Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 166, Issue 5, Pages 1684-1693Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1476-5381.2012.01878.x
Keywords
JNJ-26070109; omeprazole; gastro-oesophageal reflux disease; GORD; gastric acid secretion; acid rebound; CCK receptor; gastrin; ECL cell; parietal cell
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Funding
- La Jolla bioanalytical group of Janssen Pharmaceutical Companies of Johnson Johnson
- Janssen Pharmaceutical Companies of Johnson Johnson, USA
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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 CCK2 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 CCK2 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.
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