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https://www.readbyqxmd.com/read/27925230/role-of-abc-transporters-in-trans-epithelial-transport-of-vitamin-k-antagonists
#1
Bernadette Espana, Solange Couturier, Caroline Prouillac
Vitamin K antagonists remain (VKAs) the oral anticoagulant of choice of venous thromboembolic disease. These drugs are characterized by a large inter-individual variability requiring frequent dose tailoring. Genetic polymorphisms for cytochrome CYP2C9 and VKORC1 explain some of the variability, especially in warfarin and acenocoumarol responses. The aim of this study is to assess on cell models the role of ABC transporters in the intestinal transfer of the main coumarin derivatives (warfarin, acenocoumarol) and indanedione derivatives (phenindione, fluindione)...
December 7, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27879469/frequency-of-common-vkorc1-polymorphisms-and-their-impact-on-warfarin-dose-requirement-in-pakistani-population
#2
Aisha Qayyum, Muzammil Hasan Najmi, Qaisar Mansoor, Muhammad Irfan, Abdul Khaliq Naveed, Andleeb Hanif, Ali Raza Kazmi, Muhammad Ismail
Polymorphisms in vitamin K epoxide reductase complex subunit 1 (VKORC1) gene lead to interindividual variability in warfarin dose requirement. The characterization of genotype frequency distribution is required in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common VKORC1 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations...
November 21, 2016: Clinical and Applied Thrombosis/hemostasis
https://www.readbyqxmd.com/read/27878474/quantitative-assessment-of-cyp2c9-genetic-polymorphisms-effect-on-the-oral-clearance-of-s-warfarin-in-healthy-subjects
#3
Chanan Shaul, Simcha Blotnick, Mordechai Muszkat, Meir Bialer, Yoseph Caraco
BACKGROUND: Genetic polymorphisms in CYP2C9 account for 10-20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions...
November 22, 2016: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/27864383/use-of-pharmacogenetic-information-in-the-treatment-of-cardiovascular-disease
#4
REVIEW
Kevin Friede, Josephine Li, Deepak Voora
BACKGROUND: In 1964, Robert A. O'Reilly's research group identified members of a family who required remarkably high warfarin doses (up to 145 mg/day, 20 times the average dose) to achieve appropriate anticoagulation. Since this time, pharmacogenetics has become a mainstay of cardiovascular science, and genetic variants have been implicated in several fundamental classes of medications used in cardiovascular medicine. CONTENT: In this review, we discuss genetic variants that affect drug response to 3 classes of cardiovascular drugs: statins, platelet P2Y12 inhibitors, and anticoagulants...
November 18, 2016: Clinical Chemistry
https://www.readbyqxmd.com/read/27864202/implementation-of-inpatient-models-of-pharmacogenetics-programs
#5
Larisa H Cavallari, Craig R Lee, Julio D Duarte, Edith A Nutescu, Kristin W Weitzel, George A Stouffer, Julie A Johnson
PURPOSE: The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided drug therapy in pharmacogenetics programs at three institutions is highlighted. SUMMARY: Pharmacists are well positioned to assume important roles in facilitating the clinical use of genetic information to optimize drug therapy given their expertise in clinical pharmacology and therapeutics...
December 1, 2016: American Journal of Health-system Pharmacy: AJHP
https://www.readbyqxmd.com/read/27855643/evaluation-of-a-pharmacogenetic-based-warfarin-dosing-algorithm-in-patients-with-low-time-in-therapeutic-range-study-protocol-for-a-randomized-controlled-trial
#6
Leiliane Rodrigues Marcatto, Luciana Sacilotto, Carolina Tosin Bueno, Mirella Facin, Celia Maria Cassaro Strunz, Francisco Carlos Costa Darrieux, Maurício Ibrahim Scanavacca, Jose Eduardo Krieger, Alexandre Costa Pereira, Paulo Caleb Junior Lima Santos
BACKGROUND: Time in therapeutic range (TTR) is a measurement of quality of warfarin therapy and lower TTR values (<50%) are associated with greater risk of thromboembolic and bleeding events. Recently, we developed a pharmacogenetic-based warfarin dosing algorithm specifically calibrated for a Brazilian patient sample. The aims of this study are: to evaluate the impact of a genetic-based algorithm, compared to traditional anticoagulation, in the time to achieve the therapeutic target and in TTR percentage; and to assess the cost-effectiveness of genotype-guided warfarin dosing in a specific cohort of patients with low TTR (<50%) from a tertiary cardiovascular hospital...
