Dutasteride treatment for reducing heavy drinking in AUD: Predictors of efficacy

度他雄胺治疗减少酗酒的澳元：疗效的预测因素

基本信息

批准号：
10626840
负责人：
JONATHAN M COVAULT
金额：
$ 45.3万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-06 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626840
关键词：
5 Alpha-Reductase Inhibitor Agonist Alcohol abuse Alcohol consumption Alcohol dependence Alcoholic beverage heavy drinker Alcohols Alleles Androgen Receptor Animals Anxiety Benign Prostatic Hypertrophy Biological Biological Markers Chronic Clinical Clinical Trials Connecticut Disease Disulfiram Double-Blind Method Drug Prescriptions Dutasteride Environmental Risk Factor Enzymes Etiology FDA approved Female Generations Genes Genetic Genetic Polymorphism Genetic Variation Genotype Glucocorticoid Receptor Glucuronides Hair Health Heavy Drinking Human Individual Life Life Stress Measures Mediating Modeling Molecular Chaperones Monitor Naltrexone Oxidoreductase Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Phase Placebo Control Placebos Play Production Progesterone Receptors Proteins Randomized Recommendation Recording of previous events Regulation Relapse Role Safety Sampling Serum Markers Stanolone Stress System Trauma Treatment Efficacy Universities Woman acamprosate alcohol abuse therapy alcohol effect alcohol measurement alcohol research alcohol use disorder androgenic anxiety states arm behavioral response biological adaptation to stress design drinking early life adversity enzyme activity experience hormonal signals innovation male men negative affect negative mood neurosteroids non-smoking novel personalized pharmacotherapy phase 1 study phosphatidylethanol preclinical study problem drinker randomized placebo controlled study receptor receptor function response self-reported anxiety steroid hormone stress reactivity stress resilience stressor topiramate treatment responders treatment response university student

项目摘要

Abstract Pharmacotherapy options for alcohol use disorders remain limited, with only three FDA approved compounds (disulfiram, naltrexone and acamprosate). Recent studies highlight the potential for medications used for the treatment of other indications to be useful in helping patients reduce drinking. Study of additional agents, particularly those that act through novel mechanisms, is needed to expand the range of pharmacotherapy options for alcohol use problems. Additionally, identification of individual subject level predictors of efficacy are needed to better personalize pharmacotherapy treatment recommendations. Extensive preclinical studies indicate that neuroactive steroids mediate important effects of alcohol and support the examination of neuroactive steroid modulators as treatment options for alcohol use disorders (AUD). Dutasteride, a widely prescribed medication for benign prostatic hypertrophy and androgenic hair loss, blocks a key step in the production of neuroactive steroids and represents a promising candidate for treatment of AUD. Interim analysis from the first 12-week RCT of dutasteride for AUD in a sample of male heavy drinkers indicates that dutasteride is well tolerated in alcoholics and has efficacy in helping subjects reduce drinking. Results suggest that dutasteride may be particularly helpful for patients with baseline negative mood or are carriers of a stress-reactive allele of a chaperone protein, FKBP5, involved in regulation of glucocorticoid, androgen and progesterone receptor function. This 24-week treatment study will use an innovative step therapy randomized placebo controlled design to examine the safety and efficacy of dutasteride to reduce drinking among a sample of 190 treatment seeking men and women with hazardous levels of alcohol use. At 12-weeks placebo non-responders will transition to dutasteride and dutasteride non-responders will transition to naltrexone, an FDA approved medication with demonstrated efficacy for reducing heavy drinking. Baseline measures of anxiety and perceived life stress will be examined separately and in conjunction with stress resilient vs. reactive genotypes of FKBP5 as predictors of dutasteride treatment efficacy.

抽象的酒精使用障碍的药物治疗选择仍然有限，只有三种 FDA 批准的化合物（双硫仑、纳曲酮和阿坎酸）。最近的研究强调了用于治疗的药物的潜力治疗其他适应症有助于帮助患者减少饮酒。其他药物的研究，特别是那些通过新机制发挥作用的药物，需要扩大药物治疗的范围酒精使用问题的选择。此外，个体受试者水平预测功效的确定是需要更好地个性化药物治疗建议。广泛的临床前研究表明，神经活性类固醇介导酒精和支持的重要作用检查神经活性类固醇调节剂作为酒精使用障碍（AUD）的治疗选择。度他雄胺是一种广泛用于治疗良性前列腺肥大和雄激素性脱发的药物，可阻断神经活性类固醇生产的关键步骤，是治疗 AUD 的有希望的候选者。度他雄胺在男性重度饮酒者样本中的第一个 12 周 RCT 的中期分析表明度他雄胺在酗酒者中具有良好的耐受性，并且能够有效帮助受试者减少饮酒。结果表明，度他雄胺可能对基线消极情绪或情绪低落的患者特别有帮助。伴侣蛋白 FKBP5 的应激反应等位基因的携带者，参与糖皮质激素的调节，雄激素和孕激素受体功能。这项为期 24 周的治疗研究将采用创新步骤治疗随机安慰剂对照设计，以检查度他雄胺的安全性和有效性，以减少在 190 名寻求治疗的男性和女性样本中饮酒，这些男性和女性的饮酒水平达到危险水平。在 12 周安慰剂无反应者将过渡到度他雄胺，度他雄胺无反应者将过渡纳曲酮是 FDA 批准的一种药物，已被证明可以有效减少酗酒。基线焦虑和感知生活压力的测量将单独进行检查，并与压力结合起来进行检查 FKBP5 的弹性与反应性基因型作为度他雄胺治疗效果的预测因子。