Antisecretory and Antiulcer Effects of YM020, a New H+,K+-ATPase Inhibitor, in Rats and Dogs

Yuki, Hidenobu; Kamato, Takeshi; Nishida, Akito; Ohta, Mitsuaki; Shikama, Hisataka; Yanagisawa, Isao; Miyata, Keiji

doi:10.1254/jjp.67.59

Cited by 7 publications

(1 citation statement)

References 17 publications

(19 reference statements)

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“…After showing that bosentan inhibited WIRS‐stimulated acid secretion, they concluded that the antisecretory properties of bosentan are likely to be responsible for prevention of gastric damage 23 . This conclusion would make bosentan about three times less potent than omeprazole in attenuating gastric lesions in WIRS rats 28 –30 . However, this does not reflect the range of potency on acid seen in the in vitro assay ( Figure 4), where the inhibition of acid by bosentan and Ro 48‐5695 at a 10 −4 M dose was about 50% and both compounds were at least 1000 times less potent on cAMP‐stimulated acid secretion than omeprazole.…”

Section: Discussionmentioning

confidence: 99%

Anti‐ulcerogenic properties of endothelin receptor antagonists in the rat

Padol

Huang

Hunt

1999

Aliment Pharmacol Ther

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Background : Endothelins have been implicated in gastric mucosal damage in a variety of animal models. Exogenous ET‐1 and ET‐3 are causally associated with experimental gastric ulcers. Furthermore, clinical reports also show elevated plasma and gastric mucosal endothelin‐1 levels in patients suffering from peptic ulcers. Aim : To study the possibility that endothelin receptor antagonists may have beneficial effects and prevent the development of gastric ulcers. We have tested in rats the orally‐active endothelin antagonist bosentan (Ro 47‐0203) and Ro 48‐5695, which is 10–30 times more potent than bosentan on endothelin receptors. Methods : Water immersion restrained stress (WIRS) and indomethacin were used to provoke gastric mucosal damage. Endothelin receptor antagonists were administered orally prior to the induction of gastric damage. The gastric lesion index (mm), assessed macroscopically, and myeloperoxidase (MPO) activity were used as markers of the extent of mucosal injury. Results : Bosentan at 100 and 30 mg/kg administered orally caused attenuation of gastric damage in the WIRS model by 58% and 42%, respectively. Bosentan also caused complete reduction of MPO activity. In indomethacin‐induced gastric damage, 100 mg/kg bosentan attenuated gastric damage by 45% and 61% as measured by the gastric lesion index and MPO activity respectively. Ro 48‐5695 was at least 30 times more potent than bosentan in reducing indomethacin‐induced mucosal damage and at 3 mg/kg, caused a decrease of 49% in the gastric lesion index and a reduction in MPO activity of 41%. Bosentan and Ro 48‐5695 possess weak antisecretory properties as tested in the mouse gastric gland assay, than cannot, alone, account for their anti‐ulcer properties. Conclusions : Both endothelin receptor antagonists prevented the development of gastric mucosal injury in the rat. Disturbances in the gastric microcirculation are responsible for the development of experimental gastric ulcers. The anti‐ulcer properties of these two endothelin antagonists suggest possible new therapeutic approaches to controlling gastric inflammation.

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Section: Discussionmentioning

confidence: 99%

Anti‐ulcerogenic properties of endothelin receptor antagonists in the rat

Padol

Huang

Hunt

1999

Aliment Pharmacol Ther

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Inhibitors of Gastric Acid Secretion

Roberts¹,

McDonald²

2003

Burger's Medicinal Chemistry and Drug Discovery

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The discovery of potent and selective inhibitors of gastric acid secretion now negates the need for surgical intervention in the treatment of many hypersecretory disorders. The side effects associated with cholinergic antagonists has led to their being superseded by the use of selective histamine H 2 ‐receptor antagonists (cimetidine, ranitidine, famotidine) and the more potent irreversible proton‐pump inhibitors (omeprazole, rabeprazole, lansoprazole, pantoprazole, esomeprazole). Current therapeutic regimes for the treatment of ulcer disease recommend concurrent proton‐pump administration while eradicating Helicobacter pylori , a bacterial infection that is strongly associated with ulcer formation. Because achlorhydria increases the likelihood of gastrointestinal infection, current research within this area is now targeting the design of reversible proton‐pump inhibitors and CCK 2 /gastrin‐receptor antagonists. These newer therapeutic approaches, however, are unlikely to produce the rapid and potent inhibition of acid secretion realized by the irreverisble PPIs, which in addition have few side effects and a proven track record of success. Key drug developments in the treatment of acid hypersecretion, from the anticholinergic agents to the highly potent and effective proton‐pump inhibitors currently in use, are covered in this chapter.

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Biochemical and pharmacological properties of a new proton pump inhibitor, 2-amino-4,5-dihydropyrido[1,2-a]thiazolo [5,4-g] benzimidazole (YJA20379-5)

Shon¹,

Chang²,

Chung³

et al. 1998

Arch. Pharm. Res.

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This study was designed to determine biochemical and pharmacological properties of a newly synthesized benzimidazole derivative, 2-amino-4,5-dihydropyrido [1,2-a] thiazolo [5,4-g] benzimidazole (YJA20379-5) in vitro and in vivo. In the leaky membrane vesicles of pig gastric mucosa, YJA20379-5 inhibited the K(+)-stimulated H+,K(+)-ATPase activity in a concentration- and time-dependent manner, with IC50 values being 43 microM and 31 microM at pH 6.4 and 7.4, respectively. YJA20379-5, given intraduodenally, had a potent inhibitory effect on the gastric acid secretion in pylorus-ligated rats. The ED50 value for acid secretion was 15.4 mg/kg. YJA20379-5, administered orally, also suppressed gastric damages induced by water-immersion stress, indomethacin and ethanol, and duodenal damage induced by mepirizole in rats; the ED50 values were 17.6, 4.7, 3.0 and 18.7 mg/kg, respectively. Furthermore, repeated oral administration of YJA20379-5 accelerated the spontaneous healing of acetic acid-induced gastric ulcers in rats. It is concluded that the antisecretory activity of YJA20379-5 appears to be associated with inhibition of H+,K(+)-ATPase, while its antigastric and antiduodenal lesion activities are primarily related to the antisecretory effect.

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Antisecretory and Antiulcer Effects of YM020, a New H+,K+-ATPase Inhibitor, in Rats and Dogs

Cited by 7 publications

References 17 publications

Anti‐ulcerogenic properties of endothelin receptor antagonists in the rat

Anti‐ulcerogenic properties of endothelin receptor antagonists in the rat

Inhibitors of Gastric Acid Secretion

Biochemical and pharmacological properties of a new proton pump inhibitor, 2-amino-4,5-dihydropyrido[1,2-a]thiazolo [5,4-g] benzimidazole (YJA20379-5)

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