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

摘要 自主神经衰竭是一组罕见的神经退行性疾病，主要影响自主神经。 神经系统。主要有两种亚型：1)MSA，其中自主神经损害合并 锥体外系或小脑运动障碍或两者兼有；2)出现自主神经损害的PAF 独自一人。仰卧位去甲肾上腺素(NE)水平(MSA正常，PAF低)在立位时未能增加。 这会导致交感神经介导的血管收缩受损，从而导致神经源性直立。 低血压(NOH)、脑低灌注以及头晕、头晕、晕厥和 导致这一人群发病率、残疾和死亡的跌倒。 我推测药物托莫西汀是一种去甲肾上腺素转运体(NET)阻滞剂 通过阻止去甲肾上腺素的再摄取，在突触水平上增加去甲肾上腺素的利用率，可以诱导 血压升高，可作为自主神经衰竭的潜在治疗方法。在普通人身上， 托莫西汀对血流动力学的影响最小，因为它的中枢和外周之间保持平衡 对自主神经系统的作用。在中枢自主神经通路中，升高的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，NE含量增加 水平可能通过作用于节后α-1肾上腺素能受体来刺激交感神经活动。患有疾病的患者 自主神经衰竭在这些中枢和外周自主神经通路之间存在不平衡。在MSA中， 外周交感神经纤维从其中央输入断开，暴露了任何外周交感神经- 点赞效应和血压反应。 在一项概念验证临床试验中，我确定了18毫克托莫西汀对坐姿和站姿的影响 21例自主神经衰竭患者的血压(MSA 10例，PAF 11例)。这些初步数据显示， 与对照组相比，急性剂量18毫克的托莫西汀使坐位收缩压(SBP)升高约50毫米汞柱 仅在MSA中使用安慰剂。在另一项单独的交叉研究中，我们比较了单剂量18毫克 托莫西汀联合米多君(5，10 mg)和安慰剂治疗高血压病69例 NOH和自主神经功能衰竭。我们的结果显示，托莫西汀和米多君增加了坐位血压。 同样的震级。然而，18毫克的托莫西汀在改善站立方面比米多君更有效 SBP(7.5毫米汞柱)。 然而，对急性应用升压剂的反应并不能预测长期疗效 这种药物的疗效。我们建议测试长时间(4周)服用蚊帐的假设 阻滞剂，托莫西汀，改善临床症状，日常生活能力，并增加站立血 MSA患者及早期MSA患者的压力变化。

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.