Norepinephrine Transporter Blockade in Neurogenic Orthostatic Hypotension

The clinical picture of autonomic failure is dominated by disabling orthostatic hypotension. Recent developments in the understanding of the underlying pathophysiology of the discrete clinical forms of autonomic failure have revealed that participants with multiple system atrophy (MSA) are characterized by impairment of central autonomic pathways crucial for autonomic cardiovascular control, but have intact peripheral postganglionic noradrenergic fibers. Participants with MSA have peripheral residual sympathetic tone that is no longer modulated by central autonomic centers and is not under baroreflex control and, therefore, cannot be harnessed to improve their orthostatic hypotension. On the other hand, participants with pure autonomic failure (PAF) and with Parkinson' s disease (PD) are characterized by neurodegeneration and loss of peripheral noradrenergic fibers, as evidenced by low levels of plasma norepinephrine and absent cardiac uptake of labeled catechols. Pharmacological inhibition of the norepinephrine transporter (NET) is an example of an approach that can take advantage of the participants' own residual sympathetic tone. NET inhibition will increase synaptic norepinephrine that is tonically released in MSA participants by preventing its reuptake. This should result in an increase in blood pressure. This is a longitudinal study of 50 participants, age 18-80 years with neurogenic orthostatic hypotension associated with impaired reflexes. The purpose of this study is to determine if the magnitude of the pressor response to atomoxetine at study entry, will be useful as a biomarker to differentiate those participants that will ultimately be shown to have pre-ganglionic (central) lesions (MSA) with those shown to have post ganglionic (peripheral) lesions (PAF and PD). ]]> Autonomic Function TestsAutonomic Symptom ProfileConcomitant MedicationsDemographicsEcgEnrollmentGeneral Medical HistoryInternational Cooperative Ataxia Rating Scale (ICARS)Inclusion ExclusionLabsMedication TrialNeuro HistoryOrthostatic Hypotension Questionnaire - For Medication TrialPhone Follow-upPhysical ExamPost Study DiagnosisPosture StudyPre Study DiagnosisQSARTQuestionnaire ScoresTiltUnified Parkinson's Disease Rating Scale - Part 3 (UPDRS III)Inclusion Criteria Age 18-80 years Neurogenic orthostatic hypotension, ≥ 30 mmHg drop in SBP within 5 minutes of standing Associated with impaired autonomic reflexes, as determined by absence of blood pressure overshoot during phase IV of the Valsalva maneuver Absence of other identifiable causes of autonomic neuropathy, and Able and willing to provide informed consent Exclusion Criteria Pregnancy Systemic illnesses known to produce autonomic neuropathy, including but not limited to diabetes mellitus, amyloidosis, monoclonal gammopathy of unknown significance, and autoimmune neuropathies. Known intolerance to atomoxetine Pre-existing sustained severe hypertension (BP ≥ 180/110 mmHg in the sitting position) Clinically unstable coronary artery disease, or major cardiovascular or neurological event in the past 6 months Any other significant systemic, hepatic, cardiac or renal illness Use of MAO-I within 14 days Known closed-angle glaucoma Life-threatening arrhythmias ]]> Study Activated February 01, 2011 First Accrual March 7, 2011 Last Accrual May 10, 2013 ]]>自主神经衰竭的临床表现以致残性体位性低血压为核心特征。近年来，针对不同亚型自主神经衰竭的潜在病理生理学研究取得进展，揭示出多系统萎缩（multiple system atrophy, MSA）患者的核心特征为：调控心血管自主神经功能的关键中枢自主神经通路受损，但外周节后去甲肾上腺素能纤维结构完整。MSA患者的外周残余交感张力不再受中枢自主神经中枢调控，亦不处于压力反射调控范围内，因此无法被用于改善其体位性低血压。 与之相对，纯自主神经衰竭（pure autonomic failure, PAF）与帕金森病（Parkinson's disease, PD）患者则表现为神经退行性变及外周去甲肾上腺素能纤维丢失，该特征可通过血浆去甲肾上腺素水平降低、心脏对标记儿茶酚胺摄取缺失得以证实。 针对去甲肾上腺素转运体（norepinephrine transporter, NET）的药理学抑制，是一类可利用患者自身残余交感张力的干预策略。NET抑制可通过阻断突触间隙去甲肾上腺素的重摄取，提升MSA患者中枢调控缺失的突触间隙去甲肾上腺素水平，进而升高血压。 本研究为一项纳入50名18~80岁神经源性体位性低血压伴自主反射受损患者的纵向研究。本研究旨在明确：研究入组时受试者对托莫西汀的升压反应幅度，能否作为生物标志物，用以区分最终确诊为节前（中枢）病变（MSA）的患者，与确诊为节后（外周）病变（PAF与PD）的患者。 评估项目包括：自主功能检测、自主神经症状问卷、合并用药、人口学资料、心电图、入组筛查、既往病史、国际合作共济失调评定量表（International Cooperative Ataxia Rating Scale, ICARS）、纳入/排除标准、实验室检查、药物试验、神经病史、体位性低血压问卷（药物试验专用）、电话随访、体格检查、研究后诊断、姿势试验、研究前诊断、定量发汗轴突反射试验（Quantitative Sudomotor Axon Reflex Test, QSART）、问卷评分、倾斜试验、统一帕金森病评定量表第三部分（Unified Parkinson's Disease Rating Scale - Part 3, UPDRS III） 纳入标准： 1. 年龄18~80岁； 2. 神经源性体位性低血压：站立5分钟内收缩压（SBP）下降≥30 mmHg； 3. 伴自主反射受损：瓦尔萨尔瓦动作IV期无血压反弹； 4. 无其他可明确的自主神经病变病因； 5. 能够且愿意签署知情同意书。 排除标准： 1. 妊娠； 2. 已知可引发自主神经病变的系统性疾病，包括但不限于糖尿病、淀粉样变性、意义未明单克隆丙种球蛋白血症及自身免疫性神经病； 3. 已知对托莫西汀不耐受； 4. 既往存在持续性重度高血压（坐位血压≥180/110 mmHg）； 5. 临床不稳定型冠状动脉疾病，或过去6个月内发生过重大心血管或神经系统事件； 6. 存在其他显著系统性、肝脏、心脏或肾脏疾病； 7. 14天内使用过单胺氧化酶抑制剂（MAO-I）； 8. 已知闭角型青光眼； 9. 危及生命的心律失常。 本研究于2011年2月1日启动，首次患者入组时间为2011年3月7日，最后一例患者入组时间为2013年5月10日。