Gastric antisecretory effect of FRG-8813, a new histamine H2 receptor antagonist, in rats and dogs

Shibata, Masahiro; Yamaura, Tetsuaki; Inaba, Niro; Onodera, Sadayoshi; Chida, Yuriko; Ohnishi, Haruo

doi:10.1016/0014-2999(93)90143-6

Cited by 62 publications

(68 citation statements)

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“…This compound has potent and long-lasting acid antisecretory activities in rats and dogs (9)(10)(11). The trials carried out in normal human volunteers revealed that FRG-8813 given orally produced prolonged inhibition of gastric acid secretion like it did in animals (Mori et al, unpublished data).…”

Section: Frg-8813 ((±)-2-(furfurylsulfinyl)-n-[4-[4-(piperidinomethylmentioning

confidence: 99%

Gastroprotective Activity of FRG-8813, a Novel Histamine H2-Receptor Antagonist, in Rats

Onodera

Shibata

Tanaka

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-FRG-8813 ((±)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2-butenyl]acetamide) is a novel histamine H2-receptor antagonist with gastric antisecretory and gastroprotective activities. The present study was designed to investigate the property of gastroprotective action. The oral ED50 values for inhibition of mucosal lesions against 1076 NH3-, 60% ethanol in 0.15 N HCl-, 100% ethanol-, 0.6 N HCl-and sodium taurocholate in 0.4 N HCl-induced damage were 3.3, 11.1, 14.9, 23.3 and 23.1 mg/kg, respectively. FRG-8813 was gastroprotective despite pretreatment with omeprazole, suggesting that the protective effect is independent of its antisecretory activity. It is unlikely that FRG-8813 works as a mild irritant because it showed a gastroprotective effect after intraperitoneal injection, but oral administration itself did not influence the rat gastric mucosa. Although pretreatment with indomethacin or N-ethylmaleimide did not affect the gastroprotection of FRG-8813, chemical deafferentation induced by capsaicin abolished the gastroprotection.Furthermore, prior administration of tetrodotoxin, the calcitonin generelated peptide (CGRP) antagonist hCGRP8_37 or N~-nitro-L-arginine attenuated the gastroprotection of FRG-8813 as well as that of capsaicin. In contrast to capsaicin, repeated administration of FRG-8813 neither enhanced the susceptibility of the mucosa to damage nor affected the gastroprotective action of short-term treatment. In conclusion, these results suggest that FRG-8813 has gastroprotective activity independently of acid antisecretory activity and that capsaicin-sensitive nerves may be partially or fully involved in the gastroprotective mechanisms of FRG-8813. Keywords:FRG-8813, Gastroprotection, Histamine H2-receptor antagonist, Capsaicin-sensitive nerve, Antiulcer drug Successful peptic ulcer therapy depends on the restoration of the compromised integrity of the gastroduodenal mucosa by either reducing the aggressive factors or enhancing the defensive process in the mucosa. This has been mainly accomplished by reducing intraluminal acid with an histamine H2-receptor antagonist for more than 10 years. The histamine H2-receptor antagonists are among the most frequently employed drugs worldwide, and their leading position can be explained by their proven high antisecretory potency (1, 2). However, numerous reports showed that the incidence of ulcer relapse after discontinuation of the histamine H2-receptor antagonist reaches the same level as that in patients receiving a placebo (3 -5). From these viewpoints, further improvement in ulcer therapy, with regard to quality of ulcer healing and/or ulcer relapse, might be achieved if the agent could enhance the mucosal defensive capacity in addition to decreasing gastric acid secretion.The property of agents that protect the gastric mucosa against necrotizing agents such as ethanol was defined as so-called "cytoprotection"by Robert et al. (6). Subsequent observations demonstrated that although the gastric cells localized deep in the mu...

