olcapone, an inhibitor of catechol-O-methyltransferase (COMT) is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa therapy.

It is a yellow, odorless, non-hygroscopic, crystalline compound with a relative molecular mass of 273.25. The chemical name of tolcapone is 3.4-dihydroxy-5-nitrobenzophenone. Its empirical formula is C13H9NO5 and its structural formula is:

Mechanism of Action: Tolcapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). In mammals, COMT is distributed throughout various organs. The highest activities are in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L methionine to the phenolic group of substrates that contain a cathechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxilated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.

The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa.

Tolcopone (click here for the 3D- Structure)

Levodopa (click here for the 3D- Structure)

Suspension in the European Union (Press release from Tasmar manufactures - Roche)

Evolving safety information about the anti-parkinson drug Tasmar¨ (tolcapone) has led Roche to revise the recommendations to physicians on the appropriate use of the drug. These changes reflect additional information obtained through post-marketing experience in approximately 100'000 patients worldwide.

After careful review of all available information and in consultation with outside medical experts, Roche is of the opinion that for a restricted group of patients suffering from Parkinson's Disease, the addition of Tasmar to standard therapy is providing a clinically significant benefit that outweighs the risks. Cases of rare and unexpected adverse events, including three fatal cases of unpredictable, fulminant hepatitis, have been reported.

Parkinson's Disease is a chronic, increasingly debilitating disease afflicting almost 2 million people for whom only a limited number of treatments are available. In consultation with the Food and Drug Administration FDA, Roche is issuing in the United States a revised label, indicating that the drug should be used as an adjunctive therapy in patients with Parkinson's Disease who do not respond satisfactorily to other therapies. This and other important safety information are being communicated immediately to all physicians.

In the European Union, the Commission has initiated the procedure asking member states to suspend the use of Tasmar as of Tuesday, 17th November 1998.

Roche's principle concern is to implement the Commission's decision with the patients' interest in mind. Roche and regulatory authorities in other countries are working closely to ensure that the revised recommendations for the appropriate use of Tasmar are implemented.

Patients taking Tasmar should consult their physicians and should not precipitately stop treatment, since inappropriate change in therapy might trigger serious adverse events. Roche is informing physicians and other health care professionals accordingly. Tasmar (tolcapone), a COMT inhibitor used in combination with levodopa preparations for the treatment of Parkinson's Disease, has been first launched in August 1997 and is currently available in 38 countries.