Assessment Of A Cannabinoid Antagonist In Humans

Delta-9- tetrahydrocannabinol（THC）是一种主要的精神活性大麻素，通过与G蛋白连接的大麻素CB 1受体相互作用发挥其大部分中枢神经系统作用。第二种大麻素结合七跨膜受体亚型，称为CB 2，已被克隆，似乎与免疫功能的调节有关。SR 141716或利莫那班是第一个被鉴定的中枢大麻素受体CB 1的拮抗剂。它拮抗大麻素受体激动剂对小鼠输精管收缩和大鼠脑膜腺苷酸环化酶活性的抑制作用。纯大麻素受体拮抗剂的可用性有助于评估内源性大麻素系统的作用。这种拮抗剂在调节大量似乎表达大麻素CB 1受体的脑系统中的潜在治疗效用特别有趣。大麻素对“奖赏”系统的作用可能是通过腹侧被盖区和延髓核的中等受体密度介导的。我们首次证明了利莫那班能够阻断THC对人体的急性作用，从而证实了在人类和动物中的作用的平行性。我们进行了一项利莫那班对吸食大麻的主观和心血管效应的拮抗作用的I期临床试验。此外，正在确定利莫那班单独给予轻度大麻使用者或与THC联合吸入的安全性以及利莫那班和THC的药代动力学。有大麻使用史的健康男性受试者在吸烟安慰剂或活性大麻之前接受安慰剂或活性利莫那班。监测生理、生化和行为指标，以评价药效学效应。我们进行了利莫那班的第二个I期研究，利用多剂量来显示阻断大麻的效果是用较小的多剂量药物完成的。

Delta-9- tetrahydrocannabinol (THC), the primary psychoactive cannabinoid, exerts the majority of its central nervous system effects through interaction with the G-protein linked cannabinoid CB1 receptor. A second cannabinoid-binding seven-transmembrane spanning receptor subtype, termed CB2, has been cloned and appears to be involved with regulation of immunological functions. SR 141716 or Rimonabant is the first antagonist of the central cannabinoid receptor CB1 to be identified. It antagonizes the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and adenylcyclase activity in rat brain membranes. Availability of a pure cannabinoid receptor antagonist has helped to assess the role of the endogenous cannabinoid system. The potential therapeutic utility of this antagonist in modulating the large number of brain systems that appear to express cannabinoid CB1 receptors is especially interesting. Cannabinoid effects on "reward" systems could be mediated through moderate receptor densities in ventral tegmental area and the nucleus accumbens. We have shown for the first time the ability of Rimonabant to block the acute effects of THC in humans, thus confirming the parallelism of effects in humans and animals. We conducted a phase I clinical trial of the antagonism of the subjective and cardiovascular effects of smoked cannabis by Rimonabant. In addition, the safety of Rimonabant when given alone to light cannabis users, or in combination with THC via inhalation and the pharmacokinetics of Rimonabant and THC are being determined. Healthy male subjects with a history of cannabis use receive placebo or active Rimonabant prior to smoking placebo or active cannabis. Physiological, biochemical and behavioral measures are being monitored to evaluate pharmacodynamic effects. We conducted a second phase I study of Rimonabant utilizing multiple doses to show that blockade a cannabis's effects were accomplished with smaller multiple doses of drug.