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 groups, according to different content of a 24-h i.v. infusion performed 1 h after intrabiliary injection of enterokinase/sodium taurocholate to induce acute pancreatitis (AP): (1) Saline; (2) 5 micrograms/kg/h nafamostat mesilate (FUT-175); (3) 10 micrograms/kg/h FUT-175; and (4) 25 micrograms/kg/h FUT-175. Peritoneal fluid was removed and exchanged with 1 mL 3.33 M fluorescein-isothiocyanate-conjugated (FITC) dextrans of 4000-40,000 Dalton. Serial blood samples were withdrawn and examined for FITC-dextrans, phospholipase A2 (PLA2), blood gases, amylase, and lipase. As compared to control (55%), FUT-175 brought about a lower (5 micrograms/kg/h: 25%) or no mortality (10 and 25 micrograms/kg/h), and a milder histological and biochemical evidence of AP. Untreated animals with PLA2 values over two times the standard deviation showed a respiratory distress. Further, unlike group 1, FUT-175 doses as low as 5 micrograms/kg prevented the increase in peritoneal permeability to small-size molecules (up to 20,000 Dalton). In a second experiment under the same drug protocol, 1000 U/mL of PLA2 and 2 mL of pancreatitis ascites were instilled ip. Peritoneal permeability to FITC-dextrans up to 30,000 Dalton and to PLA2 significantly increased in the saline group and in the 5 micrograms/kg FUT-175 group. However, 10 micrograms/kg and 25 micrograms/kg FUT-175 doses prevented such phenomenon. In conclusion, FUT-175 proves to be a potent antiprotease molecule with a biochemical activity also against PLA2 in vivo and prevents significant transperitoneal-blood access of pancreatic enzymes.
Marotta
F
F
Liver Unit Crespi, Niguarda Hospital, Milano, Italy.
Fesce
E
E
Rezakovic
I
I
Chui
D H
DH
Suzuki
K
K
Idéo
G
G
D000208:Acute Disease; D000818:Animals; D001550:Benzamidines; D003911:Dextrans / Q000493:pharmacokinetics; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006146:Guanidines / Q000627:therapeutic use*; D008297:Male; D010195:Pancreatitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010537:Peritoneum / Q000187:drug effects* / Q000378:metabolism; D010539:Permeability; D010740:Phospholipases / Q000378:metabolism; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012131:Respiratory Insufficiency / Q000209:etiology / Q000517:prevention & control*
D001550:Benzamidines; D003911:Dextrans; D006146:Guanidines; D011480:Protease Inhibitors; C015219:fluorescein isothiocyanate dextran; D010740:Phospholipases; D016650:Fluorescein-5-isothiocyanate; C032855:nafamostat