Assessment,Treatment, and Pharmacological Interventions in Alcoholic Patients

酗酒患者的评估、治疗和药理学干预

• 批准号: 8344670
• 负责人: Markus Heilig
• 金额: $ 207.3万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8344670
• 关键词: Adrenergic Antagonists; Affect; Affective; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Anger; Animals; Anterior; Anxiety; Archives; Area; Back; Behavioral; Biological Markers; Blood; Blood Tests; Brain; Brain scan; CNR1 gene; Case Study; Characteristics; Chronic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Clinical assessments; Cognitive; Collaborations; Comorbidity; Complex; Contractor; Cooperative Research and Development Agreement; Corticotropin; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Creatine; Data; Data Analyses; Data Set; Databases; Deep Brain Stimulation; Disease; Double-Blind Method; Drug Metabolic Detoxication; Electrophysiology (science); Eligibility Determination; Emotional; Endocannabinoids; Endocrine; Enrollment; Ethanol; Evaluation; Extramural Activities; Female; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Genome; Genotype; Glutamates; Good Clinical Practice; Guided imagery; Heavy Drinking; Hormone Antagonists; Hospitalization; Hospitals; Human; Hydrocortisone; Image; Impaired cognition; Indium; Individual; Informatics; Infusion procedures; Inpatients; Insula of Reil; Intervention; Joints; Magnetic Resonance Spectroscopy; Measures; Medial; Mediation; Medicine; Mental Health; Military Personnel; Modeling; Molecular; Monitor; Naltrexone; National Institute of Drug Abuse; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Alcohol Abuse and Alcoholism; Neurosecretory Systems; Newspapers; Nurses; Nursing Staff; Opioid Receptor; Pathology; Patient Care; Patient Recruitments; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pilot Projects; Placebo Control; Placebos; Play; Population; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Process; Prolactin; Property; Protocols documentation; Psychiatry; Psychopharmacology; Publishing; Questionnaires; Randomized; Recruitment Activity; Relapse; Reporting; Research; Research Infrastructure; Research Personnel; Rewards; Role; Safety; Saline; Severities; Signal Transduction; Social Workers; Spermatogenesis; Staging; Stimulus; Stream; Stress; Substance P; Surrogate Markers; Symptoms; System; TACR1 gene; Temporal Lobe; Testing; Therapeutic; Time; Toxicology; Training; Translations; Treatment Protocols; Ventral Striatum; Visual; Withdrawal; Woman; Work; Yohimbine; acamprosate; addiction; alcohol craving; alcohol cue; alcohol exposure; alcohol seeking behavior; alcoholism therapy; base; behavioral health; blood oxygenation level dependent response; brain morphology; cingulate cortex; clinical care; craving; design; dopamine system; drug development; drug efficacy; emotional stimulus; endogenous opioids; gray matter; improved; male; men; neurotoxicity; novel; pre-clinical; pre-clinical research; prevent; problem drinker; programs; research study; response; social; social stress; stressor; theories; therapeutic target; tool; use alcohol to cope; vigilance

