Effects of a new
cholecystokinin (
CCK)A-receptor antagonist,
T-0632 [
sodium (S)-1-(2-fluorophenyl)-2, 3-dihydro-3-[(3-isoquinolinylcarbonyl) amino]-6-methoxy-2-oxo-1H-
indole-3-
propanoate], on
caerulein-induced and pancreatic duct
ligation-induced
pancreatitis models were studied and compared with the CCKA-receptor antagonist
loxiglumide and the orally active
protease inhibitor camostate, respectively. In rats, orally administered
T-0632 potently prevented the
caerulein-induced increases in pancreatic digestive
enzymes in plasma and suppressed the histological changes in the pancreas. The estimated ED50 values of
T-0632 and
loxiglumide were 0.0092 and 8.9 mg/kg, respectively. In dogs,
T-0632 (0.1, 1 mg/kg, i.d.) prevented the
caerulein-induced increase in plasma
amylase activity in a dose-dependent manner.
Loxiglumide (100 mg/kg, i.d.) did not show any preventive effects. In pancreatic duct
ligation (6 hr)-induced
pancreatitis of the rat,
T-0632 (0.001-0.1 mg/kg, p.o.) partially prevented both the increase in plasma
amylase activity and the histological changes in the pancreas, whereas
camostate (10, 100 mg/kg, p.o.) did not show any preventive effects. In pancreatic duct
ligation (3 hr)-induced
pancreatitis,
caerulein injection (1 microgram/kg, s.c.) caused a further increase in plasma
amylase activity, and
T-0632 (0.01, 0.1 mg/kg, p.o.) dose-dependently decreased the aggravation by
caerulein. We conclude that
T-0632 showed preventive effects on all of these
pancreatitis models by oral or intraduodenal administration. These results suggest that CCK plays an important role in progression and aggravation of
acute pancreatitis, and
T-0632 may have a therapeutic value in these disease states.