首页> 外文期刊>Toxicology and Applied Pharmacology >Determination of myocardium to plasma concentration ratios of five antipsychotic drugs: comparison with their ability to induce arrhythmia and sudden death in clinical practice.
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Determination of myocardium to plasma concentration ratios of five antipsychotic drugs: comparison with their ability to induce arrhythmia and sudden death in clinical practice.

机译:测定五种抗精神病药的心肌与血浆浓度之比:在临床实践中与它们引起心律不齐和猝死的能力进行比较。

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Reviewing available data shows that most of antipsychotic drugs are associated with arrhythmia and sudden death. Experimental studies have shown a HERG channel blockade, a dose-dependent increase in duration of action potential or of QT interval, with various degrees of indicators of serious arrhythmogenicity. However, it seems difficult to relate these in vitro and in vivo preclinical models to clinical findings, in part, because the relationship between concentrations used and in vivo tissue concentrations during treatment in man is not known. Consequently, we established the myocardium to plasma concentration ratios for a series of antipsychotic drugs by intraperitoneal administration of different level doses to the guinea pig. Then, we compared these values to their ability to induce arrhythmia or torsade de pointes in clinical practice. The myocardium to plasma concentration ratios were 2.2 for clozapine, 2.7 for olanzapine, 3.1 for sertindole, 4.5 for risperidone, and 6.4 for haloperidol. These data suggest that when the ratio is higher than 4, arrhythmia and sudden death may be expected. On the contrary, when the ratio is less than 3, little effect may be predicted. These results underscore the importance of interpreting HERG channel data and electrophysiological data in the context of other pharmacokinetic parameters such as myocardium to plasma distribution.
机译:审查现有数据表明,大多数抗精神病药物与心律不齐和猝死有关。实验研究表明,HERG通道阻滞是动作电位持续时间或QT间隔持续时间的剂量依赖性增加,具有严重心律失常性的各种指标。但是,将这些体外和体内临床前模型与临床发现联系起来似乎有些困难,部分原因是,在人类治疗期间使用的浓度与体内组织浓度之间的关系尚不清楚。因此,我们通过向豚鼠腹膜内给予不同水平的剂量,建立了一系列抗精神病药物的心肌与血浆的浓度比。然后,我们将这些值与它们在临床实践中诱发心律不齐或扭转性扭转的能力进行了比较。氯氮平的心肌与血浆的浓度比为2.2,奥氮平为2.7,塞多多为3.1,利培酮为4.5,氟哌啶醇为6.4。这些数据表明,当该比率高于4时,可能会出现心律不齐和猝死。相反,当该比率小于3时,几乎不能预测效果。这些结果强调了在其他药代动力学参数(例如心肌到血浆分布)的背景下解释HERG通道数据和电生理数据的重要性。

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