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。一种治疗可卡因成瘾的有效药物是