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

基本信息

批准号：
10576815
负责人：
Anna Rose Childress
金额：
$ 65.02万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10576815
关键词：
Acceleration 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 Eligibility Determination 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 Outcome Outpatients Patients Pennsylvania Pharmaceutical Preparations Philadelphia Placebos Positron-Emission Tomography Randomized Relapse Research Research Personnel Resources Rewards Risk Taking Signal Transduction Speed Subgroup Substance Use Disorder Testing Tracer Universities Urine Ventral Striatum Ventral Tegmental Area Withdrawal Symptom Work addiction antagonist behavioral response clinical efficacy cocaine cue 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

项目摘要

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.

随着芬太尼（高效合成阿片类药物）的推动，该国严峻的阿片类药物危机愈演愈烈前所未有的死亡率。药物过量死亡现在是未成年人死亡的主要原因。 50，2017 年有超过 47,000 名美国人死于阿片类药物过量。截至 2018 年 12 月，费城阿片类药物过量死亡率全国第三（仅次于匹兹堡和巴尔的摩）。费城 84% 的致命阿片类药物过量用药中都含有芬太尼。对于阿片类药物使用障碍 – 无论是完全阿片类药物激动剂（美沙酮）、部分阿片类药物激动剂（丁丙诺啡）还是阿片类药物完全拮抗剂（纳曲酮）——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，这些救命药物的依从性往往很差，需要辅助使用非阿片类药物（尤其是可卡因）是阿片类药物过量死亡中近一半的常见罪魁祸首。费城。确定有希望的辅助药物，以减少 MAT 期间可卡因和其他非法药物的使用此外，测量这些药物的效果可以提高依从性并每年挽救数千人的生命。 “参与”预期的大脑目标将加速合理的药物开发，以实现这两个目标。将凝聚当地重要的成瘾资源和研究优势（例如，在临床试验和人类神经影像学）建立一个综合神经科学（CLIN）临床实验室，用于评估宾夕法尼亚大学成瘾研究中心的药物使用障碍药物。 UG1 最初为期 2 年的示范项目将测试卡利拉嗪（一种候选抗复发药物）的前景具有高 D3 亲和力的药物，既可用于初步临床疗效（减少非法药物使用，又可改善坚持使用救生纳曲酮），以及目标参与（例如，减弱药物提示触发的边缘系统）该项目将招募阿片类药物戒毒患者（最多 75 名）。符合条件的患者将被随机分配（2:1 比例）至 10 个临床治疗中心的近端网络内。卡利拉嗪（Vraylar，每天 1.5 毫克）与安慰剂对比，所有人都将接受最多 3 个月的缓释注射在一项为期 12 周的门诊试验中注射纳曲酮（Vivitrol，380 mg）（早期疗效亚组）。符合条件的患者还将接受住院患者目标参与措施（大脑成像探针奖励和在开始门诊试验之前，我们还将检查（探索性目标）的影响。大脑和临床上的假设驱动的遗传多态性（例如 DA D3 受体的 rs6280）对 D3 药物的反应摘要：经验丰富的 CLIN 团队、创新的大脑工具以及对 D3 药物进行新测试以提高纳曲酮的依从性，是最初的明显优势示范项目，并增加其提供新知识和拯救生命的可能性。年 CLIN 的优势包括新候选药物的前景（例如 GABA B PAM、食欲素拮抗剂、大麻二酚）和用于测量阿片受体和药物的新型高选择性 PET 示踪剂占用。