التفاصيل البيبلوغرافية
| العنوان: |
The cholecystokinin CCK2 receptor antagonist, JNJ-26070109, inhibits gastric acid secretion and prevents omeprazole-induced acid rebound in the rat. |
| المؤلفون: |
Barrett, TD, Lagaud, G, Wagaman, P, Freedman, JM, Yan, W, Andries, L, Rizzolio, MC, Morton, MF, Shankley, NP |
| المصدر: |
British Journal of Pharmacology; Jul2012, Vol. 166 Issue 5, p1684-1693, 10p |
| مصطلحات موضوعية: |
CHOLECYSTOKININ receptors, GASTRIC acid, OMEPRAZOLE, LABORATORY rats, GASTROESOPHAGEAL reflux treatment, PARIETAL cells, GASTRIN, PROTON pump inhibitors |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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