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The cholecystokinin CCK 2 receptor antagonist, JNJ‐26070109, inhibits gastric acid secretion and prevents omeprazole‐induced acid rebound in the rat
Author(s) -
Barrett TD,
Lagaud G,
Wagaman P,
Freedman JM,
Yan W,
Andries L,
Rizzolio MC,
Morton MF,
Shankley NP
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.01878.x
Subject(s) - omeprazole , gastric acid , proton pump inhibitor , medicine , gastrin , cholecystokinin , endocrinology , pentagastrin , histamine , cholecystokinin b receptor , antagonist , stomach , chemistry , pharmacology , secretion , receptor
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.