November 17, 2016: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/27855133/influence-of-genotype-on-warfarin-maintenance-dose-predictions-produced-using-a-bayesian-dose-individualization-tool
#7
Shamin M Saffian, Stephen B Duffull, Rebecca L Roberts, Robert C Tait, Leanne Black, Kirstin A Lund, Alison H Thomson, Daniel F B Wright
BACKGROUND: A previously established Bayesian dosing tool for warfarin was found to produce biased maintenance dose predictions. In this study, we aimed (1) to determine whether the biased warfarin dose predictions previously observed could be replicated in a new cohort of patients from 2 different clinical settings, (2) to explore the influence of CYP2C9 and VKORC1 genotype on predictive performance of the Bayesian dosing tool, and (3) to determine whether the previous population used to develop the kinetic-pharmacodynamic model underpinning the Bayesian dosing tool was sufficiently different from the test (posterior) population to account for the biased dose predictions...
December 2016: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/27816002/strain-differences-in-intestinal-toxicity-of-warfarin-in-rats
#8
Ivana Mirkov, Aleksandra Popov Aleksandrov, Marina Ninkov, Dina Mileusnic, Jelena Demenesku, Lidija Zolotarevski, Vesna Subota, Debora Stefik, Dragan Kataranovski, Milena Kataranovski
Intestinal hemorrhage characterizes effectiveness of warfarin (WF) as rodenticide and is among adverse effects of therapy in humans. Having in mind genetic variations in the effectiveness of WF in wild rats and in the doses required for therapeutic effect, strain differences in the intestinal toxicity of oral warfarin in rats were examined in this study. High WF dose (3.5mg/l) led to mortality in Albino Oxford (AO) rats, with no lethality in Dark Agouti (DA) rats. Higher values of prothrombin time were noted at low WF dose (0...
December 2016: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/27768243/prenatal-exposure-to-environmental-factors-and-congenital-limb-defects
#9
Peter G Alexander, Karen L Clark, Rocky S Tuan
Limb congenital defects afflict approximately 0.6:1000 live births. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants, represents a major contributing factor to limb defects. Examples of well-recognized limb teratogenic agents include thalidomide, warfarin, valproic acid, misoprostol, and phenytoin. While the mechanism by which these agents cause dymorphogenesis is increasingly clear, prediction of the limb teratogenicity of many thousands of as yet uncharacterized environmental factors (pollutants) remains inexact...
October 21, 2016: Birth Defects Research. Part C, Embryo Today: Reviews
https://www.readbyqxmd.com/read/27752976/pharmacogenomics-and-pharmacogenetics-for-the-intensive-care-unit-a-narrative-review
#10
Meghan MacKenzie, Richard Hall
PURPOSE: Knowledge of how alterations in pharmacogenomics and pharmacogenetics may affect drug therapy in the intensive care unit (ICU) has received little study. We review the clinically relevant application of pharmacogenetics and pharmacogenomics to drugs and conditions encountered in the ICU. SOURCE: We selected relevant literature to illustrate the important concepts contained within. PRINCIPAL FINDINGS: Two main approaches have been used to identify genetic abnormalities - the candidate gene approach and the genome-wide approach...
October 17, 2016: Canadian Journal of Anaesthesia, Journal Canadien D'anesthésie
https://www.readbyqxmd.com/read/27743182/linkage-disequilibrium-between-the-cyp2c19-2-17-and-cyp2c9-1-alleles-and-impact-of-vkorc1-cyp2c9-cyp2c19-gene-polymorphisms-and-gene-gene-interactions-on-warfarin-therapy
#11
Koroush Khalighi, Gang Cheng, Seyedabbas Mirabbasi, Bahar Khalighi, Yin Wu, Wuqiang Fan
Warfarin therapy is complicated by its large inter-individual and intra-individual variability. Both genetic and non-genetic factors can affect warfarin therapy. This study aims to investigate the allele distribution of VKORC1, CYP2C9 and CYP2C19, contribution of different allele variants and possible gene-gene interaction on warfarin therapy. Four hundreds and ninety-two patients were enrolled and single nucleotide polymorphisms for vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 CYP2C9 and cytochrome P450 CYP2C19 were genotyped...
