Regional effects of nafamostat, a novel potent protease and complement inhibitor, on severe necrotizing pancreatitis

Abstract

Background: We evaluated the effect of the novel protease inhibitor nafamostat on rat necrotizing pancreatitis through different routes of administration.

Methods: Three hours after the induction of severe pancreatitis, the rats received intravenous gabexate or intravenous or local mesenteric intra-arterial nafamostat. At 9 hours, ascites and bronchoalveolar lavage fluid were collected for the evaluation of capillary leakage (Evans blue extravasation). Pancreas and lung were excised for histologic features, myeloperoxidase, and trypsinogen activation peptide. Twenty-four hour survival was evaluated.

Results: Only the intravenous infusion of nafamostat significantly reduced myeloperoxidase (11.7 +/- 2.3 vs 18.3 +/- 1.8 mU/mg; P <.05) and capillary leakage in lungs (Evans blue dye, 1.6 +/- 0.3 vs 2.6 +/- 0.3; P <.05). Only intra-arterial infusion of nafamostat significantly diminished capillary peritoneal leakage (Evans blue dye, 3.6 +/- 0.9 vs 9.4 +/- 0.4; P <.01). Typsinogen activation peptide levels were significantly reduced in all groups, but only intra-arterial infusion did so to baseline. Histologic inflammation in the pancreas was most significantly reduced after intra-arterial infusion (0.92 +/- 0.08 vs 2.91 +/- 0.06; P <.05). No form of protease inhibition reduced mortality rates.

Conclusions: The effects of protease inhibition depend on the route of administration. Nafamostat has maximal effects on the pancreas and peritoneal capillary leakage when delivered by way of local intra-arterial infusion, and shows a greater reduction of lung leukocyte infiltration and capillary leakage by the intravenous route. Nafamostat is more effective than gabexate.