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Benefits of Levodopa Therapy |
Levodopa therapy: delivering dopamine to the brain
Because dopamine itself does not naturally cross into the brain, it is administered
as levodopa (or L-Dopa), which passes into the brain where it is transformed
into dopamine. Levodopa is usually given as a tablet or capsule.
Levodopa is highly effective in controlling most symptoms of Parkinson's disease. More
than 30 years after its discovery it remains the cornerstone of Parkinson's disease therapy, and a
large majority of patients receive levodopa therapy. Once in the body, levodopa is broken down by
molecules called enzymes—this reduces the amount of medication that can reach the brain.
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There are two main enzymes involved in the breakdown of levodopa: peripheral dopa-decarboxylase (DDC) and catechol-O-methyltransferase (COMT). Inhibiting these enzymes can prevent levodopa's breakdown, thus making more levodopa available in the brain and improving symptom control. Unfortunately the effectiveness of levodopa can decline after years of treatment—which means that managing the long-term treatment of Parkinson's can be challenging.
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Levodopa is broken down by two enzymes
Once in the body levodopa is broken down by two enzymes, peripheral dopa-decarboxylase (DDC) and cathechol-O-methyltransferase (COMT), which reduce the amount of levodopa able to reach the brain. Using a DDC inhibitor in combination with levodopa reduces conversion of levodopa to dopamine in the blood stream, and enables more levodopa to cross the blood-brain barrier into the brain where it can be converted into dopamine. COMT inhibitors are used to enhance levodopa/DDC therapy. They prevent the breakdown of levodopa to 3-OMD (3-methoxy-4-hydroxy-1-phenylalanime) in the body, which results in
a greater and more sustained delivery of levodopa to the brain.
Peripheral dopa-decarboxylase inhibitors:
These block one of the two enzymes that remove levodopa before it can reach the brain. In the 1970s, peripheral dopa-decarboxylase inhibitor (DDC) was the first of these two enzyme inhibitors to be identified, soon after levodopa was introduced. Using a DDC inhibitor ensures that more of the levodopa medication reaches the brain. There are two DDC inhibitor medications available: carbidopa and benserazide.
COMT Inhibitors:
These block the other enzyme that removes levodopa before it can reach the brain. In the 1990s, COMT inhibitors were developed. COMT inhibition provides extended and smoother exposure of levodopa to the brain. This can improve and lengthen the response to each levodopa dose, thus increasing the amount of time when the symptoms of Parkinson's are well controlled.
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Why does levodopa become less effective over time?
Researchers now believe that the complications associated with traditional
levodopa therapy may relate to a combination of factors:
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As Parkinson's disease progresses the number of dopamine cells in the brain
continues to decrease and the brain has fewer cells that can take up and
store the drug for later release—in these circumstances the brain is said to
have lost its 'buffering' capacity.
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As a result of this loss of 'buffering,' changes in the levels of the drug in the
blood (peaks and troughs) with standard levodopa formulations can no
longer be compensated for and these variations are associated with
variations in the availability of dopamine in the brain. |
Early in the course of the disease, levodopa is converted to dopamine and
stored in the nerve cells. This results in a 'buffering' of dopamine levels, allowing a
more consistent level of dopamine to be available for use in the brain.
Later in the course of the disease, when there are fewer nerve cells,
dopamine can no longer be taken up and stored for later release as well as before.
This means that the 'buffering' is lost and the availability of dopamine in the
brain becomes more variable.
Researchers believe that the fluctuating levels of levodopa in the blood and brain
in the advanced stages of Parkinson's disease result in changes to the internal circuitry of
the brain. This changes how the brain processes information and causes the
development of dyskinesia.
It is currently thought that by maintaining more stable levodopa levels in the
blood stream and reducing the variations of dopamine levels in the brain these
complications may be reduced, delayed, and perhaps reversed. Dopamine agonists provide smoother dopaminergic stimulation by mimicking the
activity of dopamine in the brain. Continuous intravenous infusion of levodopa is an experimental way of providing smoother, more stable levodopa blood levels in Parkinson's disease, and providing more continuous levels of the drug to the brain.
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