Clinical Pharmacology of 3,4-Methylenedioxy Amphetamines

描述(申请人提供)：MDMA是一种新兴的滥用药物，在美国，高达14.6%的年轻人尝试过这种可能会上瘾和有毒的药物。由于MDMA及其近亲的日益流行，我们建议进行人体研究来表征药理作用。我们将测试MDMA(摇头丸)和一种活性代谢物丙二醛的剂量、对映体和性别相关的药代动力学(PK)和药效学(PD)反应。我们的数据表明，MDMA具有非线性和对映体选择动力学，随着剂量的增加，药物暴露不成比例地增加。我们将确定提高生物利用度和/或抑制代谢对S(+)和R(-)-MDMA动力学和影响的贡献。利用手性毛细管GC-MS和LC-Tandem MS，我们建立并验证了灵敏和特异的分析方法，以测定血浆、尿液和汗液中MDMA及其代谢物的异构体(使用贴片和通风胶囊方法，用于MDMA滥用的生物监测)。用于表征药物和代谢物的生物利用度和清除性的药物对映体的合成和给药将被用于MDMA和丙二醛的合成和给药。精神药理学效应是在控制良好的实验室条件下进行评估的，受试者被安置在加州大学旧金山分校的GCRC。用经胸二维超声心动图和心阻抗心动图无创测量心血管PD效应。我们有一个用于MDMA人体研究的有效IND，并且在给药安全和可耐受剂量方面经验丰富，产生的生理反应最小。实验1将确定氚标记的MDMA可能的同位素效应和静脉注射MDMA的药效学效应。实验2将评估光学纯S(+)和R(-)-MDMA的生物利用度以及性别和剂量对药理的影响。实验3将研究单一中等剂量口服丙二醛的PK和PD。丙二醛是一种MDMA的代谢物，也是一种滥用药物。本实验将有助于明确丙二醛的作用机制，并为研究MDMA的代谢途径提供有用的数据。实验4将调查MDMA引起的低钠血症的机制，这是MDMA滥用的一个重要并发症，主要见于女性“狂欢”派对参与者。病例报告提示，水滞留和钠丢失可能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(血管加压素)分泌。运动和水负荷对钠和水平衡的影响将在接受低剂量MDMA口服的受试者中进行测试。在实验5中，我们将研究α-阻滞剂哌唑嗪对MDMA反应的影响。(-阻滞剂可能会减弱MDMA在人体内的作用。本实验将探讨(-1肾上腺素能受体)在MDMA作用中的作用，并为可能使用哌唑嗪治疗MDMA急性毒性提供初步数据。

DESCRIPTION (provided by applicant): 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 labeled 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-labeled 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 underlying 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. (-blockers may attenuate MDMA actions in humans. This experiment will investigate the role of (-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.