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https://www.readbyqxmd.com/read/28322896/pharmacokinetics-of-opicapone-a-third-generation-comt-inhibitor-after-single-and-multiple-oral-administration-a-comparative-study-in-the-rat
#1
Daniela Gonçalves, Gilberto Alves, Ana Fortuna, Patrício Soares-da-Silva, Amílcar Falcão
Opicapone is a novel potent, reversible and purely peripheral catechol-O-methyltransferase inhibitor that has been developed to be used as an adjunct to levodopa/aromatic L-amino acid decarboxylase inhibitor therapy for Parkinson's disease. Thus, this study aimed to compare the plasma pharmacokinetics of opicapone and its active metabolite (BIA 9-1079) after the administration of single and multiple oral doses to rats. Wistar rats (n=8 per group) were orally treated with single (30, 60 or 90mg/kg) or multiple (30mg/kg once-daily for seven consecutive days) oral doses of opicapone...
March 16, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28289795/-pharmacological-treatment-of-motor-symptoms-in-parkinson-s-diseases
#2
W H Jost
Since the 1960s many substance classes have been introduced for treatment of idiopathic Parkinson's disease. The most important and effective medication is levodopa (L-dopa) always in combination with a decarboxylase inhibitor. In addition, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, catechol-o-methyltransferase (COMT) inhibitors, N‑methyl-D-aspartate (NMDA) antagonists and very rarely anticholinergics are administered depending on the motor symptoms, age and a multitude of other factors. Fortunately, within the substance classes there are various preparations, which also have different effects...
March 13, 2017: Der Nervenarzt
https://www.readbyqxmd.com/read/28279509/-medical-and-surgical-treatment-of-parkinson-s-disease
#3
Luc Defebvre, Caroline Moreau
The treatment of Parkinson's disease is symptomatic with the use of dopaminergic medications: levodopa, dopaminergic agonists and enzymatic inhibitors. At the initial stage, the main goals are to improve the quality of life of patients and delay the onset of motor complications, using a combination of these therapies taking into account both clinical disability and tolerance of different treatments. At the stage of motor and non-motor fluctuations inhibitors of MAO-B and COMT are proposed; amantadine may limit moderate dyskinesias...
March 6, 2017: La Presse Médicale
https://www.readbyqxmd.com/read/28273839/parkinson-s-disease-from-pathogenesis-to-pharmacogenomics
#4
REVIEW
Ramón Cacabelos
Parkinson's disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer's disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson's disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects...
March 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28247504/epigallocatechin-3-gallate-augments-the-therapeutic-effects-of-benzo-a-pyrene-mediated-lung-carcinogenesis
#5
Meghan M Cromie, Zhongwei Liu, Weimin Gao
Our previous study found curcumin and vitamin E to have protective effects against benzo[a]pyrene (BaP) exposure in human normal lung epithelial BEAS-2B cells. The first objective of this study was to determine whether epigallocatechin-3-gallate (EGCG) elicited the same response. Co-treatment with 5 µM BaP and 20 µM EGCG in BEAS-2B promoted a significant reduction in cell viability and greater G2/M cell cycle arrest, induction of ROS, and reductions in BaP-induced CYP1A1/CYP1B1/COMT, EGFR, p-Akt (Ser473), p-p53 (Thr55), and survivin mRNA/protein expression, as well as an increase in p-p53 (Ser15)...
March 1, 2017: BioFactors
https://www.readbyqxmd.com/read/28124620/monoamine-oxidase-b-inhibitors-in-parkinson-s-disease
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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...
February 4, 2017: 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
#12
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
#13
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
#14
REVIEW
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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