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A Study Comparing the Antisecretory Effect of TAK-438, a Novel Potassium-Competitive Acid Blocker, with Lansoprazole in Animals.
MedLine Citation:
PMID:  21411494     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. However, several medical needs such as suppression of night-time acid secretion and rapid symptom relief remain unmet. In this study, we investigated the effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker (P-CAB), on acid secretion in rats and dogs under various conditions, in comparison with the PPI lansoprazole, in order to characterize the antisecretory action of TAK-438. TAK-438 showed a more potent and longer-lasting inhibitory effect than lansoprazole on the histamine-stimulated gastric acid secretion in rats and dogs. A pharmacokinetic study in rats showed that TAK-438 accumulated and was retained in the gastric tissue for more than 24 h, unlike that in the plasma. TAK-438 showed significant antisecretory activity with or without cimetidine pretreatment, in contrast to lansoprazole, which did not show antisecretory activity after cimetidine pretreatment in rats. TAK-438 increased the pH of the gastric perfusate to 5.7 in an unstimulated condition, and this effect was maintained in the presence of subsequent histamine stimulation. On the other hand, lansoprazole also increased the pH in an unstimulated condition, but this effect diminished after histamine stimulation. These results indicated that TAK-438 exerted a more potent and longer-lasting antisecretory effect than lansoprazole through high accumulation and slow clearance from the gastric tissue. In addition, TAK-438 was unaffected by the gastric secretory state, unlike PPIs. Therefore, TAK-438 can provide a novel mechanism of action to improve the present PPI-based treatment of acid-related diseases.
Authors:
Yasunobu Hori; Jun Matsukawa; Toshiyuki Takeuchi; Haruyuki Nishida; Masahiro Kajino; Nobuhiro Inatomi
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-3-16
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  -     ISSN:  1521-0103     ISO Abbreviation:  -     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-3-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1 Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd.;
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