title: 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.
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, USA.
authors.forename: T
authors.initials: T
authors.lastname: Keck
authors.forename: J H
authors.initials: JH
authors.lastname: Balcom
authors.forename: B A
authors.initials: BA
authors.lastname: Antoniu
authors.forename: K
authors.initials: K
authors.lastname: Lewandrowski
authors.forename: A L
authors.initials: AL
authors.lastname: Warshaw
authors.forename: C F
authors.initials: CF
authors.lastname: Fernández-del Castillo
mesh_terms: D000818:Animals; D001550:Benzamidines; D002199:Capillary Permeability / Q000187:drug effects; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D005070:Evans Blue / Q000493:pharmacokinetics; D016670:Gabexate / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D008168:Lung / Q000201:enzymology; D008297:Male; D009842:Oligopeptides / Q000378:metabolism; D010179:Pancreas / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010537:Peritoneum / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015996:Survival Rate
chemical_list: D001550:Benzamidines; D003169:Complement Inactivator Proteins; D006146:Guanidines; D009842:Oligopeptides; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; C080396:trypsinogen activation peptide; D005070:Evans Blue; D016670:Gabexate; D009195:Peroxidase; C032855:nafamostat