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

基本信息

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
项目类别：
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

项目摘要

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，具有难以估量的医疗、社会和经济影响尽管对药物滥用的神经生物学进行了数十年的研究，但尚无 FDA 批准的药物。一种减少获得候选药物所需时间的策略。进入临床是为了重新利用 FDA 已批准用于其他适应症的药物，以治疗兴奋剂滥用，提高药物治疗效果的一种策略是将其与第二种药物联合使用我们和其他人已经证明，药物可以阻断作用机制。 DA（丁螺环酮 [Buspar®]；一种 DA D2 样 [D2、D3 和 D4] 受体拮抗剂，FDA 批准用于治疗焦虑症）或调节 DA 传输（lorcaserin [Belviq®]；一种血清素 [5-HT]2C 受体激动剂，FDA 批准用于治疗肥胖）减弱兴奋剂（例如可卡因）对动物的增强和/或复发相关作用。在对雄性和雌性恒河猴进行的非常有希望的试点研究中，我们寻求一种联合疗法包含针对 DA 前（氯卡色林）和后（丁螺环酮）突触调节剂的固定剂量药物神经传递的治疗效果（例如，减少吸毒）大于我们的初步数据支持这一假设并表明：将丁螺环酮与氯卡色林相结合将产生一种高度可转化的新颖方法来治疗兴奋剂滥用。目标 1 下的研究测试了针对前（氯卡色林）和后（丁螺环酮）靶向药物混合物的假设 DA 神经传递的突触调节因子导致增强（渐进性）的超加性抑制比例和可卡因-食物选择）和可卡因的复发相关（恢复）影响，并且这些影响因性别而异（例如，女性对单独的丁螺环酮不太敏感，但对丁螺环酮更敏感）氯卡色林：丁螺环酮混合物）。目标 2 测试了心血管和运动功能的假设。氯卡色林和丁螺环酮在混合物中组合时不会改变，并且氯卡色林和丁螺环酮的混合物丁螺环酮不会恶化并可能减弱可卡因的心血管作用，这些作用是预期之外的；拟议的研究以令人信服的初步数据为基础，并对小说进行了测试。假设联合疗法包含 FDA 批准的针对突触前的固定剂量药物 DA（5-HT2C 受体；氯卡色林）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影响方面更有效和/或更有效可卡因比基于任一药物单独作用的预期效果（即超加成相互作用），这些研究不仅会加剧可卡因对心血管的影响。关于针对 5-HT2C 和 DA D3 受体的药物混合物的影响的信息（4 年内），但因为氯卡色林和丁螺环酮已获得 FDA 批准用于人类，这些结果将是高度可转化为临床，显着减少确定有效性所需的时间和成本氯卡色林和丁螺环酮的混合物用于治疗可卡因滥用。