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Section: Frg-8813 ((±)-2-(furfurylsulfinyl)-n-[4-[4-(piperidinomethylmentioning

confidence: 99%

Gastroprotective Activity of FRG-8813, a Novel Histamine H2-Receptor Antagonist, in Rats

Onodera

Shibata

Tanaka

et al. 1995

Japanese Journal of Pharmacology

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“…20 Thus, it cannot be assumed that proton-pump inhibitors always have stronger gastric acid suppression potency than H 2 -RAs in all genotype groups. Lafutidine is a newly developed H 2 -RA [21][22][23][24] that was approved for clinical use in Japan in 2000. Unlike conventional H 2 -RAs, lafutidine strongly inhibits gastric acid secretion not only at night but also in the daytime, 25 and it also has gastroprotective activity via capsaicin-sensitive afferent neurones.…”

Section: Introductionmentioning

confidence: 99%

Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H₂‐receptor antagonist

Shimatani

Inoue

Kuroiwa

et al. 2003

Aliment Pharmacol Ther

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SUMMARYBackground: Omeprazole 10 mg is used as maintenance therapy for gastro-oesophageal reflux disease, but previous reports have not mentioned the potency of its acid suppression. Aim: To evaluate the potency of acid suppression with omeprazole 10 mg, in relation to CYP2C19 genotypes. Methods: Eighteen healthy subjects without Helicobacter pylori participated. After a 7-day regimen of omeprazole 10 mg, 20 mg, lafutidine 20 mg (a novel H 2 -receptor antagonist) or water only (baseline data), intragastric pH was measured for 24 h. Results: With omeprazole 10 mg, greater differences were observed than 20 mg in median pH values and pH > 4 holding time ratios between poor metabolizers (PMs, n ¼ 6) and the others [homozygous extensive metabolizers (homo-EMs, n ¼ 6) and heterozygous extensive metabolizers (hetero-EMs, n ¼ 6)]. With lafutidine 20 mg, these parameters were not influenced by the genotype. The potency of acid suppression was: omeprazole 20 mg lafutidine 20 mg > omeprazole 10 mg in homo-EMs, omeprazole 20 mg > omeprazole 10 mg lafutidine 20 mg in hetero-EMs, and omeprazole 20 mg omeprazole 10 mg > lafutidine 20 mg in PMs. Conclusions: Omeprazole 10 mg strongly suppresses acid secretion, but depending on the CYP2C19 genotypes shows greater interindividual variations in suppression than 20 mg.

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“…Lafutidine is a histamine H 2 -receptor antagonist with both antisecretory and gastroprotective action [17,18]. Onodera et al [19] reported that the mucosal protective action of lafutidine was mediated by capsaicin-sensitive sensory neurons and independent of the antisecretory activity, because the action was not mimicked by cimetidine, another H 2 -receptor antagonist, and was totally abolished by chemical deafferentation of sensory neurons.…”

Section: Commentarymentioning

confidence: 99%

“…Lafutidine, a histamine H 2 -receptor antagonist, has been shown to exhibit a potent gastroprotective activity in addition to gastric antisecretory action [17,18]. Onodera et al [19] reported that the gastroprotective action of lafutidine was independent of its antisecretory effect and partially mediated by capsaicin-sensitive sensory neurons.…”

Section: Introductionmentioning

confidence: 99%

Lafutidine Protects the NSAID-Induced Small Intestinal Lesions Mediated by Capsaicin-Sensitive Afferent Neurons

Amagase¹,

Takeuchi²

2014

Capsaicin - Sensitive Neural Afferentation and the Gastrointestinal Tract: From Bench to Bedside

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Gastric antisecretory effect of FRG-8813, a new histamine H2 receptor antagonist, in rats and dogs

Cited by 62 publications

References 13 publications

Gastroprotective Activity of FRG-8813, a Novel Histamine H2-Receptor Antagonist, in Rats

Gastroprotective Activity of FRG-8813, a Novel Histamine H2-Receptor Antagonist, in Rats

Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H₂‐receptor antagonist

Lafutidine Protects the NSAID-Induced Small Intestinal Lesions Mediated by Capsaicin-Sensitive Afferent Neurons

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Gastric antisecretory effect of FRG-8813, a new histamine H2 receptor antagonist, in rats and dogs

Cited by 62 publications

References 13 publications

Gastroprotective Activity of FRG-8813, a Novel Histamine H2-Receptor Antagonist, in Rats

Gastroprotective Activity of FRG-8813, a Novel Histamine H2-Receptor Antagonist, in Rats

Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H2‐receptor antagonist

Lafutidine Protects the NSAID-Induced Small Intestinal Lesions Mediated by Capsaicin-Sensitive Afferent Neurons

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Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H₂‐receptor antagonist