CARBIDOPA IN FAMILIAL DYSAUTONOMIA

项目摘要/摘要 研究目的是确定卡比多巴(Lodosyn®)是否安全和耐受性 家族性自主神经障碍(FD)患者，并了解它是否能抑制儿茶酚胺- 诱发阵发性高血压和降低其夸大血压(BP) 可变性。FD是一种残酷的遗传性疾病，由初发期发育缺陷引起 感觉神经元。从动脉压力感受器传递信息的神经是 受影响尤其严重，导致BP不稳定。即使是轻微的焦虑也会引发明显的 儿茶酚胺的释放会引起阵发性高血压和心动过速。这个 随后放大的血压变异性与FD的靶器官损害密切相关。 目前的药物治疗几乎没有疗效或无法忍受的副作用，而且没有特效药。 目标是BP变异性。卡比多巴是芳香族化合物L-氨基的可逆竞争抑制剂 酸性脱羧酶(DOPA-脱羧酶)。它不能越过血脑屏障，而且只有 防止儿茶酚胺在外周形成。我们最近展示了 卡比多巴减少了多巴胺进入循环的溢出，并降低了频率 功能性消化不良患者的恶心症状。初步观察表明，卡比多巴也可能会减少 通过减少脑外去甲肾上腺素的形成来夸大血压的变异性。 为跟进这项研究结果，我们建议进行一项有足够动力的研究，以测试 卡比多巴可能抑制去甲肾上腺素驱动的发作期的假说 可降低FD患者的高血压，从而降低血压变异性。我们将使用随机的、双倍的 一项为期14周的盲法交叉研究，比较了两种剂量的卡比多巴和安慰剂。样本 大小将为30名FD患者，他们将作为自己对照的两个活跃对象 剂量和安慰剂。按随机顺序，患者将接受大剂量卡比多巴(600毫克/天)， 小剂量卡比多巴(300毫克/天)或匹配的安慰剂，分别治疗3次，为期4周 句号。我们将全程监测不良事件和安全性/耐受性参数。这个 主要疗效终点将是收缩压变异性的标准差。至 了解卡比多巴的生理作用，我们将测定24小时儿茶酚胺 排泄量、血压昼夜变异性和短期变异性。如果成功，这将是一个重大的 为FD患者的治疗突破，并可作为使用的基础 卡比多巴在其他更常见的BP疾病中具有相似的病理生理学。

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.