A Clinical Laboratory with Integrated Neuroscience (CLIN) for Early Evaluation of Medications for Substance Use Disorders

综合神经科学 (CLIN) 临床实验室，用于药物滥用障碍药物的早期评估

• 批准号: 10348202
• 负责人: Anna Rose Childress
• 金额: $ 72.79万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348202
• 关键词: Adherence; Adjuvant Analgesic; Affective; Affinity; Age; Agonist; Alcohols; American; Amygdaloid structure; Attention; Automobile Driving; Baltimore; Behavioral; Brain; Brain imaging; Buprenorphine; Cannabidiol; Cannabis; Cause of Death; Clinical; Clinical Treatment; Clinical Trials; Cocaine; Country; Cues; Data; Development; Dopamine; Evaluation; Fentanyl; Genetic Polymorphism; Globus Pallidus; Goals; Human; Image; Injectable; Injections; Inpatients; Knowledge; Laboratories; Life; Measures; Medial; Methadone; Motivation; Naltrexone; Neurosciences; Nicotine; Opioid; Opioid Receptor; Opioid agonist; Outpatients; Patients; Pennsylvania; Pharmaceutical Preparations; Philadelphia; Placebos; Positron-Emission Tomography; Randomized; Relapse; Research; Research Personnel; Resources; Rewards; Risk-Taking; Savings; Signal Transduction; Speed; Subgroup; Substance Use Disorder; Testing; Tracer; Universities; Urine; Ventral Striatum; Ventral Tegmental Area; Withdrawal Symptom; Work; addiction; antagonist; base; behavioral response; clinical efficacy; clinical outcome measures; cocaine use; drug craving; experience; gamma-Aminobutyric Acid; hypocretin; illicit drug use; imaging probe; improved; innovation; medication compliance; medication-assisted treatment; mortality; neuroimaging; non-opioid analgesic; novel; opioid epidemic; opioid mortality; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; overdose death; patients who use opioids; pre-clinical; prescription opioid; prevent; primary endpoint; receptor; recruit; response; secondary endpoint; synthetic opioid; tool; treatment site

The nation’s grim opioid crisis surges on, with the fentanyls (high potency synthetic opioids) driving unprecedented mortality rates. Drug overdose deaths are now the leading cause of death in those under age 50, with more than 47,000 Americans dying of opioid overdose in 2017. As of December 2018, Philadelphia had the third highest rate of opioid overdose deaths in the country (out-ranked only by Pittsburgh and Baltimore). Fentanyl is present in 84% of the fatal opioid overdoses in Philadelphia. Medication-assisted treatment (MAT) for opioid use disorders – whether full opioid agonist (methadone), partial opioid agonist (buprenorphine), or a full antagonist (naltrexone) – is critical for reducing opioid use, and for preventing overdose deaths. Unfortunately, compliance with these life-saving medications is often poor, with ancillary use of non-opioid drugs (especially cocaine) as a common culprit. Cocaine is found in almost half of the opioid overdose deaths in Philadelphia. Identifying promising adjunctive medications that reduce cocaine and other illicit drug use during MAT could improve adherence and save thousands of lives each year. Further, measuring how these medications “engage” the intended brain targets will speed rational medication development. Toward both these goals, we will cohere significant local addiction resources and research strengths (e.g., in clinical trials and human neuroimaging) to establish a Clinical Laboratory with Integrated Neuroscience (CLIN) for Evaluation of Medications for Substance Use Disorders at the University of Pennsylvania Center for Studies of Addiction. The initial 2-year demonstration project in the UG1 will test the promise of cariprazine, a candidate anti-relapse medication with high D3-affinity, both for preliminary clinical efficacy (reduced illicit drug use, and improved adherence to life-saving naltrexone), and for target engagement (e.g., blunting of drug cue-triggered limbic activation) in patients with opioid use disorders. The project will recruit detoxified opioid patients (up to n=75) within a proximal network of 10 clinical treatment sites. Eligible patients will be randomly-assigned (2:1 ratio) to cariprazine (Vraylar, 1.5 mg daily) vs. placebo, and all will receive up to 3 monthly injections of extended release injectable naltrexone (Vivitrol, 380 mg) in a 12 week outpatient trial (Early Efficacy). A subgroup of imaging- eligible patients will also receive inpatient Target Engagement measures (brain imaging probes for reward and inhibition) prior to beginning the outpatient trial. We will also examine (Exploratory Aim) the impact of hypothesis- driven genetic polymorphisms (e.g., rs6280 for DA D3 receptor) on both the brain and clinical response to the D3 medication. Summary: The highly experienced CLIN team, innovative brain tools, and the novel testing of a D3 medication to improve adherence to naltrexone, are clear strengths of the initial demonstration project, and increase the likelihood that it will both provide new knowledge and save lives. Out- years CLIN strengths include the promise of new candidate medications (e.g., GABA B PAMs, orexin antagonists, cannabidiol) and new, highly-selective PET tracers for measuring opioid receptors and medication occupancy.

