EFFECT OF DIFFERENT IMMUNOSUPPRESSIVE AGENTS ON ACUTE-PANCREATITIS - A COMPARATIVE-STUDY IN AN IMPROVED ANIMAL-MODEL

Background. Immunosuppressive drugs have been associated with the deve lopment and progression of acute pancreatitis after organ transplantat ion. Consequently, a reduction or a change in immunosuppressive therap y has been recommended once posttransplantation pancreatitis has been suspected. However, it is not known which of the available immunosuppr essive agents is most harmful to the pancreas and which may be used sa fely in this situation. The objective of this study was to investigate the effect of different immunosuppressive drugs in various dosages on intrapancreatic protease activation, acinar cell necrosis, and mortal ity in an improved model of acute necrotizing pancreatitis in the rat. The rat model of acute necrotizing pancreatitis, like posttransplanta tion pancreatitis, is characterized by ischemia and microcirculatory d isorders. Method. Acute pancreatitis was induced in rats by using a co mbination of low-dose controlled intraductal glycodeoxycholic acid sup erimposed on intravenous cerulein hyperstimulation. Six hours thereaft er, animals were randomized to intravenous therapy with a, 10, or 50 m g/kg/day prednisolone (PRED); 3, 15, or 60 mg/kg/day cyclosporine A (C sA); 10 mg/kg/day azathioprine (AZA); 0.6 mg/kg/day orthoclone ORT3 (O KT3); or saline. After 36 hr, surviving animals were killed to determi ne acinar cell necrosis and trypsinogen activation peptides levels (TA P) in blood and ascites. Results. Compared with saline-treated control rats, animals treated with 60 mg/kg/day CsA developed significantly m ore acinar cell necrosis and had increased amounts of TAP in ascites. Likewise, there was more extensive acinar cell necrosis in animals sub jected to AZA therapy. However, this was not associated with increment al TAP. Animals treated with 3 or 15 mg/kg/day CsA, OKT3, or PRED show ed no significant changes in these target parameters. Animals given 10 or 50 mg/kg/day PRED even had decreased hematocrit values and produce d significantly less ascites than animals in the other groups. Conclus ion. The present results suggest that AZA and high doses of CsA aggrav ate acute pancreatitis and should, therefore, be avoided once posttran splantation pancreatitis has been suspected, whereas lower doses of Cs A, OKT3, and PRED may be used safely. PRED can even be used at higher doses as may be required when graft rejection is suspected.