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

本项目的重点是I期和II期临床研究，以评估所选草药改变酒精或药物滥用的急性效应，改变酒精或药物寻求行为的有效性，并开始探索这些产品的主要作用机制。简而言之，在项目1中，使用基于细胞的κ受体结合和功能测定，将新的草药制剂进行初始标准化、纯化和表征，并在项目2中在连续动物模型中测试减少药物或酒精摄入的功效和辨别刺激特性，然后是 在项目1和2中仍然有效，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，因此该项目的前两年将重点研究中草药（NPI-028）对酒精中毒和饮酒行为的影响。在随后的几年里，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，可用于研究任何数量的可能候选产品。使用多学科的主观电池， 生理和行为的措施以及血浆乙醇水平，我们提出了三个主要的研究，以系统地评估NPI-028在成年男性和女性重度饮酒者中改变酒精的急性中毒作用和药代动力学特征的功效。将在自然环境中测量NPI-028对乙醇饮用的影响，以模拟真实的饮用条件。最后，使用脑成像技术，我们将探索这种草药制剂的可能作用机制，使用质子磁共振波谱（MRS），以确定预处理是否改变实际进入大脑的乙醇量。我们计划继续和扩大这项实验，此外，将测量脑血流和脑血管的变化，使用功能性磁共振成像（fMRI）。的结果 这些研究将有助于确定草药在治疗与酒精有关的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.