Development of a Complete Proarrhythmic Safety Profile for Drugs

开发完整的药物致心律失常安全性概况

• 批准号: 7156898
• 负责人: JAMES William KRAMER
• 金额: $ 14.93万
• 依托单位: CHANTEST, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7156898
• 关键词: action potentials; adrenergic agents; anesthesia; arrhythmia; arrhythmic agent; beta adrenergic agent; beta adrenergic receptor; blood pressure; disease /disorder model; drug discovery /isolation; electrocardiography; heart Purkinje' s fiber; heart rate; heart surgery; injection /infusion; ion transport; laboratory rabbit; membrane channels; methoxamine; model design /development; pharmacokinetics; protein kinase C; stimulant /agonist

DESCRIPTION (provided by applicant): Project Summary/Abstract: ChanTest's goal is to commercialize a comprehensive non-clinical proarrhythmic profile that will screen compounds through a battery of models that span from the molecular (ion channels) to the multicellular (Purkinje fibers) to whole organ (Langendorff perfused heart) and finally the intact animal (open chest rabbit). This battery of assays will help identify arrhythmogenic drugs. Ideally, 1 would like a model that can directly identify a drug's ability to initiate TdP but the occurrence of TdP is very rare; making it unlikely that 1 would observe TdP in a typical human trial. Also, in order to initiate TdP in a torsadogenic model it is frequently necessary to greatly increase the sensitivity of the model, which may make false positives more likely. Since the occurrence of TdP for NARDs is unlikely, other markers or surrogates of TdP are used. Some examples are as follows. The hERG patch-clamping assay is a very sensitive assay, but it has falsely identified drugs as being torsadogenic. The strength of the Purkinje fiber model lies in its ability to identify compounds that have multiple ion channel effects. However, it is possible for false negatives to occur in this assay. For instance, the canine Purkinje fiber is insensitive to bepridil, a known torsadogenic drug. The isolated, Langendorff perfused rabbit heart model allows one to measure the effects of compounds on a wide range of parameters, including the QT interval and the monophasic action potential duration (MAPD) as well as other cardiac electrical parameters such as early afterdepolarizations (EADs), electrical instability, and alternans of the monophasic action potential duration (MAPD), which have been shown to be predictive of arrhythmogenic drugs. However, it should be stated that in vitro and ex vivo models are isolated. They are not influenced by autonomic or metabolic systems. Therefore, compounds also need to be tested in an intact animal model in order to have a complete proarrhythmic profile. The specific aim of this project is to develop an in vivo anesthetized rabbit model to complement the molecular cellular tissue and organ assays we already have in place, thereby providing the most complete proarrhythmic profile with both sensitivity and specificity to detect proarrhythmic drugs. We propose to infuse 1 group (A) of rabbits with methoxamine before and during dosage of the drugs. Another group (B) of rabbits will not be exposed to methoxamine. Instead, the rabbit will only be sensitized using an alternans pacing stimulation procedure. We will test 5 torsadogenic (cisapride, quinidine, clofilium, dl-sotalol and DPI 201-106) and 2 non-torsadogenic compounds (verapamil and amiodarone). We will measure and compare changes in heart rate (HR), blood pressure (BP), the QT interval, MAPD, occurrence of EADs, incidence of arrhythmias and alternans of the MAPD50. Finally, we will compare the 2 groups of rabbits and the 1 with the most sensitive and specific responses will be our intact animal model. Project Narrative: The specific aim of this project is to develop an in vivo anesthetized rabbit model to complement the molecular cellular tissue and organ assays we already have in place, thereby providing the most complete proarrhythmic profile with both sensitivity and specificity to detect proarrhythmic drugs before first use in humans.

描述（由申请人提供）：项目摘要/摘要：Chantest的目标是将全面的非临床性促性动力学特征进行商业化，该概况将通过跨越分子（离子频道）到多细胞（Purkinje纤维）到整个器官（Langendorff灌注心）的多种模型（langendorff perfused Heart）（langendorff perfused Heart）（最终是胸部的动物）。这种测定电池将有助于鉴定心律不齐的药物。理想情况下，1希望可以直接识别药物启动TDP的能力，但TDP的发生非常罕见。使1在典型的人类试验中观察到TDP的不可能。同样，为了在扭转模型中启动TDP，通常需要大大提高模型的灵敏度，这可能会使假阳性更有可能。由于不太可能发生TDP的TDP出现，因此使用了TDP的其他标记或替代物。一些示例如下。 HERG斑块夹测定是一种非常敏感的测定法，但错误地识别出药物是托纳德的。 Purkinje纤维模型的强度在于其识别具有多个离子通道效应的化合物的能力。但是，在本测定中可能会发生假否定性。例如，犬Purkinje纤维对已知的扭曲药物Bepridil不敏感。 The isolated, Langendorff perfused rabbit heart model allows one to measure the effects of compounds on a wide range of parameters, including the QT interval and the monophasic action potential duration (MAPD)​​ as well as other cardiac electrical parameters such as early afterdepolarizations (EADs), electrical instability, and alternans of the monophasic action potential duration (MAPD)​​, which have been shown to be predictive of arrhythmogenic毒品。但是，应该指出的是在体外和离体模型是分离的。它们不受自主或代谢系统的影响。因此，还需要在完整的动物模型中对化合物进行测试，以具有完整的心律失常。该项目的具体目的是开发一个体内麻醉的兔模型，以补充我们已经进行的分子细胞组织和器官测定，从而提供了最完整的促性动脉症状，既具有敏感性和特异性，又可以检测促头动性药物。我们建议在药物剂量之前和期间将1组（a）用甲氧胺注入甲氧胺。另一组（b）的兔子不会暴露于甲氧胺。取而代之的是，兔子只会使用替代的起搏刺激程序敏感。我们将测试5个肌酸（Cisapride，quinidine，clofilium，dl-Sotalol和DPI 201-106）和2种非氧化化合物（Verapamil和Amiodarone）。我们将测量和比较心率（HR），血压（BP），QT间隔，MAPD，EAD的发生，心律不齐的发生率和MAPD50的替代品。最后，我们将比较两组兔子，其中1组与最敏感和特定的反应将是我们完整的动物模型。项目叙述：该项目的具体目的是开发一个体内麻醉的兔模型，以补充我们已经实施的分子细胞组织和器官测定，从而提供了具有最完整的灵敏度和特异性，既具有敏感性和特异性，又可以在人类中首次使用proarranththmic药物。