The effects of a newly developed compound having antiulcer action, (Z)-2-(4-methylpiperazin-1-yl)-1-[4-(2-phenyl-ethyl)phenyl]-eth anone
oxime hydrochloride monohydrate (MCI-727), on pancreatic exocrine secretion were studied in anesthetized rats and evaluated its preventive and
therapeutic effects on
acute pancreatitis in two experimental rat models. Intraduodenal administration of
MCI-727 [25, 50, or 100 mg/kg
body weight (wt)] stimulated a dose-dependent increase in pancreatic juice and
bicarbonate output without increasing the
protein output or plasma
cholecystokinin concentration. MCI-727-stimulated pancreatic exocrine secretion was completely abolished by antisecretin serum but not by the
cholecystokinin receptor antagonist
loxiglumide (50 mg/kg body wt/h) or
cholinergic receptor antagonist atropine (100 mu g/kg body wt/h). In rats with
acute pancreatitis induced by four
subcutaneous injections of 20 mu g/kg body wt
cerulein at hourly intervals over 3 h,
MCI-727 administered orally at a dose of 100 mg/kg body wt 30 min before the first
cerulein injection significantly reduced the increases in serum
amylase and
lipase activity and pancreatic wet weight and induced improvements in the results of histologic examination. Moreover, when given 30 min before and 90 min after the first
cerulein injection,
MCI-727 had even more dramatic protective effects on all these parameters. In addition, even when administered immediately after the last
cerulein injection,
MCI-727 effectively ameliorated all these alterations of
acute pancreatitis. However,
MCI-727 had no apparent beneficial effects on the biochemical and histologic alterations of
acute pancreatitis in the severe form induced by retrograde intraductal injection of 1.0 ml/kg body wt of 4%
sodium taurocholate. These findings suggest that
oral administration of
MCI-727 stimulates pancreatic exocrine secretion by endogenous
secretin release and that it has therapeutic as well as preventive effects on mild forms of
acute pancreatitis in rats.