Reducing Methadone's Arrhythmic potential

描述（申请人提供）：美沙酮是一种重要的药物成瘾长期维持疗法，目前常用于镇痛。然而，美沙酮延长了心电图上的QT间期，这增加了危及生命的心律失常的风险，因此FDA在美沙酮的标签上标注了“黑框”警告。我们实验室的初步研究表明，美沙酮的一种立体异构体引起的QT间期延长明显减少，而且这种异构体具有美沙酮的镇痛作用。拨款中概述的研究建议在模型中确认R异构体的安全性，以获得FDA提出的用于心律失常风险动物评估的心律失常，然后确定与外消旋美沙酮相比，R异构体在治疗性和高于常规治疗剂量的R美沙酮中是否会导致更少的QT延长。这些是提交新药申请的必要步骤，也是美沙酮异构体作为一种更安全的镇痛和成瘾治疗的最终商业可用性的必要步骤。

DESCRIPTION (provided by applicant): Methadone is an important long-term maintenance therapy for drug addiction and currently is frequently used for analgesia. However, methadone prolongs the QT interval on the electrocardiogram and this increases risk for life threatening arrhythmias and has led to the FDA's placing a "black box" warning on methadone's label. Initial studies in our laboratory have shown that one of the stereoisomers of methadone causes significantly less QT prolongation and this isomer possesses the analgesic effect of methadone. The studies outlined in the grant propose to confirm the safety of the R isomer in a model to access proarrhythmia that the FDA proposes for the animal evaluation of arrhythmic risk and then to determine if the isomer causes less QT prolongation in the dog at therapeutic and higher than routine therapeutic doses of R methadone as compared to racemic methadone. These are necessary steps for the submission of a new drug application and the eventual commercial availability of the methadone isomer as a safer treatment for analgesia and addiction. PUBLIC HEALTH RELEVANCE: Methadone is frequently used for pain treatment and drug addiction, but the current formulation poses a serious risk of arrhythmias. The R isomer of methadone does not cause the same electrophysiologic changes (QT prolongation) and thus would not pose the same risk for arrhythmias. Studies in this grant set out to show that the R isomer is a safer methadone and would pose less of a risk for life threatening arrhythmias to patient.