lafutidine and Duodenal-Ulcer

We examined the prophylactic effect of lafutidine, a novel histamine H(2)-receptor antagonist [(+/-)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyr idyl]oxy- (Z)-2 butenyl]acetamide], on indomethacin-induced small intestinal ulcers in rats and investigated the relation of this action to capsaicin-sensitive sensory neurons.. Subcutaneously administered indomethacin (10 mg/kg) provoked ulceration in the small intestine, mainly the jejunum and ileum, accompanied by increases in myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities as well as the enterobacterial numbers invading the mucosa. Intestinal ulcerogenic response to indomethacin was prevented by 16,16-dimethyl prostaglandin E(2) (10 microg/kg, p.o.) and capsaicin (10 mg/kg, p.o. ) as well as ampicillin (800 mg/kg, p.o.), but not omeprazole (100 mg/kg, p.o.). Likewise, lafutidine (1-10 mg/kg, p.o.), but not cimetidine (100 mg/kg, p.o.), reduced the occurrence of intestinal ulcers in response to indomethacin in a dose-dependent manner, and a significant effect was observed at 3 mg/kg or greater. The protective action of lafutidine as well as capsaicin was almost totally abolished by chemical ablation of capsaicin-sensitive sensory neurons. Both lafutidine and capsaicin significantly suppressed the increases in MPO and iNOS activities as well as enterobacterial numbers in the mucosa. These agents also significantly enhanced mucus secretion in the small intestine.. These results suggest that lafutidine protects the small intestine against ulceration via stimulation of capsaicin-sensitive sensory neurons. This action may be attributable to inhibition of enterobacterial invasion in the intestinal mucosa, probably by increasing the mucus secretion.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Ampicillin; Animals; Capsaicin; Dose-Response Relationship, Drug; Duodenal Ulcer; Histamine H2 Antagonists; Indomethacin; Intestinal Mucosa; Male; Neurons, Afferent; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley

We examined the anti-ulcer effects of FRG-8813, a new type histamine H2-receptor antagonist, on various experimental gastric and duodenal lesions in rats. FRG-8813, administered orally, inhibited the formation of lesions dose-dependently in experimental models with the exception of the Shay ulcer model. The anti-ulcer potency of FRG-8813 was 4 approximately 10 times greater than that of cimetidine when the ED50 values of both compounds were compared. Famotidine and cimetidine inhibited lesion formation at higher doses than the anti-secretory doses. The anti-ulcer action of FRG-8813, however, appeared at even lower doses than those of anti-secretory action. These results suggest that FRG-8813 is able to prevent lesion formation with anti-secretory action plus other mechanisms unlike typical histamine H2-receptor antagonists.

Topics: Acetamides; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Duodenal Ulcer; Gastric Acid; Histamine H2 Antagonists; Male; Piperidines; Pyridines; Rats; Rats, Wistar; Stomach Ulcer

We examined the anti-ulcer effects of FRG-8813, a new-type histamine H2-receptor antagonist, in chronic ulcer models of rats and mice (W/WV). FRG-8813, given orally twice a day for 7 days, accelerated the healing of gastric or duodenal ulcer induced by acetic acid injection or application at the non-antisecretory doses (0.3 approximately 3 mg/kg). Administration of FRG-8813 to rats with ulcers increased the amounts of mucus in the gastric mucosa. These actions of FRG-8813 were more potent than those of famotidine or cimetidine. In W/WV mice, several ulcers spontaneously developed on gastric mucosa during the 8 weeks after the birth. The ulcers were aggravated by several unknown factors after the ulcer generation in W/WV mice. The aggravation of ulcers was inhibited by the 4-week administration of FRG-8813 with diet at the dose of 1 or 10 mg/kg/day, but was not inhibited by cimetidine at the dose of 100 mg/kg/day. From these results, we suggest that FRG-8813 is able to accelerate the healing of ulcers by antisecretory plus increasing actions on the integrity of the gastric mucosal defense mechanisms; therefore FRG-8813 is expected to be a useful drug for the treatment of gastric or duodenal ulcers in humans.

Topics: Acetamides; Animals; Chronic Disease; Disease Models, Animal; Duodenal Ulcer; Gastric Acid; Histamine H2 Antagonists; Male; Mice; Piperidines; Pyridines; Rats; Rats, Wistar; Stomach Ulcer