwardena
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001120:Arginine; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007274:Injections, Intraperitoneal; D008049:Lipase / Q000097:blood; D008297:Male; D010179:Pancreas / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D010182:Pancreatic Diseases / Q000139:chemically induced / Q000175:diagnosis; D010195:Pancreatitis / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D011486:Protein C / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D016896:Treatment Outcome
D000890:Anti-Infective Agents; D011486:Protein C; D011994:Recombinant Proteins; D001120:Arginine; D008049:Lipase; D000681:Amylases; C421124:drotrecogin alfa activated