Oral administration of sepimostat mesilate prevents acute alcohol pancreatic injury in rats.
The preventive effect of a novel synthetic serine protease inhibitor, sepimostat mesilate (sepimostat), on acute alcohol pancreatic injury, induced by exocrine hyperstimulation and ethanol administration, was assessed and compared with that of a similar protease inhibitor, camostat mesilate (camostat). Conscious rats were infused with 1 microg mL(-1) h(-1) caerulein intravenously for 6 h and with 0.1 g mL(-1) h(-1) ethanol for 9 h, with the latter infusion beginning 3 h after the start of the caerulein infusion. Sepimostat or camostat was administered orally 1 h before the caerulein infusion. Rats infused with caerulein plus ethanol showed increased plasma amylase and lipase activities, and aggravated pancreatic interstitial oedema when compared with rats given caerulein alone. Sepimostat at 10 and 30 mg kg(-1) prevented the increase in plasma amylase and lipase activities caused by caerulein plus ethanol infusion. Sepimostat at 30 mg kg(-1) suppressed the histological change. Camostat did not show any preventive effects at the equivalent dose. When conscious rats were infused with 1 microg mL(-1) h(-1) caerulein alone intravenously for 6 h, plasma amylase and lipase activities were increased compared with rats given saline. Neither drug prevented the increase in these activities at 30mg kg(-1). Our results suggest that sepimostat has superior preventive effects on alcohol-induced acute pancreatic injury compared with camostat. Sepimostat may thus be a useful drug in the therapy of alcohol-induced pancreatitis.
Yuasa
C
C
Pharmacology Research Laboratory, R&D Headquarters, Tokishima Research Center, Taiho Pharmaceutical Co. Ltd, Tokushima, Japan.
Irimura
K
K
Oda
M
M
Fukui
K
K
Oka
T
T
D000208:Acute Disease; D000284:Administration, Oral; D000681:Amylases / Q000097:blood / Q000187:drug effects; D000818:Animals; D002108:Ceruletide / Q000009:adverse effects; D004952:Esters; D000431:Ethanol / Q000009:adverse effects*; D016670:Gabexate / Q000031:analogs & derivatives*; D006146:Guanidines / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008049:Lipase / Q000097:blood / Q000187:drug effects; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000517:prevention & control*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D004952:Esters; D006146:Guanidines; D007093:Imidazoles; D011480:Protease Inhibitors; C034532:camostat; C058875:sepimostate mesilate; D000431:Ethanol; D016670:Gabexate; D002108:Ceruletide; D008049:Lipase; D000681:Amylases