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https://www.readbyqxmd.com/read/29318005/precision-medicine-does-ethnicity-information-complement-genotype-based-prescribing-decisions
#1
REVIEW
Rashmi R Shah, Andrea Gaedigk
Inter-ethnic differences in drug response are all too well known. These are underpinned by a number of factors, including pharmacogenetic differences across various ethnic populations. Precision medicine relies on genotype-based prescribing decisions with the aim of maximizing efficacy and mitigating the risks. When there is no access to genotyping tests, ethnicity is frequently regarded as a proxy of the patient's probable genotype on the basis of overall population-based frequency of genetic variations in the ethnic group the patient belongs to, with some variations being ethnicity-specific...
January 2018: Therapeutic Advances in Drug Safety
https://www.readbyqxmd.com/read/29283396/pharmacogenomics-of-cyp2c9-functional-and-clinical-considerations
#2
REVIEW
Ann K Daly, Allan E Rettie, Douglas M Fowler, John O Miners
CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions...
December 28, 2017: Journal of Personalized Medicine
https://www.readbyqxmd.com/read/29277691/genetic-polymorphisms-of-drug-metabolizing-cytochrome-p450-enzymes-in-cynomolgus-and-rhesus-monkeys-and-common-marmosets-in-preclinical-studies-for-humans
#3
REVIEW
Yasuhiro Uno, Shotaro Uehara, Hiroshi Yamazaki
Cynomolgus monkeys (Macaca fascicularis, Old World Monkeys) and common marmosets (Callithrix jacchus, New World Monkeys) have been widely, and expectedly, used as non-human primate models in drug development studies. Major drug-metabolizing cytochrome P450 (P450) enzymes information is now available that supports these primate species as animal models, and it is established that multiple forms of cynomolgus monkey and common marmoset P450 enzymes have generally similar substrate recognition functionality to human P450 enzymes...
December 22, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29243335/comparative-performance-of-pharmacogenetics-based-warfarin-dosing-algorithms-derived-from-caucasian-asian-and-mixed-races-in-thai-population
#4
Supatat Chumnumwat, Kong Yi, Aroonrut Lucksiri, Wichit Nosoongnoen, Busba Chindavijak, Suvatna Chulavatnatol, Ajjima Sarapakdi, Surakit Nathisuwan
AIM: This study was conducted to compare predictive accuracy of the available pharmacogenetics (PGx)-guided warfarin-dosing algorithms derived from Caucasian, Asian and mixed population to identify a suitable algorithm for Thai population. METHODS: Ten warfarin-dosing algorithms derived from different population including Caucasian, East Asian, Southeast Asian and mixed races were selected and tested with clinical and genetic data of Thai patients. Comparative performances of these algorithms were tested using mean dose error (MDE) between actual warfarin maintenance dose (AWMD) and predicted dose generated by each dosing algorithm, and percentage of ideal dose prediction (IDP)...
December 15, 2017: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/29237680/personalized-anticoagulation-optimizing-warfarin-management-using-genetics-and-simulated-clinical-trials
#5
Kourosh Ravvaz, John A Weissert, Christian T Ruff, Chih-Lin Chi, Peter J Tonellato
BACKGROUND: Clinical trials testing pharmacogenomic-guided warfarin dosing for patients with atrial fibrillation have demonstrated conflicting results. Non-vitamin K antagonist oral anticoagulants are expensive and contraindicated for several conditions. A strategy optimizing anticoagulant selection remains an unmet clinical need. METHODS AND RESULTS: Characteristics from 14 206 patients with atrial fibrillation were integrated into a validated warfarin clinical trial simulation framework using iterative Bayesian network modeling and a pharmacokinetic-pharmacodynamic model...
