Effects of KB-5492, 1-(3,4,5-Trimethoxybenzyl)-4-((4-Methoxyphenyl)oxycarbonylmethyl)piperazine Monofumarate Monohydrate, on Gastric Lesions and Gastric Secretion in Rats

Shimohara, Koichi; Niida, Hiromichi; Okabe, Susumu

doi:10.1254/jjp.53.275

Japanese Journal of Pharmacology

1990

DOI: 10.1254/jjp.53.275

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Effects of KB-5492, 1-(3,4,5-Trimethoxybenzyl)-4-((4-Methoxyphenyl)oxycarbonylmethyl)piperazine Monofumarate Monohydrate, on Gastric Lesions and Gastric Secretion in Rats

Koichi Shimohara

Hiromichi Niida

Susumu Okabe

Abstract: Abstract-Effects of a newly synthesized compound, KB-5492, on gastric lesions and gastric secretion were studied in rats.

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Cited by 9 publications

(9 citation statements)

References 11 publications

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“…1). Shimohara et al have already reported that KB-5492 inhibits various ex perimental gastric mucosal lesions more potently than sofalcone (6). In addition, they speculated that the anti-ulcer activity of KB 5492 was mediated by enhancing mucosal de fensive factors, since KB-5492 did not affect either basal or histamine-stimulated gastric acid secretion.…”

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confidence: 98%

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.

Morimoto¹,

Shimohara²,

Oshima³

et al. 1991

Jpn.J.Pharmacol

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176

115

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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...

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mentioning

confidence: 98%

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.

Morimoto¹,

Shimohara²,

Oshima³

et al. 1991

Jpn.J.Pharmacol

Self Cite

176

115

View full text Add to dashboard Cite

show abstract

“…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.…”

mentioning

confidence: 89%

“…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).…”

mentioning

confidence: 99%

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

Morimoto¹,

Shimohara²,

Oshima³

et al. 1994

Japanese Journal of Pharmacology

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ABSTRACT-The effect of KB-5492, a new anti-ulcer agent with a selective affinity for the sigma-receptor, on aspirin-induced disruption of the gastric mucosal barrier was studied in rats. Intragastric instillation of aspirin at 200 mg/kg rapidly decreased the gastric transmucosal potential difference (PD) in anesthetized rats. The PD recovered gradually following the removal of aspirin from the instillation solution. Aspirin, ad ministered orally at 200 mg/kg, also reduced the amount of gastric covering mucus and induced a decrease in gastric H+ concentration and an increase in gastric Na+ concentration in pylorus-ligated rats. KB-5492, administered intraduodenally at 200 mg/kg, significantly prevented the aspirin-induced decrease in PD and accelerated the recovery of PD. In addition, KB-5492 at 200 mg/kg significantly prevented the reduction of gastric covering mucus, the decrease in gastric H+ concentration and the increase in gastric Na+ concentra tion induced by aspirin. These effects were similar to those of 0.01 mg/kg of 16,16-dimethyl prostaglandin E2 (dmPGE2). Teprenone at 200 mg/kg did not show any effect except for the inhibitory effects on the changes in gastric H+ and Na+ concentration. In the histological study, marked reduction of PAS-positive epithelial mucus and the exfoliation of surface epithelial cells were observed in the gastric mucosa exposed to aspirin. KB-5492 and dmPGE2 almost completely prevented the former, whereas both drugs prevented the latter incompletely. These findings indicate that KB-5492 protects the gastric mucosal barrier against the disruption by aspirin, which may be mainly exerted by retention of the gastric covering mucus.

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“…KB-5492, 4-methoxyphenyl 4-(3,4,5-trimethoxybenzyl) 1-piperazineacetate monofumarate monohydrate, is a new anti-ulcer agent previously shown to prevent various experimental gastric mucosal lesions in rats (1,2). Although KB-5492, at anti-ulcer doses, did not affect either basal or histamine-stimulated gastric acid secretion (1,2), it increased gastric mucosal blood flow (2), prevent ed aspirin-induced reduction of gastric mucus (2) and pro tected the gastric mucosal barrier (3).…”

mentioning

confidence: 99%

“…Although KB-5492, at anti-ulcer doses, did not affect either basal or histamine-stimulated gastric acid secretion (1,2), it increased gastric mucosal blood flow (2), prevent ed aspirin-induced reduction of gastric mucus (2) and pro tected the gastric mucosal barrier (3). Therefore, KB-5492 has been considered to enhance gastric mucosal defensive factors.…”

mentioning

confidence: 99%

4-Methoxyphenyl 4-(3,4,5-Trimethoxybenzyl)-1-Piperazineacetate Monofumarate Monohydrate (KB-5492), a New Anti-Ulcer Agent with a Selective Affinity for the Sigma Receptor, Prevents Cysteamine-Induced Duodenal Ulcers in Rats by a Mechanism Different from That of Cimetidine

Morimoto

Shimohara

Tanaka

et al. 1994

Japanese Journal of Pharmacology

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ABSTRACT-Both KB-5492, a new anti-ulcer agent, and cimetidine, administered orally at 25 200 mg/kg, dose-dependently prevented cysteamine (400 mg/kg, s.c.)-induced duodenal ulcers in rats with ED50 values of 63 and 40 mg/kg, respectively. Anti-ulcer doses of cimetidine, but not KB-5492, inhibited gastric acid hypersecretion induced by cysteamine (400 mg/kg, s.c.). In contrast, anti-ulcer doses of KB-5492, but not cimetidine, increased duodenal HC03 secretion in normal anesthetized rats. These findings suggest that KB-5492 prevents cysteamine-induced duodenal ulcers by stimulating duodenal HC03 secretion, whereas cimetidine does so by inhibiting cysteamine-induced gastric acid hypersecretion.

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Effects of KB-5492, 1-(3,4,5-Trimethoxybenzyl)-4-((4-Methoxyphenyl)oxycarbonylmethyl)piperazine Monofumarate Monohydrate, on Gastric Lesions and Gastric Secretion in Rats

Abstract: Abstract-Effects of a newly synthesized compound, KB-5492, on gastric lesions and gastric secretion were studied in rats.

Cited by 9 publications

References 11 publications

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.

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.

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

4-Methoxyphenyl 4-(3,4,5-Trimethoxybenzyl)-1-Piperazineacetate Monofumarate Monohydrate (KB-5492), a New Anti-Ulcer Agent with a Selective Affinity for the Sigma Receptor, Prevents Cysteamine-Induced Duodenal Ulcers in Rats by a Mechanism Different from That of Cimetidine

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