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https://www.readbyqxmd.com/read/28124620/monoamine-oxidase-b-inhibitors-in-parkinson-s-disease
#1
Livia Dézsi, László Vécsei
BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential. OBJECTIVE: To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials...
January 24, 2017: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/28123288/spotlight-on-opicapone-as-an-adjunct-to-levodopa-in-parkinson-s-disease-design-development-and-potential-place-in-therapy
#2
REVIEW
Ádám Annus, László Vécsei
Parkinson's disease (PD) is a progressive, chronic, neurodegenerative disease characterized by rigidity, tremor, bradykinesia and postural instability secondary to dopaminergic deficit in the nigrostriatal system. Currently, disease-modifying therapies are not available, and levodopa (LD) treatment remains the gold standard for controlling motor and nonmotor symptoms of the disease. LD is extensively and rapidly metabolized by peripheral enzymes, namely, aromatic amino acid decarboxylase and catechol-O-methyltransferase (COMT)...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28071803/effects-of-catechol-o-methyl-transferase-inhibition-on-anti-inflammatory-activity-of-luteolin-metabolites
#3
Sang Keun Ha, Jin-Ah Lee, Eun Jung Cho, Inwook Choi
Although luteolin is known to have potent anti-inflammatory activities, much less information has been provided on such activities of its hepatic metabolites. Luteolin was subjected to hepatic metabolism in HepG2 cells either without or with catechol O-methyl transferase (COMT) inhibitor. To identify hepatic metabolites of luteolin without (luteolin metabolites, LMs) or with COMT inhibitor (LMs+CI), metabolites were treated by β-glucuronidase and sulfatase, and found that they were composed of glucuronide and sulfate conjugates of diosmetin in LMs or these conjugates of luteolin in LMs+CI...
January 10, 2017: Journal of Food Science
https://www.readbyqxmd.com/read/28066708/right-inferior-frontal-cortex-activity-correlates-with-tolcapone-responsivity-in-problem-and-pathological-gamblers
#4
Andrew S Kayser, Taylor Vega, Dawn Weinstein, Jan Peters, Jennifer M Mitchell
Failures of self-regulation in problem and pathological gambling (PPG) are thought to emerge from failures of top-down control, reflected neurophysiologically in a reduced capacity of prefrontal cortex to influence activity within subcortical structures. In patients with addictions, these impairments have been argued to alter evaluation of reward within dopaminergic neuromodulatory systems. Previously we demonstrated that augmenting dopamine tone in frontal cortex via use of tolcapone, an inhibitor of the dopamine-degrading enzyme catechol-O-methyltransferase (COMT), reduced delay discounting, a measure of impulsivity, in healthy subjects...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/28027332/opicapone-as-adjunct-to-levodopa-therapy-in-patients-with-parkinson-disease-and-motor-fluctuations-a-randomized-clinical-trial
#5
Andrew J Lees, Joaquim Ferreira, Olivier Rascol, Werner Poewe, José-Francisco Rocha, Michelle McCrory, Patricio Soares-da-Silva
Importance: Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects. Objective: To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations...
February 1, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/27890888/cloning-and-expression-of-a-novel-catechol-o-methyltransferase-in-common-marmosets
#6
Shotaro Uehara, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of endogenous catechol amines and estrogens and exogenous catechol-type of drugs. A Parkinson's disease model of common marmoset (Callithrix jacchus) has been widely used in preclinical studies to evaluate inhibitory potential of new drug candidates on marmoset COMT. Despite COMT inhibitors could potentiate the pharmacological action of levodopa on Parkinson's disease in animal models, marmoset COMT cDNA has not yet been identified and characterized...
November 26, 2016: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/27826992/the-val158met-polymorphism-in-comt-gene-and-cancer-risk-role-of-endogenous-and-exogenous-catechols
#7
Katrin Sak
Catechol-O-methyltransferase, COMT, is an important phase II enzyme catalyzing the transfer of a methyl-group from S-adenosylmethionine to a catechol-containing substrate molecule. A genetic variant Val158Met in the COMT gene leads to a several-fold decrease in the enzymatic activity giving rise to the accumulation of potentially carcinogenic endogenous catechol estrogens and their reactive intermediates and increasing thus the risk of tumorigenesis. However, numerous association studies between the COMT genotype and susceptibility to various malignancies have shown inconsistent and controversial findings indicating that additional gene-gene and gene-environment interactions might be crucial in modulating the physiological role of the COMT...
November 23, 2016: Drug Metabolism Reviews
https://www.readbyqxmd.com/read/27685665/design-of-potent-and-druglike-nonphenolic-inhibitors-for-catechol-o-methyltransferase-derived-from-a-fragment-screening-approach-targeting-the-s-adenosyl-l-methionine-pocket
#8
Christian Lerner, Roland Jakob-Roetne, Bernd Buettelmann, Andreas Ehler, Markus Rudolph, Rosa María Rodríguez Sarmiento
A fragment screening approach designed to target specifically the S-adenosyl-l-methionine pocket of catechol O-methyl transferase allowed the identification of structurally related fragments of high ligand efficiency and with activity on the described orthogonal assays. By use of a reliable enzymatic assay together with X-ray crystallography as guidance, a series of fragment modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained. For the first time nonphenolic and small low nanomolar potent, SAM competitive COMT inhibitors are reported...
