Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
Br J Pharmacol. 2012 Jul;166(5):1684-93. doi: 10.1111/j.1476-5381.2012.01878.x.
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.
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.
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.
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.
JNJ-26070109[（R）4-溴-N-[1-（2,4-二氟苯基）-乙基]-2-（喹喔啉-5-磺酰基氨基）-苯甲酰胺]是一种新型的胆囊收缩素 CCK（2）受体拮抗剂，具有良好的药代动力学特性，代表了治疗胃食管反流病（GORD）的一种新机制。本研究的目的是确定 JNJ-26070109 的慢性治疗是否既能预防，也能治疗大鼠的酸反弹。
通过手术将一个慢性瘘管插入大鼠的胃中，以便在基础、五肽胃泌素和组胺刺激条件下测量胃酸分泌。单独和联合使用 JNJ-26070109 和奥美拉唑进行治疗。
单独和联合使用奥美拉唑持续给药可抑制胃酸分泌>90%。然而，在停止治疗 3 天后，奥美拉唑治疗的动物出现了约 1.5 倍的胃酸分泌反弹。单独使用 JNJ-26070109 或联合使用 JNJ-26070109 和奥美拉唑均未观察到这种酸反弹。JNJ-26070109 在胃黏膜中的抗营养作用与酸反弹的作用相平行。在停止奥美拉唑治疗后 3 天给予 JNJ-26070109 治疗可预防酸反弹的发生。有趣的是，JNJ-26070109 的慢性治疗而不是急性治疗也抑制了组胺刺激的胃酸分泌。
JNJ-26070109 的慢性给药可有效抑制胃酸分泌，并抑制大鼠中质子泵抑制剂（PPI）诱导的酸反弹。这项工作通过证明一种竞争性 CCK（2）受体拮抗剂的适度剂量在胃黏膜中有显著的、具有重要功能的抗营养作用，推进了这一领域的研究。这些特性使 JNJ-26070109 成为治疗 GORD 的临床研究的合适候选药物。
