Guanfacine Target Engagement and Validation to Improve Substance Use Outcomes in Women

胍法辛目标参与和验证以改善女性药物使用结果

• 批准号: 9899239
• 负责人: Rajita Sinha
• 金额: $ 81.11万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899239
• 关键词: Abstinence; Address; Adrenergic Agonists; Alcohol or Other Drugs use; Alcohols; Ambulatory Care; Anxiety; Attention; Basic Science; Cannabis; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Cocaine; Cocaine Abuse; Cognitive; Corpus striatum structure; Cues; Data; Decision Making; Development; Disease; Dose; Drug Targeting; Drug usage; Exposure to; FDA approved; Gender; Guanfacine; Health; Heterogeneity; Inpatients; Investigational Therapies; Laboratories; Laboratory Animals; Lead; Measures; Mediating; Medical; Moods; Morbidity - disease rate; National Institute of Drug Abuse; Neurocognitive; Nicotine; Outcome; Outcome Study; Outpatients; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Placebo Effect; Placebos; Post-Traumatic Stress Disorders; Preparation; Process; Public Health; Randomized; Relapse; Reporting; Research; Rewards; Role; Sex Differences; Short-Term Memory; Site; Stress; Substance Use Disorder; Substance abuse problem; Testing; Treatment outcome; Up-Regulation; Urine; Validation; Woman; Work; base; biobehavior; clinical research site; cocaine use; comorbidity; drug craving; drug seeking behavior; experimental study; flexibility; improved; men; noradrenergic; novel; personalized medicine; psychiatric symptom; relapse prediction; relapse risk; relating to nervous system; response; sex; social; stressor; treatment duration; week trial

Abstract Substance Use Disorders (SUDs) present a serious public health problem with significant health-related morbidity, and no FDA-approved treatments target cocaine use disorder (CUD) or co-occurring substance abuse. A major obstacle to SUD treatment are the high relapse rates, and high drug craving and reduced cognitive flexibility, particularly in stress, drug cue and challenge contexts, are target processes that contribute to such high relapse rates. Furthermore, CUD women show greater drug craving and poor cognitive flexibility during stress and drug cue challenge contexts, and preliminary data show that treatment with the alpha-2 adrenergic agonist, Guanfacine (GUA) at 3mg/s day versus placebo (PBO) reverses these effects in CUD women but not men. Preliminary data also show that GUA 3 mg/day vs. PBO led to higher drug-negative urines in an 8- week outpatient setting in CUD women than men. On the basis of this previous development work, we propose a 3- year R01 pilot clinical and laboratory outcome study to test the overall hypothesis that GUA (3mg/day) will reduce target drug craving and improve cognitive flexibility processes in CUD women, and that such targeted engagement will result in lower cocaine and other drug use outcomes in women with CUD. One hundred treatment seeking CUD women will be randomly assigned to GUA (3 mg/day) vs Placebo (PBO) over a 10-week clinical trial across 2 sites (N=50 per site), and will also be assessed in a pre-treatment and week 9 laboratory challenge test with exposure to stress and drug cue provocation. The primary target engagement outcome will be reduction in drug craving and improved cognitive flexibility and the primary target validation outcome will be reduced cocaine use as measured by percent negative drug urines and last three weeks of abstinence. The following aims will be addressed. Aim #1 - Target Engagement: To examine whether GUA will reduce drug craving and improve cognitive flexibility in laboratory challenge and in clinical assessments over the 10-week period. Aim #2: Target Validation: To evaluate whether GUA vs PBO effects on drug craving and cognitive flexibility significantly predicts CUD clinical outcomes in the 10-week trial. Aim #3: Data Replication and Scalability: To replicate target engagement and validation outcomes across two sites (Yale and SUNY-Stony Brook) and inform scalability for larger clinical trials. Exploratory Aim 1: To explore GUA’s role in mediating the relationship between target drug craving and cognitive flexibility processes and cocaine use and other drug use outcomes. Exploratory Aim 2: To explore the role of co-morbid psychiatric symptoms (mood, anxiety and PTSD) in moderating the proposed target engagement and validation processes. Acknowledging the heterogeneity in CUD and significant sex differences, this project utilizes an experimental therapeutics approach to further develop and test whether GUA’s targeted effects on drug craving and cognitive flexibility impacts substance use clinical outcomes, thereby providing critical data on whether such a personalized medicine approach to the development of GUA in the treatment of women with CUD is warranted.

抽象的 药物使用障碍（SUD）带来了严重的公共卫生问题，与健康有关 发病率，没有FDA批准的治疗靶向可卡因使用障碍（CUD）或同时出现的物质 滥用SUD信托的主要障碍是高复发率和渴望 认知灵活性，尤其是在压力，药物提示和挑战环境中，是贡献的目标过程 此外，这么高的复发率。 在压力和药物提示挑战环境中，初步数据显示了使用alpha 2的处理 肾上腺素能激动剂，鸟法汀（GUA），每天3mg/s与安慰剂（PBO）（PBO）逆转CUD妇女的影响 但不是男人。 在以前的发展工作的基础上，在男性的门诊环境中，我们提出了3- R01年级试点临床和实验室结果研究，以测试GUA（3mg/天）的总体假设 靶向药物渴望并改善CUD妇女的认知灵活性过程 将导致可卡因较低的可卡因和其他CUD女性的其他局限器。 在为期10周的临床试验中 跨两个站点（每个站点n = 50），也将在预处理和第9周的实验室挑战中进行评估 暴露于压力和药物提示的测试。 渴望药物和强制性灵活性以及主要目标验证结果将是 可卡因减少了用尿液百分比测量的使用，而戒酒的几周 以下目标将被解决。 渴望并提高实验室挑战和临床评估的认知灵活性10周 时期。目标＃2：目标验证：评估GUA与PBO对毒品的影响 灵活性可显着预测10周的AIM＃3：数据复制和 可伸缩性：复制目标英语（耶鲁大学和纽约州立大学史诗般的stony stony stony（耶鲁大学和纽约州立大学） Brook）并为可伸缩性临床试验提供信息。 靶向药物渴望与认知Procaine Procaine使用与其他药物之间的关系 使用结果。 PTSD）在调节拟议的目标英语和验证过程中。 在CUD和显着性别差异的异质性，该项目利用实验性治疗剂 进一步发展和测试GUA是否对药物认知灵活性的影响的方法 影响物质使用临床结果，他们通过提供有关这种个性化的关键数据 有必要对GUA的发展进行医学方法来治疗CUD妇女。