November 23, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27577098/current-and-experimental-treatments-of-parkinson-disease-a-guide-for-neuroscientists
#9
Wolfgang Oertel, Jörg B Schulz
Over a period of more than 50 years, the symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been optimized using pharmacotherapy, deep brain stimulation, and physiotherapy. The arsenal of pharmacotherapies includes L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine. In the later course of the disease, motor complications occur, at which stage different oral formulations of L-Dopa or dopamine agonists with long half-life, a transdermal application or parenteral pumps for continuous drug supply can be subscribed...
October 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27498199/opicapone-a-review-in-parkinson-s-disease
#10
Lesley J Scott
Oral opicapone (Ongentys(®)), a potent, third-generation, long-acting, peripheral catechol-O-methyltransferase (COMT) inhibitor, is approved as adjunctive treatment to levodopa (L-Dopa)/dopa-decarboxylase inhibitor (DDCI) therapy in adults with Parkinson's disease (PD) and end-of-dose motor fluctuations who cannot be stabilized on those combinations. In 14- to 15-week, double-blind, multinational trials and in 1-year, open-label extension studies in this patient population, opicapone was an effective and generally well tolerated adjunctive therapy to L-Dopa plus a DDCI and other PD therapy...
September 2016: Drugs
https://www.readbyqxmd.com/read/27493964/homocysteine-levels-in-parkinson-s-disease-is-entacapone-effective
#11
Bilge Kocer, Hayat Guven, Selim Selcuk Comoglu
Plasma homocysteine (Hcy) levels may increase in levodopa-treated patients with Parkinson's disease (PD) as a consequence of levodopa methylation via catechol-O-methyltransferase (COMT). Results from previous studies that assessed the effect of COMT inhibitors on levodopa-induced hyperhomocysteinemia are conflicting. We aimed to evaluate the effects of levodopa and entacapone on plasma Hcy levels. A hundred PD patients were enrolled to the study and divided into three treatment groups (group I: levodopa and/or dopamine agonists; group II: levodopa, entacapone, and/or a dopamine agonist; and group III: dopamine agonist alone)...
2016: BioMed Research International
https://www.readbyqxmd.com/read/27476416/initial-treatment-of-parkinson-s-disease-in-2016-the-2000-consensus-conference-revisited
#12
C Laurencin, T Danaila, E Broussolle, S Thobois
In 2000, a French consensus conference proposed guidelines for the treatment of Parkinson's disease (PD). Since then, new drugs have been concocted, new studies have been published and clinicians have become aware of some drug-induced adverse effects that were little known in the past. This has led us to reconsider the recommendations published 16 years ago. Thus, the aim of the present review is to present the recent data related to the different medications and non-pharmacological approaches available for PD, with a special focus on early-stage PD...
August 2016: Revue Neurologique
https://www.readbyqxmd.com/read/27463695/development-of-blood-brain-barrier-permeable-nitrocatechol-based-catechol-o-methyltransferase-inhibitors-with-reduced-potential-for-hepatotoxicity
#13
Tiago Silva, Tarek Mohamed, Arash Shakeri, Praveen P N Rao, Loreto Martínez-González, Daniel I Pérez, Ana Martínez, Maria João Valente, Jorge Garrido, Eugenio Uriarte, Paula Serrão, Patrício Soares-da-Silva, Fernando Remião, Fernanda Borges
Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range. Druglike derivatives 13, 15, and 16 were predicted to cross the blood-brain barrier in vitro and were significantly less toxic than tolcapone and entacapone when incubated at 50 μM with rat primary hepatocytes...
August 25, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27456338/3-o-methyldopa-inhibits-astrocyte-mediated-dopaminergic-neuroprotective-effects-of-l-dopa
#14
Masato Asanuma, Ikuko Miyazaki
BACKGROUND: We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of L-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of L-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with L-DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes. RESULTS: The number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by L-DOPA treatment in mesencephalic neurons alone...
2016: BMC Neuroscience
https://www.readbyqxmd.com/read/27445153/subsecond-regulation-of-synaptically-released-dopamine-by-comt-in-the-olfactory-bulb
#15
Renee Cockerham, Shaolin Liu, Roger Cachope, Emi Kiyokage, Joseph F Cheer, Michael T Shipley, Adam C Puche
UNLABELLED: The efficacy of neurotransmission depends on multiple factors, including presynaptic vesicular release of transmitter, postsynaptic receptor populations and clearance/inactivation of the transmitter. In the olfactory bulb (OB), short axon cells (SACs) form an interglomerular circuit that uses GABA and dopamine (DA) as cotransmitters. Selective optical activation of SACs causes GABA and DA co-release, resulting in a fast, postsynaptic GABA inhibitory response and a slower G-protein-coupled DA rebound excitation...
