project 2 - Autonomic Rare Diseases Clinical Research Consortium

禁用直立性低血压在自主神经衰竭的临床表现中占主导地位，也是导致 发病率很高。大多数患者需要降压剂来维持直立血压高于 更低的阈值，克服了脑血流自动调节。阿尔法激动剂米多君，唯一的 批准用于直立性低血压的药物，在相当大比例的患者中无效，因为 缺乏疗效，或无法忍受的副作用。因此，开发替代增压机将是有用的 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 网络研究发现，多系统萎缩(Shy-Drager综合征)患者的中枢神经系统受损 自主神经通路对自主心血管控制至关重要，但外周神经节后完整 去甲肾上腺素能纤维，血浆去甲肾上腺素水平接近正常和存在 心脏对儿茶酚胺的摄取。后一种观察结果意味着两者的存在都完好无损 去甲肾上腺素能神经末梢和儿茶酚胺再摄取机制。因此，患有多发性骨髓瘤的患者 系统萎缩有外周残余交感神经张力，不受中枢自主神经中心的调节 或压力感受性反射控制，但可以用来改善直立性低血压。药理抑制 去甲肾上腺素的再摄取可用于增强突触去甲肾上腺素的作用 多系统萎缩患者，血压升高。事实上，我们的概念验证研究 提示去甲肾上腺素转运体托莫西汀对这些患者是一种有效的升压剂。 显著提高立位耐受性。我们现在建议进行两阶段临床试验，以确定疗效 托莫西汀治疗直立性低血压的安全性。托莫西汀的应答者将 在急性剂量的阿莫西汀、安慰剂(对照组)或米多君(标准 关爱)。在第二号议定书中，阿托莫西汀应答者将在开放标签中接受为期1个月的阿托莫西汀治疗 研究，然后将在住院CRC环境中随机选择继续服用托莫西汀或给予 安慰剂，采用随机双盲停药设计。

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.