比较当代对照组、历史对照组和交叉实验室对照组在评估意识清醒的非人灵长类动物 QTc 时的表现。

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Journal of pharmacological and toxicological methods Pub Date : 2024-05-01 DOI:10.1016/j.vascn.2024.107510
Matthew M. Abernathy, Derek D. Best, Derek J. Leishman
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引用次数: 0

摘要

心血管安全药理学和毒理学研究在大多数研究中都包括车辆对照动物。有关常见载体的心电图数据积累相对较快。为了遵守 3R 原则,利用这些历史信息来减少动物的使用或提高研究的灵敏度可能会有所帮助。我们使用了一项大型非人灵长类动物(NHP)心血管研究(n = 48)中的植入遥测数据来评估莫西沙星的效果。我们抽取了 24 只动物进行 n = 3/性别/组分析。剩余的 24 只动物用于产生 1000 个由 3 只雄性和 3 只雌性 NHP 组成的独特组合,作为 n = 3/性别/组分析中三个治疗组的对照组。从这 1000 项研究中收集了治疗效果的分布、最小可检测差异(MDD)的中位值。这些数值代表当代对照组。在同一实验室使用相同技术进行的另外 3 项研究中,42 只 NHP 提供了数据。这些数据被用来生成 1000 个由 6、12、18、24 和 36 只 NHP 组成的独特组合,作为莫西沙星研究中受治疗组 18 只动物的历史对照动物。另外一个实验室还提供了 20 只 NHP 的数据。三个来源的 QT、RR 和 QT-RR 数据具有可比性。不过,由于两个实验室的载体数据中 QTc 影响的时间过程存在差异,因此无法使用跨实验室对照。如果使用同一实验室的历史对照组,则可代替当代对照组来确定治疗效果。使用较大(≥18 个)的历史对照组似乎更有优势。这些数据支持使用历史对照组来减少新的心血管研究中使用的动物数量。
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A comparison of the performance of contemporary, historical, and cross-lab controls in QTc assessment in conscious nonhuman primates

Cardiovascular safety pharmacology and toxicology studies include vehicle control animals in most studies. Electrocardiogram data on common vehicles is accumulated relatively quickly. In the interests of the 3Rs principles it may be useful to use this historical information to reduce the use of animals or to refine the sensitivity of studies.

We used implanted telemetry data from a large nonhuman primate (NHP) cardiovascular study (n = 48) evaluating the effect of moxifloxacin. We extracted 24 animals to conduct a n = 3/sex/group analysis. The remaining 24 animals were used to generate 1000 unique combinations of 3 male and 3 female NHP to act as control groups for the three treated groups in the n = 3/sex/group analysis. The distribution of treatment effects, median minimum detectable difference (MDD) values were gathered from the 1000 studies. These represent contemporary controls.

Data were available from 42 NHP from 3 other studies in the same laboratory using the same technology. These were used to generate 1000 unique combinations of 6, 12, 18, 24 and 36 NHP to act as historical control animals for the 18 animals in the treated groups of the moxifloxacin study. Data from an additional laboratory were also available for 20 NHP.

The QT, RR and QT-RR data from the three sources were comparable. However, differences in the time course of QTc effect in the vehicle data from the two laboratories meant that it was not possible to use cross-lab controls. In the case of historical controls from the same laboratory, these could be used in place of the contemporary controls in determining a treatment's effect. There appeared to be an advantage in using larger (≥18) group sizes for historical controls. These data support the opportunity of using historical controls to reduce the number of animals used in new cardiovascular studies.

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来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
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