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

描述(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治疗。通过进行临床I/II期药物开发和评估研究，确定L-延胡索乙素(L-THP)作为一种抗可卡因依赖成瘾药物的有效性和安全性，DP1提案直接解决了这一问题。L-THP是从中草药延胡索中分离得到的一种主要活性单体化合物，在中国作为止痛药(商标名：罗通定)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，也与D3受体相互作用。此外，它与α1和5HT1a受体的亲和力较低。L-THP可减弱大鼠对可卡因的自我给药和脑刺激奖赏，减轻海洛因成瘾者的渴求。L-THP的这一作用机制尚不清楚。这可能与其DA受体活性有关，因为多巴胺能系统在脑奖励通路的激活中起着关键作用。更重要的是，L-THP可能与多个单胺受体结合，从而提供“一种天然的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体。然而，独特的药理学特征使L-三羟色胺成为抗成瘾药物的极佳候选药物。中国数十年来对L-三羟色胺的大量动物和临床前药理和毒性研究数据为我们拟议的翻译研究提供了坚实的安全性基础。我们计划获得FDA对L-THP的IND批准，之后我们将进行临床I期和II期试验。如果这种从动物研究到人类临床研究的成功过渡，将为L-THP是一种治疗可卡因成瘾的有效药物提供概念证据。

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.