PHARMACOLOGIC PROBES IN NEURALLY-MEDIATED SYNCOPE

神经介导性晕厥的药理学探索

• 批准号: 6662533
• 负责人: Italo Biaggioni
• 金额: $ 22.73万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6662533
• 关键词: alpha adrenergic receptor; chemoprevention; clinical research; clinical trial phase I; desipramine; disease /disorder classification; drug screening /evaluation; human subject; human therapy evaluation; nervous system disorder diagnosis; neuropharmacology; neurotransmitter transport; norepinephrine; sympathetic nervous system; syncope; vascular smooth muscle nervous control; vasomotion; yohimbine

The overall goal of these studies is to define the critical pathophysiological features of subtypes of neurally-mediated syncope, a disorder that cause substantial morbidity in young and middle-aged patients. Syncope is a common problem, accounting for as many as 3% of all emergency department visits. While attention has appropriately focused on life-threatening causes, the 30-65% of patients who are categorized as having either "reflex" or "unknown" causes suffer significant capacity as well. The underlying hypothesis of these studies, supported by recent preliminary data, is that patients with neurally- mediated syncope may be categorized by differential abnormalities of autonomic cardiovascular regulation that will predict therapeutic responses. We will address both central and peripheral autonomic mechanisms in hypothesis-driven clinical studies, and follow with a 2- year clinical trial, based on the results of these investigations. We will study patients and matched normal control subjects, assessing autonomic responses directly using recordings of muscle sympathetic nerve activity and determination of norepinephrine spillover and clearance, as well as plasma levels of circulating catecholamines and their metabolites, both at yeast and in response to sympathetic stimulation with well-characterized cortical stressors (modified Stroop and mental arithmetic with interpersonal provocation), physiological stressors (isometric handgrip and cold) and graded head-up tilt. We will also define whether peripheral vascular responses are altered. In patients with reduced sympathetic responses, we will assess alternative approaches to enhancing such responses, using alpha2 receptor antagonism with yohimbine or inhibition of the norepinephrine transporter with desimipramine. We will define the effect of sub-acute (5d) treatment with these agents on central and peripheral alpha-adrenergic responses, and determine whether a withdrawal phenomenon exists. Finally, depending on the results of these studies, we will conduct a 24 month, placebo-controlled, randomized clinical trial of these agents, assessing their efficacy in preventing syncopal episodes, their effect on cardiac rhythm, their possible central side effects, and the potential adverse effects of increased sympathetic tone on cardiac mass and chamber size with echocardiography. These studies will be directly applicable to the evaluation and treatment of patients with these incapacitating disorders.

这些研究的总体目的是定义神经介导的晕厥亚型的关键病理生理特征，这种疾病会导致年轻和中年患者的大量发病率。晕厥是一个常见的问题，占所有急诊室就诊的3％。尽管注意力已适当地集中在威胁生命的原因上，但被归类为具有“反射”或“未知”的患者中的30-65％也会产生重大容量。这些研究的基本假设得到了最近的初步数据的支持，即神经介导的晕厥患者可以通过自主性心血管调节的差异异常来分类，这将预测治疗反应。我们将在假设驱动的临床研究中介绍中央和外围自主神经机制，并根据这些研究的结果进行2年的临床试验。 We will study patients and matched normal control subjects, assessing autonomic responses directly using recordings of muscle sympathetic nerve activity and determination of norepinephrine spillover and clearance, as well as plasma levels of circulating catecholamines and their metabolites, both at yeast and in response to sympathetic stimulation with well-characterized cortical stressors (modified Stroop and mental arithmetic with interpersonal provocation),生理压力源（等距手工束和冷）和渐变的头部倾斜。我们还将定义周围血管反应是否改变。在降低交感神经反应的患者中，我们将使用Yohimbine使用alpha2受体拮抗作用或抑制去氨甲胺的去甲肾上腺素转运蛋白来评估增强此类反应的替代方法。我们将定义这些药物对中央和周围α-肾上腺素能反应的亚急性（5D）处理的影响，并确定是否存在戒断现象。最后，根据这些研究的结果，我们将对这些药物进行24个月的，安慰剂对照的，随机的临床试验，评估它们在预防晕厥发作的功效，对心脏节律的影响，可能的中心副作用以及与eCharcartiography相关的交感神经和室内尺寸增加的交感神经和腔室大小的潜在不利影响。这些研究将直接适用于对这些无能为力疾病患者的评估和治疗。