December 2017: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/29234073/identification-of-two-novel-genes-slc15a2-and-slco1b3-associated-with-maintenance-dose-variability-of-warfarin-in-a-chinese-population
#6
Liang-Liang Cai, Wen-Qing Huang, Zhi-Ying Su, Hui-Ming Ye, Lian-Sheng Wang, Yuan Wu, Zhong-Ying Zhang, Wei Zhang, Chi-Meng Tzeng
Warfarin is a commonly prescribed and effective oral anticoagulant. Genetic polymorphisms associated with warfarin metabolism and sensitivity have been implicated in the wide inter-individual dose variation that is observed. Several algorithms integrating patients' clinical characteristics and genetic polymorphism information have been explored to predict warfarin dose. However, most of these algorithms could explain only over half of the variation in a warfarin maintenance dose, suggesting that additional genetic factors may exist and need to be identified...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29218901/using-simulation-and-optimization-approach-to-improve-outcome-through-warfarin-precision-treatment
#7
Chih-Lin Chi, Lu He, Kourosh Ravvaz, John Weissert, Peter J Tonellato
We apply a treatment simulation and optimization approach to develop decision support guidance for warfarin precision treatment plans. Simulation include the use of ∼1,500,000 clinical avatars (simulated patients) generated by an integrated data-driven and domain-knowledge based Bayesian Network Modeling approach. Subsequently, we simulate 30-day individual patient response to warfarin treatment of five clinical and genetic treatment plans followed by both individual and subpopulation based optimization. Sub-population optimization (compared to individual optimization) provides a cost effective and realistic means of implementation of a precision-driven treatment plan in practical settings...
2018: Pacific Symposium on Biocomputing
https://www.readbyqxmd.com/read/29209208/the-clinical-pharmacokinetics-and-pharmacodynamics-of-warfarin-when-combined-with-compound-danshen-a-case-study-for-combined-treatment-of-coronary-heart-diseases-with-atrial-fibrillation
#8
Chunxiao Lv, Changxiao Liu, Zhuhua Yao, Xiumei Gao, Lanjun Sun, Jia Liu, Haibo Song, Ziqiang Li, Xi Du, Jinxia Sun, Yanfen Li, Kui Ye, Ruihua Wang, Yuhong Huang
Warfarin is used as anticoagulant and Compound Danshen prescription (CDP) is able to promote blood circulation. The combination might produce a synergic effect for patients of coronary heart diseases (CHDs) with atrial fibrillation (AF). Whether the combination increases the bleeding risk of warfarin is unclear, so the effects of Compound Danshen dripping pill (CDDP) on the pharmacokinetics (PK) and pharmacodynamics (PD) profiles of warfarin was investigated in patients. The dose and blood concentrations of warfarin, the four indicators of blood coagulation, prothrombin time, activated partial thromboplatin time, thrombin time, fibrinogen, and international normalized ratio value were compared when with and without CDDP treatment...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29201112/association-of-warfarin-therapy-with-apoe-and-vkorc1-genes-polymorphism-in-iranian-population
#9
Sajad Rafiee, Masoumeh Rajabibazl, Reza Meshkani, Azam Daraei, Mehryar Zargari, Fahimeh Sharafeddin, Zahra Fazeli, Attabak Toffani Milani, Maryam Taherkhani
Warfarin is a vitamin K antagonist that genetic and non-genetic factors affected on its dose requirement in the patients with cardio vascular disease. The aim of this study was whether the APOE and VKORC1 polymorphisms influence on warfarin dose requirements in the part of Iranian patients. Blood samples were collected from 86 warfarin-treated patients. After extraction of genomic DNA, the VKORC1 (rs9923231) and the APOE (rs429358 and rs7412) polymorphisms were genotyped by PCR-RFLP technique. We found that the Iranian patients carrying genotypes GA or AA of VKORC1 polymorphism tended to receive lower dose of warfarin (p = 0...
