清醒Beagle犬安全药理心血管遥测系统验证研究

Validation Study for Telemetry System of the Safety Pharmacological Cardiovascular Function in Conscious Beagle Dogs

目的选用临床上报道的对QT间期延长有影响的2种阳性药和无影响的1种阴性药在符合GLP条件下对心血管遥测系统进行验证。方法验证研究中,清醒Beagle犬分别静脉注射给予生理盐水(1 mL.kg-1,iv,n=2)、卡托普利(3 mg.kg-1,iv,n=2)、特非那丁(3 mg.kg-1,iv,n=2)和索他洛尔(10 mg.kg-1,iv,n=2)。DSI遥测系统连续获取给予上述4种供试品后至少24 h数据,数据包括血压、心电图、心率等指标。DSI Ponemah ECG分析程序使用Fridericia心率校正公式对QT间期进行校正。结果生理盐水对心血管参数没有明显的影响。卡托普利除导致心率显著增加和平均压下降外,对ECG参数无明显影响。特非那丁和索他洛尔在实验设计剂量下导致Beagle犬经心率校正的QT间期(QTcf)显著增加,增加大于10%。结论实验数据显示,遥测系统能够检测到清醒Beagle犬中心血管功能的相关变化。在符合ICH安全药理S7B指南的条件下,遥测系统可用作药物所致QT间期延长的模型。

OBJECTIVE To validate telemetry system of the cardiovascular function in conscious Beagle dogs using two positive compounds reported to induce QT interval prolongation in clinical use and one negative compound without such an effect in accordance with the principles of GLP.METHODS For validation,conscious dogs received saline（1 mL·kg^-1,iv,n=2）,captopril（3 mg·kg^-1,iv,n=2）,terfenadine（3 mg·kg^-1,iv,n=2） and sotalol（10 mg·kg^-1,iv,n=2）.The blood pressure（diastolic,systolic and mean blood pressure（MBP）,ECG（PR,RR,QRS,QT,QTcf）,and heart rate（HR） were continuously monitored for at least 24 h after the intravenous dosing of four test articles.The QT intervals were corrected with Fridericia heart rate formula（QTcf） using the DSI Ponemah ECG analysis program.RESULTS Saline had no significant effect on cardiovascular parameters.Captopril had no significant effect on any ECG parameters,though it induced a significant increase HR and decrease in MBP.Both terfenadine and sotalol caused a significant increase in the QTcf intervals,by more than 10% at the designed doses.CONCLUSION The telemetry system is capable of detecting relevant changes of the cardiovascular function in conscious Beagle dogs.The validated telemetry canine model is useful for the assessment of QT interval prolongation induced by human pharmaceuticals in accordance to the ICH safety pharmacology S7B guideline.