Healing of duodenal ulcers induced by indomethacin + histamine was investigated in rats. Animals were treated with indomethacin (5 mg/kg, s.c, once daily) and histamine (40 mg/kg, s.c, 3 times every 2.5 h after indomethacin treatment) for 2 days under fasting conditions, and they were fed normally thereafter. The duodenal ulcers so induced were confined to the proximal part of the duodenum and penetrated to the muscular mucosa with an incidence of over 80% when determined 32 h after the first injection of indomethacin (day 1). The ulcers became smaller and shallower within 7 days with granulation from the ulcer base, the mucosa grew in from the edges over the surface of granulation tissue, and they had healed almost completely after 15 days with epithelial regeneration from the edge of the ulcers. The healing of ulcers was significantly promoted by a 5-day treatment with an antacid (Al(OH)₃) as well as antisecretory agents (omeprazole, cimetidine, propantheline bromide) and 16,16-dimethyl prostaglandin E₂ at the dose which produced a potent inhibition of acid output and a marked increase in duodenal alkaline secretion. These results suggest that the duodenal ulcers induced in rats by indomethacin + histamine may provide a useful model for studying the healing process of duodenal ulcers and for the evaluation of the drugs with possible effects on ulcer healing.

ABSTRACT-Lactitolhas been reported to decrease the blood ammonia concentration in various experimental hyperammonemia models such as portacaval shunted rats. The mechanism responsible for this lowering of blood ammonia levels was investigated in rats. When lactitol was given orally twice a day for 7 days at doses of 3 and 10 g/kg/day and at half that daily dose on day 8, it significantly decreased the ammonia concentration of the portal blood by 27.3-43.2%, cecal ammonia contents by 49.2-57.6%, and the pH of the cecal contents from 6.52 to 5.92 -5.54, 4 hr after the final administration. Lactitol also inhibited increases in the portal ammonia concentration induced by the intracecal administration of ammonium acetate (300 mg/kg) 4 hr after the final administration. When lactitol was given orally at bolus doses of 1 and 3 g/kg simultaneously with a charcoal meal, lactitol significantly facilitated small intestinal transit by 12-13%. At a bolus dose of 3 g/kg, given 1 hr before the administration of a charcoal meal into the proximal colon, lactitol significantly facilitated colonic transit by 29.5%. These effects of lactitol were similar to those of lactulose. These findings suggest that lactitol decreases blood ammonia concentration by inhibiting both the production and the absorption of ammonia through reducing intestinal pH and shortening the residence time of intestinal contents in the intestinal tract.Keywords: Lactitol, Mechanism, Blood ammonia level, Intestinal transit Hepatic encephalopathy is a metabolic disorder in which symptoms of psychosis/neuropathy and consciousness disorder caused by acute or chronic hepatic failure are manifested. The mechanism underlying the development of hepatic encephalopathy is not known. Since hyperammonemia is frequently observed in the development of this disease, however, ammonia has been noted as an important factor (1-3).Lactitol has been shown to decrease blood ammonia levels in portacaval shunted (PCS) rats treated with carbontetrachloride or dimethylnitrosamine (4). In addition, lactitol inhibits the increase of ammonia content in the brain and coma after administration of ammonium acetate in PCS rats treated with carbontetrachloride or dimethylnitrosamine (4).In the present study, we investigated the mechanism whereby lactitol lowers blood ammonia levels in rats. MATERIALS AND METHODS AnimalsMale Sprague-Dawley rats, 5 -7 weeks of age, were purchased from Japan SLC and used at 6-8 weeks of age.The rats were fed F-2 chow (Funabashi Farm, Funabashi) and received tap water ad libitum. They were kept in a room that was ventilated more than 15 times/hr, at a temperature of 21-251C and humidity of 45 % -65 % . DrugsLactitol monohydrate [(+)-4-0-~-D-galactopyranosyln-glucitol monohydrate; NS-4, Zyma, Nyon, Switzerland; regarded as lactitol only] (Fig. 1) is a white odorless crystalline or crystallic powder that has a sweet taste. Lactitol was given as a solution in distilled water. As a reference drug, lactulose (Fig. 1, lactulose syrup containing 60% lactulose; Nikken, Tok...

The effects of TY-10957, a stable PGI₂ derivative, on gastroduodenal lesions and secretory responses were examined in rats and compared with those of ornoprostil, a PGE₁ derivative. Orally administered TY-10957 dose dependently prevented gastric lesions induced by ethanol/HCl (60% ethanol in 150 mM HCl) and duodenal ulcers induced by mepirizole (200 mg/kg); a significant effect was obtained at 3 μg/kg or greater in the former and at 300 μg/kg in the latter. Intraduodenally administered TY-10957 had minimal effects on gastric acid secretion, and at the highest dose (300 μg/kg) both the basal acid output and that stimulated by histamine (20 mg/kg) were significantly reduced by about 40%. TY-10957 (30–300 μg/kg s.c.) produced a marked increase of alkaline secretion in both stomach and duodenum of anesthetized rats, and these effects were significant at 30 μg/kg in the stomach and at 100 μg/kg in the duodenum. On the other hand, ornoprostil produced a potent and significant inhibition against ethanol/HCl-induced lesions ( > 1 μg/kg), but had no effect on mepirizole-induced duodenal ulcers. This PGE₁ derivative had no influence on both basal and stimulated acid secretion and did not significantly affect alkaline secretion even at 100 μg/kg. These results suggest that TY-10957 has a protective action on both gastric and duodenal mucosa. The mechanism of duodenal antiulcer effect may involve both inhibition of acid and stimulation of alkaline secretion, while the gastroprotective action of this agent may be attributed to other factors.

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We studied the effect of alpha-2 adrenoceptor antagonists on colonic function stimulated by water-avoidance stress, 5-hydroxytryptamine (5-HT), bethanechol and castor oil by comparison with the effects of atropine and a 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, ondansetron. Yohimbine, idazoxan and atropine, but not ondansetron, significantly inhibited water-avoidance stress-stimulated faecal excretion. Yohimbine and idazoxan inhibited neither 5-HT- nor bethanechol-stimulated faecal excretion. In contrast, atropine inhibited both 5-HT- and bethanechol-stimulated faecal excretion and ondansetron inhibited 5-HT-stimulated faecal excretion. Yohimbine did not inhibit the incidence of diarrhoea induced by castor oil, but idazoxan significantly inhibited diarrhoea observed during a 1-h period after the administration of castor oil. Both atropine and ondansetron inhibited diarrhoea during a 2-h period after the administration of castor oil. These findings suggest that alpha-2 adrenoceptor antagonists specifically inhibit colonic motor function stimulated by stress in rats.