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https://www.readbyqxmd.com/read/28715128/sibiriline-a-new-small-chemical-inhibitor-of-receptor-interacting-protein-kinase-1-prevents-immune-dependent-hepatitis
#1
Fabienne Le Cann, Claire Delehouzé, Sabrina Penna-Leverrier, Aveline Filliol, Arnaud Comte, Olivier Delalande, Nathalie Desban, Blandine Baratte, Isabelle Gallais, Claire Piquet-Pellorce, Florence Faurez, Marion Bonnet, Yvette Mettey, Peter Goekjian, Michel Samson, Peter Vandenabeele, Stéphane Bach, Marie-Thérèse Dimanche-Boitrel
Necroptosis is a regulated form of cell death involved in several disease models including in particular liver diseases. Receptor-Interacting Protein Kinases, RIPK1 and RIPK3, are the main serine/threonine kinases driving this cell death pathway. We screened a non-commercial kinase-focused chemical library allowed us to identify Sibiriline as new inhibitor of necroptosis induced by TNF in Fas-Associated protein with Death Domain (FADD)-deficient Jurkat cells. Moreover, Sib inhibits necroptotic cell death induced by various death ligands in human or mouse cells while not protecting from caspase-dependent apoptosis...
July 17, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28611642/a-case-report-of-severe-delirium-after-amantadine-withdrawal
#2
Franz Marxreiter, Jürgen Winkler, Martin Uhl, Dominik Madžar
Amantadine is frequently used in addition to dopaminergic substances like dopamine agonists or L-Dopa in advanced Parkinson disease (PD). However, adverse effects like hallucinations limit its use. PD patients developing severe psychotic symptoms upon treatment with either dopaminergic substances and/or amantadine need to stop intake of any psychotropic substance. Here, we report the case of a 71-year-old PD patient without previously known cognitive impairment. He presented with drug-induced psychotic symptoms due to changes in his therapeutic regimen (increase in COMT inhibitors, newly introduced MAO B inhibitors)...
January 2017: Case Reports in Neurology
https://www.readbyqxmd.com/read/28580819/opicapone-for-the-management-of-end-of-dose-motor-fluctuations-in-patients-with-parkinson-s-disease-treated-with-l-dopa
#3
Andrew J Lees, Joaquim Ferreira, Olivier Rascol, Heinz Reichmann, Fabrizio Stocchi, Eduardo Tolosa, Werner Poewe
Opicapone is a third generation, highly potent and effective catechol O‑methyltransferase (COMT) inhibitor that optimizes the pharmacokinetics and bioavailability of L-DOPA therapy. Areas covered: In this review, the authors describe the preclinical and clinical development of opicapone. In PD patients with motor fluctuations, once daily opicapone administration was well-tolerated and consistently reduced OFF-time and increased ON-time without increasing the frequency of troublesome dyskinesia, and these benefits were maintained over at least a year of continued open-label therapy...
July 2017: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/28494719/levodopa-in-parkinson-s-disease-current-status-and-future-developments
#4
N Tambasco, M Romoli, P Calabresi
Ever since the pioneering reports in the 60s, L-3,4-Dioxyphenylalanine (levodopa) has represented the gold standard for the treatment of Parkinson's Disease (PD). However, long-term levodopa (LD) treatment is frequently associated with fluctuations in motor response, often challenging to resolve, with serious impact on patients quality of life. The pharmacokinetic and pharmacodynamics properties of LD are pivotal to such motor fluctuations: discontinuous drug delivery, short half-life, poor bioavailability, and narrow therapeutic window are all crucial for such fluctuations...
May 10, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/28461606/catechol-o-methyltransferase-deficiency-leads-to-hypersensitivity-of-the-pressor-response-against-angiotensin-ii
#5
Norikazu Ueki, Keizo Kanasaki, Megumi Kanasaki, Satoru Takeda, Daisuke Koya
Catechol-O-methyltransferase (COMT) metabolizes 2-hydroxyestradiol into 2-methoxyestradiol (2-ME); COMT deficiency has shown to be associated with hypertension in men and preeclampsia, the disease associated with hypersensitivity of pressor response against angiotensin II (Ang II). Here, we found that COMT deficiency could explain the hypersensitivity of pressor response against Ang II in mice because of the lack of 2-ME-dependent suppression of angiotensin II receptor type 1 (AT1R). Male C57BL/6 mice were subjected to COMT inhibitor (COMTi: 25 mg/kg per day) or oil (control) for 4 weeks, with or without low-dose Ang II infusion (ANGII: 70 ng/kg per minute) for the last 3 weeks...
June 2017: Hypertension
https://www.readbyqxmd.com/read/28429453/tolcapone-induces-oxidative-stress-leading-to-apoptosis-and-inhibition-of-tumor-growth-in-neuroblastoma
#6
Tyler Maser, Maria Rich, David Hayes, Ping Zhao, Abhinav B Nagulapally, Jeffrey Bond, Giselle Saulnier Sholler
Catechol-O-methyltransferase (COMT) is an enzyme that inactivates dopamine and other catecholamines by O-methylation. Tolcapone, a drug commonly used in the treatment of Parkinson's disease, is a potent inhibitor of COMT and previous studies indicate that Tolcapone increases the bioavailability of dopamine in cells. In this study, we demonstrate that Tolcapone kills neuroblastoma (NB) cells in preclinical models by inhibition of COMT. Treating four established NB cells lines (SMS-KCNR, SH-SY5Y, BE(2)-C, CHLA-90) and two primary NB cell lines with Tolcapone for 48 h decreased cell viability in a dose-dependent manner, with IncuCyte imaging and Western blotting indicating that cell death was due to caspase-3-mediated apoptosis...
June 2017: Cancer Medicine
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
#7
COMPARATIVE STUDY
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...
May 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28289795/-pharmacological-treatment-of-motor-symptoms-in-parkinson-s-diseases
#8
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
#9
REVIEW
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 2017: La Presse Médicale
https://www.readbyqxmd.com/read/28273839/parkinson-s-disease-from-pathogenesis-to-pharmacogenomics
#10
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
#11
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
#12
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
#13
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
#14
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...
February 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
#15
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
#16
RANDOMIZED CONTROLLED TRIAL
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
#17
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
#18
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
#19
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
#20
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
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