2017: Iranian Journal of Pharmaceutical Research: IJPR
https://www.readbyqxmd.com/read/29185625/unusual-warfarin-dose-to-achieve-therapeutic-inr-in-a-4-month-old-child-non-genetics-risk-factors-are-still-a-challenge
#10
Lucas Miyake Okumura, Giovanna Webster Negretto, Clarissa Gutiérrez Carvalho
OBJECTIVE: To report a case of a 4-month old girl that required 0.7 mg/kg/day (5 mg) of warfarin and discuss relevant risk factors for requiring higher doses. CASE DESCRIPTION: In November 2015, a 5 kg female infant (36-week preterm) was admitted to the hospital due to status epilepticus and fever. Diazepam, phenytoin and ceftriaxone were prescribed. Cerebrospinal fluid contained 7 leukocytes, 150 mg/dL proteins, 1 mg/dL glucose and gram positive cocci were observed...
October 2017: Revista Paulista de Pediatria: Orgão Oficial da Sociedade de Pediatria de São Paulo
https://www.readbyqxmd.com/read/29178968/cohort-specific-imputation-of-gene-expression-improves-prediction-of-warfarin-dose-for-african-americans
#11
Assaf Gottlieb, Roxana Daneshjou, Marianne DeGorter, Stephane Bourgeois, Peter J Svensson, Mia Wadelius, Panos Deloukas, Stephen B Montgomery, Russ B Altman
BACKGROUND: Genome-wide association studies are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into "gene level" effects. METHODS: Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions...
November 24, 2017: Genome Medicine
https://www.readbyqxmd.com/read/29156869/impact-of-ggcx-polymorphisms-on-warfarin-dose-requirements-in-atrial-fibrillation-patients
#12
Nian-Xin Jiang, Ying-Hui Xu, Jing-Wen Xia, Bing Jiang, Yan-Song Li
Background/aim: Warfarin is a common anticoagulant with large interindividual differences and a narrow therapeutic range. The polymorphisms of gamma-glutamyl carboxylase (GGCX) are important genetic factors for warfarin dose requirements. Materials and methods: Polymerase chain reaction and direct sequencing methods were used to detect the GGCX rs699664 genotype in 215 atrial fibrillation (AF) patients with warfarin administration. The effects on warfarin dose by different genotypes were analyzed. A warfarin dosing algorithm was developed based on age, height, CYP2C9, VKORC1, and GGCX genotype...
August 23, 2017: Turkish Journal of Medical Sciences
https://www.readbyqxmd.com/read/29095091/an-assessment-of-the-impact-of-pharmacogenomics-on-health-disparities-a-systematic-literature-review
#13
Antony Martin, Jennifer Downing, Michelle Maden, Nigel Fleeman, Ana Alfirevic, Alan Haycox, Munir Pirmohamed
This review assessed evidence of disparities in benefits of pharmacogenomics related to 'model performance' in subgroups of patients and studies which reported impact on health inequalities. 'Model performance' refers to the ability of algorithms including clinical, environmental and genetic information to guide treatment. A total of 4978 abstracts were screened by one reviewer and 30% (1494) were double screened by a second independent reviewer, after which data extraction was performed. Additional forward and backward citation searching of reference lists was conducted...
November 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/29054760/polymorphisms-of-vitamin-k-related-genes-ephx1-and-vkorc1l1-and-stable-warfarin-doses
#14
Jee-Eun Chung, Kyung Eun Lee, Byung Chul Chang, Hye Sun Gwak
The aim of this study was to investigate the possible effects of EPHX1 and VKORC1L1 polymorphisms on variability of responses to warfarin. Sixteen single nucleotide polymorphisms (SNPs) in 201 patients with stable warfarin doses were analyzed including genes of VKORC1, CYP2C9, CYP4F2, GGCX, EPHX1 and VKORC1L1. Univariate analysis was conducted for the association of genotypes with stable warfarin doses. Multiple linear regression analysis was used to investigate factors that independently affected the inter-individual variability of warfarin dose requirements...
October 17, 2017: Gene
https://www.readbyqxmd.com/read/29040422/pharmacogenetics-a-general-review-on-progress-to-date
#15
Ann K Daly
Background: Pharmacogenetics is not a new subject area but its relevance to drug prescribing has become clearer in recent years due to developments in gene cloning and DNA genotyping and sequencing. Sources of data: There is a very extensive published literature concerned with a variety of different genes and drugs. Areas of agreement: There is general agreement that pharmacogenetic testing is essential for the safe use of drugs such as the thiopurines and abacavir...
