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Development of I-THP as New Medication for Drug Addiction (DP1)

I-THP作为戒毒新药的开发（DP1）

基本信息

批准号：
8106787
负责人：
Jia Bei Wang
金额：
$ 75万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8106787
关键词：
Abstinence Address Adverse effects Affinity Agonist Analgesics Animals Attenuated Award Binding Blood Brain Cardiovascular system Chemistry China Chinese Herbs Clinical Clinical Research Cocaine Cocaine Dependence Cocaine Users Data Development Dopamine Dopamine Receptor Dose Double-Blind Method Drug Addiction Drug Formulations Drug Interactions Drug Kinetics Ensure Evaluation Evaluation Studies FDA approved Foundations Goals Herbal Medicine Heroin Human Illicit Drugs Maryland Measures Mental disorders Monitor Names National Institute of Drug Abuse Opioid Outcome Measure Outpatients Pathway interactions Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacology and Toxicology Pharmacotherapy Pharmacy Schools Phase Phase I/II Trial Placebos Play Protocols documentation Public Health Publishing Randomized Rattus Reporting Research Rewards Role Safety Sampling Self Administration Solid Source Specimen Standard Preparations Study Subject System Toxic effect Universities Urine addiction base clinical efficacy clinical practice cocaine exposure cocaine use craving design drug addiction pharmacotherapy drug development drug testing effective therapy experience healthy volunteer member monoamine novel phase 1 study placebo controlled study pre-clinical primary outcome programs psychologic psychosocial receptor success tetrahydropalmatine translational study

项目摘要

DESCRIPTION (provided by applicant): The foremost challenge to the effective treatment of cocaine addiction is the lack of FDA approved pharmacotherapy for this illicit drug. This DP1 proposal directly addresses this concern by performing clinical Phase I/II medication development and evaluation studies to determine the efficacy and safety of l-tetrahydropalmatine (l-THP) as an anti-addiction medication for cocaine dependence. l-THP, a major active single compound isolated from the Chinese herbal medicine Yanhusuo, has been used in clinical practice as an analgesic (commercial name: Rotundine) in China for more than 40 years. It has been reported that l-THP acts on dopamine (DA) receptors as a DP1 partial agonist/D2 antagonist and also interacts with D3 receptor. In addition, it has low affinity binding to alpha1 and 5HT1A receptors. l-THP attenuates cocaine self-administration and brain-stimulation reward in rats and relieves craving in heroin addicts. The mechanism for this action of l-THP is unknown. It could be related to its DA receptor activity, as the dopaminergic system plays a critical role in the activation of brain reward pathways. More importantly, it could be that l-THP binds to multiple monoamine receptors that provide efficacy as "a natural cocktail-like cocaine antagonist." Since, it is well known that cocaine non-selectively inhibits several monoamine transporters. Nevertheless, the unique pharmacological profile makes l-THP an excellent candidate for anti-addiction medication. The extensive animal and preclinical pharmacology and toxicity data resulting from decades of studies on l-THP in China provide a solid safety foundation for our proposed translational study. We plan to obtain IND approval of l-THP from the FDA, after which we will conduct clinical phase I and phase II trials. If this transition from animal studies to human clinical studies is successful, it will provide proof of concept that l-THP is an effective medication for cocaine addiction.

描述（由申请人提供）：有效治疗可卡因成瘾的首要挑战是缺乏 FDA 批准的针对这种非法药物的药物疗法。该 DP1 提案通过进行临床 I/II 期药物开发和评估研究来确定左旋四氢延胡索乙素 (l-THP) 作为可卡因依赖的抗成瘾药物的有效性和安全性，从而直接解决了这一问题。 l-THP是从中草药延胡索中分离出来的一种主要活性单一化合物，在中国作为镇痛药（商品名：Rotundine）用于临床已有40多年的历史。据报道，l-THP 作为 DP1 部分激动剂/D2 拮抗剂作用于多巴胺 (DA) 受体，并且还与 D3 受体相互作用。此外，它与 α1 和 5HT1A 受体的结合亲和力较低。 l-THP 可减弱大鼠的可卡因自我给药和大脑刺激奖赏，并缓解海洛因成瘾者的渴望。 l-THP 的这种作用机制尚不清楚。这可能与其 DA 受体活性有关，因为多巴胺能系统在大脑奖赏通路的激活中发挥着关键作用。更重要的是，l-THP 可能与多个单胺受体结合，从而提供“天然鸡尾酒样可卡因拮抗剂”的功效。因为众所周知，可卡因非选择性地抑制几种单胺转运蛋白。然而，独特的药理学特征使 l-THP 成为抗成瘾药物的绝佳候选者。中国数十年的 l-THP 研究得出的广泛的动物和临床前药理学和毒性数据为我们提出的转化研究提供了坚实的安全基础。我们计划获得FDA的l-THP IND批准，之后我们将进行临床I期和II期试验。如果从动物研究到人类临床研究的转变成功，它将提供 l-THP 是治疗可卡因成瘾的有效药物的概念证明。