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正在迅速增加，可卡因成瘾的有效药物是 迫切需要。该提案旨在确定克拉夫拉酸（CLAV）是否有效治疗 可卡因使用障碍。动物研究表明，激活GLT-1，主要的星形胶质谷氨酸 负责清除细胞外谷氨酸的转运蛋白可能为管理提供突破性的方法 可卡因成瘾。对啮齿动物的研究表明，Clav是通常的非抗生素成分 使用的抗生素增强素具有短期影响a）增加GLT-1活性，从而减少细胞外 与成瘾有关的大脑区域的谷氨酸，即伏隔核（NAC）及其传入的边缘 区域，前扣带回皮层（AC）和b）在模型中抑制可卡因的增强强度 可卡因自我管理。我们已经得出了一项由FDA要求的住院研究，表明该研究是 给予CLAV和可卡因以自愿非治疗的可卡因使用障碍成年人是 与可卡因渴望降低有关，不会产生严重的毒性。使用磁共振 光谱法（MRS）在3T时，我们有人类的先导数据，证明了AC中脑谷氨酸的变化 在第一次剂量的CLAV之后，将其维持10天的每日CLAV剂量。我们现在建议两个 评估CLAV的治疗有效性的人体试验：1）我们将确定CLAV是否保持 每天口服一次可卡因渴望可卡因的治疗作用，因为Clav很短 血清中的半衰期。在停止CLAV剂量后测量的AC中的谷氨酸水平将用作A 生物标志物评估是否可以每天服用一次CLAV。静止状态功能连接将 确定AC是否会增加目标与NAC的参与以及网络缺陷是否相关 通过重复的CLAV改善了慢性可卡因的使用。 2）在耐受CLAV 500毫克/天的受试者中，我们 将确定CLAV 750 mg/天的效果，安全性和耐受性。 3）最后，我们将进行 可卡因成瘾患者的CLAV的随机，安慰剂控制的多站点，门诊疗效研究 寻求治疗，使用公式进行每日一次的配方，如2）。如果确认疗效（GO- 没有GO决策点），该项目将过渡到我们的制药公司合作伙伴Vistagen，他们将成为 支持制定制定，知识产权和监管策略以及临床和 在此提案中的临床前发展。与Vistagen一起，我们将安排一次FDA会议以探索 突破疗法状态并讨论开发计划，导致新药申请提交。