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COMT INHIBITORS

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https://www.readbyqxmd.com/read/29697034/nitrocatechol-derivatives-of-chalcone-as-inhibitors-of-monoamine-oxidase-and-catechol-o-methyltransferase
#1
Idalet Engelbrecht, Jacobus P Petzer, Anel Petzer
The efficacy of L-dopa in the treatment of Parkinson's disease depends on its metabolic conversion to dopamine in the brain, however extensive peripheral metabolism of L-dopa diminishes its availability for uptake into the brain. L-Dopa is extensively decarboxylated in the gastrointestinal tract and peripheral tissues by aromatic L-amino acid decarboxylase (AADC), and AADC inhibitors are thus frequently combined with L-dopa therapy. When AADC is inhibited, 3-O-methylation catalysed by catechol-O-methyltransferase (COMT) becomes a dominant metabolic pathway for L-dopa, and COMT inhibitors may thus also be used as adjuncts to L-dopa in Parkinson's disease...
April 26, 2018: Central Nervous System Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/29696585/improved-bioavailability-of-levodopa-using-floatable-spray-coated-microcapsules-for-the-management-of-parkinson-s-disease
#2
Jong-Suep Baek, Jie Kai Tee, Yi Yun Pang, Ern Yu Tan, Kah Leong Lim, Han Kiat Ho, Say Chye Joachim Loo
Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations...
June 2018: Neuromolecular Medicine
https://www.readbyqxmd.com/read/29688484/effect-of-the-catechol-o-methyltransferase-inhibitors-tolcapone-and-entacapone-on-fatty-acid-metabolism-in-heparg-cells
#3
David Grünig, Andrea Felser, Urs Duthaler, Jamal Bouitbir, Stephan Krähenbühl
Tolcapone and entacapone are catechol-O-methyltransferase (COMT) inhibitors used in patients with Parkinson's disease. For tolcapone, patients with liver failure have been reported with microvesicular steatosis observed in the liver biopsy of one patient. We therefore investigated the impact of tolcapone and entacapone on fatty acid metabolism in HepaRG cells exposed for 24 hours and on acutely exposed mouse liver mitochondria. In HepaRG cells, tolcapone induced lipid accumulation starting at 100µM, whereas entacapone was ineffective up to 200µM...
April 23, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29614697/are-there-benefits-in-adding-catechol-o-methyltransferase-inhibitors-in-the-pharmacotherapy-of-parkinson-s-disease-patients-a-systematic-review
#4
Irene Katsaiti, John Nixon
BACKGROUND: A qualified consensus suggests that a combination of levodopa with a peripherally acting dopa decarboxylase inhibitor continues to present the gold standard treatment of Parkinson's disease (PD). However, as the disease progresses the therapeutic window of levodopa becomes narrowed. Pharmacological strategies for motor fluctuations are focused on providing less pulsatile and more continuous dopaminergic stimulation. Peripheral catechol-O-methyltransferase (COMT) inhibition improves the bioavailability of levodopa and results in a prolonged response...
March 26, 2018: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/29589656/-what-s-new-in-the-management-of-atopic-dermatitis-in-children-and-adolescents
#5
Justine Czernielewski, Émilie Comte Krieger, Stéphanie Christen-Zaech
A better understanding of the atopic dermatitis (AD) pathogenesis and the need for more efficient and safer treatments in severe AD promoted the development of new therapies. Several underwent and are still undergoing clinical trials, but due to safety reasons, they include mainly adults for now. AD is however predominant in childhood with a prevalence 20 % in children compared to only 5 % in adults. Regarding the pediatric population, the new pipeline relies on two selective immunosuppressive agents, notably crisaborole (phosphodiesterase-4 inhibitor) and dupilumab (IL-4 and IL-13 inhibitor)...
March 28, 2018: Revue Médicale Suisse
https://www.readbyqxmd.com/read/29578580/mao-b-and-comt-genetic-variations-associated-with-levodopa-treatment-response-in-patients-with-parkinson-s-disease
#6
Tiago Furtado Sampaio, Erinaldo Ubirajara Damasceno Dos Santos, Gessica Dayane Cordeiro de Lima, Rute Salgues Gueiros Dos Anjos, Ronaldo Celerino da Silva, Amdore Guescel C Asano, Nadja Maria Jorge Asano, Sergio Crovella, Paulo Roberto Eleutério de Souza
The most commonly used Parkinson's disease (PD) treatment is the replacement of dopamine by its levodopa precursor (l-dopa). Monoamine oxidase-B (MAO-B) and catechol-o-methyl transferase (COMT) are enzymes involved in the metabolism and regulation of dopamine availability. In our study we investigated the possible relation among selected single-nucleotide polymorphisms (SNPs) in the MAO-B (rs1799836) and COMT (rs4680) genes and the therapeutic response to levodopa (l-dopa). A total of 162 Brazilian patients from the Pro-Parkinson service of Clinics Hospital of Pernambuco diagnosed with sporadic PD and treated with levodopa were enrolled...
