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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：
8337841
负责人：
Jia Bei Wang
金额：
$ 73.87万
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 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8337841
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 Receptor Dose Double-Blind Method Drug Addiction Drug Evaluation Drug Formulations Drug Interactions Drug Kinetics Ensure Evaluation Studies FDA approved Foundations Herbal Medicine Heroin Human Illicit Drugs Maryland Measures Mental disorders Monitor Names National Institute of Drug Abuse 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最大挑战是缺乏FDA批准的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直接解决这一问题，以确定l-四氢巴马汀（l-THP）作为可卡因依赖的抗成瘾药物的有效性和安全性。l-THP是从中药延胡索中分离得到的一种主要活性单体化合物，在中国作为镇痛药（商品名：罗通定）已在临床上使用了40多年。据报道，l-THP作为DP 1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α 1和5HT1A受体的结合亲和力较低。l-THP减弱大鼠可卡因自我给药和脑刺激奖赏，并减轻海洛因成瘾者的渴求。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激活大脑奖赏途径中起着关键作用。更重要的是，它可能是l-THP结合到多个单胺受体，提供作为“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得l-THP成为抗成瘾药物的优秀候选者。在中国对l-THP进行了数十年的研究，获得了广泛的动物和临床前药理学和毒性数据，为我们拟定的转化研究提供了坚实的安全性基础。我们计划从FDA获得l-THP的IND批准，之后我们将进行I期和II期临床试验。如果这种从动物研究到人类临床研究的过渡是成功的，它将提供l-THP是一种有效的可卡因成瘾药物的概念证明。