Nahas Kamil, Geffray Brigitte
Amboise Laboratories, Pfizer Inc. Global Research and Development-safety Science Europe, B.P. 159, Amboise 37401, France.
J Pharmacol Toxicol Methods. 2004 Nov-Dec;50(3):201-7. doi: 10.1016/j.vascn.2004.05.004.
An accurate measurement of the QT interval is dependent on the accurate identification of the end of the T wave. Although chest leads have been recommended in dog toxicology studies, their use has not been widely put into practice, as shown by a recent survey on methodology for ECG collection in the pharmaceutical industry. Therefore, there is little published data on dog QT measurement from chest leads.
Electrocardiograms (ECGs) were taken from 100 beagle dogs (50 males, 50 females), with the dogs restrained in a sling. On the day of recording, measurements were performed at time zero and 1 h later. Recordings were repeated 7 to 10 days later. QT interval measurements were taken simultaneously from Lead II and the chest Lead CV5RL. Heart rate was taken from Lead II. Statistical analyses included the calculation of a QT correction formula, comparison of the mean values and variability of QT and QTc measurements from Leads II and CV5RL, the comparison of T-wave polarity from both leads, and a power analysis for QT and QTc.
The T wave was positive in almost all dogs (99/100) in the Lead CV5RL at all measurement periods, while it was either positive or negative in Lead II (64-75/100), and the incidence of positive T wave varied between measurement periods. The QT interval was significantly shorter (194+/-11 to 197+/-12 vs. 197+/-13 to 200+/-12 ms) when measured from the CV5RL lead at all recording periods and in both sexes. In addition, the standard deviation for QT measurement within each individual ECG record demonstrates less intra-animal variation when QT is measured from Lead CV5RL compared with Lead II (3.8 vs. 13.2 ms). The linear regression between QT and heart rate was improved when QT measurements were taken from CV5RL, as shown by the percentage of variability R2.
Estimates of the sample sizes showed that fewer animals would be required to detect a change at both the high and the mid-doses when using the chest Lead CV5RL. Using Lead II, we are able to detect within-animal changes of 10% in either QT or QTc; with Lead CV5RL, we are able to detect 10% change in QT and 5% change in QTc.
QT间期的准确测量取决于T波终点的准确识别。尽管在犬类毒理学研究中推荐使用胸导联,但正如最近对制药行业心电图采集方法的一项调查所示,其应用尚未广泛付诸实践。因此,关于从胸导联测量犬类QT间期的已发表数据很少。
从100只比格犬(50只雄性,50只雌性)身上采集心电图(ECG),犬被限制在吊带中。在记录当天,在时间零点和1小时后进行测量。7至10天后重复记录。同时从II导联和胸导联CV5RL测量QT间期。心率从II导联获取。统计分析包括计算QT校正公式、比较II导联和CV5RL导联QT和QTc测量值的平均值及变异性、比较两个导联的T波极性,以及对QT和QTc进行功效分析。
在所有测量期间,几乎所有犬(99/100)的CV5RL导联T波均为正向,而II导联T波可为正向或负向(64 - 75/100),且正向T波的发生率在测量期间有所不同。在所有记录期间和两性中,从CV5RL导联测量时QT间期显著更短(194±11至197±12 vs. 197±13至200±12毫秒)。此外,与II导联相比,当从CV5RL导联测量QT时,每个个体心电图记录中QT测量的标准差显示动物内变异更小(3.8对13.2毫秒)。从CV5RL导联测量QT时,QT与心率之间的线性回归得到改善,如变异百分比R2所示。
样本量估计表明,使用胸导联CV5RL时,在高剂量和中剂量下检测变化所需的动物数量更少。使用II导联,我们能够检测到动物体内QT或QTc有10%的变化;使用CV5RL导联,我们能够检测到QT有10%的变化和QTc有5% 的变化。