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project 2 - Autonomic Rare Diseases Clinical Research Consortium

项目 2 - 自主神经罕见疾病临床研究联盟

基本信息

批准号：
7901211
负责人：
Italo Biaggioni
金额：
$ 26.75万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7901211
关键词：
Acute Adverse effects Affect Agonist Autonomic Pathways Baroreflex Blood Blood Pressure Cardiac Cardiovascular system Catecholamines Cerebrovascular Circulation Clinical Clinical Research Clinical Trials Development Dose Double-Blind Method Drops Effectiveness Failure Fiber Functional disorder Heart Homeostasis Impairment Inpatients Label Midodrine Morbidity - disease rate Multiple System Atrophy Nerve Norepinephrine Orthostatic Hypotension Participant Patients Peripheral Phase Piloerection Pilot Projects Placebo Control Placebos Plasma Protocols documentation Randomized Rare Diseases Research Residual state Safety Scalp structure Severities Shy-Drager Syndrome Symptoms Synapses Syncope Urinary Retention Withdrawal atomoxetine base cerebral hypoperfusion design effective therapy improved member noradrenaline transporter noradrenergic novel open label prevent reuptake standard of care uptake

项目摘要

Disabling orthostatic hypotension dominates the clinical picture of autonomic failure and is the cause of substantial morbidity. Most patients require pressor agents to maintain upright blood pressure above the lower threshold that overcomes cerebral blood flow autoregulation. The alpha agonist midodrine, the only agent approved for orthostatic hypotension, is not effective in a significant proportion of patients because of lack of efficacy, or intolerable side effects. It would be useful, therefore, to develop alternative pressor agents for the treatment of orthostatic hypotension. Recent findings by participants of this Rare Disease Network, revealed that patients with multiple system atrophy (Shy-Drager syndrome) have impaired central autonomic pathways crucial for autonomic cardiovascular control, but intact peripheral postganglionic noradrenergic fibers, as evidenced by the near normal levels of plasma norepinephrine and the presence of uptake of catecholamine in the heart. This latter observation implies the presence of both intact noradrenergic nerve terminals and catecholamine reuptake mechanisms. Thus, patients with multiple system atrophy have peripheral residual sympathetic tone that is unregulated by central autonomic centers or baroreflex control, but could be harnessed to improve orthostatic hypotension. Pharmacological inhibition of the norepinephrine reuptake could be used to potentiate the effects of synaptic norepinephrine present in multiple system atrophy patients and increase their blood pressure. Indeed, our proof-of-concept studies indicate that the norepinephrine transporter atomoxetine is an effective pressor agent in these patients, and acutely improves orthostatic tolerance. We now propose a two phase Clinical Trial to determine the efficacy and safety of atomoxetine in the treatment of orthostatic hypotension. Atomoxetine responders will be identified in Protocol #1 after an acute dose of atomoxetine, placebo (control) or midodrine (standard of care). In Protocol #2 atomoxetine responders will be treated with atomoxetine for 1 month in an open-label study and will then be randomized in an inpatient CRC setting to continue on atomoxetine or be given placebo, using a randomized double blind withdrawal design.

致残性体位性低血压在自主神经衰竭的临床表现中占主导地位，是引起