March 26, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29472644/effects-of-comt-genotype-and-tolcapone-on-lapses-of-sustained-attention-after-sleep-deprivation-in-healthy-young-men
#7
Amandine Valomon, Sebastian C Holst, Alessandro Borrello, Susanne Weigend, Thomas Müller, Wolfgang Berger, Michael Sommerauer, Christian R Baumann, Hans-Peter Landolt
Tolcapone, a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties, improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT. The impact of this common genetic variant on behavioral and neurophysiological markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of sleep homeostasis in humans...
February 5, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29445781/membrane-bound-comt-isoform-is-an-interfacial-enzyme-general-mechanism-and-new-drug-design-paradigm
#8
Aniket Magarkar, Petteri Parkkila, Tapani Viitala, Tatu Lajunen, Edouard Mobarak, Giuseppe Licari, Oana Cramariuc, Eric Vauthey, Tomasz Róg, Alex Bunker
The enzyme catechol-O-methyltransferase (COMT) has water soluble (S-COMT) and membrane associated (MB-COMT), bitopic, isoforms. Of these MB-COMT is a drug target in relation to the treatment of Parkinson's disease. Using a combination of computational and experimental protocols, we have determined the substrate selection mechanism specific to MB-COMT. We show: (1) substrates with preferred affinity for MB-COMT over S-COMT orient in the membrane in a fashion conducive to catalysis from the membrane surface and (2) binding of COMT to its cofactor ADOMET induces conformational change that drives the catalytic surface of the protein to the membrane surface, where the substrates and Mg2+ ions, required for catalysis, are found...
April 3, 2018: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29441484/real-life-evaluation-of-safinamide-effectiveness-in-parkinson-s-disease
#9
Francesca Mancini, Alessio Di Fonzo, Giulia Lazzeri, Linda Borellini, Vincenzo Silani, Marco Lacerenza, Cristoforo Comi
In this retrospective study, we evaluated both efficacy and effectiveness of safinamide 50 and 100 mg in the treatment of motor fluctuations and disabling dyskinesias in a cohort of patients with idiopathic Parkinson's disease (PD). Ninety-one PD patients were evaluated during the first year of commercialization of the drug, both prior to starting safinamide and at the last available follow-up. Evaluations were based on the Unified Parkinson's Disease Scale part III (UPDRS III), Hoehn & Yahr (HY), Unified Dyskinesia Rating Scale (UDysRS) walking and balance item 9 score, daily time spent in OFF and in ON with disabling dyskinesias (1 week diary), mean daily dose of levodopa (LD), dopamine-agonists (DA), catechol-O-methyl transferase inhibitor (COMT-I), monoamine oxidase B inhibitor (MAOB-I), and their LD equivalent dose (LEDD)...
April 2018: Neurological Sciences
https://www.readbyqxmd.com/read/29436602/the-expression-and-activation-of-sex-steroid-receptors-in-the-preeclamptic-placenta
#10
Mee-Na Park, Kyung-Hee Park, Jae-Eon Lee, Ye Young Shin, Sung-Min An, Seong Soo Kang, Wan-Seob Cho, Beum-Soo An, Seung Chul Kim
Estrogen and progesterone are the main pregnancy hormones produced by the placenta. It is well understood that estrogen stimulates angiogenesis in the uterus during the reproductive cycle. Although the estrogen and progesterone signaling pathways are assumed to be associated with placental vascularization and preeclampsia, expression of estrogen receptors (ESRs) and progesterone receptor (PGR) in the placenta have not been well studied. The present study examined the expression patterns of steroid hormone receptors in placentas...
