Mitchell Andrea Z, Bills Andrew J, Wittwer Gary T, Foley C Michael, Kremer John J, Chen Hepei, Osinski Mark A
Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI 53704,USA.
J Pharmacol Toxicol Methods. 2013 Jul-Aug;68(1):62-73. doi: 10.1016/j.vascn.2013.04.006. Epub 2013 Apr 29.
Dogs are commonly used in cardiovascular drug safety assessment, and implanted telemetry models include subcutaneous or epicardial electrocardiogram (ECG) electrode placements. The purpose of this study was to determine the sensitivity of a canine telemetry model with intravenous ECG lead placement: the negative ECG lead (solid tip) inserted into the jugular vein and the positive lead sutured to the diaphragm. Reference drugs were administered to test the sensitivity to drug-induced changes.
Twenty-four dogs were implanted with PCT or PCTP transmitters [Data Sciences International (DSI)]. Three reference drugs were administered: sotalol to eight PCT and milrinone to eight PCTP transmitter-implanted dogs. Twenty-four dogs received moxifloxacin (12 dogs/transmitter type). Telemetry data were collected for 25h and analyzed using double Latin squares for sotalol and milrinone data or a 4×4 or 3×6 parallel design for moxifloxacin data. Evaluated parameters were PR, QT, corrected QT (QTc), QRS, heart rate, left ventricular function, and hemodynamic data. Various correction factors for QTc interval were tested. Retrospective power analysis was performed to detect minimal absolute changes comparing a single to a double Latin square or the two parallel designs.
Expected changes on ECG and hemodynamic parameters were observed after administration of all reference drugs. The individual animal corrected QT (QTci) interval provided the optimal correction factor. Retrospective power analysis confirmed detection of smaller differences in double versus single Latin squares. Minimal detectable differences were smaller in both Latin squares compared to parallel designs, with smaller detectable differences in a 3×6 compared to a 4×4 parallel design.
The solid tip intravenous ECG lead configuration in dogs is a viable radiotelemetry model to detect drug-induced changes with high sensitivity. This model yields comparable signal quality and represents a refinement over epicardial ECG leads and allows for possible reduction in the number of animals if study design and size are selected based on needed assay sensitivity.
狗常用于心血管药物安全性评估，植入式遥测模型包括皮下或心外膜心电图（ECG）电极放置。本研究的目的是确定静脉内放置心电图导联的犬遥测模型的敏感性：将负性心电图导联（实心尖端）插入颈静脉，正性导联缝合至膈肌。给予参比药物以测试对药物诱导变化的敏感性。
24只狗植入PCT或PCTP发射器[数据科学国际公司（DSI）]。给予三种参比药物：索他洛尔给予8只植入PCT发射器的狗，米力农给予8只植入PCTP发射器的狗。24只狗接受莫西沙星（每种发射器类型12只狗）。收集遥测数据25小时，并使用双拉丁方分析索他洛尔和米力农数据，或使用4×4或3×6平行设计分析莫西沙星数据。评估的参数包括PR、QT、校正QT（QTc）、QRS、心率、左心室功能和血流动力学数据。测试了QTc间期的各种校正因子。进行回顾性效能分析以检测单拉丁方与双拉丁方或两种平行设计之间的最小绝对变化。
给予所有参比药物后，观察到心电图和血流动力学参数的预期变化。个体动物校正QT（QTci）间期提供了最佳校正因子。回顾性效能分析证实双拉丁方比单拉丁方能检测到更小的差异。与平行设计相比，两种拉丁方中的最小可检测差异更小，3×6平行设计中的最小可检测差异比4×4平行设计更小。
狗的实心尖端静脉内心电图导联配置是一种可行的无线电遥测模型，可高灵敏度地检测药物诱导的变化。该模型产生可比的信号质量，是心外膜心电图导联的改进，如果根据所需的测定灵敏度选择研究设计和规模，则可能减少动物数量。