October 11, 2017: British Medical Bulletin
https://www.readbyqxmd.com/read/28973620/effect-of-genotype-guided-warfarin-dosing-on-clinical-events-and-anticoagulation-control-among-patients-undergoing-hip-or-knee-arthroplasty-the-gift-randomized-clinical-trial
#16
RANDOMIZED CONTROLLED TRIAL
Brian F Gage, Anne R Bass, Hannah Lin, Scott C Woller, Scott M Stevens, Noor Al-Hammadi, Juan Li, Tomás Rodríguez, J Philip Miller, Gwendolyn A McMillin, Robert C Pendleton, Amir K Jaffer, Cristi R King, Brandi DeVore Whipple, Rhonda Porche-Sorbet, Lynnae Napoli, Kerri Merritt, Anna M Thompson, Gina Hyun, Jeffrey L Anderson, Wesley Hollomon, Robert L Barrack, Ryan M Nunley, Gerard Moskowitz, Victor Dávila-Román, Charles S Eby
Importance: Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown. Objective: To determine whether genotype-guided dosing improves the safety of warfarin initiation. Design, Setting, and Patients: The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers...
September 26, 2017: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/28949423/influence-of-kidney-transplant-status-on-warfarin-dose-anticoagulation-control-and-risk-of-hemorrhage
#17
Megan V Yanik, Marguerite R Irvin, T Mark Beasley, Pamala A Jacobson, Bruce A Julian, Nita A Limdi
STUDY DESIGN: To assess whether warfarin dose requirement, anticoagulation control, and risk of hemorrhage differ in kidney transplant recipients (KTRs) compared with patients without kidney transplants (non-KTRs). DESIGN: Analysis of data from the Warfarin Pharmacogenetics Cohort, a prospective cohort of first-time warfarin users followed at two anticoagulation clinics. SETTING: Two outpatient anticoagulation clinics at two large, academic, tertiary care hospitals...
November 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28933798/pharmacokinetics-of-tecarfarin-and-warfarin-in-patients-with-severe-chronic-kidney-disease
#18
Mark Midei, Detlef Albrecht, Mintu P Turakhia, Daniel Ries, Thomas Marbury, William Smith, Debbie Dillon, Peter G Milner, Mark G Midei
Chronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis (n = 13) were matched to healthy volunteers (HVs) (n = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug...
September 21, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28931618/predicting-major-bleeding-in-ischemic-stroke-patients-with-atrial-fibrillation
#19
RANDOMIZED CONTROLLED TRIAL
Nina A Hilkens, Ale Algra, Jacoba P Greving
BACKGROUND AND PURPOSE: Performance of risk scores for major bleeding in patients with atrial fibrillation and a previous transient ischemic attack or ischemic stroke is not well established. We aimed to validate risk scores for major bleeding in patients with atrial fibrillation treated with oral anticoagulants after cerebral ischemia and explore the net benefit of oral anticoagulants among bleeding risk categories. METHODS: We analyzed 3623 patients with a history of transient ischemic attack or stroke included in the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy)...
November 2017: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/28889200/prevalence-of-common-hereditary-risk-factors-for-thrombophilia-in-somalia-and-identification-of-a-novel-gln544arg-mutation-in-coagulation-factor-v
#20
Abshir Ali Abdi, Abdimajid Osman
Thrombophilia, commonly manifested as venous thromboembolism (VTE), is a worldwide concern but little is known on its genetic epidemiology in many parts of the globe particularly in the developing countries. Here we employed TaqMan genotyping and pyrosequencing to evaluate the prevalence of known common nucleotide polymorphisms associated with thrombophilia in a Somali population in the Puntland region of Somalia. We also employed next generation sequencing (NGS) to investigate other genetic variants in a Somali patient with deep venous thrombosis (DVT)...
November 2017: Journal of Thrombosis and Thrombolysis
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