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.

1991-01-01·Japanese Journal of Pharmacology

Effects of MCI-727, a New Anti-Ulcer Agent, on Plasma Secretin Concentration in Rats and Dogs and Pancreatic Exocrine Secretion in Rats

作者: Watanabe, Shinichiro ; Takeuchi, Tadashi ; Yamazaki, Satoshi ; Tobe, Akihiro ; Kawamura, Makoto

The present study investigated the effects of MCI-727 (I), a new anti-ulcer agent, on plasma immunoreactive secretin concentration in rats and dogs using secretin-specific RIA with the ethanol extraction method.Plasma secretin levels were increased dose-dependently 10 min after oral administration of 10, 30 and 100 mg/kg of MCI-727 in rats.Teprenone also caused a significant increase of plasma secretin at 10 min after oral administration at the doses of 30, 100 and 300 mg/kg.Under the same conditions, MCI-727 and teprenone did not alter the plasma immunoreactive gastrin concentration in rats.From the results of the time course study, the increasing effect of MCI-727 (30 mg/kg, p.o) on plasma secretin remained for at least 240 min after administration.On the other hand, the increasing effect of teprenone (200 mg/kg, p.o.) was only observed at 30 and 60 min after administration.Furthermore, MCI-727 had increasing effects on plasma secretin concentration in dogs, but teprenone had no effects in this species.The volume of pancreatic secretion and the pancreatic bicarbonate output increased after intra-duodenal administration of MCI-727 at 30 and 100 mg/kg in rats.Similar effects were also observed with teprenone (30-300 mg/kg i.d.) or secretin (Secrepan, 0.1-1.0 unit/kg, i.v.).

1991-01-01·The Japanese Journal of Pharmacology

Effects of MCI-727, a New Antiulcer Agent, on Various Gastric and Duodenal Lesions in Experimental Animals.

Article

作者: Makoto Kawamura ; Kentaro Ando ; Issei Nitta ; Susumu Okabe ; Akihiro Tobe ; Satoshi Yamazaki ; Mariko Kitsukawa

Effects of a new antiulcer drug, MCI-727, on gastric and duodenal lesions, gastric secretion and gastric motility were studied in comparison with cimetidine and teprenone. MCI-727 dose-dependently (3-100 mg/kg, p.o. or i.d.) inhibited the development of acute gastric or duodenal lesions such as pyrolus ligation-, water-immersion stress-, indomethacin-, HCl-, HCl-ethanol-induced gastric lesions and cysteamine-induced duodenal lesions in rats and histamine-induced duodenal lesions in guinea pigs. These antiulcer effects exceeded those of cimetidine or teprenone. Repeated administration of MCI-727 (0.3-3 mg/kg/day, p.o., for 10 days) significantly promoted the spontaneous healing of acetic acid-induced chronic gastric ulcers. Concerning gastric acid secretion, MCI-727 selectively inhibited tetragastrin-stimulated acid secretion without effecting basal acid secretion and acid secretion by other stimuli. Cimetidine and teprenone inhibited acid secretion in several cases. MCI-727 and teprenone had inhibitory effects on gastric motility, although cimetidine had no effect. These results suggest that MCI-727 has a wide spectrum of antiulcer activity, and its mode of antiulcer action is different from that of cimetidine or teprenone.

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