October 14, 2016: Journal of Thrombosis and Thrombolysis
https://www.readbyqxmd.com/read/27740732/identification-of-novel-variants-associated-with-warfarin-stable-dosage-by-use-of-a-two-stage-extreme-phenotype-strategy
#12
Z Luo, X Li, M Zhu, J Tang, Z Li, X Zhou, G Song, Z Liu, H Zhou, W Zhang
: Essentials Required warfarin doses for mechanical heart valves vary greatly. A two-stage extreme phenotype design was used to identify novel warfarin dose associated mutation. We identified a group of variants significantly associated with extreme warfarin dose. Four novel identified mutations account for 2.2% of warfarin dose discrepancies. SUMMARY: Background The variation among patients in warfarin response complicates the management of warfarin therapy, and an improper therapeutic dose usually results in serious adverse events...
October 14, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27714756/cardiovascular-pharmacogenetics-a-promise-for-genomically-guided-therapy-and-personalized-medicine
#13
REVIEW
M Zaiou, H El Amri
Cardiovascular disease (CVD) is the leading cause of death worldwide. The basic causes of CVD are not fully understood yet. Substantial evidence suggests that genetic predisposition plays a vital role in the physiopathology of this complex disease. Hence, identification of genetic contributors to CVD will likely add diagnostic accuracy and better prediction of an individual's risk. With high-throughput genetics and genomics technology and newer genome-wide study approaches, a number of genetic variations across the human genome were uncovered...
October 6, 2016: Clinical Genetics
https://www.readbyqxmd.com/read/27660039/recurrent-hemorrhagic-venous-infarctions-caused-by-thrombosis-of-a-pontine-developmental-venous-anomaly-and-protein-s-mutation
#14
Yuri Nakamura, Kei-Ichiro Takase, Takuya Matsushita, Satoshi Yoshimura, Ryo Yamasaki, Hiroyuki Murai, Kazufumi Kikuchi, Jun-Ichi Kira
A 34-year-old man presented with an acute onset of upbeat nystagmus, slurred speech, and limb and truncal ataxias. The patient had a history of limb ataxia and gait disturbance previously treated as brainstem encephalitis with corticosteroids 3 years previously. Brain magnetic resonance imaging showed pontine developmental venous anomaly (DVA) and hemorrhagic infarction within the drainage territory of the DVA. Three months later, the patient exhibited recurrent limb ataxia, double vision, and numbness of the left side of the body...
September 19, 2016: Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association
https://www.readbyqxmd.com/read/27639441/human-teratogens-and-genetic-phenocopies-understanding-pathogenesis-through-human-genes-mutation
#15
Matteo Cassina, Giulia A Cagnoli, Daniela Zuccarello, Elena Di Gianantonio, Maurizio Clementi
Exposure to teratogenic drugs during pregnancy is associated with a wide range of embryo-fetal anomalies and sometimes results in recurrent and recognizable patterns of malformations; however, the comprehension of the mechanisms underlying the pathogenesis of drug-induced birth defects is difficult, since teratogenesis is a multifactorial process which is always the result of a complex interaction between several environmental factors and the genetic background of both the mother and the fetus. Animal models have been extensively used to assess the teratogenic potential of pharmacological agents and to study their teratogenic mechanisms; however, a still open issue concerns how the information gained through animal models can be translated to humans...