The following projects have been or are currently being conducted by SCATE. Each study employs a number of dependents measures that are designed to study pathology and measure efficacy. 1) Modulation of central glutamate by acamprosate A prevalent theory states that progressive emergence of a hyperglutamatergic state is key to the pathophysiology of alcoholism, and is associated both with emotional dysregulation (leading to craving and relapse), and neurotoxicity (leading to loss of grey matter and cognitive impairment). Acamprosate is a medication thought to target the hyperglutamatergic state. Here we used magnetic resonance spectroscopy (MRS) as a translational biomarker to obtain a measure of central glutamate using single-voxel 1H-MRS at 3T in the anterior cingulate cortex. Results showed a highly significant suppression of the glutamate to creatine ratio over time by acamprosate. This suggests that MRS offers an attractive biomarker for early human evaluation of candidate therapeutics that target the glutamatergic system. The results of this study have been published in Archives of General Psychiatry, 2010. 2) Alcohol craving induced by pharmacological stressors: yohimbine and mCPP Craving is a key element in the relapse process; therefore, a valid model of pharmacologically-induced alcohol craving might be useful to predict the efficacy of new pharmacotherapys for alcoholism, thereby accelerating drug development. To develop such a model, we tested two pharmacological challenges against a clinically established drug (acamprosate) for the treatment of alcoholism. In this protocol, we utilized a double-blind, placebo-controlled paradigm in which we administered: 1) an alpha 2-adrenergic antagonist (Yohimbine) which reliably induces reinstatement of alcohol seeking behavior in experimental animals, 2) a serotonergic compound (mCPP) which robustly increases alcohol craving in human alcoholics, and 3) placebo. Results showed cravings were significantly higher following both yohimbine and mCPP challenge compared with saline infusion. mCPP, but not yohimbine significantly increased anxiety ratings. Both challenges produced robust ACTH, cortisol and prolactin responses. Supporting the construct validity of the yohimbine response, we found a significant correlation between yohimbine-induced craving and the degree of alcoholism severity. Acamprosate administration did not influence craving. The results of this study have been published in Neuropsychopharmacology, 2011. 3) Effect of naltrexone on craving and ethanol-induced brain activity Findings from animal and human studies indicate that the rewarding properties of ethanol arise in part from a complex interaction between alcohol, endogenous opioids, and dopamine systems. Naltrexone (NTX), an opioid receptor antagonist, has been studied widely in both preclinical and clinical research for the treatment of alcoholism. Numerous clinical studies have shown that short-term use of NTX in alcohol-dependent patients effectively prevents relapse and reduces the level of craving. This protocol is the first study which involves administering IV alcohol to treatment-seeking alcohol dependent patients. Following detoxification, patients are randomized, using a double-blind design, to receive NTX or placebo throughout the course of their hospitalization. This study examines interactions between brain alcohol exposure and naltrexone treatment on processing of positive and negative emotional stimuli using fMRI. Patient recruitment for this study is complete, and data analysis is ongoing. 