Pharmacological studies of FUT-175, nafamostat mesilate. V. Effects on the pancreatic enzymes and experimental acute pancreatitis in rats.
Effects of FUT-175 on the pancreatic enzymes in vitro and in vivo in the enterokinase-induced experimental acute pancreatitis were investigated, and they were compared with those of gabexate and aprotinin. In in vitro experiments, FUT-175 inhibited the pancreatic protease activities 10 to 100 times more potently than gabexate. Furthermore, FUT-175 inhibited the enterokinase activity. Unlike aprotinin, FUT-175 inhibited alpha 2-macroglobulin bound trypsin activity as well as free trypsin. In in vivo experiments, at doses of 0.5-50 micrograms/kg/min, FUT-175 suppressed the elevated protease activities in the experimental acute pancreatitis more potently than gabexate. Differently from the action of aprotinin, FUT-175 suppressed trypsin activities both in the pancreas and in the plasma to the same extent. Furthermore, FUT-175 reduced the mortality of rats in the experimental acute pancreatitis in a dose-dependent manner. These data strongly support that FUT-175 is clinically useful in the therapy of acute pancreatitis.
D000208:Acute Disease; D000818:Animals; D001550:Benzamidines; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010179:Pancreas / Q000201:enzymology*; D010195:Pancreatitis / Q000188:drug therapy*; D010770:Phosphotransferases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism
D001550:Benzamidines; D006146:Guanidines; D011480:Protease Inhibitors; C028939:alpha-2-macroglobulin-trypsin complex; D000511:alpha-Macroglobulins; D010770:Phosphotransferases; D014357:Trypsin; C032855:nafamostat