The role of acid in the pathogenesis of aspirin-induced gastrointestinal erosions and hemorrhage

Cooke, Allan R.

doi:10.1007/bf01071977

Cited by 82 publications

(25 citation statements)

References 56 publications

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“…Therefore, it is pre sumed that cimetidine could hardly restore the biochemical function (i.e., glycoprotein synth esis) in the gastric mucosa under such severe experimental conditions as in the present study, even though it could inhibit the macro scopic lesion formation. It is considered that not only the reduction of gastric mucus, but also the aggression of gastric acid, contributes to the lesion formation by aspirin (29,30). Therefore, it would appear that the inhibitory effect of cimetidine on aspirin-induced lesions in the present study is due mainly to its anti secretory activity (31,32).…”

Section: Discussionmentioning

confidence: 64%

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: 64%

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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“…This result is predictable since the pKA value for aspirin is 3.5, and at higher pH values the lipid solubility and rate of absorption of the compound are diminished (Cooke, 1973). The role of acid back-diffusion in the aetiology of aspirin-induced gastric mucosal damage is a more contentious subject.…”

Section: Discussionmentioning

confidence: 83%

“…This was prepared by dissolving sufficient aspirin for a 20 mm solution with an equimolar amount of NaOH. The osmolarity of the solution was made up to 300 mosm/kg by the addition of mannitol, and the pH was 4.5; at this pH, 91 % of the drug is ionized (Cooke, 1973).…”

Section: Methodsmentioning

confidence: 99%

“…However, the precise role of acid in the development of these lesions is unclear. It is well established that an acidic environment is required to maintain aspirin (pKA 3.5) in its non-ionized form, thus increasing the lipid solubility of the molecule and the rate of absorption across the mucosal membrane (Cooke, 1973;Fromm, 1978). Following absorption, it is possible that aspirin causes gastric mucosal damage through a direct irritant effect (Rainsford, 1977), perhaps involving such mechanisms as the inhibition of active ion transport (Fromm, 1978) and the inhibition of oxidative metabolism (Rainsford & Whitehouse, 1980).…”

Section: Introductionmentioning

confidence: 99%

“…The formation of gastric mucosal lesions following topical acetylsalicylic acid (aspirin) is dependent on the presence of luminal acid (Cooke, 1973;Fromm, 1978). However, the precise role of acid in the development of these lesions is unclear.…”

Section: Introductionmentioning

confidence: 99%

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RELATIONSHIP BETWEEN LESION FORMATION AND PERMEABILITY OF RAT GASTRIC MUCOSA TO H⁺ AND OTHER CATIONS

Bunce

McCarthy

Spraggs

et al. 1982

British J Pharmacology

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1 The relationship between lesion formation and ionic permeability has been investigated in rat gastric mucosa in vivo. Changes in these parameters were measured in the mucosa treated topically with prostaglandins E2 and A2 and/or aspirin. Particular attention was paid to the net flux of H+ ions across the gastric mucosa. 2 The effect of aspirin concentrations of 5 mM, 20 mm and '40 mm' (the latter, a suspension in a saturated solution) was investigated. Aspirin concentrations of 20 mM and '40 mm' produced a marked increase in lesion formation and increased the net mucosal to serosal flux of H+ ions. Aspirin 5 mm produced a significant increase in lesion formation but did not cause a significant change in net H+ ion flux. This result suggests that aspirin can have a direct irritant effect on the gastric mucosa and that the back diffusion of H+ ions is not a pre-requisite for the development of overt mucosal ulceration. 3 The effect of topically applied prostaglandin E2 (PGE2) on aspirin-induced gastric mucosal damage was investigated. Concentrations of PGE2 of 105 M and 10 4M ameliorated aspirininduced damage, but these changes were not necessarily accompanied by a significant reduction in net H+ ion flux. Again, this result is not consistent with a direct relationship between lesion formation and mucosal permeability to H+ ions. 4 Since PGA2 did not ameliorate aspirin-induced mucosal damage, the protective effect of PGE2 could not be attributed to its conversion to PGA2 in the acidic environment of the gastric lumen.5 Changes in gastric mucosal potential difference (p.d.) and net fluxes of Na+ and K+ ions may occur without a concomitant change in the permeability of the gastric mucosa to acid back-diffusion. Thus, the assumption cannot be made that a change in the permeability of the gastric mucosa to one particular ion reflects a general increase in ionic permeability.

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Ranitidine Protects Against Gastroduodenal Mucosal Damage Associated With Chronic Aspirin Therapy

Berkowitz¹

1987

Arch Intern Med

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The role of acid in the pathogenesis of aspirin-induced gastrointestinal erosions and hemorrhage

Cited by 82 publications

References 56 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.

RELATIONSHIP BETWEEN LESION FORMATION AND PERMEABILITY OF RAT GASTRIC MUCOSA TO H⁺ AND OTHER CATIONS

Ranitidine Protects Against Gastroduodenal Mucosal Damage Associated With Chronic Aspirin Therapy

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The role of acid in the pathogenesis of aspirin-induced gastrointestinal erosions and hemorrhage

Cited by 82 publications

References 56 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.

RELATIONSHIP BETWEEN LESION FORMATION AND PERMEABILITY OF RAT GASTRIC MUCOSA TO H+ AND OTHER CATIONS

Ranitidine Protects Against Gastroduodenal Mucosal Damage Associated With Chronic Aspirin Therapy

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Product

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RELATIONSHIP BETWEEN LESION FORMATION AND PERMEABILITY OF RAT GASTRIC MUCOSA TO H⁺ AND OTHER CATIONS