Clinical Pharmacology of 3,4-Methylenedioxy Amphetamines

MDMA是一种新兴的滥用药物，美国高达14.6%的年轻人可能尝试过这种药物 成瘾性和毒性药物。由于MDMA及其亲属的日益普及，我们建议人类 研究以表征药理学作用。我们将测试剂量，对映体，和性别依赖性 对MDMA（“摇头丸”）和一种活性代谢物的药代动力学（PK）和药效学（PD）反应， MDA我们的数据表明，MDMA具有非线性和对映体选择性动力学， 在药物暴露中的作用我们将确定增加生物利用度和/或 代谢对S（+）-和R（-）-MDMA动力学和影响的抑制。使用手性毛细管GC-MS和 我们已经开发并验证了灵敏和特异的分析方法来测量异构体 血浆、尿液和汗液中的MDMA及其代谢物（使用贴片和通气胶囊法， MDMA滥用的生物监测）。氘标记的MDMA对映体的合成和给药 MDA将用于表征药物和代谢物的生物利用度和清除率。精神药理 在良好控制的实验室条件下，用安置在UCSF GCRC上的受试者评价效果。 心血管PD效应通过经胸二维超声心动图进行非侵入性测量， 阻抗心动描记术我们有一个活跃的IND用于MDMA的人体研究，并且在以下方面经验丰富： 给药安全和可耐受的剂量，产生最小的生理反应。实验1将 确定氘标记MDMA的可能同位素效应和静脉注射MDMA的药效学效应 摇头丸光学纯S（+）-和R（-）-的生物利用度以及性别和剂量对药理学的影响 将在实验2中评估MDMA。实验3将研究单次适度口服给药的PK和PD。 剂量的MDA，一种MDMA代谢物，也是一种滥用药物。这个实验将有助于确定 为研究MDMA的代谢途径提供了有用的数据。实验4将研究 MDMA引起的低钠血症是MDMA滥用的一个重要并发症， 主要是参加狂欢派对的女性病例报告表明，水潴留和钠的损失可能发挥作用， 在低钠血症的发生中起作用，可能是由于MDMA诱导的抗利尿激素（加压素） 分泌物将在受试者中测试运动和水负荷对钠和水稳态的影响 服用低剂量的摇头丸在实验5中，我们将研究α-受体阻滞剂哌唑嗪对 对MDMA的反应α-受体阻滞剂可减弱MDMA对人体的作用。这个实验将研究 α-1肾上腺素能受体在MDMA作用中的作用，并将提供关于可能的 哌唑嗪在治疗急性MDMA毒性中的用途。

MDMA is an emerging drug of abuse with up to 14.6% of young adults in the US having tried this potentially addictive and toxic drug. Because of the increasing popularity of MDMA and its relatives we propose human studies to characterize pharmacologic effects. We will test the dose-, enantiomer-, and gender- dependent pharmacokinetic (PK) and pharmacodynamic (PD) response to MDMA ("Ecstasy") and one active metabolite, MDA. Our data show that MDMA has non-linear and enantiomer selective kinetics with disproportional increases in drug exposure with increasing doses. We will determine the contributions of increasing bioavailability and/or inhibition of metabolism on the kinetics and effects of S(+)- and R(-)-MDMA. Using chiral capillary GC-MS and LC-tandem MS we have developed and validated sensitive and specific analytic methods to measure the isomers of MDMA and metabolites in plasma, urine and sweat (using patches and a ventilated capsule method, useful in biomonitoring of MDMA abuse). Synthesis and administration of deuterium labelled enantiomers of MDMA and MDA will be used to characterize bioavailability and clearance of drug and metabolite. Psychopharmacologic effects are evaluated under well-controlled laboratory conditions with subjects housed on the UCSF GCRC. Cardiovascular PD effects are measured non-invasively with trans-thoracic 2-dimensional echocardiography and impedance cardiography. We have an active IND for the human study of MDMA and are well experienced with administration of safe and tolerable doses that produce minimal physiological response. Experiment 1 will determine possible isotope effects of deuterium-labelled MDMA and the pharmacodynamic effects of intravenous MDMA. The bioavailability and effects of gender and dose on the pharmacology of optically pure S(+)- and R(-)- MDMA will be assessed in Experiment 2. Experiment 3 will investigate the PK and PD of a single modest oral dose of MDA, an MDMA metabolite that is also a drug of abuse. This experiment will help define the mechanism of action of MDA and also provide a useful data on metabolic pathways of MDMA. Experiment 4 will investigate the mechanisms undedying MDMA-induced hyponatremia, a significant complication of MDMA abuse seen in primarily female "rave" party participants. Case reports suggest that water retention and loss of sodium may play a role in the development of hyponatremia, possibly due to MDMA-induced antidiuretic hormone (vasopressin) secretion. The effect of exercise and water loading on sodium and water homeostasis will be tested in subjects receiving a low oral dose of MDMA. In Experiment 5 we will investigate the effect of the alpha-blocker prazosin on the response to MDMA. Alpha-blockers may attenuate MDMA actions in humans. This experiment will investigate the role of alpha-1 adrenergic receptors in the action of MDMA and will provide preliminary data on the possible use of prazosin in the treatment of acute MDMA toxicity.