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: 7564835
• 负责人: JOHN E. MENDELSON
• 金额: $ 43.26万
• 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/7564835
• 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; 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; 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，高达14.6%的美国年轻人潜在地尝试过这种药物 令人上瘾的有毒毒品。由于MDMA及其亲缘关系的日益流行，我们建议人类 描述药理作用的研究。我们将测试与剂量、对映体和性别相关的 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具有不成比例增加的非线性和对映体选择动力学。 随着剂量的增加，药物暴露的风险也越来越大。我们将确定提高生物利用度和/或 代谢抑制对S(+)-和R(-)-亚甲基四氢叶酸的动力学及影响。利用手性毛细管气相色谱-质谱法 LC-Tandem MS我们开发和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MDMA和代谢物的含量(使用贴片和通风胶囊方法，在 滥用MDMA的生物监测)。氚标记的MDMA和MDMA对映体的合成及给药 丙二醛将用于表征药物和代谢物的生物利用度和清除性。精神药理学 效果是在控制良好的实验室条件下进行评估的，受试者住在加州大学旧金山分校的GCRC。 应用经胸二维超声心动图无创测量心血管PD效应。 阻抗心动图。我们有一个活跃的人类研究MDMA的IND，并有很好的经验 给予产生最小生理反应的安全和可耐受的剂量。实验1将 氚标记MDMA的可能同位素效应及静脉给药的药效学效应 摇头丸。光学纯S(+)和R(-)-的生物利用度及性别和剂量对药理的影响 MDMA将在实验2中被评估。实验3将调查单个适度口腔的PK和PD 剂量的丙二醛，一种MDMA代谢物，也是一种滥用药物。这项实验将有助于确定这种机制 同时也为研究MDMA的代谢途径提供了有用的数据。实验4将研究 MDMA引起的低钠血症的机制，MDMA滥用的一个重要并发症 主要是女性“狂欢派对”参与者。病例报告表明，水分保留和钠的丧失可能起到了作用 在低钠血症发展中的作用，可能是由于MDMA诱导的抗利尿激素(加压素) 分泌物。运动和水负荷对钠和水平衡的影响将在受试者中进行测试 接受低剂量的MDMA口服。在实验5中，我们将研究α-受体阻滞剂哌唑嗪对血管紧张素转换酶活性的影响。 对MDMA的反应。α-受体阻滞剂可能会减弱MDMA在人体内的作用。这项实验将调查 α-1肾上腺素能受体在MDMA作用中的作用，将提供可能的初步数据 哌唑嗪在治疗MDMA急性中毒中的应用。