May 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29427081/effects-of-tolcapone-and-bromocriptine-on-cognitive-stability-and-flexibility
#11
Ian G M Cameron, Deanna L Wallace, Ahmad Al-Zughoul, Andrew S Kayser, Mark D'Esposito
RATIONALE: The prefrontal cortex (PFC) and basal ganglia (BG) have been associated with cognitive stability and cognitive flexibility, respectively. We hypothesized that increasing PFC dopamine tone by administering tolcapone (a catechol-O-methyltransferase (COMT) inhibitor) to human subjects should promote stability; conversely, increasing BG dopamine tone by administering bromocriptine (a D2 receptor agonist) should promote flexibility. OBJECTIVE: We assessed these hypotheses by administering tolcapone, bromocriptine, and a placebo to healthy subjects who performed a saccadic eye movement task requiring stability and flexibility...
April 2018: Psychopharmacology
https://www.readbyqxmd.com/read/29415596/the-launch-of-opicapone-for-parkinson-s-disease-negatives-versus-positives
#12
REVIEW
Ana Castro Caldas, Tiago Teodoro, Joaquim J Ferreira
Opicapone is a novel, third generation COMT inhibitor approved for the treatment of Parkinson's disease. Safety and tolerability data is critical to determine the benefit-harm balance and anticipate therapeutic adherence. Areas covered: This review evaluates the tolerability and safety profile of opicapone. These data were extracted from all published clinical trials, including preclinical, phase I, phase II and phase III studies as well as postmarketing data. Opicapone was safe and well tolerated, with frequencies of treatment-emergent adverse events similar to placebo...
March 2018: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/29375679/the-efficacy-of-homemade-tolcapone-in-the-treatment-of-patients-with-parkinsons-disease
#13
Pei-Lan Zhang, Yu-Xin Wang, Yan Chen, Chen-Hao Zhang, Chen-Hua Li
The aim of the study was to investigate the efficacy of homemade tolcapone in treatment of patients with Parkinson's disease (PD). Eighty patients with PD were subjected to randomized, double-blind, placebo-controlled and parallel-group study. PD patients were randomly divided into the tolcapone treatment group (41 cases) and placebo group (39 cases). Each patient received 1 pill of tolcapone or placebo, 3 times per day for 26 weeks. Efficacy was evaluated using the internationally used unified Parkinson's disease rating scale (UPDRS) scoring system for PD symptoms...
January 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29345156/pharmacokinetic-drug-evaluation-of-opicapone-for-the-treatment-of-parkinson-s-disease
#14
Marina Svetel, Aleksandra Tomić, Nikola Kresojević, Vladimir Kostić
Opicapone (OPC) is a novel, potent, reversible, and purely peripheral third-generation COMT inhibitor, which provides an enhancement in levodopa (L-Dopa) availability. It represents adjunctive therapy for L-Dopa treated patients with PD and motor fluctuations. Areas covered: The purpose of this study was to evaluate pharmacokinetic of OPC for the treatment of PD. Expert commentary: Oral OPC exhibits linear, dose-dependent absorption. However, following concomitant ingestion of a high-fat, high-calorie meal, the maximum plasma concentration will be decreased...
January 24, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29281938/pharmacophore-based-virtual-screening-of-catechol-o-methyltransferase-comt-inhibitors-to-combat-alzheimer-s-disease
#15
Chirag N Patel, John J Georrge, Krunal M Modi, Moksha B Narechania, Daxesh P Patel, Frank J Gonzalez, Himanshu A Pandya
Alzheimer's disease (AD) is one of the most significant neurodegenerative disorders and its symptoms mostly appear in aged people. Catechol-o-methyltransferase (COMT) is one of the known target enzymes responsible for AD. With the use of 23 known inhibitors of COMT, a query has been generated and validated by screening against the database of 1500 decoys to obtain the GH score and enrichment value. The crucial features of the known inhibitors were evaluated by the online ZINC Pharmer to identify new leads from a ZINC database...
December 27, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29107002/chronic-treatment-with-caffeine-and-its-withdrawal-modify-the-antidepressant-like-activity-of-selective-serotonin-reuptake-inhibitors-in-the-forced-swim-and-tail-suspension-tests-in-mice-effects-on-comt-slc6a15-and-adora1-gene-expression
#16
Aleksandra Szopa, Urszula Doboszewska, Mariola Herbet, Sylwia Wośko, Elżbieta Wyska, Katarzyna Świąder, Anna Serefko, Agnieszka Korga, Aleksandra Wlaź, Andrzej Wróbel, Marta Ostrowska, Joanna Terlecka, Adam Kanadys, Ewa Poleszak, Jarosław Dudka, Piotr Wlaź
Recent preclinical and clinical data suggest that low dose of caffeine enhances the effects of common antidepressants. Here we investigated the effects of chronic administration of caffeine (5mg/kg, twice daily for 14days) and its withdrawal on day 15th on the activity of per se ineffective doses of fluoxetine (5mg/kg) and escitalopram (2mg/kg) given on day 15th. We found decreased immobility time in the forced swim and tail suspension tests in mice in which caffeine was administered simultaneously with antidepressants on day 15th following a 14-day caffeine treatment and no alterations in the spontaneous locomotor activity...
