project 2 - Autonomic Rare Diseases Clinical Research Consortium

失能性直立性低血压在自主神经功能衰竭的临床表现中占主导地位， 严重的发病率。大多数患者需要升压剂来维持直立血压高于 克服脑血流自动调节的低阈值。阿尔法激动剂米多君，唯一的 批准用于治疗体位性低血压的药物对很大一部分患者无效，因为 缺乏疗效或无法忍受的副作用。因此，开发一种替代性加压剂将是有益的。 治疗直立性低血压的药物。这种罕见疾病参与者的最新发现 网络，揭示了多系统萎缩（Shy-Drager综合征）患者的中枢神经系统功能受损， 自主神经通路对自主心血管控制至关重要，但完整的外周节后神经通路 去甲肾上腺素能纤维，如通过血浆去甲肾上腺素的接近正常水平和 心脏对儿茶酚胺的摄取后一种观察结果表明， 去甲肾上腺素能神经末梢和儿茶酚胺再摄取机制。因此，患有多种 系统萎缩具有不受中枢自主神经中枢调节外周残余交感神经紧张 或压力反射控制，但可以利用来改善直立性低血压。药理学抑制 去甲肾上腺素再摄取的增加可用于增强突触去甲肾上腺素的作用， 多系统萎缩的患者，并增加他们的血压。事实上，我们的概念验证研究 表明去甲肾上腺素转运体托莫西汀在这些患者中是一种有效的升压药， 显著改善立位耐力。我们现在提出一个两阶段的临床试验，以确定疗效 托莫西汀治疗直立性低血压的安全性。托莫西汀应答者将 在方案#1中确定的急性剂量的托莫西汀、安慰剂（对照）或米多君（ 护理）。在方案2中，托莫西汀应答者将在开放标签中接受托莫西汀治疗1个月 研究，然后将在住院CRC环境中随机分配，继续接受托莫西汀治疗或 安慰剂，采用随机双盲退出设计。

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.