芬太尼（高效力合成OIOIDS）驾驶，该国严峻的Oioid危机席卷了 空前的死亡率。药物过量死亡现在是年龄段人的主要死亡原因 50，2017年12月，有超过47,000名美国人死于阿片类药物过量。2018年12月，费城 该国的阿片类药物过量死亡率是第三高的率（仅在匹兹堡和巴尔的摩排名）。 费城致命的阿片类药物过量的84％存在于芬太尼。药物辅助治疗（MAT） 用于绿o-杀症 - 无论是全绿蛋白激动剂（美沙酮），部分opioid agonist（丁丙诺啡）还是 完全拮抗剂（Naltrexone） - 对于减少阿片类药物的使用和预防过量死亡至关重要。 不幸的是，遵守这些挽救生命的药物通常很差，辅助使用非阿片类药物 （尤其是可卡因）作为常见的罪魁祸首。可卡因在几乎一半的阿片类药物过量死亡中发现 费城。 确定有希望的辅助药物，以减少可卡因和其他非法药物使用 每年可以提高依从性并挽救数千人的生命。此外，测量这些药物如何 “参与”预期的大脑目标将加快理性药物开发。达到这两个目标，我们 将融合大量的当地成瘾资源和研究优势（例如，在临床试验和人类中 神经影像学）以建立具有综合神经科学（临床）的临床实验室来评估 宾夕法尼亚大学成瘾研究中心的药物使用障碍药物。这 UG1中最初的2年示威项目将测试甲虫的承诺，Cariprazine是候选人的反对者 具有较高D3亲和力的药物，既用于初步的临床效率（降低非法药物的使用，又提高了 遵守挽救生命的纳曲酮）和目标参与度（例如，药物提示触发的边缘的钝器 激活）患有杀菌性疾病的患者。该项目将招募排毒的绿木药患者（最高n = 75） 在10个临床治疗部位的近端网络中。合格的患者将被随机分配（2：1比率） Cariprazine（Vraylar，每天1.5毫克）与安慰剂，所有人最多将每月注射延长释放 在12周的门诊试验（早期功效）中，可注射的纳曲酮（Vivitrol，380 mg）。成像子组 符合条件的患者还将接受住院目标参与度措施（大脑成像问题以获得奖励和 抑制）在开始门诊试验之前。我们还将研究（探索目的） 假设驱动的遗传多态性（例如，DA D3受体的RS6280）在大脑和临床上均已 对D3药物的反应。摘要：经验丰富的临床团队，创新的大脑工具和 D3药物的新型测试以提高对纳曲酮的依从性，是初始的明确优势 示范项目，并增加了提供新知识并挽救生命的可能性。出去- 临床优势包括新候选药物的承诺（例如，GABA B PAMS，OREXIN 拮抗剂，大麻二酚）和新的，高度选择性的宠物示踪剂，用于测量阿片类药物和药物 占用。