Journal ArticleDOI
Influence of COMT inhibition on levodopa pharmacology and therapy
TLDR
It is reasonable to suggest that COMT inhibition will be associated with prolonged effects of levodopa in PD, without increased peak dose toxicity in the form of dyskinesias and hallucinations.Abstract:
Catechol O-methyltransferase (COMT) is an important enzyme that is linked directly to therapy with levodopa. Considering the demonstrated mechanism of action and pharmacologic profiles of COMT inhibitors, it is reasonable to hypothesize that these agents would improve the disability associated with Parkinson's disease. Two basic classes of COMT inhibitors are being studied in patients with PD: those that act exclusively extracerebrally or peripherally (e.g., entacapone) and those that cross the blood-brain barrier (e.g., tolcapone). With COMT inhibition, greater peripheral bioavailability of levodopa occurs in humans without an enhancement of peak plasma levels. It is reasonable to suggest that COMT inhibition will be associated with prolonged effects of levodopa in PD, without increased peak dose toxicity in the form of dyskinesias and hallucinations.read more
Citations
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Journal ArticleDOI
Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys.
Tomoyuki Kanda,Michael J. Jackson,Lance A. Smith,R. K. B. Pearce,Joji Nakamura,Hiroshi Kase,Yoshihisa Kuwana,Peter Jenner +7 more
TL;DR: The novel selective adenosine A(2A) receptor antagonist KW-6002 improves motor disability in MPTP-treated parkinsonian marmosets without provoking dyskinesia and did not exacerbate L-DOPA-induced dysKinesia in MP TP-treated common marmoset previously primed to exhibit dyskine by prior exposure to L- DOPA.
Journal ArticleDOI
Functional Effect of Adeno-associated Virus Mediated Gene Transfer of Aromatic L-Amino Acid Decarboxylase into the Striatum of 6-OHDA-Lesioned Rats
TL;DR: Following adeno-associated virus (AAV)-AADC transduction, the transgenic AADC is able to decarboxylate exogenous L-DOPA more efficiently so that a dose of L- DOPA ineffective before gene transfer elicits a motor asymmetry (rotational behavior) following gene transfer.
Journal ArticleDOI
Orientation and cellular distribution of membrane-bound catechol-O-methyltransferase in cortical neurons: implications for drug development.
Jingshan Chen,Jian Song,Peixiong Yuan,Qingjun Tian,Yuanyuan Ji,Renee F. Ren-Patterson,Guangping Liu,Yoshitasu Sei,Daniel R. Weinberger +8 more
TL;DR: It is demonstrated that MB-COMT is located in the cell body and in axons and dendrites of rat cortical neurons and that the COMT inhibitor tolcapone induces cell death via the mechanism of apoptosis, and its cytotoxicity is dependent on dosage and correlated with COMT Val/Met genotypes in human lymphoblastoid cells.
Journal ArticleDOI
Economic and health-related quality of life considerations of new therapies in Parkinson's disease.
TL;DR: There is not yet substantial evidence that health-related quality of life (HR-QOL) measures will be responsive to changes in patients over time and that the results will provide patients and health professionals with clinically meaningful information useful in making decisions about treatment strategies.
Journal ArticleDOI
Switch-over from tolcapone to entacapone in severe Parkinson's disease patients.
TL;DR: Forty patients affected by severe Parkinson’s disease were treated with tolcapone as an adjunctive therapy to L-DOPA, for 3–7 months, until this drug was discontinued because of side-effects or because of mandatory indications of the European drugs authority.
References
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Journal ArticleDOI
D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons
Charles R. Gerfen,Thomas M. Engber,Lawrence C. Mahan,Zvi Susel,Thomas N. Chase,Frederick J. Monsma,David R. Sibley +6 more
TL;DR: The differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D1 and D2 dopamine receptor subtypes, respectively.
Journal ArticleDOI
Pharmacological mechanisms of opioid analgesics.
TL;DR: The relief of pain involves the complex interaction of at least six receptor systems, and the implications of opiate receptor multiplicity on the control of pain are discussed.
Journal ArticleDOI
Effect of peripheral catechol-O-methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients
J. G. Nutt,William R. Woodward,R. M. Beckner,C. K. Stone,K. Berggren,Julie H. Carter,S. T. Gancher,John P. Hammerstad,A. Gordin +8 more
TL;DR: It is concluded that inhibition of COMT by entacapone increases the plasma half-life of levodopa and augments the antiparkinsonian effects of single and repeated doses of Levodopa.
Book ChapterDOI
Characteristics of catechol O-methyltransferase (COMT) and properties of selective COMT inhibitors
Pekka T. Männistö,I. Ulmanen,Kenneth Lundstrom,Jyrki Taskinen,Jukka Tenhunen,Carola Tilgmann,Seppo Kaakkola +6 more
TL;DR: The enzyme-catalyzed O-methylation of catecholamines was first described by Axelrod and coworkers in the late 1950’s and was extensively reviewed by Guldberg and Marsden in 1975.
Journal ArticleDOI
General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase.
TL;DR: In the first clinical studies in patients with Parkinson's disease, both entacapone and tolcapone potentiate and prolong the therapeutic effect of L-dopa, thus improving its bioavailability and brain penetration and potentiating its behavioural effects.