Methadone Studies

美沙酮研究

• 批准号: 7761495
• 负责人: THOMAS Richard KOSTEN
• 金额: $ 27.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761495
• 关键词: Adrenergic Antagonists; Adrenergic Receptor; Adverse effects; Alleles; Attenuated; Behavior; Behavior Therapy; Biology; Clinical Trials; Cocaine; Cocaine Dependence; Code; Cognitive Therapy; Dependence; Disease; Disulfiram; Dopamine; Dopamine-beta-monooxygenase; Dose; Double-Blind Method; FDA approved; Genetic; Genetic Polymorphism; Genotype; Haplotypes; Heart failure; Hour; Human; Instruction; Knowledge; Laboratories; Lead; Literature; Measures; Medical; Methadone; Methamphetamine; Methods; Norepinephrine; Norepinephrine Receptors; Nucleus Accumbens; Opioid; Participant; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Placebo Control; Placebos; Post-Traumatic Stress Disorders; Prazosin; Promoter Regions; Public Health; Randomized; Randomized Clinical Trials; Reaction; Receptor Gene; Reporting; Rewards; Role; Safety; Screening procedure; Side; Testing; Therapeutic; Treatment Efficacy; Treatment outcome; United States; Urinalysis; Variant; Work; aged; alpha-1 adrenergic receptors; base; cocaine use; experience; improved; inhibitor/antagonist; nepicastat; neurotransmission; noradrenergic; primary outcome; promoter; prospective; response; treatment response

PROJECT SUMMARY (See instructions): Comorbid cocaine dependence among methadone maintained patients interferes with treatment outcomes. Prazosin (alphai-adrenergic antagonist) and DpH inhibition (disulfiram) have shown promising results in the treatment of cocaine dependence. While inhibition of DpH activity is hypothesized to increase dopamine (DA) but decrease norepinephrine neurotransmission and to intensify the dysphoric experience of cocaine use, the selective inhibition of alphai-adrenergic receptor antagonist is hypothesized to attenuate DA neurotransmission primarily in the nucleus accumbens and to reduce the reinforcing effects of cocaine use. The objective of this proposal is to determine to what extend does prospective screening for a functional polymorphism of dopamine beta hydroxylase (DBH-1021C¿vT) or polymorphisms in the promoter region and the coding region ofthe alpha-la-adrenoceptor receptor gene (ADRAIA) predict the treatment efficacy of nepicastat (a new DpH inhibitor) or prazosin among newly admitted methadone treated patients. Based on our previous studies, we hypothesize that carriers ofthe low-OpH associated T allele will have significant reductions in cocaine use, because they are more susceptible to inhibition of DpH by nepicastat. We also will assess post-hoc the impact of functional variants ofthe ADRAIA on the response to prazosin. This 12- week double-blind, placebo controlled randomized clinical trial will provide treatment for 150 cocainedependent opioid dependent patients who have 2-weeks of methadone induction and 4 week discontinuation for 18-weeks total. Participants, aged 18-65 years, will be randomized to receive prazosin 10 mg/day, nepicastat 120mg/day, or placebo while concurrently receiving treatment with methadone. All participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment). The primary outcomes will be reduction in opioid and cocaine use, as assessed by self-report and confirmed by thrice-weekly urinalyses. The proposed study is expected to provide a better understanding ofthe role ofthe DpH inhibitor nepicastat and the selective alphaiA adrenergic receptor antagonist prazosin on cocaine using behavior among distinct DBH -1021C-+T genotypes or the functional variants in the promoter and coding region of ADRA1A.

项目总结（见说明）： 美沙酮维持患者中共病可卡因依赖干扰治疗结果。 哌唑嗪（α-肾上腺素能拮抗剂）和DpH抑制剂（双硫仑）在治疗可卡因依赖方面显示出有希望的结果。而DpH活性的抑制被认为是增加多巴胺（DA）而减少去甲肾上腺素神经传递和加强可卡因的烦躁体验 使用时，假设α 1-肾上腺素能受体拮抗剂的选择性抑制减弱主要在延髓核中的DA神经传递，并降低可卡因使用的强化作用。 本提案的目的是确定多巴胺β羟化酶（DBH-1021 C <$vT）功能多态性或α-α-肾上腺素受体基因（ADRAIA）启动子区和编码区多态性的前瞻性筛查在多大程度上预测了内匹司他（一种新的DpH抑制剂）或哌唑嗪在新入院接受美沙酮治疗的患者中的疗效。基于我们以前的研究，我们假设低OpH相关T等位基因携带者可卡因使用会显著减少，因为他们更容易受到内匹司他抑制DpH的影响。我们还将评估ADRAIA功能变体对哌唑嗪反应的影响。这12- 一项为期一周的双盲、安慰剂对照随机临床试验将为150名可卡因依赖性阿片类药物依赖患者提供治疗，这些患者接受2周美沙酮诱导和4周停药，共18周。年龄在18-65岁之间的受试者将随机接受哌唑嗪10 mg/天， 内匹司他120 mg/天或安慰剂，同时接受美沙酮治疗。所有参与者每周接受1小时的心理治疗（认知行为治疗）。主要结果将是减少阿片类药物和可卡因的使用，通过自我报告评估并通过每周三次尿液分析证实。 本研究将有助于更好地了解DpH抑制剂内匹司他和选择性α 1A肾上腺素能受体拮抗剂哌唑嗪在不同DBH-1021 C-+T基因型或ADRA 1A启动子和编码区功能变异体中对可卡因使用行为的作用。