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Catechol‐O‐methyltransferase inhibitors: Clinical potential in the treatment of Parkinson's disease
Author(s) -
Dingemanse Jasper
Publication year - 1997
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199709)42:1<1::aid-ddr1>3.0.co;2-i
Subject(s) - entacapone , levodopa , catechol o methyl transferase , pharmacology , cmax , tolerability , pharmacokinetics , parkinson's disease , medicine , benserazide , bioavailability , chemistry , adverse effect , disease , biochemistry , allele , gene
Substitution therapy with levodopa and a peripheral inhibitor of aromatic L‐ amino acid decarboxylase (AADC) is the cornerstone in the treatment of Parkinson's disease. Chronic therapy with levodopa, however, is associated with the occurrence of motor complications that are partially related to the pharmacokinetics of levodopa. The formation of 3‐O‐methyldopa (3‐OMD), a long‐lived metabolite that confers no clinical benefit, is catalyzed by catechol‐O‐methyltransferase (COMT), an enzyme that is particularly abundant in the gastrointestinal tract, liver, and kidneys. Potent, reversible, selective, and orally active COMT inhibitors have become available. The nitrocatechols, entacapone and tolcapone, have undergone extensive clinical testing as adjuncts to levodopa in the therapy of Parkinson's disease. Studies in healthy subjects and parkinsonian patients have shown the inhibitory effect of both drugs on the formation of 3‐OMD, leading to an increase in levodopa bioavailability and elimination half‐life, without a change in peak plasma concentrations (C max ) or time to reach C max (t max ). In patients, COMT inhibitors significantly prolong and smooth, i.e., reduce peak‐trough fluctuations, the effects of levodopa, as reflected in improved motor scores and lengthened duration of ON time (periods of good response) without an influence on the time to onset of action or the peak effect. Entacapone 200 mg is given in conjunction with each levodopa dose, whereas tolcapone is administered in a fixed 100 to 200 mg t.i.d. dosing regimen. The tolerability profiles of the two drugs are similar, with urine discoloration and an increase in dopaminergic side effects such as nausea, orthostatic hypotension, and dyskinesias being most prominent. Tolcapone induces a higher incidence of diarrhea and liver enzyme abnormalities. It is anticipated that COMT inhibitors will prove beneficial in extending and smoothing the effects of levodopa in patients with Parkinson's disease and end‐of‐dose wearing‐off fluctuations. Drug Dev. Res. 42:1–25, 1997. © 1997 Wiley‐Liss, Inc.