Drug development of clavulanic acid, a GLT-1 activator: proof of concept for cocaine use disorder

GLT-1 激活剂克拉维酸的药物开发：可卡因使用障碍的概念证明

• 批准号: 10597589
• 负责人: Mary F. Morrison
• 金额: $ 138.83万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597589
• 关键词: Abstinence; Address; Adult; Amoxicillin-Potassium Clavulanate Combination; Animals; Anterior; Antibiotics; Area; Back; Behavior; Behavior Therapy; Biological Markers; Brain; Brain region; Cause of Death; Censuses; Cessation of life; Chronic; Clavulanic Acids; Clinical; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine use disorder; Corpus striatum structure; Cues; Data; Death Rate; Dedications; Development; Development Plans; Disease remission; Dose; Effectiveness; Extracellular Space; Formulation; Functional Magnetic Resonance Imaging; Glutamate Transporter; Glutamates; Goals; Half-Life; Human; Inpatients; Intellectual Property; Intravenous; Investigation; Magnetic Resonance Spectroscopy; Measures; Mediating; Methamphetamine; Modeling; Motivation; Mus; Neurotransmitters; Nucleus Accumbens; Oral; Outpatients; Overdose; Patient Self-Report; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Placebo Control; Placebos; Publishing; Randomized; Rattus; Reporting; Research; Rest; Rodent; Safety; Schedule; Serum; Site; Testing; Therapeutic Effect; Titrations; Toxic effect; Urine; addiction; alcohol preferring rats; benzoylecgonine; beta-Lactams; cingulate cortex; clinical development; cocaine craving; cocaine cue; cocaine exposure; cocaine seeking; cocaine self-administration; cocaine use; conditioned place preference; craving; drug development; efficacy study; extracellular; improved; meetings; novel therapeutics; overdose death; preclinical development; preclinical study; psychostimulant; response; safety study; therapeutic effectiveness; timeline; volunteer

Cocaine-related overdose deaths are rapidly rising in the U.S. An effective medication for cocaine addiction is urgently needed. This proposal aims to determine whether clavulanic acid (CLAV) is effective in treating cocaine use disorder. Animal studies suggest that activation of GLT-1, the dominant astroglial glutamate transporter responsible for clearing extracellular glutamate, may provide a breakthrough approach to managing cocaine addiction. Studies in rodents demonstrate that CLAV, a non-antibiotic component of the commonly used antibiotic Augmentin, has short-term effects to a) increase GLT-1 activity, thus reducing extracellular glutamate in brain areas associated with addiction, i.e., the nucleus accumbens (NAc) and its afferent limbic region, the anterior cingulate cortex (AC), and b) inhibit the reinforcing strength of cocaine in a model of cocaine self-administration. We have concluded an inpatient study, required by the FDA, showing that the co- administration of CLAV and cocaine to volunteer non-treatment-seeking adults with cocaine use disorder is associated with decreased cocaine craving and produces no serious toxicity. Using magnetic resonance spectroscopy (MRS) at 3T, we have human pilot data demonstrating changes in brain glutamate in the AC after the first dose of CLAV, and this is maintained for 10 days of daily CLAV dosing. We now propose two human trials to assess the therapeutic effectiveness of CLAV: 1) We will determine whether CLAV maintains its therapeutic effects to reduce cocaine craving when given orally once-a-day, since CLAV has a very short half-life in the serum. Glutamate levels in the AC, measured after cessation of CLAV dosing, will be used as a biomarker to assess whether CLAV can be dosed once daily. Resting state functional connectivity will determine whether the AC increases target engagement with the NAc, and whether network deficits associated with chronic cocaine use are improved by repeated CLAV. 2) In subjects who tolerate CLAV 500 mg/day, we will determine the effects, safety and tolerability of CLAV 750 mg/day. 3) Finally, we will conduct a randomized, placebo controlled multi-site, outpatient efficacy study of CLAV in cocaine-addicted patients seeking treatment, using a formulation for once-daily dosing as determined in 2). If efficacy is confirmed (Go- No Go decision point), the project will transition to our pharmaceutical company partner, VistaGen, who will be supporting formulation development, intellectual property and regulatory strategy, as well as clinical and preclinical development during this proposal. With VistaGen, we will schedule an FDA meeting to explore breakthrough therapy status and discuss development plans leading to a New Drug Application submission.

在美国，与可卡因过量相关的死亡人数正在迅速上升。治疗可卡因成瘾的有效药物是 急需。该提案旨在确定克拉维酸（CLAV）是否能有效治疗 可卡因使用障碍。动物研究表明，GLT-1（主要的星形胶质细胞谷氨酸）的激活 负责清除细胞外谷氨酸的转运蛋白可能提供突破性的管理方法 可卡因成瘾。对啮齿动物的研究表明，CLAV（一种常见抗生素成分） 使用抗生素 Augmentin，具有短期效果 a) 增加 GLT-1 活性，从而减少细胞外 与成瘾相关的大脑区域中的谷氨酸，即伏隔核（NAc）及其传入边缘 区域、前扣带皮层 (AC)，以及 b) 在模型中抑制可卡因的增强强度 可卡因自我给药。我们已经完成了 FDA 要求的一项住院研究，表明共同 向患有可卡因使用障碍的非寻求治疗的志愿者提供 CLAV 和可卡因 与减少可卡因渴望有关，并且不会产生严重的毒性。使用磁共振 3T 光谱 (MRS)，我们有人类试点数据，证明 AC 中大脑谷氨酸的变化 第一次注射 CLAV 后，每日 CLAV 给药维持 10 天。我们现在提出两个 评估 CLAV 治疗效果的人体试验： 1) 我们将确定 CLAV 是否​​维持 每天口服一次，其治疗效果可减少对可卡因的渴望，因为 CLAV 的作用时间很短 血清中的半衰期。停止 CLAV 给药后测量的 AC 中的谷氨酸水平将用作 评估 CLAV 是否​​可以每天给药一次的生物标志物。静息状态功能连接将 确定 AC 是否增加了与 NAc 的目标参与度，以及网络缺陷是否相关 长期使用可卡因的患者可通过重复 CLAV 得到改善。 2) 在耐受 CLAV 500 mg/天的受试者中，我们 将确定 CLAV 750 毫克/天的效果、安全性和耐受性。 3）最后，我们将进行 CLAV 对可卡因成瘾患者的随机、安慰剂对照、多中心、门诊疗效研究 寻求治疗，使用 2) 中确定的每日一次给药制剂。如果疗效得到确认（Go- 没有 Go 决策点），该项目将移交给我们的制药公司合作伙伴 VistaGen，他将 支持配方开发、知识产权和监管策略以及临床和 本提案期间的临床前开发。我们将与 VistaGen 一起安排一次 FDA 会议来探讨 突破性治疗状态并讨论导致新药申请提交的开发计划。