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Eur Heart J Case Rep 2021 Jun 5;5(6):ytab206. Epub 2021 Jun 5.

Service d'hématologie biologique, Hôpital Lariboisière, 2rue Ambroise Pare ´,75010 Paris, Université de Paris, Paris, France.

Background: Severe acute respiratory syndrome coronavirus 2 disease is strongly associated with a high incidence of thrombotic events. Anticoagulation could be a cornerstone in successfully managing severe forms of coronavirus disease 2019 (COVID-19). However, optimal anticoagulant dosing in elderly patients is challenging because of high risk of both thrombosis and bleeding. Read More

Pediatr Cardiol 2021 Jun 10;42(5):1082-1087. Epub 2021 Apr 10.

Heart Failure, Transplant and Mechanical Assistance Program Unit, Bambino Gesù Children Hospital, Rome, Italy.

Warfarin is prescribed in patients with ventricular assist devices (VADs). Dosage depends on several factors including the underlying genotype. These include polymorphisms of genes encoding cytochrome P450 enzymes, the main ones being CYP2C9, VKORC1, and CYP4F2. Read More

Pharmacol Rep 2021 Apr 3. Epub 2021 Apr 3.

RCSI-MUB, Manama, Kingdom of Bahrain.

Background: Warfarin is the most commonly evaluated drug in pharmacogenetic-guided dosing studies. However, gaps remain regarding the influence of the genetic polymorphisms of CYP2C9, VKORC1, and CYP4F2 on specific pharmacodynamic parameters like the warfarin sensitivity index (WSI), prothrombin time international normalized ratio (PT-INR), and log-INR variability.

Methods: A cross-sectional study was conducted in non-smoking adults receiving warfarin for at least 6 months. Read More

J Thromb Haemost 2021 Mar 28. Epub 2021 Mar 28.

Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Korea.

Background: Personalized warfarin dosing is influenced by various factors including genetic and non-genetic factors. Multiple linear regression (LR) is known as a conventional method to develop predictive models. Recently, machine learning approaches have been extensively implemented for warfarin dosing due to the hypothesis of non-linear association between covariates and stable warfarin dose. Read More

Iran J Pharm Res 2020 ;19(3):77-85

Department of Cardiovascular Surgery, Seyyed-al-Shohada Heart Center, Urmia University of Medical Sciences, Urmia, Iran.

The requirement of varying doses of warfarin for different individuals can be explained by environmental and genetic factors. We evaluated the frequency of vitamin K epoxide reductase complex subunit 1 () and cytochrome P450 2C9 () variants together with patientdemographic characteristics and investigated their association with warfarin dose requirement with the objective to suggest a warfarin dosing algorithm. In this study, 185 patients with heart valve replacement from West Azerbaijan, Iran were genotyped for (-1639 G>A) and (*2 and *3 alleles) by PCR-RFLP. Read More

Front Pharmacol 2021 11;12:619339. Epub 2021 Feb 11.

The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Beijing, China.

Warfarin is a widely prescribed anticoagulant but the doses required to attain the optimum therapeutic effect exhibit dramatic inter-individual variability. Pharmacogenomics-guided warfarin dosing has been recommended to improve safety and effectiveness. We analyzed the cytochrome P450 2C9 () and vitamin K epoxide reductase complex subunit 1 () genes among 120 patients taking warfarin. Read More

J Clin Pharm Ther 2021 Jun 21;46(3):640-648. Epub 2020 Dec 21.

Department of Dental Training, Ministry of Health, Manama, Kingdom of Bahrain.

What Is Known And Objectives: Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype-based warfarin dosing. We carried out a network meta-analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies.

Methods: Electronic records were searched for RCTs comparing genotype-based warfarin with traditional-dosing strategies. Read More

Pharmacotherapy 2021 Mar 21;41(3):265-276. Epub 2020 Dec 21.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

Introduction: Warfarin's narrow therapeutic index and high variability in dosage requirements make dosage selection critical. Genetic factors are known to impact warfarin dosage selection. The Hmong are a unique Asian subpopulation numbering over 278,000 in the United States whose participation in genetics-based research is virtually nonexistent. Read More

Br J Clin Pharmacol 2021 Apr 18;87(4):1717-1729. Epub 2020 Nov 18.

The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, United Kingdom.

Aims: Numerous algorithms have been developed to guide warfarin dosing and improve clinical outcomes. We reviewed the algorithms available for various populations and the covariates, performances and risk of bias of these algorithms.

Methods: We systematically searched MEDLINE up to 20 May 2020 and selected studies describing the development, external validation or clinical utility of a multivariable warfarin dosing algorithm. Read More

Indian J Thorac Cardiovasc Surg 2019 Oct 22;35(4):539-547. Epub 2019 Apr 22.

Department of Cardiothoracic and Vascular Surgery, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India.

