Repurposing drugs in mixtures to treat drug abuse

重新利用混合物中的药物来治疗药物滥用

• 批准号: 9920702
• 负责人: Gregory Thomas Collins
• 金额: $ 36.17万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920702
• 关键词: Abstinence; Acute; Agonist; Animals; Anxiety; Attention; Attenuated; Behavior; Biological; Buspirone; Cardiovascular system; Choice Behavior; Clinic; Clinical; Cocaine; Cocaine Abuse; Combined Modality Therapy; Cues; Data; Dopamine; Dose; Double-Blind Method; Drug Modelings; Drug Targeting; Drug abuse; Effectiveness; Electrocardiogram; FDA approved; Female; Food; Future; Heart Rate; Human; Knowledge; Macaca mulatta; Medical; Monkeys; Neurobiology; Neurons; Obesity; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase II Clinical Trials; Pilot Projects; Placebos; Procedures; Public Health; Randomized; Reinforcement Schedule; Relapse; Research; Role; Self Administration; Serotonin; Serotonin Receptor 5-HT2C; Signal Transduction; Synapses; Testing; Therapeutic Effect; Time; Toxic effect; Translating; addiction; base; cost; dopamine D3 receptor; economic impact; improved; male; neurotransmission; non-drug; novel; novel strategies; pre-clinical; pressure; receptor; sex; smoking cessation; stimulant abuse; therapeutic effectiveness; transmission process

SUMMARY/ABSTRACT Stimulant abuse is a serious public health problem with untold medical, societal, and economic impact worldwide. Despite decades of research into the neurobiology of drug abuse, there are no FDA-approved pharmacotherapies for stimulant abuse. One strategy to reduce the time required to get candidate medications into the clinic is to repurpose drugs, already approved by the FDA for other indications, to treat stimulant abuse, and one strategy to improve the therapeutic effectiveness of a drug is to administer it in combination with second drug with a complimentary mechanism of action. We and others have shown that drugs that block the effects of DA (buspirone [Buspar®]; a DA D2-like [D2, D3, & D4] receptor antagonist, FDA-approved for treating anxiety) or modulate DA transmission (lorcaserin [Belviq®]; a serotonin [5-HT]2C receptor agonist, FDA-approved for treating obesity) attenuate the reinforcing and/or relapse-related effects of stimulants such as cocaine in animals. Based on very promising pilot studies in male and female rhesus monkeys, we hypothesize that a combination therapy comprising fixed-doses of drugs that target both pre- (lorcaserin) and post- (buspirone) synaptic regulators of DA neurotransmission will have a therapeutic effect (e.g., decrease in drug-taking) that is greater than the effect of either drug alone (i.e., supra-additive interaction). Our preliminary data support this hypothesis and suggest that combining buspirone with lorcaserin will yield a highly translatable and novel approach to treat stimulant abuse. Studies under Aim 1 test the hypotheses that mixtures of drugs targeting pre- (lorcaserin) and post- (buspirone) synaptic regulators of DA neurotransmission result in a supra-additive inhibition of the reinforcing (progressive ratio and cocaine-food choice) and relapse-related (reinstatement) effects of cocaine, and that these effects differ as a function of sex (e.g., females being less sensitive to buspirone alone, but more sensitive to lorcaserin:buspirone mixtures). Aim 2 tests the hypotheses that the cardiovascular and locomotor effects of lorcaserin and buspirone are not altered when combined in a mixture, and that mixtures of lorcaserin and buspirone do not exacerbate, and may blunt, the cardiovascular effects of cocaine; these effects are not expected to differ as a function of sex. The proposed studies build on compelling preliminary data and test the novel hypothesis that a combination therapy comprising fixed-doses of FDA-approved drugs that target pre-synaptic (5-HT2C receptors; lorcaserin) and post-synaptic (DA D3 receptors; buspirone) regulators of DA neurotransmission are more potent and/or effective at reducing the reinforcing and relapse-related effects of cocaine than would be expected based on the effect of either drug alone (i.e., a supra-additive interaction), without also exacerbating the cardiovascular effects of cocaine. These studies will not only provide new information (within 4 years) about the effects of drug mixtures targeting 5-HT2C and DA D3 receptors, but because lorcaserin and buspirone are already approved by the FDA for use in humans, these results will be highly translatable to the clinic, significantly reducing the time and cost required to determine the effectiveness of mixtures of lorcaserin and buspirone to treat cocaine abuse.

摘要/摘要 兴奋剂滥用是一个严重的公共卫生问题，具有无法估量的医疗、社会和经济影响 全世界。尽管几十年来对药物滥用的神经生物学进行了研究，但还没有FDA批准的 兴奋剂滥用的药物疗法。减少获得候选药物所需时间的一种策略 进入临床的是改变已经被FDA批准用于其他适应症的药物的用途，以治疗兴奋剂滥用， 提高药物疗效的一种策略是将其与第二种药物联合使用 具有互补作用机制的药物。我们和其他人已经证明，阻断血管紧张素转换酶活性的药物 DA(丁螺环酮[Buspar®]；一种类似DA D2[D2，D3和D4]受体拮抗剂，FDA批准用于治疗焦虑)或 调节DA传递(氯酪蛋白[Belviq®]；5-羟色胺[5-羟色胺]2C受体激动剂，FDA批准用于治疗 肥胖)可减弱可卡因等刺激剂对动物的强化和/或复发相关作用。基座 在对雄性和雌性恒河猴进行的非常有前景的先导研究中，我们假设一种联合疗法 包括针对DA突触前(氯酪蛋白)和突触后(丁螺环酮)调节剂的固定剂量的药物 神经传递的治疗效果(例如，减少吸毒)将大于 单独使用任何一种药物(即，超相加相互作用)。我们的初步数据支持这一假设，并表明 丁螺环酮和氯卡瑟林的结合将产生一种高度可翻译的新方法来治疗兴奋剂滥用。 目标1下的研究测试药物混合物靶向丁螺环酮前(氯酪蛋白)前和后(丁螺环酮)的假设 DA神经传递的突触调节导致对增强(进行性)的超加性抑制 可卡因的比例和可卡因的食物选择)和与复发(恢复)有关的影响，以及这些影响 性别差异(例如，女性对丁螺环酮不敏感，但对丁螺环酮更敏感 氯卡西林：丁螺环酮混合物)。目的2验证假设，心血管和运动的影响 氯卡菌素和丁螺环酮混合在一起时不会改变，氯卡菌素和丁螺环酮混合物 丁螺环酮不会加剧可卡因对心血管的影响，而且可能会减弱可卡因的心血管效应；这些影响是意想不到的。 因性别不同而不同。拟议的研究建立在令人信服的初步数据基础上，并测试了这部小说 假设由FDA批准的针对突触前的固定剂量药物组成的联合疗法 多巴胺(5-HT2C受体；氯酪蛋白)和突触后(DA D3受体；丁螺环酮)调节剂 神经传递在减少强化和复发相关效应方面更有效和/或更有效。 可卡因比基于任何一种药物单独作用的预期的可卡因(即，超相加相互作用)， 而不会加剧可卡因对心血管的影响。这些研究不仅将提供新的 关于针对5-HT2C和DA D3受体的药物混合物的影响的信息(在4年内)，但因为 氯卡瑟林和丁螺环酮已经被FDA批准用于人类，这些结果将是非常重要的 可翻译到临床，大大减少了确定其有效性所需的时间和成本 用于治疗可卡因滥用的氯卡瑟林和丁螺环酮的混合物。