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COMT INHIBITORS

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https://www.readbyqxmd.com/read/29445781/membrane-bound-comt-isoform-is-an-interfacial-enzyme-general-mechanism-and-new-drug-design-paradigm
#1
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 Mg 2+ ions, required for catalysis, are found...
February 15, 2018: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29441484/real-life-evaluation-of-safinamide-effectiveness-in-parkinson-s-disease
#2
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)...
February 13, 2018: Neurological Sciences
https://www.readbyqxmd.com/read/29436602/the-expression-and-activation-of-sex-steroid-receptors-in-the-preeclamptic-placenta
#3
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...
February 8, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29427081/effects-of-tolcapone-and-bromocriptine-on-cognitive-stability-and-flexibility
#4
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...
February 9, 2018: Psychopharmacology
https://www.readbyqxmd.com/read/29415596/the-launch-of-opicapone-for-parkinson-s-disease-negatives-versus-positives
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
https://www.readbyqxmd.com/read/28952032/neuroprotective-strategies-to-prevent-and-treat-parkinson-s-disease-based-on-its-pathophysiological-mechanism
#14
REVIEW
Yujeong Lee, Min-Sun Kim, Jaewon Lee
Parkinson's disease (PD) is the second most common progressive neurodegenerative disease after Alzheimer's disease. PD exhibits clinical symptoms that include tremors, rigidity, and bradykinesia. Many drugs are available to treat PD, such as, L-dopa, COMT inhibitor, MAO-B inhibitor, and dopamine agonists, but these drugs simply compensate for dopamine loss in PD, and therefore, cannot completely suppress its symptoms or progression. Although the causes of PD are not clearly understood, common pathophysiological pathways, such as, oxidative stress, mitochondrial dysfunction, and neuroinflammation are considered to be etiological factors, and thus, many treatments and interventions have been developed to target these pathophysiological factors...
September 26, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28916530/elucidation-of-the-impact-of-p-glycoprotein-and-breast-cancer-resistance-protein-on-the-brain-distribution-of-catechol-o-methyltransferase-inhibitors
#15
Joana Bicker, Ana Fortuna, Gilberto Alves, Patricio Soares-da-Silva, Amilcar Falcao
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are clinically important efflux transporters that act cooperatively at the blood-brain barrier, limiting the entry of several drugs into the CNS and affecting their pharmacokinetics, therapeutic efficacy and safety. In the present study, the interactions of catechol-O-methyltransferase (COMT) inhibitors (BIA 9-1059, BIA 9-1079, entacapone, nebicapone, opicapone and tolcapone) with P-gp and BCRP were investigated in order to determine the contribution of these transporters in their access to the brain...
September 15, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28867940/genetics-of-generalized-anxiety-disorder-and-related-traits
#16
Michael G Gottschalk, Katharina Domschke
This review serves as a systematic guide to the genetics of generalized anxiety disorder (GAD) and further focuses on anxiety-relevant endophenotypes, such as pathological worry fear of uncertainty, and neuroticism. We inspect clinical genetic evidence for the familialityl heritability of GAD and cross-disorder phenotypes based on family and twin studies. Recent advances of linkage studies, genome-wide association studies, and candidate gene studies (eg, 5-HTT, 5-HT1A, MAOA, BDNF) are outlined. Functional and structural neuroimaging and neurophysiological readouts relating to peripheral stress markers and psychophysiology are further integrated, building a multilevel disease framework...
June 2017: Dialogues in Clinical Neuroscience
https://www.readbyqxmd.com/read/28844929/distribution-properties-and-inhibitor-sensitivity-of-zebrafish-catechol-o-methyl-transferases-comt
#17
Svetlana Semenova, Stanislav Rozov, Pertti Panula
Catechol-O-methyltransferase (COMT; EC 2.1.1.6) is an enzyme with multiple functions in vertebrates. COMT methylates and thus inactivates catecholamine neurotransmitters and metabolizes xenobiotic catechols. Gene polymorphism rs4680 that influences the enzymatic activity of COMT affects cognition and behavior in humans. The zebrafish is widely used as an experimental animal in many areas of biomedical research, but most aspects of COMT function in this species have remained uncharacterized. We hypothesized that both comt genes play essential roles in zebrafish...
December 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28825621/inhibitory-effect-of-bovine-lactoferrin-on-catechol-o-methyltransferase
#18
Masayuki Ikeda, Hiroshi Iijima, Ichizo Shinoda, Hiroshi Iwamoto, Yasuhiro Takeda
Lactoferrin (LF) is a well-known multifunctional protein. In this study, we report the inhibitory potency of bovine LF (bLF) on catechol-O-methyltransferase (COMT), which catalyzes methylation of catechol substrates. We found that bLF binds to and inhibits COMT using its N-terminal region. An N-terminal peptide fragment obtained from bLF by trypsin digestion showed a higher inhibitory activity than intact bLF. A synthetic fragment of the bLF N-terminal residues 6-50, with two pairs of disulfide bonds, also showed higher inhibitory activity than intact bLF...
August 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28793366/cadmium-induced-melatonin-synthesis-in-rice-requires-light-hydrogen-peroxide-and-nitric-oxide-key-regulatory-roles-for-tryptophan-decarboxylase-and-caffeic-acid-o-methyltransferase
#19
Kyungjin Lee, Geun-Hee Choi, Kyoungwhan Back
In plants, melatonin production is induced by stimuli such as cold and drought, and cadmium (Cd) is the best elicitor of melatonin production in rice. However, the mechanism by which Cd induces melatonin synthesis in plants remains unknown. We challenged rice seedlings with Cd under different light conditions and found that continuous light produced the highest levels of melatonin, while continuous dark failed to induce melatonin production. Transcriptional and translational induction of tryptophan decarboxylase contributed to the light induction of melatonin during Cd treatment, whereas the protein level of light-induced caffeic acid O-methyltransferase (COMT) was decreased by Cd treatment...
August 9, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/28768964/the-risk-factors-for-the-wearing-off-phenomenon-in-parkinson-s-disease-in-japan-a-cross-sectional-multicenter-study
#20
Shinji Ouma, Jiro Fukae, Shinsuke Fujioka, Shosaburo Yamamoto, Taku Hatano, Asako Yoritaka, Yasuyuki Okuma, Ken-Ichi Kashihara, Nobutaka Hattori, Yoshio Tsuboi
Objective Parkinson's disease (PD) is a common, progressive, neurodegenerative disorder. With progression of PD, the wearing-off phenomenon occurs more frequently as a motor complication, decreasing the patient's quality of life. The aim of this study was to investigate the risk factors for the wearing-off phenomenon in Japanese PD patients. Methods All of the study participants were clinically diagnosed as having PD. Each patient was assessed for the wearing-off phenomenon based on the findings of clinical assessments and interviews that were conducted during a single visit...
2017: Internal Medicine
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