Purpose: Vitamin K antagonists (VKAs), such as warfarin and acenocoumarol, exert their anti-coagulant effect by inhibiting the subunit 1 of vitamin K epoxide reductase complex (VKORC1). CYP2C9 is a hepatic drug-metabolizing enzyme in the CYP450 superfamily and is the primary metabolizing enzyme of warfarin. Three single nucleotide polymorphisms, two in the CYP2C9 gene, namely CYP2C9*2 and CYP2C9*3, and one in the VKORC1 gene (c. Read More

Front Pharmacol 2020 14;11:1041. Epub 2020 Jul 14.

Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, FL, United States.

Background: Tight monitoring of efficacy and safety of anticoagulants such as warfarin is imperative to optimize the benefit-risk ratio of anticoagulants in patients. The standard tests used are measurements of prothrombin time (PT), usually expressed as international normalized ratio (INR), and activated partial thromboplastin time (aPTT).

Objective: To leverage a previously developed quantitative systems pharmacology (QSP) model of the human coagulation network to predict INR and aPTT for warfarin and rivaroxaban, respectively. Read More

Front Pharmacol 2020 10;11:1014. Epub 2020 Jul 10.

Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.

Objectives: To verify the accuracy of the International Warfarin Pharmacogenetics Consortium (IWPC) algorithm, identify the effects of genetic and clinical factors on warfarin stable dose, and to establish a new warfarin stable dose prediction algorithm for the elderly Han-Chinese population under the guidance of pharmacogenetics.

Methods: According to the inclusion criteria, 544 non-valvular atrial fibrillation patients taking warfarin for anticoagulation treatment were enrolled. Data information of three groups including the whole population, people under 65 years old and over 65 years old were substituted into the IWPC algorithm respectively to verify its accuracy. Read More

J Clin Pharm Ther 2020 Dec 24;45(6):1466-1473. Epub 2020 Jul 24.

Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China.

What Is Known And Objective: Warfarin is an oral anticoagulant which has been widely used to treat and prevent thromboembolic events. Managing warfarin therapy requires careful monitoring and dose titration. This randomized controlled study was designed to assess the effect of genotype-guided warfarin anticoagulation in Chinese elderly patients with nonvalvular atrial fibrillation. Read More

Curr Med Res Opin 2020 09 28;36(9):1433-1439. Epub 2020 Jul 28.

Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China.

Objective: The sex, age, medical history, treatment, tobacco use, race risk (SAMe-TTR) Score; the sex, age, medical history, treatment, tobacco use, genotype combination (SAMe-TTG) Score; and the so-called modified SAMe-TTR scores have been proposed to predict the anticoagulation quality for patients with non-valvular atrial fibrillation (NVAF). The data from a prospective controlled study is used to validate the SAMe-TTR and SAMe-TTG scores in Chinese NVAF patients treated with warfarin and to evaluate the association of factors with time in therapeutic range (TTR) to predict the quality of oral anticoagulation control.

Methods: A total of 379 patients with NVAF under warfarin treatment for a three-month follow-up were included in this prospective, multicenter study. Read More

Pharmacogenomics 2020 08 19;21(12):863-870. Epub 2020 Jun 19.

Department of Electrocardiogram Room, 900 Hospital of The Joint Logistics Team, 156 North Road, West 2nd Ring Road, Fuzhou, Fujian, 350000, PR China.

This study was conducted to investigate the effects of , , and  and nongenetic factors on warfarin maintenance dose in a very elderly, frail Han-Chinese population.  16 variants of , , and were genotyped. Univariate analysis and multivariable regression model were performed for the associations of gene variants and warfarin maintenance dose. Read More

PLoS One 2020 19;15(5):e0233316. Epub 2020 May 19.

Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, United States of America.

Oral anticoagulant (OAC) therapy has been the main treatment approach for stroke prevention for decades. Warfarin is the most widely prescribed OAC in the United States, but is difficult to manage due to variability in dose requirements across individuals. Pharmacogenomics may mitigate risk concerns related to warfarin use by fostering the opportunity to facilitate individualized medicine approaches to warfarin treatment (e. Read More

Sci Rep 2020 04 24;10(1):6988. Epub 2020 Apr 24.

College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Korea.

This prospective, single-blind, randomized study was designed to evaluate the effect of genotype-based warfarin dosing compared with standard warfarin dosing in Korean patients with mechanical cardiac valves. Patients were assigned to either the genotype-based dosing group or the standard dosing group using stratified block randomization. The genotype-based dosing equation was adopted from a previous study which included VKORC1 rs9934438, CYP2C9 rs1057910, CYP4F2 rs2108622, and age. Read More

Front Pharmacol 2020 6;11:325. Epub 2020 Apr 6.

Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Santiago, Chile.

