效的，此时可改用心脏起搏器来获得固定的心率。对QT/RR（心电图中R波与R波的距离）关系进行分析可能更合适，包括用公式对个体动物QT间期数据进行校正。
在犬或猴等大动物记录ECG，是安全性评价的基本组成。药物引起QT间期显著延长将使致命性心律失常TdP发生的风险显著增加，因而ECG的QT间期被作为预测新化合物引起TdP的重要风险因素。鉴于犬、猴和小型猪等大动物在心肌离子通道构成和功能方面与人类具有高度相似性，通常用于整体QT分析研究中。整体QT分析试验可在麻醉和清醒动物进行，具体方法参见表3所列文献。
表3 整体QT研究试验常用动物
动物 麻 醉 动 物 参考文献 试验参数 Ollerstam, A et al Comparison of the QT interval ECG相关参数, 包括（形response during sinus andpaced rhythm in 态、心率、节conscious and anesthetized beagle dogs J 律、P波电压、PharmacolToxicol Methods, 2007;56: 131-44 犬 T波Chiba K, et al In vivo experimental approach for the R波电压、电压、PR间risk assessment of fluoroquinolone antibacterial 期、RR间期、 agents-induced long QT syndrome Eur J QRS时间、QTPharmacol, 2004;486:189-200 间期、QTc间Ishizaka T et al Evaluation of drug-induced QT 期） prolongation in a halothane-anesthetized monkey 猴 model: effects of sotalol J PharmacolToxicol Methods, 2009;59:86-93 Authier S et al Cardiovascular and respiratory ttingenminipigs: 猪 safety pharmacology in G? Pharmacological characterization JpharmacolToxicol Methods, 2011;64:53-9 — 98 —
遥 测 动 物 Batey AJ, Doe PA A method for QT correction based on beat-to-beat analysis of the QT/RR interval relationship in conscious telemetred beagle 犬 dogs J PharmacolToxicol Methods,2002;48: 11-9 Fossa AA Assessing QT prolongation in conscious dogs: validation of a beat-to-beat method PharmacolTher, 2008;118:231-8 Ando K et al QT PRODACT: In vivo QT assay with a consciousmonkey for assessment of the potential for drug-induced Qtinterval prolongation J Pharmacol Sci,2005;99: 487-500 猴 Haushalter TM et al The cardiovascular and pharmacokineticprofile of dofetilide in conscious telemetered beagle dogs andcynomolgus monkeys Br J Pharmacology,2008;154: 1457-64 Stubhan et al Evaluation of cardiovascular and ECG parameters in the normal, freely moving G?ttingenMinipig J Pharmacol Toxicological Methods,2008, 57: 202–11 猪 KanoM et al QT PRODACT: Usabilityof miniature pigs in safety pharmacology studies: Assessment for drug-inducedQT interval prolongation J Pharmacol Sci,2005, 99:501?11 麻 醉 动 物 Takahara A et al Effects of mexiletine on the 血流动力学canine model of sparfloxacin-induced long QT 检测，包括syndrome Eur J Pharmacol,2003,476:115-22 MAP、SBP、 Chiba K et al Proarrhythmic effects of DBP、HR、 fluoroquinolone antibacterial agents: in vivo effects ECG、单相动as physiologic substrate for Torsades 作电位(MAP)犬 ToxicolApplPharmacol, 2000, 169:8-16 等 Kimura K et al Hemodynamic and electrophysiological effects of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin in a halothane-anesthetized canine model J ToxicolSci, 2007,32:231-9
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注：G?ttingen minipigs:哥根廷小型猪。上述整体QT研究相关试验建议在GLP实验室进行
（三）追加的研究
药物对心肌动作电位（Action potential，AP）的影响：心脏的正常功能依赖于心肌细胞动作电位的产生和传导。药物引起细胞膜离子通道表达或功能异常是其导致心律失常的重要病理生理基础。因此，在离体心脏标本进行动作电位参数测定，是ICH 推荐的QT间期延长药物安全性评价体系中的重要组成之一。常用于动作电位参数测定的动物离体心脏标本及试验方法见表4，试验中重要的参数项目见表5。
表4 记录心肌AP的离体心肌标本
