NAFAMOSTAT MESILATE ON THE COURSE OF ACUTE-PANCREATITIS - PROTECTIVE EFFECT ON PERITONEAL PERMEABILITY AND RELATION WITH SUPERVENING PULMONARY DISTRESS

Three hundred sixty Sprague-Dawley rats were allocated into four group s, according to different content of a 24-h iv infusion performed 1 h after intrabiliary injection of enterokinase/sodium taurocholate to in duce acute pancreatitis (AP): (1) Saline; (2) 5 mu g/kg/h nafamostat m esilate (FUT-175); (3) 10 mu g/kg/h FUT-175; and (4) 25 mu g/kg/h FUT- 175. Peritoneal fluid was removed and exchanged with 1 mt 3.33 M fluor escein-isothiocyanate-conjugated (FITC) dextrans of 4000-40,000 Dalton . Serial blood samples were withdrawn and examined for FITC-dextrans, phospholipase A(2) (PLA2), blood gases, amylase, and lipase. As compar ed to control (55%), FUT-175 brought about a lower (5 mu g/kg/h: 25%) or no mortality (10 and 25 mu g/kg/h), and a milder histological and b iochemical evidence of AP. Untreated animals with PLA(2) values over t wo times the standard deviation showed a respiratory distress. Further , unlike group 1, EUT-175 doses as low as 5 mu g/kg prevented the incr ease in peritoneal permeability to small-size molecules (up to 20,000 Dalton). In a second experiment under the same drug protocol, 1000 U/m L of PLA(2) and 2 mL of pancreatitis ascites were instilled ip. Perito neal permeability to FITC-dextrans up to 30,000 Dalton and to PLA(2) s ignificantly increased in the saline group and in the 5 mu g/kg FUT-17 5 group. However, 10 mu g/kg and 25 mu g/kg FUT-175 doses prevented su ch phenomenon. In conclusion, FUT-175 proves to be a potent antiprotea se molecule with a biochemical activity also against PLA(2) in vivo an d prevents significant transperitoneal-blood access of pancreatic enzy mes.