Development of Ibudilast as a Novel Treatment for Alcoholism

描述(申请人提供)：酒精依赖(AD)是一种慢性和复发性疾病，影响着1000万美国人。到目前为止，只有四种药物疗法被FDA批准用于治疗酒精中毒，而且它们的疗效不大。因此，AD的药物开发是一个高度优先的领域。异丁司特(IBUD)是一种神经胶质细胞调节剂， 抑制磷酸二酯酶(PDE)-4和-10以及巨噬细胞移动抑制因子(MIF)。临床前数据表明，神经免疫调节对于包括酒精在内的滥用药物的回报特性至关重要。此外，IBUD已被证明可促进体内GDNF的释放，GDNF的调节与动物的酒精恢复有关，而PDE的抑制已被证明可减少小鼠的酒精摄入量。综上所述，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。这一开发/探索性(R21)应用的目标是通过开展治疗AD的IBUD的初始阶段II研究来促进酒精中毒的药物开发。与我们正在进行的研究计划一致，人体实验室模型被提出以获得初步疗效数据并转化有希望的临床前发现。具体地说，这项拟议的研究包括随机、双盲、安慰剂对照的受试者内交叉设计，以确定IBUD的安全性、耐受性和最初的人类实验室疗效，样本为24人。 未寻求治疗的酗酒或依赖患者接受IBUD(50 Mg Bid)和安慰剂治疗。参与者将在加州大学洛杉矶分校CTRC分别完成两次为期7天的住院治疗，在此期间，他们将服用研究药物，完成静脉酒精挑战，并参加压力暴露和线索暴露范例。具体目的是测试IBUD(A)在饮酒的情况下是否安全，(B)减弱酒精诱导的强化，以及(C)抑制应激诱导的和暗示诱导的酒精渴望。总之，这项研究将有效地评估IBUD的安全性和初步疗效，从而筛选治疗AD的新药，并阐明IBUD临床有效的潜在机制。这项研究的结果将为随后的R01申请提供依据，以进行酒精中毒IBUD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.