September 14, 2016: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/27636550/a-european-spectrum-of-pharmacogenomic-biomarkers-implications-for-clinical-pharmacogenomics
#16
Clint Mizzi, Eleni Dalabira, Judit Kumuthini, Nduna Dzimiri, Istvan Balogh, Nazli Başak, Ruwen Böhm, Joseph Borg, Paola Borgiani, Nada Bozina, Henrike Bruckmueller, Beata Burzynska, Angel Carracedo, Ingolf Cascorbi, Constantinos Deltas, Vita Dolzan, Anthony Fenech, Godfrey Grech, Vytautas Kasiulevicius, Ľudevít Kádaši, Vaidutis Kučinskas, Elza Khusnutdinova, Yiannis L Loukas, Milan Macek, Halyna Makukh, Ron Mathijssen, Konstantinos Mitropoulos, Christina Mitropoulou, Giuseppe Novelli, Ioanna Papantoni, Sonja Pavlovic, Giuseppe Saglio, Jadranka Setric, Maja Stojiljkovic, Andrew P Stubbs, Alessio Squassina, Maria Torres, Marek Turnovec, Ron H van Schaik, Konstantinos Voskarides, Salma M Wakil, Anneke Werk, Maria Del Zompo, Branka Zukic, Theodora Katsila, Ming Ta Michael Lee, Alison Motsinger-Rief, Howard L Mc Leod, Peter J van der Spek, George P Patrinos
Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes...
2016: PloS One
https://www.readbyqxmd.com/read/27632229/genetic-determinants-of-variability-in-warfarin-response-after-the-dose-titration-phase
#17
Otito F Iwuchukwu, Andrea H Ramirez, Yaping Shi, Erica A Bowton, Vivian K Kawai, Jonathan S Schildcrout, Dan M Roden, Joshua C Denny, C Michael Stein
OBJECTIVES: Genetic factors contribute considerably toward variability in warfarin dose requirements and are important in the dose-titration phase; their effects on the stability of anticoagulation later in therapy are not known. METHODS: Using deidentified electronic medical records linked to a DNA-biobank, we studied 140 African-Americans and 943 European-Americans after the warfarin dose-titration phase. We genotyped 12 single nucleotide polymorphisms in genes (CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, CALU) associated with altered warfarin dose requirements and tested their associations with international normalized ratio variability (INRVAR) and percent time in therapeutic range in European-Americans and African-Americans...
November 2016: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/27617219/impact-of-cyp2c9-vkorc1-and-cyp4f2-genetic-polymorphisms-on-maintenance-warfarin-dosage-in-han-chinese-patients-a-systematic-review-and-meta-analysis
#18
REVIEW
Jinhua Zhang, Zhijie Chen, Chunmei Chen
INTRODUCTION: Warfarin is the most commonly used antithrombotic drug. Single nucleotide polymorphisms (SNPs) of CYP2C9, CYP4F2, VKORC1 1173 and VKORC1-1639 influence warfarin maintenance dosage. We aimed to determine the impact of SNPs of these genes on mean daily warfarin dosage (MDWD) in Han-Chinese patients. METHODS: Strict literature inclusion criteria were established, and literature searching was performed on PubMed, Embase and Cochrane Library for English articles and CNKI, CBM and Wanfang database for Chinese articles before September 2, 2014...
September 2016: Meta Gene
https://www.readbyqxmd.com/read/27606428/the-active-metabolite-of-warfarin-3-hydroxywarfarin-and-correlation-with-inr-warfarin-and-drug-weekly-dosage-in-patients-under-oral-anticoagulant-therapy-a-pharmacogenetics-study
#19
Donato Gemmati, Francesco Burini, Anna Talarico, Matteo Fabbri, Cesare Bertocco, Marco Vigliano, Stefano Moratelli, Antonio Cuneo, Maria Luisa Serino, Francesco Maria Avato, Veronica Tisato, Rosa Maria Gaudio
OBJECTIVES: Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3'-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring...
2016: PloS One
https://www.readbyqxmd.com/read/27593608/impact-of-body-mass-index-and-genetics-on-warfarin-major-bleeding-outcomes-in-a-community-setting
#20
Ragan Hart, David L Veenstra, Denise M Boudreau, Joshua A Roth
BACKGROUND: Several studies have demonstrated an association between body mass index (BMI) and warfarin therapeutic dose, but none evaluated the association of BMI with the clinically important outcome of major bleeding in a community setting. To address this evidence gap, we conducted a case-control study to evaluate the association between BMI and major bleeding risk among patients receiving warfarin. METHODS: We used a case-control study design to evaluate the association between obesity (BMI >30...
September 2, 2016: American Journal of Medicine
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