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.

摘要 物质使用障碍（SUD）是一个严重的公共卫生问题， 没有FDA批准的针对可卡因使用障碍（CUD）或共存物质的治疗 虐待SUD治疗的一个主要障碍是高复发率，高药物渴望和减少 认知灵活性，特别是在压力、药物提示和挑战环境中，是有助于 如此高的复发率此外，CUD女性表现出更大的药物渴望和认知灵活性差 在压力和药物提示挑战的情况下，初步数据显示， 肾上腺素能激动剂胍法辛（GUA）在3 mg/s/天与安慰剂（PBO）相比，逆转了CUD妇女的这些作用 但不是男人初步数据还显示，GUA 3 mg/天与PBO相比，在8- 每周门诊设置在CUD女性比男性。在此基础上，我们提出了一个3- R 01年初步临床和实验室结局研究，以检验GUA（3 mg/天）将降低 有针对性的药物渴望和改善认知灵活性的过程中，CUD妇女，这种有针对性的参与， 将导致较低的可卡因和其他药物使用的结果在妇女与CUD。100寻求治疗 在为期10周的临床试验中，CUD女性将被随机分配至GUA（3 mg/天）与安慰剂（PBO）组 2个研究中心（每个研究中心N=50），还将在治疗前和第9周实验室攻毒中进行评估 测试暴露于压力和药物刺激。主要目标参与成果将是 减少药物渴求和改善认知灵活性，主要目标验证结果将是 减少可卡因的使用，以阴性药物尿液的百分比和最后三周的禁欲来衡量。的 将致力于实现以下目标。目标#1 -目标参与：检查GUA是否会减少药物 在10周的实验室挑战和临床评估中， 期目标#2：目标验证：评价GUA与PBO是否对药物渴求和认知功能有影响 在10周的试验中，灵活性显著预测了CUD的临床结局。目标#3：数据复制和 可扩展性：在两个站点（Yale和SUNY-Stony）复制目标参与和验证结果 Brook），并为大型临床试验提供可扩展性。探索性目标1：探索GUA在调解 目标药物渴求和认知灵活性过程与可卡因和其他药物使用之间关系 使用成果。探索性目标2：探索共病精神症状（情绪、焦虑和 PTSD）在缓和拟议的目标参与和验证过程。承认 在CUD的异质性和显着的性别差异，该项目利用实验疗法 进一步开发和测试GUA是否对药物渴望和认知灵活性有靶向作用的方法 影响物质使用的临床结果，从而提供关键数据， 在治疗女性CUD时，有必要采用药物方法来开发GUA。