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）或同时存在的底物 虐待。 SUD治疗的主要障碍是高继电器率，渴望和减少的药物渴望 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 如此高的继电器率。此外，cud妇女表现出更大的毒品渴望和认知灵活性不佳 在压力和药物提示挑战环境中，初步数据表明，用alpha-2治疗 肾上腺素能激动剂，鸟法汀（GUA），每天3mg/s与安慰剂（PBO）逆转CUD妇女的影响 但不是男人。初步数据还表明，GUA 3毫克/天与PBO导致8-的药物阴性尿液更高 在cud女性中，一周的门诊病人比男性。根据先前的开发工作，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 针对毒品渴望和改善CUD妇女的认知灵活性过程，并且这种针对性的参与 CUD女性的可卡因和其他药物使用结果将导致较低的可卡因。寻求一百个治疗 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周实验室挑战中进行评估 暴露于压力和药物提示挑衅的测试。主要目标参与结果将是 降低药物渴望和改善的认知灵活性，主要目标验证结果将是 减少可卡因的使用，按照负药尿液百分比和戒酒的最后三周来衡量。这 以下目标将被解决。目标＃1-目标参与：检查GUA是否会减少药物 在10周内的实验室挑战和临床评估中的认知灵活性和提高认知灵活性 时期。目标＃2：目标验证：评估GUA与PBO对药物渴望和认知的影响是否影响 灵活性可以显着预测为期10周的试验中的CUD临床结果。目标＃3：数据复制和 可伸缩性：复制两个站点之间的目标参与和验证结果（耶鲁大学和纽约州立大学 布鲁克）并为较大的临床试验提供了可伸缩性。探索目的1：探索GUA在调解中的作用 目标药物渴望与认知灵活性过程与可卡因使用与其他药物之间的关系 使用结果。探索性目标2：探索共同恐怖症状的作用（情绪，焦虑和 PTSD）在调节提出的目标参与过程和验证过程中。承认 CUD和重大性别差异的异质性，该项目利用实验疗法 进一步开发和测试GUA是否对毒品渴望和认知灵活性的影响 影响物质使用临床结果，从而提供有关这种个性化的关键数据 有必要为GUA的开发用于治疗CUD妇女的方法。