This study will evaluate the effects of the drug riluzole on Parkinson's disease symptoms
and on dyskinesias (involuntary movements) that develop as a result of long-term treatment
with levodopa. Riluzole blocks the action of the chemical messenger glutamate, thought to
be involved in producing Parkinson's symptoms. The drug is currently approved to treat
amyotrophic lateral sclerosis, another neurologic condition.
Patients with relatively advanced Parkinson's disease between 20 and 80 years of age may be
eligible for this 4-week study. Participants will have a complete medical history and
physical examination, and a detailed neurological evaluation. The evaluations will include
blood tests and an electrocardiogram, and possibly brain magnetic resonance imaging (MRI),
CT scan, and chest X-ray.
Participants will, if possible, stop taking all antiparkinsonian medications except levodopa
(Sinemet) for one month before the study begins and throughout its duration. For the first
1 to 3 days, patients will be admitted to the NIH Clinical Center to undergo a levodopa
"dose-finding" procedure. For this study, patients will stop taking their oral Sinemet and
instead will have levodopa infused through a vein for up to 8 hours/day. During the
infusions, the levodopa dose will be increased slowly until either 1) parkinsonian symptoms
improve, 2) unacceptable side effects occur, or 3) the maximum study dose is reached.
Symptoms will be monitored frequently to find two infusion rates: 1) one that is less than
what is needed to relieve symptoms (suboptimal rate), and 2) one that relieves symptoms but
may produce dyskinesias (optimal rate).
When the dose-finding phase is completed, treatment will begin. Patients will take riluzole
or placebo (a look-a-like pill with no active ingredient) twice a day, along with their
regular Sinemet, for 3 weeks. (All participants will receive placebo at some time during the
study, and some patients will receive only placebo throughout the entire 4 weeks.) At the
end of each week, patients will be readmitted to the hospital and receive the previous
week's dose of riluzole or placebo in combination with a levodopa infusion at the rate
determined in the dose-finding phase of the study. The procedure for the infusion will be
the same as that for the dose-finding phase. The dose of riluzole will be increased until
the optimum dose has been achieved or until side effects occur (at which time the dose will
be lowered or the drug stopped).
Throughout the study, parkinsonian symptoms and dyskinesias will be evaluated using
standardized rating scales and blood samples will be drawn periodically to measure drug
The objective of this study is to evaluate the acute effects of a nonselective inhibitor of
glutamate mediated synaptic transmission on the severity of parkinsonian signs and
levodopa-associated motor response complications in patients with moderately advanced
Parkinson's disease. In a controlled proof-of-principle clinical trial, the efficacy of the
glutamate release inhibitor riluzole will be assessed through the use of validated motor
function scales. Safety will be monitored by means of frequent clinical evaluations and
Males and females between the ages of 20-80 are eligible for study. Women must be either
at least one year post-menopausal, or using an adequate contraceptive method for at least
one month prior to and during participation in this study. All will carry the diagnosis of
idiopathic Parkinson's disease based on the presence of a characteristic clinical history
and neurological findings. All will have relatively advanced disease with
levodopa-associated motor response complications, including peak-dose dyskinesias and
The presence or history of any medical condition that can reasonably be expected to
subject the patient to unwarranted risk. Any clinically significant laboratory
abnormalities including liver enzyme elevations more than two times the upper limit of
normal, or neutropenia (wbc less than 3000).
Parkinson's disease patients exhibiting diphasic or end-of dose dyskinesias or disabling
dystonia will be excluded. Patients who are unable to be treated with levodopa/carbidopa
alone or with a single, relatively short-acting dopamine agonist will also be excluded.
Patients with a form of parkinsonism other than idiopathic PD or with a diagnosis of
dementia (MMSE less than 24) or major psychiatric disorder (UPDRS [Part I Item 3] greater
than or equal to 2).
Patients with unacceptable prior/concomitant medications will also be excluded.
Since the influence of any investigational compound on the unborn child and reproductive
organs is unknown, pregnant women and those not practicing effective means of birth
control will be excluded as well.
Patients with prior bilateral surgical intervention for the treatment of parkinsonian
symptoms, i.e. deep brain stimulation, pallidotomy, fetal tissue transplantation as well
as patients must at risk for hypotension, cardiac arrhythmia, and/or myocardial ischemia
secondary to intravenous levodopa challenge will be excluded.