New Treatment for Drug Dependence

药物依赖的新疗法

• 批准号: 6535461
• 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/6535461
• 关键词: AIDS education /prevention; HIV infections; cannabinoid receptor; cannabinoids; cholinesterases; cocaine; drug abuse chemotherapy; drug addiction; drug addiction antagonist; drug metabolism; enzyme activity; human subject; human therapy evaluation; laboratory rat; marijuana abuse; neuropharmacology; patient oriented research; pharmacokinetics

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. Squirrel monkeys pretreated with BChE before a cocaine challenge show a three-fold decrease in peak plasma cocaine concentrations and a parallel increase in concentrations of the cocaine metabolite ecgonine methylester. BChE added to human plasma in vitro produced a dose-dependent decrease in cocaine half-life, further suggesting the important influence of BChE activity on cocaine pharmacokinetics. Pharmacodynamic approaches being used include blockade of relevant neurotransmitter receptors. Current studies, in collaboration with the Chemistry & Drug Metabolism Section, are evaluating the effects in humans of an experimental compound, SR141716, 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 SR141716 significantly reduced the psychological (feeling of marijuana intoxication) and cardiovascular (tachycardia, symptomatic hypotension) effects of a marijuana cigarette. SR141716 by itself had no measurable effects, and did not alter THC plasma pharmacokinetics. 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。在可卡因挑战之前，用BCHE预处理的松鼠猴子表明血浆可卡因浓度降低了三倍，并且可卡因代谢物仿生甲基甲基酯的浓度平行增加。 BCHE在体外增加了人血浆，从而导致可卡因半衰期的剂量依赖性降低，进一步表明BCHE活性对可卡因药代动力学的重要影响。使用的药效方法包括阻断相关神经递质受体。目前的研究与化学和药物代谢部分合作，正在评估实验化合物SR141716的影响，该化合物在大脑1（CB1，大麻）受体中充当拮抗剂，以及与烟熏大麻的相互作用。单一的90 mg剂量的SR141716大大降低了大麻香烟的心理（大麻中毒感觉）和心血管（心动过速，症状性低血压）的影响。 SR141716本身没有可测量的效果，也没有改变THC血浆药代动力学。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。