• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The Journal of toxicological sciences >Preclinical electrophysiology assays of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin.
【24h】

Preclinical electrophysiology assays of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin.

机译：Mitemcinal（GM-611）的临床前电生理测定，这是一种新的促红细胞因子。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. Erythromycin has shown QT prolongation and torsades de pointes (TdP) in humans and cisapride, a second class of prokinetic agents typified by the 5-HT(4) receptor agonist, has been terminated due to TdP. In this study an extended series of safety pharmacology protocols and evaluations have been undertaken to assess the potential risk of mitemcinal on QT prolongation or proarrhythmic effects. Mitemcinal and its metabolites, GM-577 and GM-625, inhibited the human ether-a-go-go-related gene (HERG) tail current in a concentration-dependent manner with IC(50) values of 20.2, 41.7, and 55.0 microM, respectively. Administration of 10 mg/kg mitemcinal in anesthetized guinea pigs resulted in a slight prolongation of the monophasic action potential (MAP) duration during atrial pacing at the plasma concentration of mitemcinal 1.1 microM, with low maximum increases in MAPD(70) (6.6%) and MAPD(90) (4.6%) relative to vehicle. A 10-min infusion of 20 mg/kg of mitemcinal in a proarrhythmic rabbit model did not evoke TdP even when QT and corrected QT (QTc) intervals were significantly prolonged. In this study, the Cmax plasma-free concentration of mitemcinal indicates that the prolongation was more than 400-fold that of the therapeutic dose. Our findings of a wide safety margin and the absence of TdP within this margin suggest that mitemcinal may provide sufficient safety in clinical use.
机译：Mitemcinal（GM-611）是一种新的红霉素衍生的促运动剂，在胃动素受体上起激动剂的作用。红霉素已显示出人类的QT延长和尖端扭转型室速（TdP），而以5HT（4）受体激动剂为代表的第二类促动力剂西沙必利由于TdP而被终止。在这项研究中，已进行了一系列扩展的安全药理学方案和评估，以评估米替米星对QT延长或心律失常作用的潜在风险。 Mitemcinal及其代谢物GM-577和GM-625以浓度依赖的方式抑制了人类以太相关基因（HERG）尾电流，IC（50）值为20.2、41.7和55.0 microM。在麻醉的豚鼠中以10 mg / kg的剂量服用咪替米因会导致心房起搏期间血浆单能动作电位（MAP）持续时间稍微延长，血浆浓度为1.1 microM，而MAPD的最大增幅较低（70）（6.6％）相对于车辆而言，是MAPD（90）（4.6％）。即使在QT和校正QT（QTc）间隔显着延长的情况下，在心律不齐的兔模型中以20 mg / kg的速度注射10分钟的咪替敏也不会引起TdP。在这项研究中，Ctemmax的无Cmax血浆浓度表明该延长是治疗剂量的400倍以上。我们发现安全范围较宽且在此范围内没有TdP的发现表明，米替米安可在临床使用中提供足够的安全性。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号