In vivo analysis of the anti-atrial fibrillatory, proarrhythmic and cardiodepressive profiles of dronedarone as a guide for safety pharmacological evaluation of antiarrhythmic drugs
In vivo analysis of the anti-atrial fibrillatory, proarrhythmic and cardiodepressive profiles of dronedarone as a guide for safety pharmacological evaluation of antiarrhythmic drugs
复制标题
决奈达隆抗心房颤动、促心律失常和心脏抑制特性的体内分析作为抗心律失常药物安全药理学评价的指南
DOI：
10.1007/s12012-017-9434-y
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发表时间：
2018
影响因子：
3.2
通讯作者：
Sugiyama A
中科院分区：
文献类型：
--
作者：
Motokawa Y;Nakamura Y;Hagiwara-Nagasawa M;Goto A;Chiba K;Lubna NJ;Izumi-Nakaseko H;Ando K;Naito AT;Yamazaki H;Sugiyama A
使用氟烷麻醉的比格犬（n= 4）分析决奈达隆的抗心房激动、促心律失常和心脏抑制特征，以创建标准方案，用于阐明抗心房激动药物的疗效和不良反应。以0.3和3 mg/kg剂量静脉给予盐酸决奈达隆30 s后，血浆峰浓度分别达到61和1248 ng/mL，反映低于治疗水平至高于治疗水平。低剂量组左室收缩力和平均血压降低，高剂量组左室收缩力和平均血压增强。高剂量还降低心率和心输出量，但增加总外周阻力和左心室舒张末期压，显示其有效的心脏抑制特征。此外，高剂量除了延迟心室复极外，还延迟房室结和心室内传导，这表明其分别对原位心脏中的Ca 2+、Na+和K+通道具有抑制作用。高剂量还延长了心房的有效不应期，是心室的1.9倍，解释了其临床证明的抗房性心律失常的疗效。Dronaline以剂量相关方式显著延长Tpeak-Tendin，并有延长终末复极期和J-Tpeakc的趋势，表明诱导尖端扭转型室性心动过速的风险相当大。两种剂量的P波持续时间均未检测到显著变化，表明对体内心房Na+通道无影响。决奈达隆的当前实验方案和结果可用作新型抗心房颤动药物安全性药理学评价的指南。
Anti-atrial fibrillatory, proarrhythmic and cardiodepressive profiles of dronedarone were analyzed using the halothane-anesthetized beagle dogs (n= 4) to create a standard protocol for clarifying both efficacy and adverse effects of anti-atrial fibrillatory drugs. Intravenous administration of dronedarone hydrochloride in doses of 0.3 and 3 mg/kg over 30 s attained the peak plasma concentrations of 61 and 1248 ng/mL, respectively, reflecting sub- to supra-therapeutic ones. The low dose decreased the left ventricular contraction and mean blood pressure, which were enhanced at the high dose. The high dose also decreased the heart rate and cardiac output, but increased the total peripheral resistance and left ventricular end-diastolic pressure, showing its potent cardiodepressive profile. Moreover, the high dose delayed the atrioventricular nodal and intraventricular conductions in addition to the ventricular repolarization, suggesting its inhibitory action on the Ca2+, Na+and K+channels in the in situ heart, respectively. The high dose also prolonged the effective refractory period 1.9 times greater in the atrium than in the ventricle, explaining its clinically demonstrated efficacy against the atrial arrhythmias. Dronedarone significantly prolonged the Tpeak–Tendin a dose-related manner with a tendency to prolong the terminal repolarization period and J–Tpeakc, indicating considerable risk to induce torsade de pointes. No significant change was detected in the P-wave duration by either dose, indicating the lack of effect on the atrial Na+channel in vivo. The current experimental protocol and the results of dronedarone can be used as a guide for safety pharmacological evaluation of new anti-atrial fibrillatory drugs.