Development of Ibudilast as a Novel Treatment for Alcoholism

描述（由申请人提供）：酒精依赖（AD）是一种慢性和复发性疾病，影响1000万美国人。迄今为止，只有四种药物疗法被FDA批准用于治疗酒精中毒，其疗效不高。因此，AD的药物开发是一个高度优先的领域。异丁司特（IBUD）是神经胶质细胞调节剂， 抑制磷酸二酯酶（PDE）-4和-10和巨噬细胞移动抑制因子（MIF）。临床前数据表明，神经免疫调节对滥用药物（包括酒精）的奖励特性至关重要。此外，已显示IBUD在体内增强GDNF释放，并且GDNF调节已涉及动物中的酒精恢复，而PDE抑制已显示减少小鼠中的酒精摄入。总之，这些发现表明，神经免疫调节构成了治疗酒精中毒的新靶点。本开发/探索性（R21）申请的目的是通过开展IBUD治疗AD的初始II期研究来推进酒精中毒药物的开发。与我们正在进行的研究计划一致，提出了人类实验室模型，以获得初步疗效数据，并转化有希望的临床前研究结果。具体而言，所提出的研究由随机、双盲、安慰剂对照的受试者内交叉设计组成，以确定IBUD在24名受试者中的安全性、耐受性和初始人体实验室功效。 接受IBUD（50 mg BID）和安慰剂治疗的酒精滥用或依赖的非寻求治疗的个体。受试者将在UCLA CTRC完成两个独立的7天住院治疗，在此期间，他们将服用研究药物，完成IV酒精挑战，并参加压力暴露和线索暴露范例。具体目的是测试IBUD（a）在酒精施用的情况下是否安全，（B）是否减弱酒精诱导的强化，以及（c）是否抑制压力诱导和线索诱导的酒精渴望。总之，本研究将有效评价IBUD的安全性和初始疗效，从而筛选治疗AD的新型药物，并阐明IBUD可能临床有效的潜在机制。这项研究的结果将为随后的R 01申请提供信息，以进行IBUD治疗酒精中毒的随机对照试验。

DESCRIPTION (provided by applicant): Alcohol dependence (AD) is a chronic and relapsing condition affecting 10 million Americans. To date, only four pharmacotherapies are approved by the FDA for the treatment of alcoholism and their efficacy is modest. Therefore, medication development for AD represents a high priority area. Ibudilast (IBUD) is a glial cell modulator that inhibits phosphodiesterases (PDE) -4 and -10 and macrophage migration inhibitory factor (MIF). Preclinical data suggest that neuroimmune modulation is critical to the rewarding properties of drugs of abuse, including alcohol. Further, IBUD has been shown to enhance GDNF release in vivo and GDNF modulation has been implicated in alcohol reinstatement in animals, while PDE inhibition has been shown to reduce alcohol intake in mice. Together, these findings suggest that neuroimmune modulation constitutes a novel target for the treatment of alcoholism. The objective of this Developmental/Exploratory (R21) application is to advance medication development for alcoholism by conducting an initial Phase II study of IBUD for AD. Consistent with our ongoing program of research, human laboratory models are proposed to obtain initial efficacy data and to translate promising preclinical findings. Specifically, the proposed study consists of a randomized, double- blind, placebo-controlled within-subject crossover design to determine the safety, tolerability, and initial human laboratory efficacy of IBUD in a sample of 24 non-treatment seeking individuals with either alcohol abuse or dependence treated with IBUD (50mg BID) and placebo. Participants will complete two separate 7-day inpatient stays at the UCLA CTRC during which they will take the study medication, complete an IV alcohol challenge, and take part in a stress-exposure and cue-exposure paradigms. Specific aims are to test whether IBUD (a) is safe in the context of alcohol administration, (b) attenuates alcohol-induced reinforcement, and (c) dampens stress-induced and cue-induced alcohol craving. In sum, this study will efficiently evaluate safety and initial efficacy of IBUD thereby screening novel medications for AD and elucidating potential mechanisms by which IBUD may be clinically efficacious. Results from this study will inform a subsequent R01 application to conduct a randomized controlled trial of IBUD for alcoholism.