Identifying Biological Signatures of N-acetylcysteine for Non-Suicidal Self-Injury in Adolescents

鉴定 N-乙酰半胱氨酸在青少年非自杀性自残中的生物学特征

基本信息

批准号：
9576129
负责人：
Kathryn Regan Cullen
金额：
$ 30.79万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2018-09-15 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9576129
关键词：
Acetylcysteine Acute Address Adolescence Adolescent Adolescent and Young Adult Adult Advanced Development Antioxidants Behavior Behavioral Biological Biological Availability Biological Markers Blood Blood Circulation Brain Chronic Clinical Complex Cysteine Dangerous Behavior Development Dose Drug Kinetics Evaluation Event Female Female Adolescents Frequencies Future Glutamates Glutathione Glutathione Disulfide Hair Health Intravenous Knowledge Longevity Magnetic Resonance Spectroscopy Measures Mental Health Natural Products Neurodegenerative Disorders Oral Outcome Oxidation-Reduction Oxides Patients Pattern Pharmacodynamics Phase Placebos Plasma Preparation Randomized Research Sampling Self Destructive Behavior Skin Stress Suicide Suicide attempt Testing Tissues Uncertainty Youth aged antiporter base clinical effect clinical efficacy design dietary supplements efficacy trial improved neurotoxicity non-suicidal self injury novel open label prevent research clinical testing response suicidal transmission process week trial young adult young woman

项目摘要

Identifying Biological Signatures of N-Acetylcysteine for Non-Suicidal Self-Injury in Adolescents and Young Adults Non-suicidal self-injury (NSSI), the deliberate act of damaging one’s own tissues without suicidal intent, is a common problem in adolescents and young adults, and is associated with severe consequences including future suicide attempts. Treatments for this habitual, self-destructive behavior pattern are sorely limited. Identification of novel, biologically-informed treatments for NSSI in youth could improve health outcomes over the lifespan. N-acetylcysteine (NAC) is a natural product that is widely-available as an over-the-counter dietary supplement. It is also available as oral and intravenous (IV) prescription products, and may have promise as a novel treatment for NSSI in youth. In the first study of its kind, our open-label study showed reduced NSSI frequency (p=0.02) in female adolescents aged 13-21 after 8 weeks of oral NAC. In preparation for a definitive clinical NAC trial, a critical preliminary step is to clarify NAC’s biological signatures, or measures of the mechanisms underlying its clinical effects, which would provide the basis for biologically-informed design of optimized efficacy trials. This proposal will investigate possible biological signatures for NAC’s behavioral effects: (1) increased glutathione (GSH), the primary antioxidant in the brain; and/or (2) modulation of the glutamate (Glu)-cysteine antiporter, effectively decreasing excessive Glu transmission. Both of these mechanisms could alleviate stress-induced neurotoxicities in adolescents with NSSI, but neither mechanism has been evaluated in NSSI. Confirmation of NAC biological signatures is challenging due its complex pharmacokinetics (PK), posing uncertainty related to optimal dose. Oral NAC is primarily used in psychiatric studies because of its ease of use, but has low bioavailability (5-10%). Studies testing NAC for mental health indications have generally not paired clinical testing with PK or biological signature testing. To address knowledge gaps and advance development of NAC as a treatment for adolescent NSSI, we propose an R61/R33 project to investigate NAC’s biological signatures (changes in GSH and/or Glu) in young women with NSSI. The R61 will focus on identifying the optimal dose to achieve meaningful change in GSH and Glu during short-term NAC treatment. We will randomize 36 female adolescents and young adults aged 16-24 years with NSSI to 4 weeks of treatment with either oral NAC (3600mg or 5400mg per day) or to placebo. Go/NoGo criteria for advancing to R33 will be: “Go” if any one of the following occurs: (a) ≥ 50% increase in blood GSH redox ratio; (b) 5% increase in brain GSH concentrations; (c) 5% decrease in brain Glu concentrations. Dose and for the R33 will be selected based on the biological changes and the tolerability observed in the R61. The R33 phase will seek to replicate the biological signature findings in an 8-week trial using chronic dosing in a new sample, and examine the relationships among biological signatures, NAC PK, and clinical response.

鉴定N-乙酰半胱氨酸的生物学特征，用于青少年和年轻人的非杀伤性自我伤害在青少年和年轻人中，非自杀的自我伤害（NSSI）是有意损害自己的组织而无自杀意图的故意行为，与包括未来自杀企图在内的严重后果有关。对这种习惯性的自我毁灭行为模式的治疗受到巨大限制。在青年中，对NSSI的新型生物学疗法的鉴定可以改善整个生命的健康状况。 N-乙酰半胱氨酸（NAC）是一种天然产物，可作为非处方饮食补充剂广泛使用。它也可以作为口服和静脉（IV）处方产品可用，并且可能有望成为NSSI在青年中的新颖治疗方法。在同类的第一项研究中，我们的开放标签研究表明，口服NAC 8周后，年龄在13-21岁的女性青少年中NSSI频率降低（P = 0.02）。为了准备确定的临床NAC试验，一个关键的初步步骤是阐明NAC的生物学特征，或衡量其临床作用的机制，这将为优化有效性试验的生物学设计设计提供基础。该提案将研究NAC行为影响的可能生物学特征：（1）谷胱甘肽（GSH）增加，这是大脑中主要的抗氧化剂；和/或（2）调节谷氨酸（GLU） - 半胱氨酸抗胞酸酯，有效地减少了GLU的过度传播。这两种机制都可以减轻NSSI青少年的压力诱导的神经毒性，但在NSSI中都没有评估过任何机制。 NAC生物学特征的确认是由于其复杂的药代动力学（PK）而挑战的，这与最佳剂量相关的不确定性。口服NAC主要用于精神病研究，因为它易于使用，但生物利用度较低（5-10％）。对NAC进行心理健康适应症测试的研究通常与PK或生物签名测试配对临床测试。为了解决知识差距并提高NAC作为青少年NSSI的治疗方法，我们提出了一个R61/R33项目，以研究NSSI年轻女性的NAC生物学特征（GSH和/或GLU的变化）。 R61将着重于在短期NAC治疗期间确定最佳剂量以实现GSH和GLU的有意义变化。我们将在16-24岁的NSSI中随机将36名女性青少年和年轻人与口服NAC（每天3600mg或5400mg）或安慰剂进行4周的治疗。 GO/NOGO前进至R33的标准将是：如果发生以下任何一个，则“ GO”：（a）血液GSH氧化还原比增加≥50％；（b）脑GSH浓度增加5％；（c）脑GLU浓度降低5％。剂量和R33将根据生物学变化和R61中观察到的耐受性选择。 R33阶段将在为期8周的试验中使用新样本中的慢性剂量来复制生物学特征发现，并检查生物学特征，NAC PK和临床反应之间的关系。