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: 8746460
• 负责人: Markus Heilig
• 金额: $ 215.22万
• 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/8746460
• 关键词: Abstinence; Affect; Affective; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Anger; Animals; Anterior; Anxiety; Area; Back; Behavioral; Binding; Biological Markers; Blood; Blood Tests; Brain; Brain scan; CNR1 gene; Cannabinoids; Case Study; Characteristics; Chronic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Clinical assessments; Cognitive; Collaborations; Comorbidity; Complex; Contractor; Cooperative Research and Development Agreement; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Data Analyses; Data Set; Databases; Deep Brain Stimulation; Disease; Dose; 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; Image; Impaired cognition; Individual; Informatics; Inpatients; Institutional Review Boards; Insula of Reil; Intervention; Joints; Lipopolysaccharides; Magnetic Resonance Spectroscopy; Measures; Medial; Mediation; Medicine; Mental Health; Military Personnel; 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; Natural Immunity; Neurosecretory Systems; Newspapers; Nurses; Nursing Staff; Opioid Receptor; Patient Care; Patients; Peroxisome Proliferators; Pharmaceutical Preparations; Pharmacological Treatment; Pilot Projects; Pioglitazone; Placebos; Plasma; Play; Population; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Process; Property; Protocols documentation; Psychiatry; Psychopharmacology; Publications; Publishing; Questionnaires; Randomized; Relapse; Reporting; Research; Research Infrastructure; Research Personnel; Rewards; Role; Safety; Signal Transduction; Social Workers; Spermatogenesis; Spinal Puncture; Staging; Stimulus; Stream; Stress; Substance P; Surrogate Markers; Symptoms; System; TACR1 gene; Temporal Lobe; Testing; Therapeutic; Toxicology; Training; Translations; Treatment Protocols; Ventral Striatum; Visual; Withdrawal; Woman; Work; acamprosate; addiction; alcohol craving; alcohol cue; alcohol exposure; alcoholism therapy; base; behavioral health; blood oxygenation level dependent response; brain morphology; cingulate cortex; clinical care; craving; cytokine; design; dopamine system; drug efficacy; emotional stimulus; endogenous opioids; gray matter; improved; male; men; neurotoxicity; novel; pre-clinical; pre-clinical research; problem drinker; programs; receptor; receptor binding; research study; response; social; social stress; theories; tool; treatment effect; use alcohol to cope; vigilance

The following projects have been or are currently being conducted by CATE. 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. We are currently performing secondary analyses on biospecimens to assess the effects of treatment on cytokine levels in the CSF and plasma. 2) 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. 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 the processing of positive and negative emotional stimuli using fMRI. Data analysis reveals that at a BAL of approximately 0.8 g% there is a lack of ethanol-induced BOLD response in the ventral striatum (VS). This result is in contrast to our previous findings in social drinkers that showed activation of the VS. Results have been submitted for publication. 3) 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 would 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. Patient accrual for this protocol is complete. Results have been submitted for publication. 4) 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 GlaxoSmithKline, 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. Thirty-seven subjects have completed. 5) 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 NIAAA/NIDA investigators who will use it in a cluster of related protocols. In the pexacerfont alcohol 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. Sixty subjects have been enrolled and completed. In addition 8 subjects have been enrolled in a sub-study involving a lumbar puncture to investigate the concentration of the drug in the brain. 6) 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. Results show that alcohol dependence is associated with a widespread reduction of cannabinoid CB1 receptor binding in the human brain, and this reduction persists at least 2-4 weeks into abstinence. The correlation of reduced binding with years of alcohol abuse suggests an involvement of CB1 receptors in alcohol dependence. Initial results were published in Molecular Psychiatry (2012). Enrollment continues to study individuals with other addictions. 7) 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 approved by the IRB and the FDA. The review process of this protocol has been extensive. Patient accrual is in progress. 8) Role of proinflammatory signaling in alcohol craving Ethanol-induced activation of innate immunity has emerged as a potential mechanism for understanding the pathophysiology of alcoholism. The objective of the present study is to evaluate the role of proinflammatory signaling in alcohol craving. The peroxisome proliferator-activator receptor gamma agonist pioglitazone, which modulates glial activity, will be used as an experimental treatment. Guided imagery scripts will be used as an established set of stimuli to induce craving. Low dose lipopolysaccharide (LPS) administration, which activates proinflammatory signaling, will be used as a novel challenge and evaluated for its ability to provoke alcohol craving. If LPS in fact induces alcohol craving, the present design will allow evaluation of whether pioglitazone can inhibit this response. Nine patients have completed.

以下项目已经或目前由Cate进行。 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。 目前，我们正在对生物测量进行辅助分析，以评估治疗对CSF和血浆中细胞因子水平的影响。 2）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。 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对阳性和负面情绪刺激处理的脑饮酒与纳曲酮治疗之间的相互作用。数据分析表明，在约0.8 g％的BAL下，腹侧纹状体缺乏乙醇诱导的粗体反应（VS）。这一结果与我们以前在社交饮酒者中表现出激活V的发现相反。结果已提交出版。 3）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。该协议的患者应计入。结果已提交出版。 4）释放促糖激素的激素受体1（CRH1）拮抗作用和高焦虑症的依赖性妇女的压力引起的渴望。 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。 我们已经用葛兰素史克（Glaxosmithkline）协商了一个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，其使用会导致对精子发生的抑制，从而抑制其在男性中的使用）。假设是，GSK561679将根据Trier社会压力任务，酒精中毒和指导图像脚本的综合挑战来减少渴望酒精的渴望。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。三十七个受试者已经完成。 5）CRH1在焦虑酒精中毒中的拮抗作用 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中更广泛的效用，因此我们选择了Pexacerfont作为NIAAA/NIDA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PEXACERFONT酒精方案中，我们将检查CRH1拮抗剂是否会减少对GSK561679 CRH拮抗剂所描述的挑战的渴望。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。六十名受试者已入学并完成。 另外，已将8名受试者纳入了一个涉及腰椎穿刺的子研究中，以研究该药物在大脑中的浓度。 6）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。结果表明，酒精依赖性与人脑中大麻素CB1受体结合的广泛减少有关，这种减少至少持续了2-4周。减少结合与多年酗酒的相关性表明CB1受体参与酒精依赖性。初始结果发表在分子精神病学（2012）中。入学人数继续研究其他成瘾的人。 7）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，使用受控设计的DBS协议已获得IRB和FDA的批准。该协议的审查过程已广泛。患者应计。 8）促炎信号传导在酒精渴望中的作用 乙醇引起的先天免疫激活已成为理解酒精中毒病理生理学的潜在机制。本研究的目的是评估促炎信号在渴望中的作用。调节神经胶质活性的过氧化物酶体增生剂 - 激活剂γ激动剂丙酮酮将被用作实验治疗。指导的图像脚本将用作一组已建立的刺激集，以引起人们的渴望。激活促炎信号传导的低剂量脂多糖（LPS）给药将被用作新的挑战，并因其促进酒精渴望的能力而被评估。如果LP实际上引起了渴望酒精的渴望，那么目前的设计将允许评估吡格列酮是否可以抑制这种反应。九名患者已经完成。