December 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29074051/the-inhibitory-effects-of-%C3%AE-caryophyllene-%C3%AE-caryophyllene-oxide-and-%C3%AE-humulene-on-the-activities-of-the-main-drug-metabolizing-enzymes-in-rat-and-human-liver-in-vitro
#17
Linh Thuy Nguyen, Zuzana Myslivečková, Barbora Szotáková, Alena Špičáková, Kateřina Lněničková, Martin Ambrož, Vladimír Kubíček, Kristýna Krasulová, Pavel Anzenbacher, Lenka Skálová
Sesquiterpenes, the main components of plant essential oils, are often taken in the form of folk medicines and dietary supplements. Several sesquiterpenes possess interesting biological activities but they could interact with concurrently administered drugs via inhibition of drug-metabolizing enzymes. Therefore, the present study was designed to test the potential inhibitory effect of tree structurally relative sesquiterpenes β-caryophyllene (CAR), β-caryophyllene oxide (CAO) and α-humulene (HUM) on the activities of the main drug-metabolizing enzymes...
December 25, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29065678/bilateral-optic-neuropathy-related-to-severe-anemia-in-a-patient-with-alcoholic-cirrhosis-a-case-report-and-review-of-the-literature
#18
Lisa Humbertjean-Selton, Jérôme Selton, Nolwenn Riou-Comte, Jean-Christophe Lacour, Gioia Mione, Sébastien Richard
Anemia appears frequently in patients with alcoholic liver disease (ALD) but has never been linked to bilateral nonarteritic anterior ischemic optic neuropathy (NAION). A 65-year-old woman with a medical history of alcoholic cirrhosis was admitted for bilateral NAION. On admission, she was found to have a low arterial pressure and severe normocytic anemia (48 g/L). The anemia was related to chronic bleeding due to antral gastritis along with other factors associated with ALD. The applied treatment consisted of urgent transfusion followed by high doses of proton-pump inhibitors, iron and vitamin supplementation, and support in lifestyle measures...
October 25, 2017: Clinical and Molecular Hepatology
https://www.readbyqxmd.com/read/29021832/pharmacogenomics-in-the-treatment-of-mood-disorders-strategies-and-opportunities-for-personalized-psychiatry
#19
REVIEW
Azmeraw T Amare, Klaus Oliver Schubert, Bernhard T Baune
Personalized medicine (personalized psychiatry in a specific setting) is a new model towards individualized care, in which knowledge from genomics and other omic pillars (microbiome, epigenomes, proteome, and metabolome) will be combined with clinical data to guide efforts to new drug development and targeted prescription of the existing treatment options. In this review, we summarize pharmacogenomic studies in mood disorders that may lay the foundation towards personalized psychiatry. In addition, we have discussed the possible strategies to integrate data from omic pillars as a future path to personalized psychiatry...
September 2017: EPMA Journal
https://www.readbyqxmd.com/read/29018243/6e11-a-highly-selective-inhibitor-of-receptor-interacting-protein-kinase-1-protects-cells-against-cold-hypoxia-reoxygenation-injury
#20
C Delehouzé, S Leverrier-Penna, F Le Cann, A Comte, M Jacquard-Fevai, O Delalande, N Desban, B Baratte, I Gallais, F Faurez, M C Bonnet, M Hauteville, P G Goekjian, R Thuillier, F Favreau, P Vandenabeele, T Hauet, M T Dimanche-Boitrel, S Bach
Necroptosis is a programmed cell death pathway that has been shown to be of central pathophysiological relevance in multiple disorders (hepatitis, brain and cardiac ischemia, pancreatitis, viral infection and inflammatory diseases). Necroptosis is driven by two serine threonine kinases, RIPK1 (Receptor Interacting Protein Kinase 1) and RIPK3, and a pseudo-kinase MLKL (Mixed Lineage Kinase domain-Like) associated in a multi-protein complex called necrosome. In order to find new inhibitors for use in human therapy, a chemical library containing highly diverse chemical structures was screened using a cell-based assay...
October 10, 2017: Scientific Reports
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