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，与可卡因有关的过量死亡人数正在迅速上升。治疗可卡因成瘾的有效药物是 急需之物。这项建议旨在确定克拉维酸(CLAV)是否有效 可卡因使用障碍。动物研究表明，主要的星形胶质谷氨酸GLT-1的激活 负责清除胞外谷氨酸的转运体，可能提供一种突破性的管理方法 可卡因成瘾。在啮齿动物身上的研究表明，爪状病毒，一种常见的 使用抗生素Augentin，有短期效果：a)增加GLT-1活性，从而减少细胞外 与成瘾有关的脑区，即伏隔核(NAC)及其传入边缘的谷氨酸 前扣带回皮质(AC)和b)抑制可卡因的增强强度。 可卡因自我管理。根据FDA的要求，我们已经完成了一项住院研究，结果显示， 对患有可卡因使用障碍的未寻求治疗的成年人自愿给予CLAV和可卡因的管理是 减少对可卡因的渴求，不会产生严重的毒性。使用磁共振 波谱(MRS)在3T，我们有人类飞行员的数据显示AC中大脑谷氨酸的变化 在第一剂CLAV之后，这将维持10天的每日CLAV剂量。我们现在提出两个建议 评估CLAV治疗效果的人体试验：1)我们将确定CLAV是否维持 它的治疗作用是减少对可卡因的渴求，每天口服一次，因为CLAV的有效期很短 血清中的半衰期。停止给药后，AC中的谷氨酸水平将被用作 生物标志物，以评估CLAV是否可以每天给药一次。休眠状态功能连接将 确定AC是否增加了与NAC的目标接洽，以及网络缺陷是否相关 对于长期使用可卡因的患者，通过反复使用CLAV可以改善病情。2)在每天耐受CLAV500毫克的受试者中，我们 将决定CLAV750毫克/天的疗效、安全性和耐受性。3)最后，我们将进行一次 CLAV治疗可卡因成瘾患者的随机、安慰剂对照、多点门诊疗效研究 寻求治疗，使用2)中确定的每日一次剂量的配方。如果疗效得到确认(Go- 没有进入决策点)，该项目将过渡到我们的制药公司合作伙伴VistaGen，他将 支持配方开发、知识产权和监管战略，以及临床和 在这项提议期间的临床前发展。有了VistaGen，我们将安排一次FDA会议来探索 突破性的治疗现状，并讨论导致新药申请提交的发展计划。