Chemically modified minocycline for treatment of alcohol use disorder

项目总结： 我们的申请是为了响应RFA-AA-18-009治疗酒精使用的药物开发 无序。FDA只批准了三种酒精使用障碍(AUD)的药物治疗方法 没有一种药物被广泛使用(10%的AUD患者)，也没有一种药物对减少风险或依赖有很强的效果 长期饮酒(20%的人认为饮酒结果持续下降)。不幸的是，大约10% 超过5%的人患有AUD，超过5%的人患有高风险的酒精消费 一个根本的问题。因此，一般来说，醉酒和酒精成瘾(严重的AUD) 尤其是，是重要的临床问题。考虑到有限的药物治疗选择，有一个令人信服的 需要在AUD范围内继续开发新的治疗方法(轻度到重度DSM-V 分类)。事实上，针对高酒精摄入量和戒断相关的改进治疗 症状是可取的，因为急促戒断可能是一种有死亡风险的紧急医疗事件。到目前为止， 针对饮酒的药物不能防止戒断，用于减轻戒断症状的药物是 经常与酒精共同上瘾。我们最近发现四环素类似物在临床前对 减少高饮酒、戒断症状和酒精介导的疼痛敏感化，现在有 激动人心的初步数据显示了一种改进的化学修饰的米诺环素(CMM)的有效性。在……里面 与NIAAA药物开发部合作，我们建议为以下项目准备我们的CMM类似物 FDA批准的IND。其他监督由Adron Harris博士的外部咨询委员会提供 还有罗伯特·梅辛。我们的初步数据显示，两种哺乳动物的酒精消耗量减少 物种。我们将完成两个目标，即FDA批准我们的CMM为IND，使用小鼠和 猪AUD模型：1)C57BL/6J小鼠“暴饮暴食”(急性)和“依赖”(慢性)模型， 重要的是达到与药物相关的血液酒精水平，以及2)我们新的自愿、高酒精 偏好，猪(猪)模型。目的1：完成中药对药物的详细药代动力学评价 吸收、分布、代谢和排泄(ADME)。目标2：确定潜在的急性和慢性 中草药的毒性作用，包括致癌性、遗传毒性、免疫毒性、组织损伤和对 繁殖。负面影响将使用药物化学方法来解决，所做的更改如下 这是必要的。目前，我们还有另外六个CMM类似物，可以作为替代品。未来阶段I 计划包括对AUD患者进行测试，首先是与我们的TTUHSC临床研究所进行的一项小规模试验，然后是 与NIAAA临床研究小组(NCIG)合作。影响：一种药物的开发没有 针对AUD症状的几个重要方面的成瘾潜在性比目前具有关键优势 治疗。

PROJECT SUMMARY: Our application is in response to RFA-AA-18-009 Medications Development for the Treatment of Alcohol Use Disorder. Only three pharmacotherapeutic treatments for Alcohol Use Disorder (AUD) are FDA approved and none are widely used (<10% of AUD patients) or show a strong effect to reduce risky- or dependence-based drinking in the long-term (<20% see sustained decreased drinking outcomes). Unfortunately, approximately 10% of the population suffers from AUD and over 5% of all medical morbidities share risky ethanol consumption as an underlying issue. As a consequence, intoxication, in general, and ‘alcohol addiction’ (severe AUD), in particular, are important clinical problems. Given the limited pharmacotherapeutic choice, there is a compelling need for continued development of new treatments across the AUD spectrum (mild to severe DSM-V classification). In fact, improved treatments targeting high alcohol consumption and withdrawal-related symptoms are desirable as precipitating withdrawal can be a medical emergency with risk for death. To date, drugs targeting drinking do not protect against withdrawal, and drugs used to reduce withdrawal symptoms are often co-addictive with alcohol. We recently showed that tetracycline analogs were preclinically efficacious to reduce high alcohol consumption, withdrawal symptoms and alcohol-mediated pain sensitization and now have exciting preliminary data showing efficacy for an improved chemically modified minocycline (CMM). In collaboration with the NIAAA Division of Medications Development, we propose to prepare our CMM analog for IND approval by the FDA. Additional oversight is provided by an external advisory committee of Drs. Adron Harris and Robert Messing. Our preliminary data illustrated a reduction of alcohol consumption in two mammalian species. We will complete two aims addressing approval of our CMM as an IND by the FDA using murine and porcine AUD models as appropriate: 1) C57BL/6J mouse ‘binge’ (acute) and ‘dependence’ (chronic) models, which importantly reach pharmacologically relevant blood alcohol levels, and 2) our new voluntary, high alcohol preference, porcine (pig) model. AIM 1: to complete detailed pharmacokinetic evaluation of CMM for drug absorption, distribution, metabolism and excretion (ADME). AIM 2: to determine potential acute and chronic toxic effects of CMM, including carcinogenicity, genotoxicity, immunotoxicity, tissue damage and effects on reproduction. Negative effects will be addressed using a medicinal chemistry approach with changes made as necessary. At this time, we have six other CMM analogs, which can be used as substitutes. Future Phase I plans include testing in AUD patients, first in a small trial with our TTUHSC Clinical Research Institute and then in cooperation with the NIAAA Clinical Investigations Group (NCIG). Impact: The development of a drug without addiction potential that targets several important aspects of AUD symptoms has critical advantages over current therapies.