Medication Development for the Treatment of Alcohol Use Disorder

项目总结 我们的申请是对RFA-AA-20-007[治疗酒精使用的药物开发》的响应 无序(澳元)]。初步证据支持过度饮酒的神经免疫假说 美国将在奖励和依赖模型中测试四环素。在饮酒和急性酒精中毒方面有所减少 我们利用结构-功能数据设计了新的化学修饰的米诺环素(CMM)化合物 对于失去抗生素特性，但保留已知的先天免疫作用。与NIAAA合作 在药物开发部，我们已经创建并测试了16个CMM类似物，用于潜在的治疗 澳元。一些研究表明，米诺环素的抗菌作用有所减弱，而米诺环素的效果有所改善。 在高酒精消耗量动物模型中饮酒。在口服给药测试之后，我们现在有 确定了先导化合物(最佳选择)和后备化合物，正在完成临床前工作 药理学和毒物学筛查。美国近1500万人和全球约1亿人遭受 来自澳元。超过5%的医学疾病都有与酒精相关的风险。尽管有三个FDA 被批准用于治疗AUD的药物，以及其他几种在标签外使用的药物，仅显示出适度的药物 成功(约20%的患者接受治疗)。因此，迫切需要新的药物疗法。 跨越DSM-V AUD频谱。事实上，在这两种奖励中，减少高酒精摄入量的改进药物- 或者，寻求救济的患者将是最受欢迎的。目前，加巴喷丁在标签外使用；它减少了 酒精消费和依赖相关症状，但其适度的有效性和显著的副作用- 效果留下了相当大的改善机会。按照FDA的要求，我们的坐标测量机的初步数据 显示两种哺乳动物的酒精消耗量显著减少。我们的专利覆盖了 用于治疗神经炎症性疾病的100种四环素改良剂，包括AUD。德克萨斯理工大学 系统拥有专利权。他们已经被授权给South Plains Biotech，Inc.，AUD分公司， 有限责任公司，部分归与该项目相关的研究人员所有。因此，这项运动的成功 以下目标代表着朝着潜在商业化迈出的积极一步。我们将实现四个目标 目标1：制定制造标准；目标2：完成临床前IND 研究；目标3：I期临床试验；单次递增剂量；目标4：I期临床试验；多次递增 剂量。未来的第二阶段计划包括在寻求奖励和缓解的AUD患者中进行测试，首先是一项小型试验 我们的临床研究所，然后与NIAAA临床研究小组合作。影响： 开发一种不具有成瘾潜力的药物，成功治疗奖励和缓解驱动的药物 澳元是迫切需要的。我们的NIAAA合作、TTUHSC团队、科学顾问(Adron Harris博士和 鲍勃·梅辛)和FastTrack(FDA咨询公司)代表着完成拟议工作的独特专业知识。

PROJECT SUMMARY Our application is in response to RFA-AA-20-007 [Medications Development for the Treatment of Alcohol Use Disorder (AUD)]. Initial evidence supporting a neuroimmune hypothesis for excessive alcohol consumption led us to test tetracyclines in reward- and dependence-models. Having shown reductions in drinking and acute withdrawal, we used structure-functional data to design new chemically modified minocycline (CMM) compounds for loss of antibiotic properties, but retention of known innate immune action. In collaboration with the NIAAA Division of Medications Development, we have created and tested 16 CMM analogs for potential treatment of AUD. Several have shown both a loss of antimicrobial action and improvement over minocycline to reduce drinking in animal models of high alcohol consumption. Following oral administration tests, we have now identified a lead (best choice) and a backup compound and are in the process of completing preclinical pharmacology and toxicology screens. Nearly 15 million people in the US and ~100 million worldwide suffer from AUD. Over 5% of all medical morbidities share an ethanol-related risk. Although there are three FDA approved drugs to treat AUD, and several others are used off-label, medications have shown only modest success (in ~20% of patients treated). As a consequence, there is an urgent need for new pharmacotherapeutics across the DSM-V AUD spectrum. In fact, improved drugs that reduce high alcohol consumption in either reward- or relief-seeking patients would be most desirable. Currently, gabapentin is used off label as such; it reduces alcohol consumption and dependence-related symptoms, but its modest effectiveness and significant side- effects leave opportunity for considerable improvement. As required by the FDA, preliminary data for our CMMs show a significant reduction of alcohol consumption in two mammalian species. We have patents covering over 100 tetracycline modifications for use in neuroinflammatory diseases, including AUD. Texas Tech University System holds the patent rights. They have been licensed to South Plains Biotechnology, Inc., AUD subdivision, LLC, which is owned, in part, by researchers associated with this project. As a consequence, the success of the below aims represent a positive step toward potential commercialization. We will complete four aims addressing: Aim 1: Development of manufacturing standards; Aim 2: Completion of pre-clinical IND enabling studies; Aim 3: Phase I clinical trial; single-ascending dose; Aim 4: Phase I clinical trial; multiple-ascending dose. Future Phase II plans include testing in reward- and relief-seeking AUD patients, first in a small trial with our Clinical Research Institute and then in cooperation with the NIAAA Clinical Investigations Group. Impact: The development of a drug without addiction potential that successfully treats reward- and relief-driven AUD is critically needed. Our NIAAA collaboration, TTUHSC team, scientific advisers (Drs. Adron Harris and Bob Messing) and FastTrack (FDA consulting firm) represent unique expertise to complete the proposed work.