SYNERGISM AND MEDICATIONS DEVELOPMENT FOR DRUG ABUSE

描述：（申请人摘要） 当两种药物具有明显相似的治疗效果时 这些成分药物一起产生的效果可能大于 预期来自个体效价。 这种超加性（协同） 联合用药具有明显的临床重要性，特别是在可能的新的 药物滥用的治疗。 在治疗上，用于治疗的协同配对 允许减少剂量，从而降低频率和严重程度 的不良反应。 从毒理学角度来看， 滥用药物的新药和滥用药物（或正在服用的其他药物） 危害潜在药物的安全性。 除了这些 治疗考虑协同作用的检测提供了定量的 可能有助于发现机制信息。 另一方面，药物 相互作用可以是次加性的（拮抗的）。 数额确定方法 无论药物组合是超加性还是次加性， 定量信息和统计数据表明， 联合用药达到规定的联合剂量水平 这与简单加和性计算的结果有很大不同。 此外，协同作用或拮抗作用可以在一个剂量组合中发生， 同一药物对的另一组剂量不会发生。 统计 分析是必要的。 多年前得出的统计方法， 从那时起广泛应用的量子分析，已限于量子分析， 药物对log（剂量）的作用百分比产生平行线性回归。 非平行剂量效应数据和所有具有分级效应的实验， 直到最近，才用这些方法和许多组合进行分析。 数据，特别是来自药物歧视和强化研究的数据， 不能容易地分析协同作用。 基于实验室的 为评估与滥用药物有关的行为影响而进行的实验 可能需要新的指标用于剂量反应分析， 统计分析的基础。 这里提出的工作旨在 导出所需的度量、统计公式、相关的实验 适用于药物的设计技术和计算机程序 联合用药，特别是与药物开发有关的联合用药， 治疗药物滥用 用于评估的实验室方法 与成瘾和药物滥用相关的行为和影响，以及 这是实用和成本效益的组合研究，提供了 这些衍生的基础。 因此，至少有四个标准，但 将研究不同的实验设计，并对每种设计进行统计分析。 开发的方法，以及一个较新的响应面方法。 一 根据估计的精密度，比较各种方法 参数、所需受试者数量以及个体和 联合给药，将用于已发表的联合药物 数据

DESCRIPTION: (Applicant's Abstract) When two drugs with overtly similar therapeutic effects are administered together the constituent drugs may produce an effect that is greater than expected from the individual potencies. Such superadditive (synergistic) combinations have obvious clinical importance, especially in possible new treatments of drug abuse. Therapeutically a synergistic pair for treatment allows reduced doses and consequent reduction in the frequency and severity of adverse reactions. From a toxicological perspective synergism between a new medication for drug abuse and the abused drug (or others being taken) jeopardizes the safety of the potential medication. Besides these therapeutic considerations the detection of synergism provides quantitative information that may aid in uncovering mechanism. On the other hand, drug interactions can be subadditive(antagonistic). Methodology for determining whether a drug combination is superadditive or subadditive requires quantitative information and a statistical demonstration that the combination attains a prescribed level of effect with a combination dose that is significantly different than that calculated from simple additivity. Moreover, synergism or antagonism may occur with one dose combination and not occur with another set of doses of the same drug pair. Statistical analysis is essential. Statistical methodology, derived years ago, and widely applied since then, has been limited to quantal assays in which the drugs yield parallel linear regressions of percent effect on log(dose). Non-parallel dose-effect data and all experiments with graded effects, could not, until recently, be analyzed with these methods and much combination data, especially data from drug discrimination and reinforcement studies, cannot be readily analyzed for synergism. The kind of laboratory based experiments conducted to assess behavioral effects related to an abused drug may require new metrics for use in the dose-response analysis that is the basis of the statistical analysis. The work proposed here is aimed at deriving the needed metrics, statistical formulas, associated experimental design techniques and computer programs that are applicable to drug combinations especially as these pertain to medications development for treating drug abuse. Experimental laboratory methods used in assessing behaviors and effects associated with addiction and drugs of abuse, and which are practical and cost effective in combination studies, provide the basis of these derivations. Accordingly, at least four standard but different experimental designs will be studied and, for each, statistical methodology developed, as well as a newer response-surface methodology. A comparison of the methods, based on the precision of the estimated parameters, the number of subjects needed, and the number of individual and combination doses, will be made and applied to published combination drug data.