SUMMARYBackground : We newly synthesized YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2h-pyridyl)-1H-1,4-benzodiazepin-3-yl]-3-(3-methylamino-phenyl)urea) as a gastrin\cholecystokinin-B (CCK-B) receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo. Methods : We examined the binding properties of YF476 to the rat brain, cloned canine and cloned human gastrin\CCK-B receptors, and the effect of YF476 on secretagogue-induced gastric acid secretion in rats and Heidenhain pouch dogs. Results : YF476 replaced the specific binding of ["#&I]CCK-8 to the rat brain, cloned canine and cloned human gastrin\CCK-B receptors, with K i values of 0.068, 0.62 and 0.19 n, respectively. The affinity of
Female rats were treated orally for 13 wk with YM022 (300 mumol.kg-1.day-1) and with omeprazole (400 mumol.kg-1.day-1) or famotidine (900 mumol.kg-1.day-1) with or without YM022. At 2 h after the last dose, YM022 and omeprazole markedly inhibited basal and pentagastrin-induced acid secretion. Famotidine was less potent than YM022 and omeprazole against both secretions. The degree of increase in plasma gastrin level in the three groups was parallel to the antisecretory potencies of the drugs. At 14 days after the cessation of omeprazole treatment, the secretory response to pentagastrin increased above that of the control. This hyperresponse lasted for > or = 56 days. In the famotidine-treated group, a small increase in secretory response to pentagastrin was observed but was not statistically significant. The increase in secretory response to pentagastrin was paralleled by an increase in mucosal cell mass. In contrast, YM022 not only exhibited a long-lasting inhibition of pentagastrin-induced acid secretion but also prevented the hyperresponse to pentagastrin caused by omeprazole. These results indicate that the hypergastrinemia caused by long-term administration of antisecretory drugs increases mucosal secretory response to pentagastrin through a gastrin/cholecystokinin B receptor-mediated pathway in rats.
ABSTRACT-We examined the effect of leminoprazole (an acid pump inhibitor) on reflux esophagitis induced in rats. Intragastrically administered leminoprazole significantly and dose-dependently protected the esophageal mucosa against the reflux of gastric contents, without affecting gastric acid secretion. However, it had no effect on the esophagitis when administered intraduodenally, despite its significant inhibition (about 40%) of gastric acid secretion. Omeprazole significantly prevented the development of esophagitis, most probably through potent inhibition of gastric acid secretion. Indomethacin significantly reduced the synthesis of prostaglandin E2 in the esophagus. Since indomethacin pretreatment had no effect on the esophageal protection by leminoprazole, omeprazole or sucralfate, the involvement of endogenous prostaglandins can be ruled out as a possible underlying mechanism. Intragastrically, but not intraduodenally, administered sucralfate significantly prevented the esophagitis even at a dose not affecting gastric acid secretion. These results strongly suggest that both leminoprazole and sucralfate protect the esophageal mucosa directly.
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