4) NK1R antagonism in alcoholism co-morbid with PTSD Alcoholism is the most common co-morbidity in men with PTSD and the second most common in women with this disorder. It is theorized that stress associated with PTSD (e.g., fear/anxiety, anger, hyper vigilance) promotes negatively reinforced use of alcohol to cope with negative affect. Therefore, we hypothesized that Substance P (SP)/NK1R signaling may be an attractive target for treatment of co-morbid alcoholism and PTSD. We asked whether NK1R blockade will suppress alcohol craving induced by stress or alcohol-associated stimuli, and whether it will improve PTSD symptoms in patients with co-morbid alcoholism and PTSD. This is an ongoing study, and results are not expected for another 18 months. 5) Corticotropin-releasing hormone receptor 1 (CRH1) antagonism and stress-induced craving in alcohol dependent women with high anxiety As alcoholism evolves, a shift occurs from positively to negatively reinforced alcohol use. Along the way, stress becomes a major trigger of relapse and excessive alcohol intake. Corticotrophin-releasing hormone (CRH) plays a major role in this state. We have negotiated a CRADA with GlaxoSmitKline, obtained an IND, and initiated a protocol that uses GSK561679 (CRH antagonist) as a translational tool in anxious female alcoholics. (Preclinical toxicology studies show that its use leads to a suppression of spermatogenesis, thus precluding its use in males.) The hypothesis is that GSK561679 will reduce alcohol craving in response to the combined challenges of the Trier Social Stress Task, alcohol-cue exposure, and guided imagery scripts. We will also examine whether GSK561679 will reduce spontaneous craving, reduce fMRI BOLD responses to negative affective stimuli within the ventral visual stream, medial temporal lobe and/or the anterior insula, and modulate blood markers of endocrine function in a manner indicative of anti-stress effects. Fifteen subjects have been enrolled, and 10 have completed. 6) CRH1 antagonism in anxious alcoholics This study uses another CRH1 antagonist, pexacerfont, obtained through a CRADA with Bristol Meyers Squibb. Pexacerfont is also an orally available, brain penetrant selective CRH1 antagonist. It has the advantage that safety has been established for the administration in both males and females. Because of the broader utility of pexacerfont in a therapeutic area where the majority of patients are male, we chose pexacerfont as the tool for a consortium of NIAAANIDA investigators who will use it in a cluster of related protocols. In the pexacerfontalcohol protocol, we will examine whether the CRH1 antagonist will reduce alcohol craving in response to the challenges as previously described for the GSK561679 CRH antagonist. We will also examine whether pexacerfont will reduce fMRI BOLD responses to a novel social stress challenge developed jointly with our NIDA collaborators. Six subjects have so far been enrolled, and 3 have completed. 