| Ann Neurol. 2003;53
Suppl 3:S87-97; discussion S97-9.
Neuroprotection in Parkinson's disease: clinical trials.
Stocchi F, Olanow CW.
Department of Neuroscience and Neuromed, University La Sapienza, Rome,
Italy.
Advances in our understanding of the cause and pathogenesis of Parkinson's
disease (PD) have permitted the rational selection of putative neuroprotective
agents for study in PD. However, the list of agents that might provide
neuroprotective effects derived from laboratory studies is daunting, and
we face the challenge of determining which agents to bring to the clinic
and how to find the resources (patients and funds) to properly study so
many promising therapeutic opportunities.1 Appropriate outcome variables
that are not confounded by any symptomatic effect of the drug and are
acceptable to clinicians and regulatory authorities also remain to be
defined. The first clinical trials designed to test the capacity of putative
neuroprotective agents to alter the natural history of PD have now been
performed and illustrate some of these problems. The DATATOP (Deprenyl
and Tocopherol Antioxidant Therapy of PD) study used the time to reach
a disease milestone in untreated PD patients (ie, need for levodopa) as
the primary end point. However, interpretation of results was confounded
by the drug's symptomatic effect. The SINDEPAR (Sinemet-Deprenyl-Parlodel)
study used the change in motor score between initial visit and final visit
after washout of all study medications as the primary end point. However,
here too there were concerns about confounding symptomatic effects, because
antiparkinsonian medications have now been shown to have a long duration
response that can persist for weeks and perhaps even months after withdrawal.
More recent studies have used surrogate markers of the integrity of nigrostriatal
function such as striatal uptake of fluorodopa on positron emission tomography
(PET) or beta-CIT-on single-photon emission computerized tomography (SPECT)
as primary outcome measures. However, it has not yet been confirmed that
striatal uptake of these isotopes does in fact correlate with the remaining
number of dopamine neurons or terminals, and the possibility of a confounding
pharmacological effect has not yet been completely excluded. To date,
no drug has been established to have a neuroprotective effect in PD, and
none has been approved for a neuroprotective indication. Furthermore,
regulatory agencies have not yet agreed that any of the outcome measures
currently used will be acceptable for approval of a new drug. Resolution
of these issues is of critical importance to convince pharmaceutical companies
to expend the hundreds of millions of dollars necessary to bring a new
drug to market. Drugs that already have been approved in PD for their
symptomatic effects, such as dopamine agonists or propargylamines (eg,
selegiline), offer the best opportunity for establishing that a drug is
neuroprotective in PD in the immediate future, but herein also lies the
difficulty of establishing that any benefits observed are not solely because
of the drug's symptomatic properties. Currently, this will most likely
entail demonstrating that the drug provides benefit for PD patients for
both imaging and clinical markers of disease progression. |
| Sinemet CR is a controlled-release
tablet that may be given to help relieve the muscle stiffness, tremor,
and weakness caused by Parkinson's disease. It may also be given to relieve
Parkinson-like symptoms caused by encephalitis (brain fever), carbon monoxide
poisoning, or manganese poisoning. Sinemet CR contains two drugs, carbidopa
and levodopa. The drug that actually produces the anti-Parkinson's effect
is levodopa. Carbidopa prevents vitamin B6 from destroying levodopa, thus
allowing levodopa to work more efficiently. Parkinson's drugs such as
Sinemet CR relieve the symptoms of the disease, but are not a permanent
cure.
GENERIC NAME: levodopa-carbidopa
BRAND NAME: Sinemet
DRUG CLASS AND MECHANISM: Levodopa-carbidopa is a combination
of two drugs, levodopa and carbidopa. Levodopa-carbidopa is used in the
treatment of Parkinson's disease. Parkinson's disease is believed to be
related to low levels of dopamine in certain parts of the brain. When
levodopa is taken orally, it crosses through the "blood- brain barrier."
Once it crosses, it is converted to dopamine. The resulting increase in
brain dopamine concentrations is believed to improve nerve conduction
and assist the movement disorders in Parkinson disease. Carbidopa does
not cross the blood-brain barrier. Carbidopa is added to the levodopa
to prevent the breakdown of levodopa before it crosses into the brain.
