Effect of the oral administration of sepimostat mesilate on cerulein induced acute pancreatitis in rats.
The effect of a potent protease inhibitor, sepimostat mesilate (CAS 103926-82-5, FUT-187), on acute interstitial edematous pancreatitis induced by a supramaximal dose of cerulein, a cholecystokinin (CCK) analogue, was evaluated. The serum amylase activity increased 18-fold over normal control after the infusion of cerulein at 5 micrograms/kg/h for 6 h. The serum lipase activity showed a 235-fold increase. An elevated pancreatic water content, pancreatic interstitial edema, inflammatory infiltration and vacuolization of the acinar cells were found. Redistribution of cathepsin B shifted from the lysosomal pellet fraction to the zymogen granule pellet fraction was noted in the early stages. All these parameters of pancreatitis mentioned above were inhibited by FUT-187 pretreatment at doses of 30 to 300 mg/kg. These observations suggest that FUT-187 inhibits the redistribution of cathepsin B shift from the lysosomal fraction to the zymogen fraction in cerulein-induced acute pancreatitis and improves the parameters of acute pancreatitis.
Wang
Z H
ZH
First Department of Surgery, Faculty of Medicine, Kyoto University, Japan.
Manabe
T
T
Ohshio
G
G
Hirano
T
T
Okada
N
N
Imamura
T
T
Kawaguchi
Y
Y
Yotsumoto
F
F
Yamaki
K
K
Imamura
M
M
D000208:Acute Disease; D000284:Administration, Oral; D000681:Amylases / Q000097:blood; D000818:Animals; D001834:Body Water / Q000378:metabolism; D002401:Cathepsin B / Q000097:blood / Q000378:metabolism; D002108:Ceruletide / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005765:Gastrointestinal Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008049:Lipase / Q000097:blood; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D005765:Gastrointestinal Agents; D007093:Imidazoles; D011480:Protease Inhibitors; C058875:sepimostate mesilate; D002108:Ceruletide; D008049:Lipase; D000681:Amylases; D002401:Cathepsin B