Medications Development for Cocaine: A Translational Approach in Monkey and Human

可卡因药物开发：猴子和人类的转化方法

基本信息

批准号：
8785110
负责人：
Joshua Anthony Lile
金额：
$ 57.03万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8785110
关键词：
Address Animals Behavior Catheters Clinical Clinical Research Clinical Trials Cocaine Cocaine Abuse Cocaine Dependence Dependence Development Dextroamphetamine Disease Dopamine Dopamine Agonists Dose Drug Use Disorder Drug usage Effectiveness Ensure Environment Evaluation Exclusion Food Future Goals Gold Health Human Intravenous Laboratories Laboratory Research Laboratory Study Link Macaca mulatta Maintenance Methods Modeling Monkeys Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Population Prevalence Prevention Procedures Process Public Health Recording of previous events Reinforcement Schedule Relative (related person)Research Rodent Route Safety Schedule Self Administration Standardization Testing Translational Research Treatment Protocols base clinically relevant cocaine use design innovation instrument non-drug nonhuman primate novel pre-clinical research reinforcer research study screening stimulant abuse translational approach uptake

项目摘要

DESCRIPTION (provided by applicant): Cocaine-use disorders continue to be a significant public health concern, yet no effective pharmacological treatments have been identified. This application is founded on the proposition that translational research on development of cocaine pharmacotherapies will benefit from the use of coordinated and homologous procedures in animals and humans to study effects of Candidate medications on choice between cocaine and a non-drug reinforcer. Self-administration procedures will be used in this project because the reinforcing effects of drugs are central to their abuse and the development of dependence. An alternative reinforcer to cocaine will be offered because the choice to use cocaine to the exclusion of other behaviors is a hallmark of dependence, and an effective medication should assist patients in reducing drug use and reallocating behavior from drug use to more responsible and productive activities. Advantages of including preclinical research in the medications development process include strict control over environment and subject history, and testing novel compounds and/or extensive dose ranges not feasible in humans. Rhesus monkeys were selected as the animal subjects because they are phylogenetically more closely related to humans than rodents, and can be instrumented with chronically indwelling IV catheters, which facilitates implementation of drug vs. food choice procedures. Human laboratory research permits the testing of putative pharmacotherapy effects on challenges with the abused drug in a clinically relevant subject population. Another advantage of pairing rhesus monkey and human laboratory models is that powerful within-subjects designs can be used with both species. Despite the relative strengths of human and non-human primate approaches, translational research has been hampered by the use of widely different self-administration procedures and medication treatment regimens. The proposed project seeks to harmonize rhesus monkey and human procedures used to screen medications by first establishing parallel self-administration methods that will employ the same cocaine doses, route of cocaine administration and schedule of reinforcement, as well as a species-specific alternative reinforcer that effectively reduces drug taking. Cocaine doses, schedule parameters and alternative reinforcer magnitude will then be adjusted to obtain equivalent functional effects prior to d-amphetamine maintenance testing. The use of d-amphetamine will permit equilibration of cross-species sensitivity and provide a comparator for effects of other, non-dopaminergic Candidate medications examined in future studies. Achieving the aims of this project will exert a sustained and powerful impact by establishing a research platform for cocaine medication screening that will tightly link animal and human approaches thereby accelerating translational research on medications development. The proposed project is highly innovative in that it will develop coordinated and homologous procedures in nonhuman primates and humans using sophisticated cocaine choice procedures aimed towards medications development for cocaine-use disorders.

描述（由申请人提供）：可卡因使用疾病仍然是一个重大的公共卫生问题，但尚未确定有效的药理治疗。该应用是基于以下主张：可卡因药物疗法发展的转化研究将受益于在动物和人类中使用协调和同源程序来研究可卡因和非药水增强剂之间选择的影响。该项目将使用自我管理程序，因为药物的加强作用对于它们的滥用和依赖的发展至关重要。将提供可卡因的替代增强剂，因为选择可卡因排除其他行为是依赖的标志，有效的药物应帮助患者减少药物使用并从吸毒中重新定位行为从吸毒中实现对负责任和有生产力的活动。在药物开发过程中包括临床前研究的优点包括对环境和主题历史的严格控制，并测试新的化合物和/或在人类中不可行的剂量范围。选择恒河猴作为动物受试者，因为它们在系统发育上与人类的关系比啮齿动物更紧密，并且可以用长期留置的静脉注射导管来仪器，这有助于实施药物与食物选择程序。人类实验室研究允许测试假定的药物治疗对临床相关受试者滥用药物的挑战的影响。配对恒河猴和人类实验室模型的另一个优点是，这两种物种都可以使用强大的受试者内部设计。尽管人类和非人类灵长类动物的方法相对优势，但使用广泛不同的自我给药程序和药物治疗方案的使用仍受到了翻译研究的阻碍。拟议的项目旨在通过首先建立将采用相同的可卡因剂量，可卡因给药和增强时间表以及物种特异性的替代增强剂来统一用于筛查药物的恒河猴和人类程序，从而有效地减少了药物服用。然后，将调整可卡因剂量，时间表参数和替代增强量级，以在D-苯丙胺维持测试之前获得等效的功能效应。 D-苯丙胺的使用将允许平衡跨物种敏感性，并为未来研究中研究的其他非多巴胺能候选药物的影响提供了比较。实现该项目的目标将通过建立可卡因药物筛查的研究平台，从而产生持续和强大的影响，该平台将紧密联系动物和人类方法，从而加速有关药物开发的转化研究。拟议的项目具有很高的创新性，因为它将使用旨在用于可卡因使用疾病的药物开发的精致可卡因选择程序，在非人类灵长类动物和人类中开发协调和同源的程序。