Clinical Pharmacology of 3,4-Methylenedioxy Amphetamines

3,4-亚甲二氧基安非他明的临床药理学

• 批准号: 6870119
• 负责人: JOHN E. MENDELSON
• 金额: $ 49.36万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870119
• 关键词: 3 methoxy 4 hydroxyphenylethyleneglycol; 3,4 methylenedioxyamphetamine; 3,4 methylenedioxymethamphetamine; clinical research; drug abuse; drug administration rate /duration; drug metabolism; exercise; gender difference; human middle age (35-64); human subject; hyponatremia; intravenous administration; mass spectrometry; oral administration; pharmacokinetics; prazosin; psychopharmacology; stable isotope; stereoisomer; sulfates; sweat; vasopressins; water drinking behavior; young adult human (21-34)

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.

描述（由申请人提供）：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成瘾和有毒的药物。 由于MDMA及其亲属的日益普及，我们建议进行人体研究，以表征药理作用。 我们将测试对MDMA（“摇头丸”）和一种活性代谢物MDA的剂量、对映体和性别依赖性药代动力学（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性动力学，药物暴露量随剂量增加而不成比例增加。 我们将确定增加生物利用度和/或抑制代谢对S（+）-和R（-）-MDMA动力学和效应的贡献。 使用手性毛细管GC-MS和LC-tandem MS，我们开发并验证了测量血浆、尿液和汗液中MDMA异构体和代谢物的灵敏和特异性分析方法（使用贴片和通风胶囊法，可用于MDMA滥用的生物监测）。 氘标记的MDMA和MDA对映体的合成和给药将用于表征药物和代谢物的生物利用度和清除率。 精神药理学作用是在控制良好的实验室条件下评价的，受试者住在UCSF GCRC。 心血管PD效应通过经胸二维超声心动图和阻抗心动图进行无创测量。 我们有一个活跃的IND用于MDMA的人体研究，并且在产生最小生理反应的安全和可耐受剂量的给药方面经验丰富。 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。 将在实验2中评估生物利用度以及性别和剂量对光学纯S（+）-和R（-）- MDMA药理学的影响。 实验3将研究单次适度口服MDA（一种MDMA代谢物，也是一种滥用药物）的PK和PD。 本实验将有助于明确MDA的作用机制，并为MDMA的代谢途径提供有用的数据。 实验4将调查MDMA诱导的低钠血症，主要是女性“锐舞”党的参与者中看到的MDMA滥用的一个显着的并发症的机制。 病例报告表明，水潴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（加压素）分泌。 将在接受低剂量MDMA口服给药的受试者中检测运动和水负荷对钠和水稳态的影响。 在实验5中，我们将研究α-受体阻滞剂哌唑嗪对MDMA反应的影响。 β-受体阻滞剂可减弱MDMA对人体的作用。 本实验将研究β-1肾上腺素能受体在MDMA作用中的作用，并将为哌唑嗪治疗急性MDMA毒性提供初步数据。