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
- 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
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.
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
- INCLUSION CRITERIA:
All subjects in this Protocol will have already undergone clinical laboratory evaluations
called for in Clinical Protocol 03-N-0004, "Clinical Laboratory Evaluation of Primary
Chronic Autonomic Failure.
Age: People younger than 18 years old are excluded.
Risk: A candidate subject is excluded if, in the judgment of the Principal Investigator
or Clinical Director, Protocol participation would place the subject at substantially
increased acute medical risk. This includes the risks associated with air travel to the
NIH. A candidate subject is excluded if, in the opinion of the Principal Investigator or
Clinical Director, the medical risk outweighs the potential scientific benefit.
Disqualifying Conditions: A candidate subject is excluded if there is a disqualifying
condition. Examples of disqualifying conditions are hepatic or renal failure, symptomatic
congestive heart failure, severe anemia, psychosis, refractory ventricular arrhythmias,
and symptomatic coronary heart disease. Persons with dementia interfering with their
ability to provide informed consent are excluded. If dementia is suspected, such as by
score on the mini-mental examination of less than 24, then a bioethics consult will be
Medications: A candidate subject is excluded if clinical considerations require that the
patient continue treatment with a drug likely to interfere with the scientific results.
Examples would be treatment with levodopa/carbidopa or a tricyclic antidepressant.
Patients with known or suspected allergy or hypersensitivity to any test drug are
excluded. Patients unable to discontinue nicotine or alcohol temporarily are excluded.
Patients are not to discontinue any medications before the patient or the patient s
doctor discusses this with Dr. Goldstein, the Principal Investigator, or Sandra Pechnik,
the Research Nurse. If it is decided that discontinuing medications would be unsafe, then
the patient is excluded from the study. Subjects must discontinue use of alcohol and
tobacco throughout the period of testing. PD patients who have difficulty tolerating
withdrawal of levodopa/carbidopa treatment may be treated with a dopamine receptor agonist
during the study, with the dosing remaining the same.
Tricyclic antidepressants, drugs that inhibit L-aromatic-amino-acid decarboxylase or
catechol-O-methyltransferase, levodopa, and carbidopa will be withdrawn throughout the
period of study. Withdrawal of antiparkinsonian medications may worsen rigidity,
bradykinesia, or tremor. These effects are not thought to adversely influence the
long-term course of the disease. Withdrawal of tricyclic antidepressants may worsen
depression. Drug withdrawal will be done only in inpatients. Alternative drugs, such as
serotonin reuptake blockers, anti-anxiety agents, or dopamine receptor agonists, may be
used at constant doses during the study.
Herbal Medicines and Dietary Supplements: Certain herbal medicines or dietary supplements
are known or suspected to interfere with the experimental results, and such herbal
medicines or dietary supplements must be discontinued before enrollment in the study. For
many herbal medicines or dietary supplements, the mechanisms of action and therefore the
possible effects on the experimental results are unknown. In cases where the subjects wish
to continue their herbal medicines or dietary supplements while on study, and search of
the available medical literature fails to identify effects that are known or expected to
interfere with the experimental results, then the subjects may participate.
Practical Limitations: Subjects in whom we feel it would be difficult to insert a
catheter into a vein are excluded. Subjects who are not expected clinically to tolerate
lying still supine during the testing are excluded.
Pregnancy: Pregnant or lactating women are excluded. Women of childbearing potential must
have a negative urine or blood test for pregnancy done within 24 hours before any testing
involving radioactivity or an experimental drug.
Post-Lumbar Puncture Headache: Candidate Healthy Volunteers are excluded if they had a
headache requiring a blood patch after lumbar puncture under fluoroscopic guidance.