A tool to utilize adverse effect profiles to identify brain-active medications for repurposing.
A tool to utilize adverse effect profiles to identify brain-active medications for repurposing.
复制标题
一种利用不良反应特征来识别大脑活性药物以进行重新利用的工具。
DOI：
10.1093/ijnp/pyu078
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Perlis,RoyH
中科院分区：
文献类型：
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作者：
McCoyJr,ThomasH;Perlis,RoyH
背景：为了缩短将新疗法引入临床所需的时间，最近的努力集中在重新利用现有的食品和药物管理局（FDA）批准的具有既定安全数据的药物用于新的适应症。我们假设，通过提供化合物穿越血脑屏障能力的指示，不良反应概况可能有助于优先考虑化合物在中枢神经系统（CNS）应用中的应用。方法利用上市前和上市后的数据，对不良反应概况的相似性进行调查。一组已知的cns活性药物被用来估计数据库中所有其他FDA药物的总体相似概况。排列被用来测试任何给定药物的相似性是否超过零假设下的预期。为了评估使用这些配置文件的算法的性能，使用逻辑回归对已知cns活性和非活性药物的手动整理列表进行分类。比较了具有和不具有这种相似性数据的算法来预测CNS外显率。结果纳入不良反应相似度数据的模型对脑渗透性和非渗透性药物的区分程度高于未纳入不良反应相似度数据的模型。开发了一种可视化工具，以便评估任何药物与中枢神经系统面板或自定义面板的不良反应相似性。结论：考虑到不良反应特征，可以优先考虑化合物用于中枢神经系统适应症的随访研究。与化学筛选方法相一致，这可能会加速对假定的中枢神经系统活性药物的重新利用。
BackgroundTo shorten the time required to bring new treatments to clinics, recent efforts have focused on repurposing existing Food and Drug Administration (FDA)-approved drugs with established safety data for new indications. We hypothesized that adverse effect profiles might aid in prioritizing compounds for investigation in central nervous system (CNS) applications by providing an indication of their abilities to cross the blood-brain barrier.MethodsData were drawn from an investigation of similarity of adverse effect profiles, utilizing pre- and post-marketing data. A panel of known CNS-active drugs was utilized to estimate aggregate similarity profiles for all other FDA drugs in the database. Permutations were used to test whether similarities for any given drug exceeded that expected under the null hypothesis. To estimate the performance of algorithms using such profiles, manually-curated lists of known CNS-active and -inactive medications were classified using logistic regression. Algorithms with and without this similarity data were compared for prediction of CNS penetrance.ResultsModels incorporating adverse effect similarity data exhibited greater discrimination of brain-penetrant and non-penetrant drugs than models without this data. A visualization tool was developed to allow any medication to be evaluated for adverse effect similarity to the CNS panel or a custom panel.ConclusionsConsideration of adverse effect profiles allowsin silicoprioritization of compounds for follow-up investigation for CNS indications. In concert with chemical screening approaches, this may accelerate repurposing efforts for putative CNS-active medications.