Validation of the normal, freely moving Gottingen minipig for pharmacological safety testing
Validation of the normal, freely moving Gottingen minipig for pharmacological safety testing
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DOI：
10.1016/j.vascn.2008.12.004
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发表时间：
2009-07-01
影响因子：
1.9
通讯作者：
Guth, Brian
中科院分区：
文献类型：
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作者：
Markert, Michael;Stubhan, Miriam;Guth, Brian
简介：本研究的目的是使用新建立的心血管模型，利用自由移动的小型猪来记录已知药物的血流动力学和心电图效应。生成的数据将作为使用该新模型进行药理学药物安全性评价的基础。方法：6 只哥廷根小型猪配备了无线电遥测系统 (ITS)。恢复期后，在口服一种测试药物或载体后的整个 8 小时监测期内，连续记录主动脉压 (AP)、左心室压 (LVP)、心电图导联 II 和体温。 Notocord HEM 4.2 软件用于数据采集。使用交叉研究设计在 6 头猪中测试了一种已知的 hERG 阻滞剂（莫西沙星（30,100 或 300 mg/kg））和一种非选择性 β-肾上腺素受体拮抗剂（普萘洛尔（3,10 或 20 mg/kg））。结果：我们获得了高信号质量，并发现哥廷根小型猪在静息、治疗前条件下具有稳定的血流动力学参数和较低的固有心率。口服莫西沙星后，QT 间期持续时间会出现剂量依赖性的显着增加，正如对该药物的预期一样。服用普萘洛尔后，检测到 HR 和左心室 dP/dt 下降，正如 β-肾上腺素受体阻滞剂所预期的那样。讨论：目前的数据表明，在有意识的、长期仪器化的哥廷根小型猪中使用该模型，对六只动物进行的交叉研究足够灵敏，可以检测到当口服莫西沙星剂量导致临床相关血浆药物浓度时，剂量依赖性QT延长。此外，我们可以证明普萘洛尔对心率和心肌收缩力的预期影响，尽管这些小型猪的固有静息心率较低。这些数据支持使用哥廷根小型猪作为敏感的心血管和心电图模型来测试新的药剂。 (C) 2009 Elsevier Inc. 保留所有权利。
Introduction: The objective of this study was to use a newly established cardiovascular model using freely moving minipigs to document the hemodynamic and electrocardiographic effects of known pharmacological agents. The data generated are to serve as the basis of pharmacological drug safety evaluations using this new model. Methods: 6 Gottingen minipigs were equipped with a radiotelemetry system (ITS). Following a recovery period, aortic pressure (AP), left ventricular pressure (LVP), lead II of the ECG and body temperature were continuously recorded throughout an 8 h monitoring period following oral administration of one of the test agents or vehicle. Notocord HEM 4.2 software was used for data acquisition. One known hERG blocker (moxifloxacin (30,100or300 mg/kg)) and one non-selective beta-adrenoreceptor antagonist (propranolol (3,10 or 20 mg/kg)) were tested in the model using a cross-over study design in 6 pigs. Results: We obtained high signal quality and found stable hemodynamic parameters with low intrinsic heart rates in the Gottingen minipig under resting, pre-treatment conditions. After oral dosing of moxifloxacin, a substantial, dose-dependent increase in the QT-interval duration could be shown, as anticipated for this agent. After propranolol administration, a decrease in HR and left ventricular dP/dt was detected as expected for a beta-adrenoceptor blocking agent. Discussion: The present data demonstrate that using this model in conscious, chronically instrumented Gottingen minipigs, a cross-over study with six animals was sensitive enough to detect a dose-dependent QT prolongation when moxifloxacin was administered in oral doses leading to clinically relevant plasma drug concentrations. Additionally, we could demonstrate the expected propranolol-induced effects on heart rate and myocardial contractility, despite the low intrinsic resting heart rates in these minipigs. These data support the use of the Gottingen minipig as a sensitive cardiovascular and electrocardiographic model for the testing of new pharmaceutical agents. (C) 2009 Elsevier Inc. All rights reserved.