Parkinson Disease Clinical Trial
Official title:
L-Dihydroxyphenylserine (L-DOPS) for Norepinephrine Deficiency: Interactions With Carbidopa and Entacapone
An experimental drug called L-DOPS increases production in the body of a messenger chemical
called norepinephrine. Cells in the brain that make norepinephrine are often gone in
Parkinson disease. The exact consequences of this loss are unknown, but they may be related
to symptoms such as fatigue, depression, or decreased attention that occur commonly in
Parkinson disease. This study will explore effects of L-DOPS in conjunction with carbidopa
and entacapone, which are drugs used to treat Parkinson disease. We wish to find out what
the effects are of increasing norepinephrine production in the brain and whether carbidopa
and entacapone augment those effects.
Volunteers for this study must be at least 18 years of age and able to give consent to
participate in the study. To participate in the study, volunteers must discontinue use of
alcohol, tobacco, and certain herbal medicines or dietary supplements, and must also taper
or discontinue certain kinds of medications that might interfere with the results of the
study. Candidates will be screened with a medical history and physical exam.
Participants will be admitted to the National Institutes of Health Clinical Center for two
weeks of testing. The study will have three testing phases in a randomly chosen order for
each participant:
- Single dose of L-DOPS
- Single dose of L-DOPS in conjunction with carbidopa
- Single dose of L-DOPS in conjunction with entacapone
Each phase will last two days, with a washout day between each phase in which no drugs will
be given and no testing will be performed. In each phase, participants will undergo a series
of tests and measurements, including blood pressure and electrocardiogram tests.
Participants who are healthy volunteers will also have blood drawn and will undergo a lumbar
puncture (also known as a spinal tap) to obtain spinal fluid for chemical tests.
Objective: L-DOPS is a synthetic chemical that can be converted to norepinephrine (NE). NE
is a key messenger of the sympathetic nervous system. Failure of the sympathetic nervous
system results in orthostatic hypotension (OH), a fall in blood pressure when the person
stands up. Patients with Parkinson disease (PD) often have OH that is related to loss of
sympathetic nerves and to NE deficiency. L-DOPS can help treat OH in these patients. Drugs
used commonly to treat PD, however, probably influence effects of L-DOPS. Carbidopa, which
combined with levodopa (brand name Sinemet) is a standard treatment for PD, might prevent
L-DOPS from being turned into NE outside the brain and therefore interfere with effects of
L-DOPS on blood pressure. Entacapone (brand name Comtan) might augment production of NE
after a dose of L-DOPS, by decreasing metabolic breakdown of L-DOPS. The first goal of this
study is to test these hypotheses in patients with neurogenic OH. NE is also a chemical
messenger in the brain and is thought to participate in a variety of neuropsychiatric
phenomena such as vigilance, mood, memory, and transmission of pain sensation. Patients with
OH can have evidence of central NE deficiency. A second goal of this study is to determine
whether depressed mood, apathy, fatigue, or pain improve with L-DOPS treatment in these
patients. A third goal is to test whether carbidopa and entacapone, which both should
enhance delivery of L-DOPS to the brain, augment L-DOPS effects on these symptoms. Finally,
a fourth goal is to verify that carbidopa and entacapone augment neurochemical indices of
central neural production of NE after a dose of L-DOPS.
Study Population: The subjects are patients with PD+NOH, MSA+NOH, or pure autonomic failure
(PAF); and healthy volunteers. A total of 55 patients and 15 healthy volunteers are to be
enrolled.
Design: Patients and healthy volunteers enter this Protocol after undergoing clinical
laboratory evaluation under NIH Clinical Protocol 03-N-0004, to confirm the diagnosis,
identify NOH, and provide data related to central or peripheral NE production. Each subject
serves as his or her own control. Subjects are tested after taking a single oral dose of 400
mg of L-DOPS in a randomized crossover design study of three treatment conditions L-DOPS
alone, L-DOPS after carbidopa (200 mg), and L-DOPS after entacapone (200 mg). Healthy
volunteers have CSF drawn by lumbar puncture under fluoroscopic guidance about 3 hours after
administration of each drug combination.
Outcome Measures:
Primary: Hemodynamics, plasma catechols and their metabolites, non-motor symptom checklists
Secondary: (In healthy volunteers) CSF catechols and their metabolites
Other: (In patients with dysarthria) Speech
;
Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
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