Document Detail


The cholecystokinin CCK2 receptor antagonist, JNJ-26070109, inhibits gastric acid secretion and prevents omeprazole-induced acid rebound in the rat.
MedLine Citation:
PMID:  22300007     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: JNJ-26070109 [(R)4-bromo-N-[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide] is a novel antagonist at cholecystokinin CCK(2) receptors with good pharmacokinetic properties and represents a novel mechanism for the treatment of gastro-oesophageal reflux disease (GORD). The purpose of the present study was to determine whether chronic treatment with JNJ-26070109 could prevent, as well as treat, acid rebound in rats.
EXPERIMENTAL APPROACH: A chronic fistula was surgically inserted into the stomach of rats to enable the measurement of acid secretion under basal, pentagastrin and histamine-stimulated conditions. JNJ-26070109 and omeprazole were administered separately and in combination.
KEY RESULTS: Sustained administration of omeprazole alone and in combination with JNJ-26070109 inhibited gastric acid secretion by >90%. However, 3 days after withdrawing treatment, there was a rebound hypersecretion by ∼1.5-fold in omeprazole-treated animals. No such acid rebound was observed with JNJ-26070109 alone or with co-administration of JNJ-26070109 and omeprazole. The anti-trophic effects of JNJ-26070109 in the gastric mucosal paralleled the effects on acid rebound. Administration of JNJ-26070109 for 3 days after cessation of omeprazole prevented the occurrence of acid rebound. Interestingly, chronic, but not acute, treatment with JNJ-26070109 also inhibited histamine-stimulated acid secretion.
CONCLUSIONS AND IMPLICATIONS: Chronic administration of JNJ-26070109 effectively inhibited gastric acid secretion and suppressed proton pump inhibitor (PPI)-induced acid rebound in the rat. This work advances the field by demonstrating that modest doses of a competitive CCK(2) receptor antagonist have significant and functionally important anti-trophic actions in the gastric mucosa. These properties make JNJ-26070109 a suitable candidate for clinical investigation for the treatment of GORD.
Authors:
T D Barrett; G Lagaud; P Wagaman; J M Freedman; W Yan; L Andries; M C Rizzolio; M F Morton; N P Shankley
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  166     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-25     Completed Date:  2012-10-30     Revised Date:  2013-07-02    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1684-93     Citation Subset:  IM    
Copyright Information:
© 2012 Janssen Research and Development LLC. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Affiliation:
Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA. tbarret1@its.jnj.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Ulcer Agents / pharmacology
Gastric Acid / secretion*
Gastrins / blood
Histamine
Male
Omeprazole / pharmacology
Pentagastrin
Quinoxalines / pharmacology*
Rats
Rats, Sprague-Dawley
Receptor, Cholecystokinin B / antagonists & inhibitors*
Sulfonamides / pharmacology*
Chemical
Reg. No./Substance:
0/4-bromo-N-(1-(2,4-difluoro-phenyl)ethyl)-2-(quinoxaline-5-sulfonylamino)benzamide; 0/Anti-Ulcer Agents; 0/Gastrins; 0/Quinoxalines; 0/Receptor, Cholecystokinin B; 0/Sulfonamides; 51-45-6/Histamine; 5534-95-2/Pentagastrin; 73590-58-6/Omeprazole
Comments/Corrections

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