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.

Public Health Relevance

Patients with the rare genetic disorder familial dysautonomia (FD) suffer from frequent surges in blood pressure that irreversibly damage their organs, for which there are no adequate treatments. This clinical trial will test whether carbidopa could effectively and safely treat the problematic high blood pressure. If successful, this will have a major impact in the quality of life of these patients, and could potentially be a treatment for other disorders of uncontrolled sympathetic activation, including the rare form of acquired afferent baroreflex failure.

National Institute of Health (NIH)
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Special Emphasis Panel (ZFD1-SRC (99))
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New York University
Schools of Medicine
New York
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