Chemically modified minocycline for treatment of alcohol use disorder

用于治疗酒精使用障碍的化学修饰米诺环素

• 批准号: 9789788
• 负责人: BRITTANY Leilani BACKUS
• 金额: $ 79.88万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789788
• 关键词: Acute; Address; Administrator; Advisory Committees; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Antibiotic Resistance; Antibiotics; Behavior; Biological; Blood alcohol level measurement; Chemicals; Chronic; Classification; Clinic; Clinical; Clinical Research; Clinical Treatment; Collaborations; Comorbidity; Complex; DSM-V; Dangerousness; Data; Data Collection; Dependence; Detection; Development; Disease; Disease model; Doctor of Philosophy; Drug Kinetics; Drug Targeting; Drug usage; Ethanol; Evaluation; Excision; Excretory function; FDA approved; Family suidae; Food and Drug Administration Drug Approval; Future; Goals; Histology; Hormones; Human; Immune response; Innate Immune System; Intoxication; Investigational Drugs; Mediating; Medical; Medical emergency; Metabolism; Minocycline; Modeling; Morbidity - disease rate; Mus; National Institute on Alcohol Abuse and Alcoholism; Outcome; Pain; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Physical Dependence; Physicians; Physiological; Population; Process; Property; Relapse; Reproduction; Research; Research Institute; Resources; Scientist; Sus scrofa; Symptoms; Testing; Tetracyclines; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Transplantation; Treatment Efficacy; United States National Institutes of Health; Veterinarians; Withdrawal; Withdrawal Symptom; Work; absorption; addiction; alcohol abuse therapy; alcohol use disorder; analog; antimicrobial; base; carcinogenicity; clinical investigation; clinically relevant; cost; drinking; experience; genotoxicity; high risk drinking; immunotoxicity; improved; mortality risk; novel; pre-clinical; preference; public health relevance; response; side effect; therapy development

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.

项目概要： 我们的申请是对RFA-AA-18-009酒精使用治疗药物开发的回应 Disorder.只有三种药物治疗酒精使用障碍（AUD）是FDA批准的， 没有一种药物被广泛使用（<10%的AUD患者），也没有一种药物显示出降低风险或依赖性的强烈效果 长期饮酒（<20%见持续减少饮酒结果）。不幸的是，大约10% 的人口患有AUD，超过5%的所有医学疾病都有风险的乙醇消费， 一个潜在的问题因此，一般来说，醉酒和“酒精成瘾”（严重AUD）， 尤其是重要的临床问题。鉴于有限的药物选择，有一个令人信服的 需要继续开发AUD谱（轻度至重度DSM-V）的新治疗方法 分类）。事实上，针对高酒精消费和戒断相关的改善治疗 症状是理想的，因为突然戒断可能是具有死亡风险的医疗紧急情况。到目前为止， 针对饮酒的药物不能防止戒断，用于减少戒断症状的药物 经常和酒精一起上瘾。我们最近发现四环素类似物在临床前有效， 减少大量饮酒、戒断症状和酒精介导的疼痛敏感性， 令人兴奋的初步数据显示了改进的化学修饰的米诺环素（CMM）的功效。在 与NIAAA药物开发部门合作，我们建议准备我们的CMM类似物， FDA的IND批准。由Adron Harris博士组成的外部咨询委员会提供额外监督 罗伯特·梅辛我们的初步数据表明，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作为IND， 适当的猪AUD模型：1）C57 BL/6 J小鼠“狂欢”（急性）和“依赖”（慢性）模型， 重要的是达到了与血液酒精含量相关的水平，2）我们新的自愿，高酒精 偏好，猪（猪）模型。目的1：完成中药复方制剂的详细药代动力学评价 吸收、分布、代谢和排泄（ADME）。目的2：确定潜在的急性和慢性 CMM的毒性作用，包括致癌性、遗传毒性、免疫毒性、组织损伤和对 生殖将使用药物化学方法解决负面影响，并进行以下变更： 必要目前，我们还有其他六种CMM类似物可以作为替代品。未来一期 计划包括在AUD患者中进行测试，首先是在我们的TTUHSC临床研究所进行的小型试验中， 与NIAAA临床研究小组（NCIG）合作。影响：开发一种药物， 靶向AUD症状的几个重要方面的成瘾潜力与目前的药物相比具有关键优势。 治疗