7) Collaborative project with NIMH: Imaging Cannabinoid CB1 Receptors in Patients with Alcohol Dependence The brain endocannabinoid (EC) system involves endogenous cannabinoid agents (ECs) that act upon specific receptors (CB1 and CB2). ECs and CB1 receptors appear to modulate the brain reward system. During chronic alcohol exposure, EC levels in the brain are elevated and CB1 receptor levels are consequently reduced; this appears to be reversible following withdrawal. To what extent ECs and CB1 receptors are involved in the pathophysiology of alcohol dependence in humans is currently unknown. In this protocol, we utilize positron emission tomography to explore CB1 receptor abnormalities at various stages of alcohol withdrawal in humans. We are currently recruiting patients for this study. 8) Pilot study of deep brain stimulation (DBS) for the treatment of alcoholism Case reports of beneficial effects from DBS of the ventral striatum in alcoholism have been published, but no controlled data are available. In collaboration with NINDS and Medtronic, a DBS protocol that uses a controlled design has been developed, and is under review by the FDA.

以下项目已经或目前是由Scate进行的。每项研究采用许多旨在研究病理学和衡量功效的依赖措施。 1）通过丙型酯调节谷氨酸中央谷氨酸 一个普遍的理论指出，高谷氨酸能状态的逐渐出现是酒精中毒病理生理学的关键，并且与情绪失调（导致渴望和复发）以及神经毒性（导致灰物质丧失和认知障碍）有关。丙型酯是一种被认为靶向高谷氨​​酸能态的药物。在这里，我们使用磁共振光谱（MRS）作为转化生物标志物，在前扣带回皮层中使用单素1H-MRS获得中央谷氨酸中心酸盐的度量。 结果表明，随着时间的流逝，谷氨酸与肌酸的比率高度显着。这表明夫人为针对谷氨酸能系统的候选治疗剂提供了一种有吸引力的生物标志物，以早期人类评估。这项研究的结果已发表在《普通精神病学档案》中，2010年。 2）药理学胁迫诱导的酒精渴望：Yohimbine和MCPP 渴望是复发过程中的关键要素。因此，一种有效的药理学引起的酒精渴望模型可能有助于预测新药物对酒精中毒的功效，从而加速药物开发。为了开发这样的模型，我们测试了针对临床确立的药物（丙型酯）治疗酒精中毒的两种药理学挑战。在该协议中，我们使用了一个双盲，安慰剂控制的范式，其中我们进行了：1）一种α2-肾上腺素能拮抗剂（Yohimimbine），可靠地可靠地诱导实验动物中的酒精寻求行为，2）脑毒性化合物（MCPP），可增强葡萄酒饮酒，并在酒精中繁殖。结果表明，与盐水输注相比，在Yohimbine和MCPP挑战之后，人们的渴望明显更高。 MCPP，但Yohimbine并非显着提高焦虑评分。这两种挑战都产生了强大的ACTH，皮质醇和催乳素反应。支持Yohimbine响应的构造有效性，我们发现Yohimbine引起的渴望与酒精中毒程度之间存在显着相关性。分型给药不影响渴望。这项研究的结果已发表在神经心理药理学上，2011年。 3）纳曲酮对渴望和乙醇诱导的大脑活性的影响 来自动物和人类研究的发现表明，乙醇的奖励性能部分是由于酒精，内源性阿片类药物和多巴胺系统之间的复杂相互作用而产生。阿片类受体拮抗剂Naltrexone（NTX）在临床前和临床研究中已被广泛研究以治疗酒精中毒。许多临床研究表明，在酒精依赖性患者中短期使用NTX可以有效防止复发并降低渴望水平。 该方案是第一项研究，涉及将IV饮酒用于寻求治疗的依赖酒精的患者。解毒后，使用双盲设计随机分配患者在整个住院期间接受NTX或安慰剂。这项研究研究了使用fMRI处理脑饮酒与纳曲酮治疗之间的相互作用。这项研究的患者招募已经完成，并且数据分析正在进行中。 4）酒精中毒中的NK1R拮抗与PTSD共处 酒精中毒是PTSD男性中最常见的合并症，也是这种疾病女性中第二常见的合并症。理论上，与PTSD相关的压力（例如，恐惧/焦虑，愤怒，高警惕性）促进了对酒精的负强化使用来应对负面影响。因此，我们假设P（SP）/NK1R信号传导可能是治疗合并症酒精中毒和PTSD的有吸引力的靶标。我们询问NK1R封锁是否会抑制由压力或与酒精相关的刺激引起的酒精渴望，以及它是否会改善合并症酒精中毒和PTSD患者的PTSD症状。这是一项正在进行的研究，预计再有18个月的结果。 5）皮质激素释放激素受体1（CRH1）拮抗作用和应激诱发的耐心女性焦虑症的渴望 随着酒精中毒的发展，从积极地转变为消极的饮酒。一路上，压力成为复发和过度酒精摄入的主要触发因素。皮质营养素释放激素（CRH）在该状态下起着重要作用。 我们已经与葛兰素史克林（Glaxosmitkline）协商了Crada，获得了IND，并启动了使用GSK561679（CRH拮抗剂）作为焦虑女性酒精中毒的转化工具的方案。 （临床前毒理学研究表明，其使用会导致精子发生的抑制，从而排除其在雄性中的使用。）假设是GSK561679将减少渴望酒精的渴望，以应对Trier社会压力任务，酒精含量暴露，酒精含量暴露，酒精含量和带有指导影像学文本的综合挑战。我们还将检查GSK561679是否会减少自发的渴望，减少对腹侧视觉流中负面情感刺激的fMRI大胆反应，内侧颞叶和/或前岛岛的内侧裂片，并以表明反压力压力效应的方式调节内分泌功能的血液标记。已招募了15名受试者，其中10名已完成。 6）焦虑酒精中毒中的CRH1拮抗作用 这项研究使用了另一种CRH1拮抗剂Pexacerfont，该拮抗剂是通过Bristol Meyers Squibb获得的。 Pexacerfont也是一种口服的，脑穿透性选择性CRH1拮抗剂。它的优势是，已经为男性和女性的行政部门建立了安全性。由于Pexacerfont在大多数患者是男性的治疗区域的更广泛的效用，因此我们选择了Pexacerfont作为Niaaanida研究人员财团的工具，他们将在一系列相关方案中使用它。 在PEXACERFONTALCOHOL方案中，我们将检查CRH1拮抗剂是否会减少渴望，以应对GSK561679 CRH拮抗剂的挑战。我们还将研究Pexacerfont是否会减少对与NIDA合作者共同发展的新型社会压力挑战的fMRI大胆反应。到目前为止，已经招募了六名受试者，其中3名已经完成。 7）与NIMH的合作项目：酒精依赖患者的大麻素CB1受体成像 脑内源性大麻素（EC）系统涉及作用于特定受体（CB1和CB2）的内源性大麻素剂（EC）。 ECS和CB1受体似乎调节了大脑奖励系统。在慢性酒精暴露期间，大脑中的EC水平升高，因此CB1受体水平降低。撤回后，这似乎是可逆的。目前尚不清楚ECS和CB1受体在何种程度上涉及酒精依赖的病理生理学。 在此方案中，我们利用正电子发射断层扫描来探索人类戒酒各个阶段的CB1受体异常。我们目前正在招募这项研究的患者。 8）对酒精中毒治疗的深脑刺激（DBS）的试点研究 腹侧纹状体在酒精中毒中的有益作用的案例报告已发表，但没有可用的数据可用。与Ninds和Medtronic合作，已经开发了使用受控设计的DBS协议，并正在FDA进行审查。