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

在美国，与可卡因有关的过量死亡人数正在迅速上升。 迫切需要。该提案旨在确定克拉维酸（CLAV）是否有效治疗 可卡因使用障碍动物研究表明，GLT-1的激活，主要的星形胶质细胞谷氨酸 负责清除细胞外谷氨酸的转运蛋白，可能提供一种突破性的方法来管理 可卡因成瘾在啮齿动物中的研究表明，CLAV，一种常见的非抗生素成分， 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盐，即，中脑核及其传入边缘系统 区域，前扣带皮层（AC），和B）抑制可卡因的加强强度在一个模型中， 可卡因自我管理我们已经完成了一项FDA要求的住院患者研究，表明共同- 向患有可卡因使用障碍的非寻求治疗的志愿成年人注射CLAV和可卡因， 与减少可卡因的渴望有关，不会产生严重的毒性。使用磁共振 在3 T的磁共振波谱（MRS）中，我们有人类飞行员数据表明AC中脑谷氨酸的变化 第一剂CLAV后，并维持10天的每日CLAV给药。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 它的治疗效果，以减少可卡因渴望时，口服一天一次，因为CLAV有一个非常短的 在血清中的半衰期在停止CLAV给药后测量的AC中的谷氨酸水平将用作 生物标志物，以评估CLAV是否可以每天给药一次。静息状态功能连接将 确定AC是否增加了与NAc的目标接合，以及与AC相关联的网络缺陷是否 慢性可卡因使用者通过重复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 mg/天的效果、安全性和耐受性。3)最后，我们将进行一次 可卡因成瘾患者中CLAV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。如果确认有效（Go- 没有决定点），该项目将移交给我们的制药公司合作伙伴VistaGen， 支持制剂开发、知识产权和监管策略，以及临床和 临床前开发在此期间的建议。与VistaGen一起，我们将安排一次FDA会议， 突破性治疗状态，并讨论开发计划，以提交新药申请。

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.