SYNERGISM AND MEDICATIONS DEVELOPMENT FOR DRUG ABUSE

描述（改编自申请人的摘要）：这是一个2x修订版 一个研究者的申请，他已经做出了重要的和开创性的贡献， 有助于定量评估药物相互作用。在过去 审查时，得分为211分（第29百分位数）。当两种或多种药物 具有明显类似的动作（例如，两种镇痛药）同时存在， 组合可以协同地相互作用，也就是说， 反应 协同作用在临床上是重要的，如果它 适用于组合的不良反应;例如，新药 开发用于治疗药物滥用的药物可能与其他药物协同作用， 患者正在服用的药物。区分协同作用的方法 从简单的加性相互作用是复杂的高变异性， 数据，不精确的效果测量和药物的极端多样性， 用于研究它们的实验设计。 该项目的目标是解决这些问题 通过统计/理论方法的发展， 需要相关的实验设计和一套全面的计算机 指导实验和分析数据的程序。 私家侦探，是谁 既是药理学家又是数学家， 由于长期以来的合作， 实验学家和他自己的工作在统计设计和程序 发展 目的包括定量和分析两个定量 （全或无）效应和分级药物效应，以及新的统计学发展， 这是一个很大程度上被忽视的领域。 与经典的 20世纪20年代和30年代，主要关注简单的杀虫剂， 线性回归模型和定量终点（%杀死），申请人的 方法不限于简单的平行线回归，而是 考虑到药物剂量效应数据中常见的多样性， 影响行为、疼痛感和免疫系统。 一个主要目标是 probit理论的扩展，一个强大的加权回归程序， 适用于可测量和观测端的量子数据 药物引起的疼痛。 药代动力学考虑是另一个目的 由于给药途径、给药时间和药物的动力学特征 每种药剂都对组合实验产生深刻影响。 此外，单一药物 在两个部位给药理论上等同于药物组合 分析和探索以及进一步发展这种现场-现场方法 为照明机制提供了一个重要的新工具，这也是一个 拟议研究的具体目标是制定普遍的， 计算机驱动的组合分析指南，将提供一种 路线图适用于几乎所有的组合和现场研究。 这 指南是本次修订申请的最新目标。

DESCRIPTION (adapted from applicant's abstract): This is a 2x revised application from an investigator who has made significant and seminal contributions to quantitatively evaluating drug interactions. During the last review, a score of 211 (29th percentile) was awarded. When two or more drugs with overtly similar actions (e.g., two analgesics) are present together the combination may interact synergistically, that is, give an exaggerated response. Synergism is important clinically and is especially important if it applies to adverse effects of the combination; for example, a new drug developed to treat drug abuse may interact synergistically with other medications that the patient is on. Methodology for distinguishing synergism from simple additive interactions is complicated by high variability in the data, imprecise measures of effect(s) and extreme diversity in the drugs and experimental designs used to study them. This project's goal addresses these problems through the development of statistical/theoretical methodology, the associated experimental design needed and a comprehensive set of computer programs that guide the experiments and analyze the data. The P.I., who is both a pharmacologist and a mathematician, brings a background that addresses the problems by virtue of a long history of collaborations with experimentalists and by his own work in statistical design and program development. The aims include the quantitation and analysis of both quantal (all-or-none) effects and graded drug effects with new statistical development, an area that has been largely neglected. In contrast to the classic work of the 1920's and 1930's, which was largely concerned with pesticides in simple linear regression models and a quantal end point (% killed), the applicant's approached is not restricted to simple parallel-line regressions, instead allowing for the diversity that is commonly seen in dose-effect data from drugs that affect behavior, pain sensation and the immune system. A major aim is the expansion of probit theory, a powerful weighted regression procedure that is applicable to quantal data from both the measurable and observational end points induced by drugs. Pharmacokinetic considerations represent another aim since route of administration, the timing of doses and the kinetic profile of each agent profoundly affect combination experiments. Further, a single drug administered at two sites is theoretically equivalent to a drug combination analysis and exploration and further development of this site-site approach provides an important new tool for illuminating mechanism; this is also a specific aim of the proposed studies as is the development of universal, compute-driven, guide to combination analysis that will provide a kind of roadmap applicable to virtually all combination and site-site studies. This guide is the newest aim of this revised application.