Development Of New Pharmacologic And Biologic Treatments

新药物和生物治疗的开发

• 批准号: 7149284
• 负责人: DAVID ALAN GORELICK
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 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/7149284
• 关键词: AIDS education /prevention; HIV infections; behavioral /social science research tag; buprenorphine; cannabinoid receptor; cholinesterases; cocaine; communicable disease transmission; counseling; drug abuse chemotherapy; drug addiction; drug addiction antagonist; drug metabolism; enzyme activity; high risk behavior /lifestyle; human subject; laboratory rat; marijuana abuse; patient oriented research; therapy design /development

This project explores pharmacokinetic and pharmacodynamic approaches to developing new treatments for drug dependence and reduction of HIV transmission risk behaviors, with a current focus on cocaine and marijuana dependence. Many subjects are at high risk for contracting and spreading HIV infection. HIV transmission risk behaviors are assessed and HIV testing and risk reduction counseling are offered to all subjects. The pharmacokinetic approach being studied is blunting the rate of onset of drug effect by enhancement of drug metabolism. Rate of onset of drug effect is considered an important influence on the reinforcing effects of drugs, but this has never been systematically studied in humans with stimulants. The influence of rate has treatment implications, in that drugs from the same pharmacologic class but with slower rate of onset may have therapeutic efficacy without themselves inducing addiction. Enhancement of cocaine metabolism is being studied using butyrylcholinesterase (BChE), a major cocaine-metabolizing enzyme in humans. Increased BChE activity might reduce cocaine concentrations and thus cocaine's effects, with possible therapeutic benefits. In a collaborative study with the Behavioral Pharmacology Section and the National Institute on Aging Gerontology Research Center, rats pretreated with BChE had a 50% reduction in motor activity response to an IP cocaine challenge compared to rats pretreated with saline. BChE itself had no effect on motor activity. BChE-treated rats had 400-fold increases in plasma and 3-fold increases in cerebrospinal fluid BChE activity 24 hours after treatment, suggesting the possibility of persisting effects from a single enzyme administration. BChE pretreatment in rats significantly decreased cocaine plasma half-life from 26.2 min to 16.4 min and increased plasma and brain levels of ecgonine methylester, a cocaine metabolite that may have protective effects. These findings suggest the important influence of BChE activity on cocaine pharmacokinetics. Pharmacodynamic approaches being studied include modulation of brain mu-opiate receptors and blockade of relevant neurotransmitter receptors. The former approach is being implemented using buprenorphine, a partial mu-opiate receptor agonist. A controlled clinical trial of sublingual buprenorphine in outpatients dependent on both cocaine and opiates found that high doses (8 mg or 16 mg daily) significantly reduced both cocaine and opiate use over the 10-week maintenance treatment period, while lower doses (2 mg daily or 16 mg every other day) did not. Attendance at concurrent drug abuse counseling was associated with better treatment outcome, suggesting the importance of combined pharmacological and psychosocial treatment. The second approach is being implemented, in collaboration with the Chemistry & Drug Metabolism Section, by evaluating the effects in humans of an experimental compound, rimonabant, which acts as an antagonist at the cannabinoid 1 (CB1, marijuana) receptor in the brain, and on its interaction with smoked marijuana. A single 90 mg dose of rimonabant significantly reduced the psychological (feeling of marijuana intoxication) and cardiovascular (tachycardia, symptomatic hypotension) effects of a marijuana cigarette. Rimonabant by itself had no measurable effects, and did not alter THC plasma pharmacokinetics. Daily rimonabant dosing for 2 weeks produced similar blockade of smoked marijuana effects. These findings suggest that CB1 receptors play an important role in mediating the effects of smoked marijuana in humans.

该项目探讨了制定药代动力学和药效动力学方法，以开发用于药物依赖性和减少HIV传播风险行为的新疗法，目前侧重于可卡因和大麻依赖性。许多受试者有收缩和传播艾滋病毒感染的高风险。评估HIV传播风险行为，并向所有受试者提供艾滋病毒测试和降低风险咨询。所研究的药代动力学方法是通过增强药物代谢来使药物作用发作率降低。药物作用的发作速率被认为是对药物增强作用的重要影响，但这从未在具有兴奋剂的人类中进行系统地研究。率的影响具有治疗意义，因为来自同一药物类别但发病率较慢的药物可能具有治疗功效而不会诱发成瘾。正在使用人类中主要的可卡因 - 代谢酶丁乙酸糖苷酯酶（BCHE）研究可卡因代谢的增强。增加的BCHE活性可能会降低可卡因浓度，从而降低可卡因的作用，并具有可能的治疗益处。在与行为药理学科和美国国家老年医学研究中心的一项合作研究中，与盐水相比，用BCHE进行预处理的大鼠对IP可卡因挑战的运动活动反应降低了50％。 BCHE本身对运动活动没有影响。治疗后24小时，BCHE治疗的大鼠血浆的增加400倍，脑脊液BCHE活性增加了3倍，这表明单个酶给药会持续作用。大鼠的BCHE预处理可显着降低可卡因血浆半衰期从26.2分钟到16.4分钟，并增加了可能具有保护作用的可卡因代谢物，血浆和脑含量增加。这些发现表明BCHE活性对可卡因药代动力学的重要影响。 研究的药效方法包括调节脑MU-伴侣受体和相关神经递质受体的阻断。前一种方法正在使用丁丙诺啡（一种部分MU-opiate受体激动剂）实施。舌下丁丙诺啡在门诊患者中的对照临床试验取决于可卡因和阿片类药物，发现高剂量（每天8毫克或16毫克）显着降低了可卡因和10周维护治疗期间的可卡因和鸦片使用量，而剂量较低的剂量（每天2 mg或每天16 mg或每天）没有。同时参加药物滥用咨询与更好的治疗结果有关，这表明药理学和社会心理治疗的重要性。第二种方法正在与化学和药物代谢部分合作，通过评估人类对大脑1（CB1，大麻）在大脑中的拮抗剂以及与吸烟大麻的相互作用的拮抗剂的实验化合物Rimonabant的影响。单一的90毫克rimonabant显着降低了大麻香烟的心理（大麻中毒的感觉）和心血管（心动过速，症状性低血压）的影响。利莫班班本身没有可测量的效果，也没有改变THC血浆药代动力学。每天的三体剂量剂量2周产生了类似的烟熏大麻效应。这些发现表明，CB1受体在介导熏制大麻对人类的影响方面起着重要作用。