Project 4 - Chinese Herbal Medicine to Treat Alcohol & Drug Abuse

该项目的重点是第一阶段和第二阶段的临床研究，以评估选定的草药改变酒精或滥用药物的急性影响，改变酒精或药物寻求行为的效果，并开始探索这些产品的核心作用机制。简而言之，一种新的草药制剂将在项目1中使用基于细胞的kappa受体结合和功能分析进行初步标准化、提纯和表征，并在序贯动物模型中测试在减少药物或酒精摄入量和区分刺激特性方面的有效性，然后在项目2中测试草药(或组分) 通过项目1保持有效，项目2将进行临床研究。然而，由于我们已经根据强大的临床前数据确定了两种候选产品，该项目的头两年将专注于研究中草药(NPI-028)对酒精中毒和饮酒行为的影响。在接下来的几年里，我们将研究第二种中草药(NPI-025)，或者如果项目1和2中的药物发现过程发现了更有前途的候选药物，重点可能会转移到该产品上。无论选择哪种产品，本项目中描述的方案都很容易适应，并可用于研究任何数量的可能候选方案。使用多学科的主观性电池， 为了系统地评价NPI-028改变成年男性和女性重度饮酒者的急性醉酒效应和药代动力学特征的有效性，我们提出了三项主要的研究，以系统地评估NPI-028对成年男性和女性重度饮酒者的急性醉酒作用和药代动力学特征。将在自然环境中测量NPI-028对酒精饮酒的影响，以模拟真实的饮酒条件。最后，利用脑成像技术，我们将使用质子磁共振波谱(MRS)来探索这种草药制剂的可能作用机制，以确定预处理是否改变了实际进入大脑的乙醇量。我们计划继续并扩大这项实验，此外，我们还将使用功能磁共振成像(FMRI)测量脑血流和脑血管的变化。结果是 这些研究将有助于确定草药在治疗酒精相关问题方面可能发挥的作用。

This Project is focused on both Phase I and Phase II level clinical studies to evaluate the efficacy of selected herbal medicines to alter acute effects of alcohol or drugs of abuse, to modify alcohol- or drug-seeking behavior and to begin to explore the central mechanism of action of these products. In brief, a novel herbal preparation will be initially standardized, purified and characterized in Project 1 using cell based kappa receptor binding and functional assays and tested in a sequential animal model for efficacy in reducing drug or alcohol intake and discriminative stimulus properties in Project 2 and then a herbal remedy (or fractions) that remains efficacious through Project 1, and 2 will be studied clinically. However, as we have already identified two candidate products based on strong preclinical data, the first two years of this project will focus on studying the effects of the Chinese herbal remedy (NPI-028) on alcohol intoxication and drinking behavior. In subsequent years, we will either study the second Chinese herbal remedy (NPI-025) or if the drug discovery process in Projects 1 and 2 uncover a more promising candidate, the focus may shift to that product instead. Regardless of which products are selected, the protocols described in this project are easily adaptable and could be used to study any number of likely candidates. Using a multidisciplinary battery of subjective, physiologic and behavioral measures as well as plasma ethanol levels, we propose three main studies to systematically evaluate the efficacy of NPI-028 in altering alcohol's acute intoxicating effects and pharmacokinetic profile in adult male and female heavy drinkers. The effects of NPI-028 on ethanol drinking will be measured in a natural environment to simulate realistic drinking conditions. Finally, using brain imaging techniques, we will explore the possible mechanism of action of this herbal preparation using proton magnetic resonance spectroscopy (MRS) to determine whether pretreatment alters the amount of ethanol that actually enters the brain. We plan to continue and expand this experiment and, in addition, will measure changes in cerebral blood flow and cerebral vasculature using functional MR imaging (fMRI). The results of these studies will help define the role that herbal medicines may have in treating alcohol-related problems.