Phase 2 Norepinephrine Transporter Blockade, Autonomic Failure IND117394 12/28/12

摘要 自主神经功能衰竭是一组罕见的神经退行性疾病，主要影响自主神经功能。 神经系统有两种主要亚型：1）MSA，其中自主神经损伤与 锥体外系或小脑运动障碍或两者兼有，以及2）PAF，其中发生自主神经损伤 一个人仰卧位去甲肾上腺素（NE）水平（MSA正常，PAF低）在站立时未能增加。 这导致交感神经介导的血管收缩受损，导致神经源性直立性 低血压（NOH）、脑灌注不足和头晕、头晕、晕厥和 导致该人群发病、残疾和死亡的福尔斯。 我假设药物托莫西汀是一种去甲肾上腺素转运蛋白（NET）阻滞剂， 通过阻断NE的再摄取，增加NE在突触水平的可用性，可以诱导 增加血压，并成为自主神经功能衰竭中NOH潜在治疗方法。在正常人中， 托莫西汀具有最小的血液动力学效应，因为其中枢和外周之间的平衡 对自主神经系统的作用。在中枢自主神经通路中，增加的NE水平降低， 通过刺激α-2肾上腺素能受体的交感神经活动。在外周交感神经纤维中，增加的NE 水平可通过作用于节后α-1肾上腺素能受体来刺激交感神经活性。患者 自主神经衰竭具有这些中枢和外周自主神经通路之间不平衡。在MSA中， 外周交感神经纤维与其中枢输入断开， 比如效应和血压反应。 在一项概念验证临床试验中，我确定了18 mg托莫西汀对坐姿和站立位的影响。 21例自主神经功能衰竭患者（10例MSA和11例PAF）的血压。这些初步数据显示， 急性剂量18 mg托莫西汀使坐位收缩压（SBP）升高约50 mm Hg， 仅在MSA中使用安慰剂。在一项单独的交叉研究中，我们比较了单剂量18 mg的 托莫西汀与米多君（5，10 mg）和安慰剂对69例患者的站立位SBP和临床症状的影响 NOH和自主神经衰竭。我们的研究结果表明，托莫西汀和米多君增加坐位血压， 同样的规模。然而，18毫克托莫西汀比米多君更有效地改善站立 SBP（+7.5 mm Hg）。 然而，对升压药急性给药的反应并不能预测长期的 药物的功效。我们建议测试的假设，延长（4周）管理NET 阻滞剂托莫西汀可改善临床症状、日常生活活动，并增加常备血 MSA和早期MSA患者的压力。

ABSTRACT Autonomic failure is a group of rare neurodegenerative disorders that primarily affect the autonomic nervous system. There are two main subtypes: 1) MSA in which autonomic impairment is combined with an extrapyramidal or cerebellar movement disorder or both, and 2) PAF in which autonomic impairment occurs alone. Supine norepinephrine (NE) levels (normal in MSA and low in PAF) failed to increase upon standing. This leads to impaired sympathetic-mediated vasoconstriction that results in neurogenic orthostatic hypotension (NOH), cerebral hypoperfusion and symptoms such as lightheadedness, dizziness, syncope and falls that contributes to morbidity, disability and death in this population. I hypothesized that the pharmacological agent, atomoxetine, a norepinephrine transporter (NET) blocker that increases the availability of NE at the level of the synapse by blocking its reuptake, could induce an increase in blood pressure and be a potential treatment for NOH in autonomic failure. In normal individuals, atomoxetine has minimal hemodynamic effects because of a balance between its central and peripheral actions on the autonomic nervous system. In central autonomic pathways, the increased NE levels diminish sympathetic activity by stimulating α-2 adrenergic receptors. In peripheral sympathetic fibers, the increased NE levels may stimulate sympathetic activity by acting on postganglionic α-1 adrenergic receptors. Patients with autonomic failure have an imbalance between these central and peripheral autonomic pathways. In MSA, the peripheral sympathetic fibers are disconnected from its central input unmasking any peripheral sympathetic- like effect and blood pressure response. In a proof-of-concept clinical trial, I determined the effect of 18 mg of atomoxetine on seated and standing blood pressure in 21 autonomic failure patients (10 MSA and 11 PAF). These preliminary data showed that an acute dose of 18 mg of atomoxetine increased seated systolic blood pressure (SBP) by ~50 mm Hg compared with placebo in MSA only. In a separate crossover study, we compared the effect of a single dose of 18 mg of atomoxetine with midodrine (5,10 mg) and placebo on standing SBP and clinical symptoms in 69 patients with NOH and autonomic failure. Our results showed that atomoxetine and midodrine increased seated BP at the same magnitude. However, 18 mg of atomoxetine was more effective than midodrine in improving standing SBP (+7.5 mm Hg). The response to an acute administration of a pressor agent, however, does not predict the long-term efficacy of the drug. We propose to test the hypothesis that prolonged (4-week) administration of the NET blocker, atomoxetine, improves clinical symptoms, activities of daily living, and increases standing blood pressure in patients with MSA and early MSA.