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: 7392409
• 负责人: JOHN E. MENDELSON
• 金额: $ 41.58万
• 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/7392409
• 关键词: 3,4-Methylenedioxyamphetamine; 3-methoxyamphetamine; Acute; Adrenergic Agents; Adrenergic alpha-Antagonists; Amphetamines; Argipressin; Attenuated; Biological Assay; Biological Availability; Biological Monitoring; Blood capillaries; Cardiovascular system; Case Study; Chest; Clinical Pharmacology; Complication; Condition; Data; Deuterium; Development; Dose; Drug Exposure; Drug Kinetics; Echocardiography; Equilibrium; Excretory function; Exercise; Female; Gender; Homeostasis; Hormonal; Housing; Human; Hyponatremia; Impedance Cardiography; Inorganic Sulfates; Intravenous; Isomerism; Isotopes; Kinetics; Label; Laboratories; Measures; Metabolic Pathway; Metabolism; Methods; Neuropsychology; Norepinephrine; Oral; Participant; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Physiological; Pituitary Hormones; Plasma; Play; Prazosin; Rate; Relative (related person); Role; Sodium; Stable Isotope Labeling; Sweat; Sweating; System; Testing; Toxic effect; Unspecified or Sulfate Ion Sulfates; Urine; Vasopressins; Water; Woman; adrenergic; alpha methyldopamine; alpha-1 adrenergic receptors; capillary; capsule; drug clearance; drug of abuse; ecstasy; enantiomer; experience; human study; male; men; psychopharmacologic; research study; response; two-dimensional; urinary; volunteer; young adult

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.

MDMA 是一种新兴的滥用药物，美国高达 14.6% 的年轻人曾尝试过这种药物 成瘾性和有毒药物。由于 MDMA 及其亲属的日益普及，我们建议人类 表征药理作用的研究。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， 丙二醛。我们的数据表明，MDMA 具有非线性和对映体选择性动力学，且呈不成比例的增加 药物暴露随着剂量的增加而增加。我们将确定增加生物利用度的贡献和/或 抑制代谢对 S(+)- 和 R(-)-MDMA 的动力学和影响。使用手性毛细管 GC-MS 和 LC-串联质谱我们开发并验证了灵敏且特异的分析方法来测量异构体 血浆、尿液和汗液中的 MDMA 和代谢物（使用贴片和通气胶囊方法，可用于 MDMA 滥用的生物监测）。 MDMA 和氘标记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。精神药理学 效果是在控制良好的实验室条件下对居住在加州大学旧金山分校 GCRC 的受试者进行评估的。 通过经胸二维超声心动图无创测量心血管 PD 效应， 阻抗心动图。我们拥有活跃的 MDMA 人体研究 IND，并且在以下方面拥有丰富的经验 施用产生最小生理反应的安全且可耐受的剂量。实验1将 确定氘标记 MDMA 可能的同位素效应以及静脉注射的药效学效应 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 MDMA 将在实验 2 中进行评估。实验 3 将研究单一适度口服药物的 PK 和 PD MDA 是一种 MDMA 代谢物，也是一种滥用药物。该实验将有助于定义该机制 MDA 的作用，还提供有关 MDMA 代谢途径的有用数据。实验4将研究 MDMA 引起的低钠血症的机制不健全，低钠血症是滥用 MDMA 的一个重要并发症，见于 主要是女性“狂欢”派对参与者。病例报告表明，水潴留和钠流失可能发挥作用 在低钠血症的发生中发挥作用，可能是由于 MDMA 诱导的抗利尿激素（加压素）所致 分泌。将在受试者中测试运动和水负荷对钠和水稳态的影响 接受低剂量的口服 MDMA。在实验 5 中，我们将研究 α 阻滞剂哌唑嗪对 对 MDMA 的反应。 α-受体阻滞剂可能会减弱 MDMA 对人类的作用。本实验将调查 α-1 肾上腺素受体在 MDMA 作用中的作用，并将提供有关可能的初步数据 使用哌唑嗪治疗急性摇头丸中毒。