Effects of the New Anti-Ulcer Agent KB-5492 on Experimental Gastric Mucosal Lesions and Gastric Mucosal Defensive Factors, as Compared to Those of Teprenone and Cimetidine.

Abstract

ABSTRACT-Effectsof KB-5492, a new anti-ulcer agent, on various experimental gastric mucosal lesions and mucosal defensive factors in rats were compared with those of teprenone and cimetidine. KB-5492 administered orally at 12.5 200 mg/kg inhibited water-immersion stress and indomethacin-induced gastric mucosal lesions in a dose-dependent manner with ED50 values of 46 and 27 mg/kg, respectively, indicat ing that KB-5492 was more potent than teprenone but less potent than cimetidine. KB-5492, administered orally at 12.5 -100 mg/kg, also inhibited ethanol-induced gas tric mucosal lesions in a dose-dependent manner with an ED50 of 23 mg/kg, so KB 5492 was 3 times more potent than teprenone, whereas cimetidine produced no ob vious inhibition. In addition, KB-5492, administered orally at 25 and 50 mg/kg twice daily for 10 consecutive days, significantly accelerated the healing of acetic acid-in duced gastric ulcers more potently than teprenone and cimetidine. KB-5492 at anti ulcer doses significantly increased gastric mucosal blood flow in normal anesthetized rats and inhibited the reduction of gastric mucosal hexosamine content induced by aspirin, but did not affect gastric acid secretion in pylorus-ligated rats. These results indicate that KB-5492 has potent and broad anti-ulcer properties, which are probably exerted by its enhancement of gastric mucosal defensive factors through increasing gastric mucosal blood flow and/or retaining gastric mucus, and not by its inhibition of gastric acid secretion.It is generally accepted that peptic ulcers are caused by a disruption in the balance of aggressive factors (gastric acid and pepsin) and mucosal defensive factors (blood flow, mucus, HC03 secretion, etc.) (1). Anti-ulcer agents have therefore been used either for suppres sing aggressive factors or for enhancing mucosal defensive factors. However, in recent years, it has been considered that different anti-ulcer agents should be used for gastric and duodenal ulcers, because of the patho physiological differences between the two ulcer types. That is, as gastric acid secretion is generally greater in duodenal ulcer patients than in normal subjects (2-4), agents such as H2-receptor antagonists or proton pump in hibitors, which strongly inhibit gastric acid secretion, show prominent effects on duodenal ulcers. In contrast, since gastric acid secretion is usually normal or below normal in gastric ulcer patients, gastric ulcers are presumed to be caused by weaknesses in gastric mucosal re sistance (4, 5). Therefore, agents which en hance mucosal defensive factors would be ex pected to show desirable effects against gastric ulcers. Although various agents in this catego ry have already been developed so far, they have not been particularly effective, so anti secretory agents are used preferably, even in the treatment of gastric ulcers.Seeking a novel agent which would enhance mucosal defensive factors more potently than existing agents, we developed 4-methoxy phenyl 4-(3,4,5-trimethoxybenzyl)-1-piperazine acetate monofumarate m...

Antiulcerogenic activity of Indigofera truxillensis Kunth

“…Lansoprazole, substance orally used as a positive control in this experiment, at a dose of 30 mg.kg -1 , provided 68% protection against the gastric lesions induced by ethanol. These results indicated a promising antiulcerogenic activity of the MeOH extract and suggested that an antisecretory or cytoprotective action may be involved (Morimoto et al 1991).…”

“…These experiments were done as described by Morimoto et al (1991) Rats were fasted for 24 h and MeOH extract, lansoprazole (30 mg.kg -1 ) or vehicle (solution 0.9% NaCl) was administered orally. One hour after treatment, the animals received an oral dose of one ml of absolute ethanol and were sacrificed one hour later, as described before.…”

Anti-ulcer activity of Synadenium grantii latex

“…To confirm the results that demonstrated the gastric protective effect of the EB1 and EB3 samples against the ethanol model, the indomethacin model (a medicine that produces ulcers in laboratory animals) was carried out (Morimoto et al, 1991;Borrelli & Izzo, 2000). Regarding the application of the referred experimental model, it was verified that the sample of the latex exhibited high antiulcerogenic activity, impeding the formation of ulcerative lesions in the stomach of the rats treated with this material (Figure 3).…”

Effects of KB-5492, a New Anti-Ulcer Agent with a Selective Affinity for the Sigma-Receptor, on Aspirin-Induced Disruption of the Rat Gastric Mucosal Barrier

“…Although KB-5492 at anti-ulcer doses did not affect either basal or histamine-stimulated gastric acid secretion in rats (3,4), it increased the gastric mucosal blood flow (4) and prevented the reduction of hexosamine content induced by aspirin in rat gatric mu cosa (4). These findings strongly suggest that KB-5492 en hances gastric mucosal defensive factors.…”

“…KB-5492, 4-methoxyphenyl 4-(3,4,5-trimethoxybenz yl)-1-piperazineacetate monofumarate monohydrate, is a new anti-ulcer agent previously shown to prevent various experimental gastric mucosal lesions in rats including those induced by oral administration of aspirin or acidified aspirin (3,4). Although KB-5492 at anti-ulcer doses did not affect either basal or histamine-stimulated gastric acid secretion in rats (3,4), it increased the gastric mucosal blood flow (4) and prevented the reduction of hexosamine content induced by aspirin in rat gatric mu cosa (4).…”