Medication Development Center for Cocaine Use Disorder

可卡因使用障碍药物开发中心

• 批准号: 9113546
• 负责人: FREDERICK Gerard MOELLER
• 金额: $ 26.82万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9113546
• 关键词: Abstinence; Adverse effects; Agonist; Brain; Clinical; Clinical Data; Clinical Trials; Cocaine; Combination Drug Therapy; Consultations; Cues; Data; Development; Disease; Dose; Drug Industry; Drug Interactions; FDA approved; Genetic; Goals; HTR2A gene; Human; National Institute of Drug Abuse; Obesity; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiological; Research; Research Support; Rodent; Safety; Self Administration; Serotonin; Serotonin Receptor 5-HT2C; Therapeutic; Translational Research; base; cocaine use; cue reactivity; disorder later incidence prevention; dosage; drug mechanism; industry partner; neuroimaging; nonhuman primate; novel; pre-clinical; preclinical study; programs; receptor; response; tool

Research Theme: This U54 Center will use translational research from brain to bedside as a tool for medication development in cocaine use disorder (CocUD). Preclinical and early phase I clinical PK/PD data will provide information for go/no-go decisions on phase 11-111 clinical trials for medications that have some promise for CocUD based on drug mechanisms and early preclinical data. The overall goal of this application is to create a center that can provide important preclinical and eariy phase 1 clinical data to NIDA and pharmaceutical industry partners on novel compounds for cocaine use disorder The lack of thorough characterization of compounds prior to large-scale clinical trials is least part of the reason for the large number of negative clinical trials for CocUD (Vocci and Elkashef, 2005). The initial compounds proposed for study in the center were chosen based on 1) preclinical and genetic data from our group and others supporting these classes of medications, and 2) the fact that these compounds are either available for human use currently [the selective serotonin 5-HT2C receptor (5-HT2cR) agonist lorcaserin] or are close to FDA approval [the selective serotonin 5-HT2A receptor (5-HT2AR) antagonist pimavanserin]. Lorcaserin and other 5-HT2cR agonists have been shown to reduce cocaine self-administration and cue reactivity in rodents (Project 3 Preliminary Data and (Anastasio et al, 2014a; Anastasio et al, 2014b; Cunningham et al, 2011; Manvich etal, 2012)). In addition there is human safety data in non-cocaine using subjects for lorcaserin as it is currently FDA approved for obesity, and there is safety data from a rodent cocaine interaction study (included in detail in Appendix), but there is no human cocaine interaction/PK data and no PD data to support potential dosages for phase II clinical trials. Likewise, there is evidence to support research on pimavanserin as a potential treatment for CocUD; other 5-HT2AR antagonists have been shown by our group and others to alter cocaine cue induced reinstatement in rodents (Nic Dhonnchadha etal, 2009; Pockros et al, 2011) and non-human primates (Murnane et al, 2013), but there is no specific data on pimavanserin. Finally, our group has shown that combining these two classes of compounds produces a synergistic effect on cocaine self-administration and cue reactivity (Cunningham et al, 2013) suggesting that combining these medications could produce a greater response with lower potential side effects than using either compound alone. Preclinical studies will be carried out to examine this potential combination pharmacotherapy treatment.

研究主题：这个U54中心将使用从大脑到床边的翻译研究作为工具 可卡因使用障碍（Cocud）的药物发展。临床前和早期I期临床PK/PD数据将 提供有关有希望的药物的第11-111阶段临床试验的GO/NO-GO决定的信息 用于基于药物机制和早期临床前数据的coud。 该应用程序的总体目标是创建一个可以提供重要的临床前和eariy的中心 第1阶段的NIDA和制药行业合作伙伴的临床数据可卡因使用新颖化合物 疾病在大规模临床试验之前缺乏化合物的透彻表征是至少的一部分 Cocud进行大量阴性临床试验的原因（Vocci和Elkashef，2005）。 根据1）临床前和遗传选择了在中心研究的初始化合物 来自我们小组和其他支持这些类药物的数据，以及2）这些化合物的事实 当前可用于人类使用[选择性5-羟色胺5-HT2C受体（5-HT2CR）激动剂 Lorcaserin]或接近FDA批准[选择性5-羟色胺5-HT2A受体（5-HT2AR）拮抗剂 pimavanserin]。已证明Lorcaserin和其他5-HT2CR激动剂可减少可卡因自我管理 和啮齿动物的提示反应性（项目3初步数据和（Anastasio等，2014a； Anastasio等人，2014b； Cunningham等人，2011年； Manvich等，2012））。另外，使用非卡卡的人类安全数据使用 Lorcaserin的受试者目前已获得FDA批准的肥胖症，并且有来自啮齿动物的安全数据 可卡因相互作用研究（附录中详细包含），但没有人类可卡因互动/PK数据 并且没有PD数据来支持II期临床试验的潜在剂量。同样，也有证据支持 关于pimavanserin的研究，作为cocud的潜在治疗方法；其他5-HT2AR拮抗剂已显示 我们的小组和其他人改变可卡因提示会诱导啮齿动物的恢复原状（Nic Dhonnchadha etal，2009年； Pockros等人，2011年）和非人类灵长类动物（Murnane等，2013），但没有关于 皮马万塞林。最后，我们的小组表明，将这两类化合物结合起来会产生一个 对可卡因自我给药和提示反应性的协同作用（Cunningham等，2013）表明 将这些药物结合起来可能产生更大的反应和潜在副作用，而不是使用 要么单独化合物。将进行临床前研究以检查这种潜在的组合 药物治疗。