动物标本 参考文献 Terrar, DA et al Comparison of guinea-pig ventricular myocytes and dog Purkinje fibres for in vitro assessment of drug-induced delayed repolarization J Pharmacol Toxicol Methods, 2007; 56: 171-85 Lightbown ID et al Towards automation of a valuable 犬蒲肯野纤preclinical cardiac safety pharmacology assay: Evaluation of the effects of cardiac ion channel blockers on cardiac 维 repolarisation in vitro J Pharmacol Toxicol Methods, 2007;56:194-202 Limberis JT et al The effects of plasma proteins on delayed repolarization in vitro with cisapride, risperidone, and D, L-sotalol J Pharmacol Toxicol Methods, 2007; 56:11-7 Himmel HM Suitability of commonly used excipients for electrophysiological in-vitrosafety pharmacology assessment of effects on hERG potassiumcurrent and on rabbit Purkinje fiber 兔蒲肯野纤action potential J Pharmacol Toxicol Methods, 2007; 56: 145-58 维 Ducroq J et al Action potential experiments complete hERG assay and QT-interval measurements in cardiac preclinical studies J Pharmacol Toxicol Methods, 2007; 159-70 — 100 —
Hagiwara T et al A comparative study of the fluoroquinolone antibacterial agents on the action potential duration in guinea 豚鼠心室肌pig ventricular myocardia Jpn J Pharmacol, 2001; 87: 231–34 细胞 Shuba LM et al Action potentials, contraction, and membrane currents in guinea pig ventricular preparations treated with the antispasmodic agent terodiline JPET, 1999; 290:1417-26 豚鼠心室乳action potential assays on 21 compounds in isolated guinea-pig 头肌 papillary muscles J PharmacolSci,2005; 99:423-37 Milberg P et al Proarrhythmia as a class effect of quinolones: increased dispersion of repolarization and triangulation of action potential predict torsades de pointes J Cardiovasc Electrophysiol, 2007; 18:647-54 Clements-Jewery H et al Actions of flecainide on Langendorffsusceptibility to phase-2 ventricular arrhythmias during infarct 离体心脏 evolution in rat isolated perfused hearts British J Pharmacol, 2006; 147: 468–75 ChengHC and Incardona J Models of torsades de pointes: effects of FPL64176, DPI201106, dofetilide, and chromanol 293B in isolated rabbit and guinea pig hearts J Pharmacol Toxicol Methods, 2009; 60: 174-84 ChenX et al Use of arterially perfused rabbit ventricular wedge inpredicting arrhythmogenic potentials of drugs J 冠状动脉灌Pharmacol Toxicol Methods, 2006;54: 261-72 注兔左心室Liu T, Brown BS, Wu Y, Antzelevitch C, Kowey PR, Yan 肌楔形标本 GX.Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias Heart Rhythm 2006; 3: 948-956 上述研究相关试验建议最大可能执行GLP
Hayashi S et al QT PRODACT: a multi-site study of in vitro — 101 —
表5 心肌动作电位试验中的重要参数项目
三浓度检测参数项目 测试浓度数 测试 3 4 4 + + + + + + 检测每一个受试物所需的蒲肯野纤维数或心肌细胞数 用于对照品的蒲肯野纤维数或心肌细胞数 累积曲线 在生理温度 (37o±1o C) 下进行试验 统计学分析 如果系GLP实验室，收集样本的分析 报告 如果是GLP实验室，要求有质量保证部门(Quality Assurence Unit, QAU)的检查，包括同步、数据和报告的检查 可参考的文献
1. De Clerck F et al, In vivo measurement of QT prolongation, dispersion and arrhythmogenesis: application to the preclinical cardiovascular safety pharmacology of a new chemical entity, FundamClinPharmacol, 2002;16:125-40.
2. Sanguinetti MC, Mitcheson JS, Predicting drug-hERG channel interactions that cause acquired long QT syndrome, Trends Pharmacol Sci,2005;26: 119-24.
3. Lawrence CL et al, Nonclinical proarrhythmia models: Predicting Torsades de Pointes, J PharmacolToxicol Methods,2005; 52: 46–59
4. Guth BD, Preclinical cardiovascular risk assessment in modern drug development, ToxicolSci, 2007; 97, 4–20. — 102 —