Effects of the antiulcer drug geranylgeranylacetone on aspirin-induced gastric ulcers in rats.

Murakami, Manabu; Oketani, Kiyoshi; Fujisaki, Hideaki; Wakabayashi, Tsuneo; Ohgo, Toshiharu; Okabe, Susumu

doi:10.1254/jjp.32.299

Cited by 40 publications

(20 citation statements)

References 12 publications

(9 reference statements)

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“…Azuumi et al (20) also reported that aspirin reduced gastric mucosal glycoprotein content prior to the macroscopic lesion formation, and they suggested that aspirin-induced mucosal lesions were caused by the reduction of gastric mucus. Murakami et al (21) and Oketani et al (22) examined the effect of teprenone on the amount of gas tric mucus in aspirin-treated rats, and conse quently they speculated that teprenone inhib ited aspirin-induced mucosal lesions by pre venting the reduction of gastric mucus, parti cularly of macromolecular glycoproteins. In the present study, KB-5492, as well as tepre none, significantly inhibited both the macro scopic lesion formation and the reduction of mucosal hexosamine content induced by aspi rin.…”

Section: Discussionmentioning

confidence: 99%

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

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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Section: Discussionmentioning

confidence: 99%

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

176

115

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“…Tetraprenylacetone (TPA: teprenon, geranylgeranylacetone) is a novel anti-ulcer agent developed in Japan (1,2). It is reported that this drug has the ability to protect gastric mucosa against damaging-agents such as ethanol (ET) without inhibition of gastric acid secretion (3).…”

mentioning

confidence: 99%

Tetraprenylacetone promotes healing process of ethanol-induced gastric damage in the rat.

et al. 1991

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ABSTRACT-Tetraprenylacetone (TPA: teprenon, geranylgeranylacetone) is a novel anti-ulcer agent developed in Japan. The aim of this study was to test whether TPA has the ability to promote the healing process of rat gastric mucosal injury induced by absolute ethanol (ET). Fasted rats received orally 5 ml/kg of absolute ET . Sixty minutes later, TPA (200 mg/kg) or saline (control) was administered intragastrically . Thereafter, the same dose of TPA or saline was given orally every 8 hours. To investigate the role of endogenous prostaglandins, indomethacin was given intraperitoneally every 8 hours. Twenty four or 48 hours after the first administration of TPA or saline, rats were sacrificed and the stomachs were removed. Administration of TPA significantly reduced lesion indices from 100 ± 12.9% (control) to 57.0 ± 12.8% (24 hours, P < 0.05) and from 100 ± 15.3% (control) to 17.6 ± 3.4% (48 hours, P < 0.01). Addition of indomethacin did not significantly affect this effect of TPA . Ultrastructual studies revealed that TPA stimulated regeneration of gastric mucosa damaged by ET after 24 and 48 hours. These results indicate that TPA has the ability to promote the healing process of gastric mucosal damage induced by absolute ET. It is, however, unlikely that endogenous prostaglandins are involved in this promotive effect of TPA on the healing process of gastric injury.

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“…Murakami et al (12) demonstrated that teprenone, an anti-ulcer agent known to enhance gastric mucosal defen sive factors, prevented the aspirin-induced gastric mu cosal lesions in pylorus-ligated rats at 100 and 200 mg/kg, i.d. Terano et al (13) have reported that intra venous teprenone (200 and 400 mg/kg) prevented the aspirin-induced decrease in PD in rats.…”

Section: Discussionmentioning

confidence: 99%

“…However, in the present study, teprenone did not affect the aspirin-in duced decrease in PD even at the anti-ulcer dose of 200 mg/kg, i.d. (12). Since teprenone was administered i.d.…”

Section: Discussionmentioning

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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Effects of the antiulcer drug geranylgeranylacetone on aspirin-induced gastric ulcers in rats.

Cited by 40 publications

References 12 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.

Tetraprenylacetone promotes healing process of ethanol-induced gastric damage in the rat.

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

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