Enzyme & Receptor Antagonists of GHB, GBL & 1, 4-BD

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• 批准号: 6804135
• 负责人: LAWRENCE S QUANG
• 金额: $ 6.1万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-10 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804135
• 关键词: GABA receptor; acute disease /disorder; alcohol dehydrogenase; anticonvulsants; antidotes; behavioral /social science research tag; biotransformation; butyrolactone; cytotoxicity; diol; disease /disorder model; drug abuse chemotherapy; drug interactions; drug metabolism; drug receptors; enzyme inhibitors; ethanol; gamma hydroxybutyrate; inhibitor /antagonist; laboratory mouse; neurochemistry; nonhuman therapy evaluation; overdose; pharmacokinetics; substance abuse related behavior

DESCRIPTION: (provided by applicant) The widespread abuse of gamma-hydroxybutyrate (GHB) and its chemical precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), has resulted in escalating episodes of life-threatening acute overdoses. Because abuse of GHB and its precursors is a recently evolving phenomenon, treatment strategies for acute overdoses are currently limited. The objectives of this proposal are to address two specific research areas solicited in the request for application (DA-01-014, "Research on GHB and Its Precursors") issued by the National Institute on Drug Abuse (NIDA): 1.) overdose and toxicity of GHB and its precursors, and 2.) treatment strategies for GHB and its precursors. Although GHB and GBL were made illegal by the Hillary J. Farias and Samantha Reed Date Rape Prohibition Act of 2000 (the former is now a federal schedule I drug, and the latter is a federal list I chemical), 1,4-BD is currently recognized as a Class I Health Hazard (a potentially life-threatening hazard). This designation imposes no legal restrictions on the manufacture, distribution (in dietary supplements), or possession of 1,4-BD. Increasingly, 1,4-BD has been responsible for severe life-threatening overdoses and deaths. Thus, our laboratory has prioritized and focused its research efforts on 1,4-BD, which is currently the only legally available GHB-related drug. Additionally, 1,4-BD is the only GHB-related drug that can directly interact with ETOH, the most commonly coingested substance with GHB-related drugs, leading to dangerous interactions. Furthermore, its complete biotransformation to GHB permitted us the unique opportunity to study indirectly GHB's interactions with ETOH and GABA-B and GHB receptors. This application has three specific research aims. The first aim is to characterize 1,4-BD and GHB toxicity after acute overdoses. The second aim is to study potential interactions of 1,4-BD and GHB with ETOH. The third aim is to investigate potential antidotes for acute 1,4-BD overdose and combined acute 1,4-BD and ETOH overdose. Potentially effective antidotes exist for 1,4-BD, specifically, and for GHB, GBL, and 1,4-BD collectively. The antidote for 1,4-BD specifically is an enzyme antagonist of alcohol dehydrogenase (4-methylpyrazole, Antizol), which may block in vivo enzymatic biotransformation of 1,4-BD to GHB. The antidotes for the GHB, GBL, and 1,4-BD collectively are receptor antagonists of GABA-B receptors (CGP-35348) and GHB-specific receptors (NCS-382), the sites of pharmacologic action of GHB, GBL, and 1,4-BD. In general, a murine model (CD-l mice) will be used to assess the acute effects of 1,4-BD, GHB, and ETOH on behavioral (open field locomotion test), neuromuscular (righting reflex, rotarod test, grip strength test), and biochemical processes (blood 1,4-BD and GHB levels). This murine model will also be used to study the effects of potential therapeutic agents for acute overdoses. The results of this study will expand upon promising data from pilot studies performed in this laboratory on acute 1,4-BD and GHB toxicity as well as novel therapeutic agents for its potential medical management.

描述：(申请人提供) γ-羟基丁酸酯(GHB)及其化学品的广泛滥用 前体--伽马丁内酯(GBL)和1，4-丁二醇(1，4-BD) 在不断升级的危及生命的急性过量事件中。因为滥用 GHB及其前体是最近发展起来的现象，治疗策略 对于急性过量，目前是有限的。这项提议的目标是 针对申请书中征集的两个具体研究领域 (DA-01-014，《GHB及其前体研究》) 药物滥用研究所(NIDA)：1.羟基丁酸及其毒物的过量和毒性 前体和2)。)GHB及其前体的治疗策略。虽然 Hillary J.Farias和Samantha Reed Date将GHB和GBL定为非法 2000年《禁止强奸法案》(前者现在是联邦附表一毒品，和 后者是联邦清单I的化学品)，1，4-BD目前被公认为 I类健康危害(一种潜在的生命危险)。本称号 不对制造、分销(在饮食中)施加法律限制 补充剂)，或拥有1，4-BD。1，4-BD越来越多地被 对严重威胁生命的服药过量和死亡负责。因此，我们的 实验室已将其研究重点放在1，4-BD上，这是 目前唯一合法获得的与GHB相关的药物。此外，1，4-BD是 唯一可以与乙醇直接相互作用的GHB相关药物， 与GHB相关的药物通常含有同心物质，导致危险 互动。此外，它的完全生物转化为GHB允许我们 间接研究GHB与乙醇和 GABA-B和GHB受体。 这项申请有三个具体的研究目的。第一个目标是 描述急性过量后1，4-BD和GHB的毒性。第二个目标是 研究1，4-BD和GHB与乙醇的潜在相互作用。第三个目标是 探讨急性1，4-BD过量及合并急性中毒的潜在解毒剂 1，4-BD和乙醇过量。对于1，4-BD存在潜在有效的解毒剂， 具体地说，以及GHB、GBL和1，4-BD的总和。治疗的解药 1，4-BD是乙醇脱氢酶的特异性酶拮抗剂 (4-甲基吡唑，安替佐尔)，可阻断体内的酶 1，4-BD生物转化为GHBGHB、GBL和1，4-BD的解毒剂 共同是GABAB受体(CgP-35348)的受体拮抗剂和 GHb特异性受体(NCS-382)，GHb的药理作用部位， GBL和1，4-BD。一般来说，将使用小鼠模型(CD-L小鼠)来评估 1，4-BD、GHB和EtoH对行为(旷场运动)的急性影响 测试)、神经肌肉(翻正反射、转杆测试、握力测试)，以及 生化过程(血液1，4-BD和GHb水平)。这个小鼠模型将 也可用于研究潜在的治疗药物对急性胰腺炎的影响 吸毒过量。这项研究的结果将在Pilot提供的有希望的数据的基础上进行扩展 在本实验室进行的急性1，4-BD和GHB毒性研究 作为新的治疗剂，为其潜在的医疗管理。

项目成果

Resuscitative treatments on 1,4-butanediol mortality in mice.

复苏治疗对小鼠 1,4-丁二醇死亡率的影响。

• DOI: 10.1016/j.annemergmed.2005.10.011
• 发表时间: 2006
• 期刊: Annals of emergency medicine.
• 作者: Carai,MauroAM;Colombo,Giancarlo;Quang,LawrenceS;Maher,TimothyJ;Gessa,GianLuigi
• 通讯作者: Gessa,GianLuigi