THPB-Containing Herbal Preparations for the Treatment of Drug Abuse

描述(申请人提供)：尽管进行了大量的研究工作，但吸毒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。尽管传统草药制剂可能是有益的，但它们并不被广泛认为是管理药物成瘾的可行选择，部分原因是缺乏对其有效性和安全性进行检验的临床和临床前研究。我们的研究小组和其他人最近的研究表明，从千金藤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是一种天然存在的生物碱，存在于延胡索属和千金藤属植物中，许多传统的中草药制剂中都含有THPB。其中两个种，延胡索(延胡索)和防己草(方纪)是中草药中的50种，具有镇静、抗神经和镇痛的作用。几种THPB，最著名的是L-THP和千金藤碱的左旋异构体(L-Spd)，具有理想的药理学特征，使其非常适合于治疗药物成瘾，包括在多种多巴胺(DA)受体上的拮抗和/或部分激动剂作用。在药物滥用的临床前模型中进一步表征THPB的有效性应该有助于我们理解哪些含THPB的制剂将在治疗药物依赖人群方面具有最大的效用。这一建议建立在初步数据的基础上，该数据表明，L-THP减少了临床前大鼠模型中的可卡因寻找行为，L-THP在海洛因成瘾者康复过程中减少了药物渴求和复发。选择进行测试的两个分离的THPB成分(L-THP和L-SPD)具有不同的性质，与现有的DA受体拮抗剂药物相比，可能使它们更安全和更有效。拟议的研究将使用基于大鼠临床前自我给药的程序，在设计的范式中比较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物的效果，旨在检查这些药物在急性或长期给药时抑制可卡因使用的能力，并防止因药物再次暴露、应激开始和暴露于药物相关的条件性线索而导致的寻求可卡因的复发。还将检查由于长期服用这些化合物而导致的潜在不良反应的发生，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，我们将能够推动含有这些THPs的草药制剂作为可行的药物成瘾治疗方法的使用。

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.