Carbidopa for the Treatment of Nausea and Vomiting in Familial Dysautonomia
Carbidopa for the Treatment of Nausea and Vomiting in Familial Dysautonomia
This is a pilot clinical trial of carbidopa to treat disabling attacks of nausea and vomiting
 in patients with familial dysautonomia (FD, also known as Riley Day syndrome or hereditary
 sensory and autonomic neuropathy type III). FD is a rare autosomal recessive disease in which
 the growth and development of selective nerves is impaired. Patients with FD suffer recurrent
 uncontrollable nausea and vomiting crises accompanied by skin flushing, tachycardia and
 arterial hypertension. Current treatments of nausea are ineffective or have intolerable side
 sides. Our long-term goal is to treat nausea effectively and without side effects, a
 therapeutic intervention that would markedly improve the quality of life of patients with FD.

 The investigators have recently found that resting plasma dopamine levels are high in
 patients with FD and increase up to 40-fold during nausea and vomiting attacks. This led us
 to postulate that stimulation of dopamine receptors in the chemoreceptor trigger zone of the
 brainstem is the likely mechanism of vomiting.

 Carbidopa is a reversible competitive inhibitor of aromatic L-amino acid decarboxylase (also
 known as dopa-decarboxylase) that cannot cross the blood brain barrier. It has been used
 successfully for many years to block the extracerebral synthesis of dopamine and avoid nausea
 and vomiting in patients with Parkinson's disease taking levodopa. The investigators reasoned
 that carbidopa could have a similar antiemetic effect in patients with FD.

 The investigators propose to conduct a pilot trial to assess the safety, tolerability and
 efficacy of carbidopa for the treatment of nausea in patients with FD. The pilot trial will
 recruit 25 patients with FD who complain of severe nausea that affects their quality of life.
 The trial will be divided into two consecutive, but independent parts. Part 1, will address
 the safety and tolerability of carbidopa in patients with FD using an open-label dose
 titration phase followed by 4-weeks of open-label treatment. Part 2, will address the
 efficacy of carbidopa for the treatment of nausea in patients with FD using a randomized,
 placebo controlled, double blind, 4-week cross over design.

 The investigators hope to demonstrate that carbidopa is a safe, well-tolerated drug that
 blocks the peripheral formation of dopamine and thus prevents dopamine-induced nausea and
 vomiting attacks in patients with FD.
Patients with familial dysautonomia (FD), also called Riley Day syndrome or hereditary
 sensory and autonomic neuropathy type III, suffer recurrent attacks of uncontrollable nausea
 and vomiting that can last several hours or days and are severely disabling. Hypertension,
 tachycardia and skin blotching frequently accompany these attacks. Our long-term objective is
 to develop an effective treatment for nausea and vomiting in patients with FD.

 In preliminary studies we found that plasma levels of dopamine were very high during attacks.
 Stimulation of dopamine receptors in the chemoreceptor trigger zone in the brainstem is a
 well-known cause of nausea and vomiting. The investigators postulate that acute increases in
 circulating dopamine levels are the cause of paroxysmal nausea and vomiting in FD.

 Dopamine is synthesized by decarboxylation of the aminoacid L-dihydroxyphenylserine (L-DOPA)
 by the enzyme aromatic L-aminoacid decarboxylase, also known as DOPA decarboxylase. Patients
 with Parkinson's disease suffer nausea and vomiting when they receive treatment with L-DOPA.
 However, when L-DOPA is administered together with carbidopa, a reversible competitive
 inhibitor of DOPA decarboxylase that does not cross the blood brain barrier, nausea and
 vomiting are prevented. The investigators hypothesize that by blocking the conversion of DOPA
 to dopamine and thus preventing its increase in plasma, treatment with carbidopa will
 decrease nausea and vomiting in patients with FD.

 Although carbidopa has been used for many years in patients with Parkinson's disease, it has
 never been used in patients with FD. The first specific aim of this proposal is to assess the
 safety and tolerability of carbidopa in patients with FD.

 The second specific aim of this proposal is to determine whether blocking the peripheral
 synthesis of dopamine with carbidopa will improve recurrent nausea in patients with FD.
Inclusion Criteria:

 -  Male of female patients aged 12 and older

 -  Confirmed diagnosis of familial dysautonomia by genetic testing.

 -  Symptoms of severe nausea

 -  Written informed consent or ascent to participate in the pilot trial and understanding
 that they can withdraw consent at anytime without affecting their future care.

 -  Ability to comply with the requirements of the study procedures, including taking
 blood pressure measurements at home.

 Exclusion Criteria:

 -  Patients taking metroclopromide, domperidone, risperidone or other dopamine blockers

 -  Patients taking MAO-inhibitors

 -  Patients taking tricyclic antidepressants

 -  Patients taking neuroleptic drugs (haloperidol and chlorpromazine)

 -  Patients with a known hypersensitivity to any component of this drug.

 -  Patients with atrial fibrillation, angina or an electrocardiogram documenting
 significant abnormality that may jeopardize the patient's health.

 -  Patients with significant pulmonary, liver, renal (creatinine >2.0 mg/ml) or cardiac
 illness

 -  Patients who are unable to clearly identify and rate their symptoms of nausea.

 -  Women who are pregnant or lactating

 -  Patients who have a significant abnormality on clinical examination that may, in