THPB-Containing Herbal Preparations for the Treatment of Drug Abuse

描述（由申请人提供）：尽管进行了大量的研究工作，但药物成瘾仍然是一个严重的公共卫生问题，没有有效的治疗方法。虽然它们可能是有益的，但传统的草药制剂并没有被广泛认为是管理药物成瘾的可行选择，部分原因是缺乏临床和临床前研究来检查其疗效和安全性。我们的研究团队和其他人最近的研究表明，从草药Stephania delavayi Diels（di bu long）的粉碎根中分离出的四氢原小檗碱（THPB）生物碱左旋四氢巴马汀（L-THP）可能有助于治疗药物成瘾。THPB是天然存在的生物碱，存在于植物属Cortophila和Stephania的植物中，并包含在许多传统的中草药制剂中。其中两个物种，Corpus ambigua（yan hu suo）和Stephania tetranda（fang ji）是中国草药学中的50种基本草药之一，并因其镇静，神经安定和止痛特性而被使用。几种THPB，最值得注意的是l-THP和千金藤啶的左旋异构体（l-SPD）具有药理学特性，使得它们理想地适合于治疗药物成瘾，包括对多种多巴胺（DA）受体的拮抗剂和/或部分激动剂作用。进一步表征THPB在药物滥用临床前模型中的有效性，应有助于我们了解哪种含THPB的制剂对治疗药物依赖人群具有最大的效用。该建议建立在初步数据的基础上，这些数据表明，l-THP减少了临床前大鼠模型中的可卡因寻求行为，并且l-THP减少了恢复海洛因成瘾者的药物渴望和复发。选择用于测试的两种分离的THPB成分（l-THP和l-SPD）具有不同的性质，这可能使它们与现有的DA受体拮抗剂药物相比更安全和更有效。所提出的研究将使用基于临床前大鼠自我给药的程序来比较l-THP和l-SPD与非选择性DA受体拮抗剂氟奋乃静和“非典型”抗精神病药的作用，所述方法设计成检查这些药剂在急性或慢性给药时抑制可卡因使用和预防由药物再暴露诱导的可卡因寻求复发的能力，压力的发作，以及暴露于与药物相关的条件暗示。还将检查这些化合物长期给药导致的潜在不良反应的发生情况，包括镇静、锥体外系症状、体重增加滥用倾向和肝毒性。预计通过对分离的THPB的有效性和安全性的临床前研究，我们将能够推进使用含有这些THPB的草药制剂作为药物成瘾的可行治疗。

DESCRIPTION (provided by applicant): Despite intense research efforts, drug addiction persists as a serious public health problem for which no effective treatment exists. Although they are likely beneficial, traditional herbal preparations are not widely considered to be viable options for the management of drug addiction, due in part to the paucity of clinical and preclinical studies examining their efficacy and safety. Recent studies by our research team and others have demonstrated that the tetrahydroprotoberberine (THPB) alkaloid, levo-tetrahydropalmatine (l-THP), isolated from crushed roots of the herb Stephania delavayi Diels (di bu long) may be useful for treating drug addiction. THPBs are naturally occurring alkaloids found in plants from the botanical genera Corydalis and Stephania and are contained in many traditional Chinese herbal preparations. Two of these species, Corydalis ambigua (yan hu suo) and Stephania tetranda (fang ji) are among the 50 fundamental herbs in Chinese herbology and have been used for their sedative, neuroleptic and analgesic properties. Several THPBs, most notably l-THP and the levo isomer of stepholidine (l-SPD) have pharmacological profiles that make them ideally suited for treating drug addiction, including antagonist and/or partial agonist effects at a variety of dopamine (DA) receptors. Further characterization of the effectiveness of THPBs in preclinical models of drug abuse should facilitate our understanding of which THPB-containing preparations will have the greatest utility for treating drug-dependent populations. This proposal builds on preliminary data demonstrating that l-THP reduces cocaine-seeking behavior in preclinical rat models and that l-THP reduces drug craving and relapse in recovering heroin addicts. The two isolated THPB constituents selected for testing (l-THP and l-SPD) have distinct properties that may make them safer and more effective compared to existing DA receptor antagonist drugs. The proposed studies will use preclinical rat self-administration based procedures to compare the effects of l-THP and l-SPD with those of the non-selective DA receptor antagonist, fluphenazine, and an "atypical" anti- psychotic in paradigms designed to examine the ability of these agents, when administered acutely or chronically, to curb cocaine use and to prevent the relapse of cocaine seeking induced by drug re-exposure, the onset of stress, and exposure to drug-associated conditioned cues. The occurrence of potential undesirable effects as a consequence of chronic administration of these compounds, including sedation, extrapyramidal symptoms, weight gain abuse liability, and hepatotoxicity will also be examined. It is anticipated that, through preclinical investigation of the effectiveness and safety of isolated THPBs, we will be able to advance the use of herbal preparations containing these THPBs as viable treatments for drug addiction.