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COMT-Inhibitors
- Introduction
- Entacapone (Comtan/Comtess®)
- Tolcapone (Tasmar®)
COMT-Inhibition
A COMT inhibitor is given in combination with levodopa to enhance the delivery of levodopa to the brain, and improve the effectiveness of levodopa in alleviating the symptoms of Parkinson's Disease
Levodopa therapy (Sinemet or Madopar)
Levodopa (often called L-dopa) was developed as a treatment for Parkinson's Disease (PD) in the late 1960's. Its development was based on the important scientific discovery that people with PD experience a severe loss of a substance in the brain - a chemical messenger - called dopamine. These changes in the 'chemistry' of the brain cause the range of symptoms associated with PD. Although dopamine itself cannot pass from the rest of the body into the brain, levodopa can. Levodopa is nearly always given in tablet form. After absorption from the stomach, it is transported to the brain where it is converted to dopamine and replaces the stores of dopamine that are needed for normal movement.
Improving levodopa availability in the body
Once in the body, levodopa is broken down by molecules called enzymes. By blocking or inhibiting these enzymes in the blood stream (using enzyme inhibitors), it is possible to reduce the breakdown of levodopa before it can reach the brain.
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This means that the elimination of levodopa in the body is slowed down. More levodopa is then available to the brain over a longer period of time and this provides extended control over the symptoms of PD.
The combined administration of levodopa with a peripheral decarboxylase inhibitor and a COMT inhibitor to provide more predictable and sustained delivery of levodopa to the brain
The benefits of decarboxylase inhibition
In the 1970's, the first enzyme inhibitors to be developed were peripheral decarboxylase inhibitors. Inhibition of this enzyme resulted in a substantial reduction in the amount of levodopa required with each dose, or tablet, to effectively control the symptoms of PD. In addition, peripheral decarboxylase inhibitors prevent dopamine from building up in the body, in particular the stomach, and reduce unwanted side effects, such as nausea and vomiting. This combination is so effective that today levodopa is always given in the same tablet with a decarboxylase inhibitor (either carbidopa or benserazide).
The benefits of COMT inhibition
When peripheral decarboxylase is inhibited another enzyme - catechol-O-methyl transferase (COMT) - takes over the breakdown of levodopa. COMT inhibitors were recently developed as a way of further improving the delivery of levodopa to the brain. By stopping the breakdown of levodopa, COMT inhibition increases the time that levodopa remains in the body and further increases the time when the symptoms of PD are controlled or eliminated.
Two main COMT inhibitors have been developed to date: entacapone and tolcapone.
Entacapone is known as Comtan and/or Comtess depending on which country you live in. Stalevo is usually well tolerated and is therefore the most widely used COMT inhibitor.
How COMT inhibition works
Levodopa therapy is normally very effective when it is first used in the treatment of PD and is the cornerstone of PD therapy. Unfortunately, this effectiveness can become reduced after years of treatment. For example, you may find that your Parkinson's symptoms begin to re-emerge or become noticeably worse before it is time to take your next scheduled dose of medication. This re-emergence of symptoms is called 'wearing-off'.
As 'wearing off' becomes more noticeable, it may become more difficult to control the time when you experience a good response to levodopa (termed 'on' time) and the time when you experience a poor response to levodopa (termed 'off' time).
By improving the effectiveness and duration of each levodopa dose, COMT inhibition reduces 'wearing-off' and increases the amount of time when the symptoms of PD are well controlled. This increased symptom control may improve your quality of life. COMT inhibition can be started as soon as the symptoms of 'wearing-off' are first noticed.
Further reading on COMT inhibition
- Schapira AH, Obeso JA, Olanow CW. The place of COMT inhibitors in the armamentarium of drugs for the treatment of Parkinson's disease. Neurology 2000;55(11 Suppl 4):S65-8; discussion S69-71.
- Gordin A, Kaakkola S, Teravainen K. Position of COMT Inhibition in the Treatment of Parkinson's Disease. In: Gordin A, editor. Parkinson's Disease: Advances in Neurology. Philadelphia: Lippincott Williams & Wilkins; 2003. p. 237-250.
- Goetz CG. Influence of COMT inhibition on levodopa pharmacology and therapy. Neurology 1998;50(suppl 5):S26-S30.
- Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. Neurology 2001;56(11 Suppl 5):S1-S88.
You can obtain copies of these clinical papers through your local library.
For more information on entacapone visit the electronic Medicines Compendium (eMC) website
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