Journal ArticleDOI
Pharmacokinetics, pharmacodynamics, and tolerability of tolcapone A review of early studies in volunteers
TLDR
Tolcapone was well tolerated alone or in combination with levodopa/DCI, and the results indicated that the effective dose in patients with PD would be in the range of 50-400 mg tid.Abstract:
Tolcapone is a potent, reversible inhibitor of catechol O-methyltransferase (COMT) intended for use as an adjunct to levodopa therapy for Parkinson's disease (PD). Findings from the first pharmacokinetics/pharmacodynamics and tolerability studies of tolcapone in volunteers are reviewed. Following linear and dose-proportional pharmacokinetics, tolcapone is rapidly absorbed and eliminated after single- or multiple-dose (i.e., tid) administration. Onset of COMT inhibition is rapid, substantial, and reversible, and is not affected by the co-administration of levodopa/decarboxylase inhibitor (levodopa/DCI). When given together with levodopa/DCI, tolcapone increases the relative bioavailability and plasma elimination half-life of levodopa, without affecting its peak plasma concentration. This leads to more stable plasma levels of levodopa, and the formation of 3-O-methyldopa is effectively reduced. Tolcapone was well tolerated alone or in combination with levodopa/DCI, and the results indicated that the effective dose in patients with PD would be in the range of 50-400 mg tid.read more
Citations
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Journal Article
Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors.
Pekka T. Männistö,Seppo Kaakkola +1 more
TL;DR: The enzyme responsible for the O- methylation, catechol- O -methyltransferase (COMT) was partly purified and characterized by the same group as EC, which first described the enzyme-catalyzed O-methylation of catechlamines and other catechols in the late 1950s.
Journal ArticleDOI
Tolcapone improves cognition and cortical information processing in normal human subjects.
Jose A. Apud,Venkata S. Mattay,Jingshan Chen,Bhaskar Kolachana,Joseph H. Callicott,Roberta Rasetti,Guilna Alce,Jennifer E. Iudicello,Natkai Akbar,Michael F. Egan,Terry E. Goldberg,Daniel R. Weinberger +11 more
TL;DR: In this paper, the effects of tolcapone, a CNS penetrant specific COMT inhibitor, were explored in a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT (val158met) genotype.
Journal ArticleDOI
Catechol-O-methyltransferase and its inhibitors in Parkinson's disease.
Maria João Bonifácio,P. Nuno Palma,Luís Pereira de Almeida,Luís Pereira de Almeida,Patrício Soares-da-Silva,Patrício Soares-da-Silva +5 more
TL;DR: The current knowledge on the enzyme catechol-O-methyltransferase (COMT) and the role of COMT inhibitors in PD are reviewed and conversion of levodopa to dopamine at the target region in the brain and facilitation of the continuous action of this amine at the receptor sites are reviewed.
Journal ArticleDOI
Influence of l-dopa and pramipexole on striatal dopamine transporter in early PD
TL;DR: Short-term therapy with l-dopa and, to a lesser extent, pramipexole can modestly down-regulate striatal DAT in patients with early PD, suggesting caution in interpretation of longitudinal imaging studies employing DAT to assess disease progression and the efficacy of neuroprotective agents.
Journal ArticleDOI
COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition.
TL;DR: The data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene, and support the inverted-U model of dopamine function.
References
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Journal Article
Catechol-O-Methyl Transferase: Pharmacological Aspects and Physiological Role
Journal ArticleDOI
Control of on/off phenomenon by continuous intravenous infusion of levodopa
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Book ChapterDOI
Characteristics of catechol O-methyltransferase (COMT) and properties of selective COMT inhibitors
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Journal Article
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