Reducing Methadone's Arrhythmic potential

描述(申请人提供)：美沙酮是一种重要的长期维持药物成瘾的疗法，目前经常用于止痛。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，并导致FDA在美沙酮的标签上贴上了“黑匣子”警告。我们实验室的初步研究表明，美沙酮的一个立体异构体引起的QT延长明显减少，并且该异构体具有美沙酮的镇痛作用。赠款中概述的研究建议在FDA建议用于心律失常风险的动物评估的模型中证实R异构体的安全性，然后确定与外消旋美沙酮相比，R美沙酮的治疗剂量和高于常规治疗剂量的R美沙酮是否导致狗的QT延长较少。这些是提交新药申请和最终将美沙酮异构体作为更安全的止痛和成瘾治疗方法商业化所必需的步骤。 公共卫生相关性：美沙酮经常用于疼痛治疗和药物成瘾，但目前的配方存在严重的心律失常风险。美沙酮的R异构体不会引起相同的电生理变化(QT延长)，因此不会造成相同的心律失常风险。这项拨款中的研究表明，R异构体是一种更安全的美沙酮，对患者造成危及生命的心律失常的风险较小。

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.