The addition of carbidopa allows lower doses of levodopa to be used. This
reduces the risk of side effects from levodopa such as nausea and vomiting.
This combination medicine was approved by the FDA in 1988.
PREPARATIONS: Oval tablets (doses stated are for levodopa/carbidopa):
100mg/10mg, 200mg/20mg, 200mg/25mg, 250mg/ 25mg, and a sustained-release
preparation (Sinemet CR) containing 200mg/50mg.
STORAGE: Tablets should be kept at room temperature,
15- 30°C (59-86°F).
PRESCRIBED FOR: Levodopa-carbidopa is indicated for
the management of Parkinson's disease.
DOSING: Levodopa-carbidopa is taken several times per
day. It may be administered with food to reduce the likelihood of nausea.
However, a high-protein diet may reduce its absorption.
DRUG INTERACTIONS: The use of amantadine (Symmetrel),
benztropine (Cogentin), procyclidine (Kemadrin), or trihexyphenidyl (Artane)
with levodopa-carbidopa can enhance the anti- Parkinson's effects of levodopa.
Droperidol, haloperidol (Haldol), loxapine (Loxitane), metoclopramide
(Reglan), phenothiazines such as prochlorperazine (Thorazine); thioxanthenes
as thiothixene (Navane) inhibit dopamine in the brain. These drugs, therefore,
can worsen Parkinson's disease and reverse the beneficial effects of levodopa.
Methyldopa (Aldomet) and reserpine also can interfere with the beneficial
actions of levodopa- carbidopa and can increase the risk of side effects.
Phenytoin (Dilantin) can increases the break-down of levodopa- carbidopa,
reducing its effectiveness.
Use of levodopa-carbidopa with monoamine oxidase inhibitors (MAOI's)
antidepressants, for example, isocarboxazid (Marplan), phenelzine (Nardil),
tranylcypromine (Parnate), and procarbazine (Matulane), can result in
severe and dangerous elevations in blood pressure. MAOI's should be stopped
2-4 weeks before starting levodopa-carbidopa therapy.
The side effects associated with levodopa, including dizziness upon rising,
confusion, movement disorders, nausea, and hallucinations, all can be
increased by selegiline (Eldepryl).
PREGNANCY: Although there are no human studies that
have examined the effects of levodopa-carbidopa on the fetus, animal studies
have shown adverse effects. Therefore, in prescribing levodopa- carbidopa
for a pregnant woman, the physician must weigh the potential risks to
the fetus against the potential benefits to the mother.
NURSING MOTHERS: Levodopa is distributed into breast
milk. It also may inhibit production of milk. It is generally recommended
that levodopa-carbidopa should not be given to women who are breast- feeding.
SIDE EFFECTS: Most patients receiving levodopa-carbidopa
experience side effects, but these are usually reversible. Occasional
involuntary movements are the most common of the serious side effects
of levodopa-carbidopa therapy. These may include chewing, gnawing, twisting,
tongue or mouth movements, head bobbing, or movements of the feet, hands,
or shoulder. These may respond to a reduction in the dose. Muscle twitching,
dizziness, muscle jerks during sleep, and hand tremor also may occur.
Various psychiatric disturbances may occur during levodopa-carbidopa therapy.
Such disturbances include memory loss, anxiety, nervousness, agitation,
restlessness, confusion, inability to sleep, nightmares, daytime tiredness,
mental depression or euphoria.
Gastrointestinal side effects are common in patients receiving levodopa-carbidopa.
Nausea, vomiting, loss of appetite, and weight loss may occur. Patients
may experience dizziness upon standing up, associated with a drop in blood
pressure. Fortunately, the body develops tolerance to this side effect
within a few months.
Infrequently, patients may develop a drop in white blood cell count during
levodopa-carbidopa therapy. This is a cause to temporarily, if not permanently,
stop treatment.
Caution! Before starting
to take this medicine, it is vital that you should consult your doctor!
Do not use it on your own initiative, without medical advice.
Also, you should read carefully important health information about this
drug given here:
www.nlm.nih.gov |