July 20, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27435571/inhibition-of-human-catechol-o-methyltransferase-mediated-dopamine-o-methylation-by-daphnetin-and-its-phase-ii-metabolites
#16
Si-Cheng Liang, Guang-Bo Ge, Yang-Liu Xia, Dong Pei-Pei, Wang Ping, Xiao-Yi Qi, Tu Cai-Xia, Yang Ling
1. Finding and developing inhibitors of catechol-O-methyltransferase (COMT) from natural products is highly recommended. Daphnetin, a naturally occurring catechol from the family thymelaeaceae, has a chemical structure similar to several potent COMT inhibitors reported previously. Here the potential of daphnetin and its Phase II metabolites as inhibitors of COMT was investigated with human liver cytosol (HLC). 2. Daphnetin and its methylated metabolite (8-O-methyldaphnetin) were found to inhibit COMT-mediated dopamine O-methylation in a dose-dependent manner...
July 20, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27398042/efficacy-safety-and-cost-of-regorafenib-in-patients-with-metastatic-colorectal-cancer-in-french-clinical-practice
#17
Fabien Calcagno, Sabrina Lenoble, Zaher Lakkis, Thierry Nguyen, Samuel Limat, Christophe Borg, Marine Jary, Stefano Kim, Virginie Nerich
BACKGROUND: Regorafenib is an orally administered multikinase inhibitor that has been approved for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Even though regorafenib significantly improved survival in two international phase 3 trials (CORRECT and CONCUR), a high rate of treatment-related toxic effects and dose modifications were observed with a modest benefit. The aim of this study was to provide information concerning the efficacy, safety, and cost of regorafenib in patients with mCRC in clinical practice...
2016: Clinical Medicine Insights. Oncology
https://www.readbyqxmd.com/read/27388330/genotype-dependent-effects-of-comt-inhibition-on-cognitive-function-in-a-highly-specific-novel-mouse-model-of-altered-comt-activity
#18
Chris Barkus, Clio Korn, Katharina Stumpenhorst, Linda M Laatikainen, Dominic Ballard, Sheena Lee, Trevor Sharp, Paul J Harrison, David M Bannerman, Daniel R Weinberger, Jingshan Chen, Elizabeth M Tunbridge
Catechol-O-methyltransferase (COMT) modulates dopamine levels in the prefrontal cortex. The human gene contains a polymorphism (Val(158)Met) that alters enzyme activity and influences PFC function. It has also been linked with cognition and anxiety, but the findings are mixed. We therefore developed a novel mouse model of altered COMT activity. The human Met allele was introduced into the native mouse COMT gene to produce COMT-Met mice, which were compared with their wild-type littermates. The model proved highly specific: COMT-Met mice had reductions in COMT abundance and activity, compared with wild-type mice, explicitly in the absence of off-target changes in the expression of other genes...
December 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27385415/hispidulin-alleviated-methamphetamine-induced-hyperlocomotion-by-acting-at-%C3%AE-6-subunit-containing-gabaa-receptors-in-the-cerebellum
#19
Yu-Hsiang Liao, Hsin-Jung Lee, Wei-Jan Huang, Pi-Chuan Fan, Lih-Chu Chiou
RATIONALE: Hispidulin is a flavonoid we isolated from Clerodendrum inerme, an herb that effectively remitted a case of intractable motor tic disorders. Hispidulin was shown to be a positive allosteric modulator (PAM) of GABAA receptors, including the α6 subunit-containing subtype (α6GABAAR) that is predominantly expressed in cerebellar granule cells and insensitive to diazepam. OBJECTIVES: We explored the action mechanism(s) of hispidulin using hyperdopaminergic mouse models induced by methamphetamine and apomorphine, based on the hyperdopaminergic nature of tic disorders...
September 2016: Psychopharmacology
https://www.readbyqxmd.com/read/27378609/effect-of-abcb1-diplotype-on-tacrolimus-disposition-in-renal-recipients-depends-on-cyp3a5-and-cyp3a4-genotype
#20
T Vanhove, P Annaert, D Lambrechts, D R J Kuypers
The relevance of most genetic polymorphisms beyond CYP3A5*1 on tacrolimus disposition remains unclear. We constructed a predictive mixed model for tacrolimus dose-corrected trough concentration (C0/dose) at months 3, 12 and 24 after transplantation in a retrospective cohort of 766 predominantly Causasian adult renal recipients (n=2042 trough concentrations). All patients were genotyped for 32 single-nucleotide polymorphisms with a proven or possible relevance to tacrolimus disposition based on the previous studies...
July 5, 2016: Pharmacogenomics Journal
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