Catechol-O-methyltransferase inhibitors in the management of Parkinson’s disease

Ilana Schlesinger, Amos D. Korczyn

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

Abstract

The introduction of 3,4-dihydroxyphenylalanine (DOPA) to the treatment of Parkinson’s disease (PD) has been a major scientific and clinical breakthrough in the treatment of this devastating disease. This can be seen from two aspects. The primary one is, of course, the enormous benefit to patients, but in addition there is the realization that understanding the biochemical deficits can provide a clue as to how replacement therapy can be successfully employed even in neurodegenerative diseases, providing significant symptomatic benefit if not cure. This has had a great impact on attempts to treat other neurodegenerative disorders, particularly Alzheimer’s disease. Unfortunately, in spite of miraculous effects on patients with early and advanced PD and the motor benefits afforded to them, it became clear that DOPA does not slow the neurodegenerative process and its effects are purely symptomatic. Consequently, the dose of drug that is needed to control the motor manifestations has to be increased gradually as the disease progresses. It quickly became clear also that of the two DOPA isomers, only the levorotatory stereoisomer, l-DOPA (levodopa), was able to afford therapeutic benefits, and chemical means to separate the isomers were developed. In practice, only levodopa is now used in the treatment of PD, resulting in an improved safety profile. Soon after came the recognition that some of the adverse effects associated with the drug were the result of peripheral, rather than central, conversion of levodopa to dopamine, which, unlike levodopa, has significant autonomic activity [1]. Unlike levodopa, dopamine does not cross the blood-brain barrier, and thus this metabolite does not contribute to the clinical benefits afforded by levodopa, and in fact causes significant adverse effects, particularly autonomic. The enzyme involved in the transformation of levodopa to dopamine, l-amino acid decarboxylase (l-AAD, also called DOPA decarboxylase), is widespread in the body, with high concentrations present in the liver. Two agents were developed that could inhibit this enzyme, and both are still in use - carbidopa and benserazide. At present, practically all patients who require treatment with levodopa receive it in a fixed-dose combination with one of these inhibitors. Of course, as it is essential that levodopa be converted to dopamine in the brain, the l-AAD inhibitors should not cross the blood-brain barrier. The inhibition of peripheral l-AAD had another result, at first unappreciated, namely a prolongation of the biological half-life of levodopa (and therefore also of dopamine in the brain).

Original languageEnglish
Title of host publicationParkinson's Disease
Subtitle of host publicationCurrent and Future Therapeutics and Clinical Trials
PublisherCambridge University Press
Pages76-82
Number of pages7
ISBN (Electronic)9781107284210
ISBN (Print)9781107053861
DOIs
StatePublished - 1 Jan 2016
Externally publishedYes

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