CARBIDOPA IN FAMILIAL DYSAUTONOMIA

项目总结/摘要 研究目的是确定卡比多巴（Lodosyn®）是否安全且可耐受， 家族性自主神经功能障碍（FD）患者，并了解它是否可以抑制儿茶酚胺- 诱发阵发性高血压，降低过高的血压（BP） 可变性FD是一种严重的遗传性疾病， 感觉神经元从动脉压力感受器传递信息的神经是 尤其是血压不稳定。即使是轻微的焦虑也会引发明显的 释放儿茶酚胺，引起阵发性高血压和心动过速。的 随后的血压变异性增大与FD中的靶器官损害密切相关。 目前的药物治疗几乎没有效果或无法忍受的副作用， 目标是血压变异性。卡比多巴是芳香族L-氨基的可逆竞争性抑制剂， 酸脱羧酶（DOPA-脱羧酶）。它不能穿过血脑屏障， 防止在外周中形成儿茶酚胺。我们最近发现， 卡比多巴减少了多巴胺进入循环系统的溢出， FD患者的恶心。初步观察表明，卡比多巴也可能减少 通过减少脑外去甲肾上腺素的形成来夸大血压的变化。 为了跟进这一发现，我们建议进行一项有效的研究， 卡比多巴可能抑制去甲肾上腺素驱动的阵发性 FD患者的高血压，从而降低血压变异性。我们将使用一个随机的，双 比较卡比多巴和安慰剂两种剂量的盲法、14周交叉研究。样品 规模将是30例FD患者，他们将作为自己的对照，在两个积极的 剂量和安慰剂。以随机顺序，患者将接受高剂量卡比多巴（600 mg/天）， 低剂量卡比多巴（300 mg/天）或匹配的安慰剂，分3次进行4周治疗 时期我们将全程监测不良事件和安全性/耐受性参数。的 主要疗效终点为收缩压变异性的标准差。到 为了了解卡比多巴的生理作用，我们将测量24小时儿茶酚胺 排泄以及昼夜和短期BP变异性。如果成功，这将是一个重大的 FD患者的治疗突破，并可作为使用 卡比多巴在其他更常见的具有相似病理生理学的BP疾病中。

PROJECT SUMMARY/ABSTRACT The study objective is to determine whether carbidopa (Lodosyn®) is safe and tolerable in patients with familial dysautonomia (FD), and to learn whether it can inhibit catecholamine- induced paroxysmal hypertension and reduce their exaggerated blood pressure (BP) variability. FD is a brutal genetic disease caused by a developmental defect in primary sensory neurons. The nerves that relay information from arterial baroreceptors are particularly affected resulting in unstable BP. Even mild anxiety can trigger a pronounced release of catecholamines causing paroxysmal hypertension and tachycardia. The subsequent exaggerated BP variability correlates closely with target organ damage in FD. Current drug treatments have little efficacy or intolerable side effects, and none specifically targets BP variability. Carbidopa is a reversible competitive inhibitor of aromatic L-amino acid decarboxylase (DOPA-decarboxylase). It cannot cross the blood brain barrier, and only prevents the formation of catecholamines in the periphery. We recently showed that carbidopa reduces the spillover of dopamine into the circulation and decreases the frequency of nausea in FD patients. Preliminary observations suggest that carbidopa may also lessen the exaggerated BP variability by reducing the formation of norepinephrine outside the brain. To follow up on this finding, we propose to conduct a well-powered study to test of the hypothesis that carbidopa might dampen norepinephrine-driven periods of paroxysmal hypertension in FD patients and thus lessen BP variability. We will use a randomized, double blind, 14-week cross over study comparing two doses of carbidopa and placebo. The sample size will be 30 patients with FD, who will act as their own controls across the two active doses and placebo. In random order, patients will receive high dose carbidopa (600 mg/day), low dose carbidopa (300 mg/day) or matching placebo in three separate 4-week treatment periods. We will monitor adverse events and safety/tolerability parameters throughout. The primary efficacy end-point will be the standard deviation of systolic BP variability. To understand the physiological effects of carbidopa we will measure 24-h catecholamine excretion and diurnal and short-term BP variability. If successful, this would be a major therapeutic breakthrough for FD patients, and could serve as the basis for the use of carbidopa in other more common BP disorders with similar pathophysiology.