Neuroactive Steroid Potentiation to Decrease Alcohol Craving, Normalize HPA axis function and Prevent Alcohol Relapse

神经活性类固醇增强剂可减少酒精渴望、使 HPA 轴功能正常化并防止酒精复吸

基本信息

批准号：
10201415
负责人：
Rajita Sinha
金额：
$ 68.9万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201415
关键词：
Address Adrenal Glands Alcohol abuse Alcohol consumption Alcohol dependence Alcoholism Alcohols Allopregnanolone Anxiety Arousal Brain Characteristics Chemosensitization Chronic Clinical Clinical Research Cocaine Abuse Cognitive Corticotropin Cues Development Dose Double-Blind Method Drug usage Exposure to FDA approved Family history of Foxes Functional disorder Future Gender Health Care Costs Heavy Drinking Human Hydrocortisone Hypothalamic structure Imagery Individual Individual Differences Institutes Investigation Laboratories Laboratory Study Mediating Methods Moods Neurosecretory Systems Outcome Outcome Study Pathway interactions Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Physiological Pituitary Gland Placebos Prefrontal Cortex Pregnenolone Prevalence Progesterone Public Health Randomized Recording of previous events Regulation Relapse Reporting Research Safety Self-control as a personality trait Stress Surgeon Therapeutic Trauma Up-Regulation Woman alcohol abuse therapy alcohol craving alcohol cue alcohol prevention alcohol relapse alcohol seeking behavior alcohol use disorder alcoholism therapy anxiety reduction anxiety symptoms base clinical outcome measures cognitive change comorbidity craving drug craving executive function flexibility gamma-Aminobutyric Acid hypothalamic-pituitary-adrenal axis improved men mood symptom negative mood neurosteroids novel overtreatment pre-clinical research receptor relapse risk response secondary outcome

项目摘要

PROJECT SUMMARY/ABSTRACT Alcohol Use Disorder (AUD) is a chronic relapsing illness associated with high rates of relapse and in which there is great need to develop and evaluate novel treatments to decrease relapse rates and the associated burden of AUD. This application proposes a novel, mechanistic combined laboratory and clinical outcome study to examine whether the neuroactive steroid precursor Pregnenolone (PREG) via its conversion to the potent GABAergic neuroactive steroid Allopregnanolone (ALLO) decreases provoked alcohol craving and anxiety, normalizes stress dysregulation, and improves cognitive flexibility and alcohol use outcomes in treatment seeking individuals with AUD. Previous research by our group and others has shown that chronic alcohol abuse dysregulates brain stress pathways including the hypothalamic pituitary adrenal (HPA) axis responses and is associated high provoked alcohol craving, anxiety, and cognitive flexibility, which in turn, are predictive of subsequent alcohol relapse and clinical outcomes. Promising new preliminary findings from our laboratory indicate that potentiating ALLO via administration of its precursors, including PREG, may reverse such stress-related disruptions and decrease alcohol craving and relapse risk. However, the mechanism by which PREG, and the specific doses at which it may potentially decrease alcohol craving and relapse risk is not known. On the basis of these findings, we propose a proof-of-concept 4-year, randomized, double-blind, dose dependent laboratory and clinical study to evaluate the preliminary efficacy of PREG treatment (200/400 mg/day for 8 weeks) versus placebo (PBO) in 90 AUD men and women. The following specific aims will be addressed: Aim 1: To evaluate the safety/tolerability of 200mg and 400mg/daily of PREG in AUD individuals. Aim 2a: To evaluate the effects of PREG doses (PBO, 200 and 400 mg/day) on ALLO levels and on experimentally provoked craving, HPA dysregulation, anxiety, mood and cognitive flexibility in AUD patients. Aim 2b: To assess whether PREG-stimulated ALLO levels mediate its effects on provoked craving, HPA dysregulation, anxiety, mood and cognitive flexibility in the laboratory component. Aim 3a: To assess the preliminary efficacy of 8-week PREG doses versus PBO treatment on primary alcohol use outcomes and secondary outcomes of alcohol craving, anxiety and negative mood. Aim 3b: To assess whether PREG- stimulated ALLO levels mediate its effects on primary alcohol use outcomes and on secondary clinical outcomes during the 8-week treatment phase. Exploratory Aim: To explore whether pre-treatment patient characteristics (gender, family history of alcoholism (FH), trauma history and co-morbid drug use) influence PREG-potentiated ALLO levels and primary and secondary alcohol use outcomes. Successful completion of the proposed aims has the potential to support further development of novel neuroactive steroid targets such as PREG and ALLO in the treatment of AUD, particularly to target chronic alcohol-related stress dysregulation, alcohol craving and high alcohol relapse risk.

项目摘要/摘要酒精使用障碍（AUD）是一种与高复发率相关的慢性复发疾病非常需要开发和评估新型治疗以降低复发率和相关的奥德的负担。该应用提出了一种新颖的机械合并实验室和临床结果研究是否通过转化为有效的GABA能神经活性类固醇异烷醇（Allo）降低了渴望的酒精和焦虑，使压力失调归一化，并提高认知灵活性和酒精使用结果寻求AUD的人的治疗。我们小组和其他人的先前研究表明酒精滥用失调的大脑应力途径包括下丘脑垂体肾上腺（HPA）轴反应，并且与高挑衅的酒精渴望，焦虑和认知灵活性相关，而这反过来又是预测随后的酒精复发和临床结局。有希望的新初步发现实验室表明，通过其前体（包括Preg）来增强Allo，可能会逆转这种与压力有关的破坏和减少酒精渴望和复发风险。但是，通过哪种预先剂量以及可能降低酒精渴望和复发风险的特定剂量是不知道。根据这些发现，我们提出了概念验证4年，随机，双盲，剂量依赖实验室和临床研究评估Preg治疗的初步疗效（200/400 毫克/天8周）与安慰剂（PBO）（PBO），在90位aut男女中。以下具体目标将是地址：目标1：评估AUD个人中Preg的200mg和400mg/每日的安全性/耐受性。目标2a：评估Preg剂量（PBO，200和400 mg/天）对Allo水平以及对 AUD患者的实验引起的渴望，HPA失调，焦虑，情绪和认知灵活性。 AIM 2B：评估预刺激的Allo水平是否介导其对渴望的影响，HPA 实验室组件中的失调，焦虑，情绪和认知灵活性。目标3a：评估 8周预剂量与PBO治疗的初步疗效对主要酒精使用结果和酒精渴望，焦虑和负面情绪的次要结果。目标3b：评估是否预先刺激的Allo水平介导了其对初级饮酒结果的影响和对次级临床的影响在8周治疗阶段的结果。探索目的：探索治疗前患者是否特征（性别，酒精中毒家族史（FH），创伤历史和合并药物使用）影响预启动的Allo水平以及初级和继发性酒精使用结果。成功完成拟议的目标有可能支持这种新型神经活性类固醇靶标的进一步发展。作为AUD治疗的PreG和Allo，特别是针对慢性酒精相关的应激失调，渴望酒精和高酒精复发风险。