Background: Vitamin K antagonists (VKA) are used as prophylaxis for thromboembolic events in patients with cardiovascular diseases. The most common VKA are warfarin and acenocoumarol. These drugs have a narrow therapeutic margin and high inter-individual response variability due to clinical and pharmacogenetic variables. Read More

Clin Transl Sci 2020 09 9;13(5):941-949. Epub 2020 Apr 9.

Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Precise dosing of warfarin is important to achieve therapeutic benefit without adverse effects. Pharmacogenomics explains some interindividual variability in warfarin response, but less attention has been paid to drug-drug interactions in the context of genetic factors. We investigated retrospectively the combined effects of cytochrome P450 (CYP)2C9 and vitamin K epoxide reductase complex (VKORC)1 genotypes and concurrent exposure to CYP2C9-interacting drugs on long-term measures of warfarin anticoagulation. Read More

Clin Appl Thromb Hemost 2020 Jan-Dec;26:1076029620909154

Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Santiago, Chile.

Despite the development of new oral agents over the last decade, vitamin K antagonists (VKAs) remain the most widely used anticoagulants for treating and preventing thromboembolism worldwide. In Chile, the Ministry of Health indicates that acenocoumarol should be used in preference to any other coumarin. Complications of inappropriate dosing are among the most frequently reported adverse events associated with this medication. Read More

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2020 Apr;37(4):401-404

Qingdao Fuwai Cardiovascular Hospital, Qingdao, Shandong 266034, China.

Objective: To compare the accuracy of five warfarin-dosing algorithms and warfarin stable dose model (2.5 mg/day) for Shandong population.

Methods: One hundred and twenty five patients who achieved stable warfarin dose were enrolled. Read More

J Clin Pharm Ther 2020 Jun 13;45(3):547-560. Epub 2020 Mar 13.

Pharmaceutical Consultant, Gerrards Cross, UK.

What Is Known And Objective: Despite an apparently sound pharmacological basis, clinical studies of genotype-guided warfarin dosing have yielded mixed and conflicting results, leading to reluctance in its clinical implementation. The objective of this critique is to re-evaluate key warfarin pharmacogenetic studies with a view to explaining why this may be so.

Methods: Major widely-cited warfarin pharmacogenetic studies as well as recent meta-analyses were identified and a critical analysis of these was undertaken to identify factors that may account for poor clinical implementation of pre-treatment genotyping. Read More

Front Pharmacol 2019 17;10:1527. Epub 2020 Jan 17.

Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China.

The and genotypes are associated with anticoagulation control and the clinical events in warfarin therapy. However, the clinical utility of gene-based warfarin dosing (GBWD) is controversial. We compared the anticoagulation control and clinical events related to warfarin with GBWD to those with clinically fixed dosing (CFD). Read More

Pharmacogenomics J 2020 10 6;20(5):687-694. Epub 2020 Feb 6.

State Medical Academy, Nizhniy Novgorod, Russian Federation.

A total of 263 warfarin naive patients with indications to long-term anticoagulation were included in prospective multicenter study and randomized into Pharmacogenetics and Standard dosing groups. The loading warfarin dose in Pharmacogenetics group was calculated by Gage algorithm and corrected starting on day 5 of treatment according to INR. In Standard dosing group warfarin initial dose was 5 mg and starting on day 3 of treatment it was titrated according to INR. Read More

Pharmacogenomics 2020 03 24;21(4):257-267. Epub 2020 Jan 24.

Inter-University Centre for Genomics & Gene Technology, Department of Biotechnology, University of Kerala, Trivandrum-695 581, Kerala, India.

The role of mirSNPs in the 3'UTR of and genes that could influence warfarin dose variability via a discrete miRNA-mediated mechanism remains unexplained. Genotypic data in the 1000 Genomes dataset were analyzed for pair-wise linkage disequilibrium and allelic enrichment. MirSNP rs7294 in the 3'UTR of gene displayed varying strengths of linkage disequilibrium with rs9923231 and rs9934438 across populations, albeit consistently associated with higher warfarin dose requirements based on genome-wide association studies, meta-analysis and population-based association studies. Read More

Saudi J Biol Sci 2020 Jan 23;27(1):456-459. Epub 2019 Nov 23.

Department of Pharmacy Practice, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Saudi Arabia.

Warfarin doses are greatly affected by polymorphism altering cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) gene. This study evaluated the prevalence of alleles (either single or double) and carriers of single nucleotide polymorphisms (SNPs) in both genotypes CYP2C9 and VKORC1 in alkharj area, Saudi Arabia and its association with warfarin use risk. Total 112 samples were collected and genotyped using FlexiGene DNA Kit for isolation and StepOnePlus Real-Time PCR System by TaqMan allelic discrimination methods. Read More

Pharmacotherapy 2020 02 14;40(2):142-152. Epub 2020 Jan 14.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.

Objectives: Implementing pharmacogenetics for very important pharmacogenes (VIPs) holds the promise of improving clinical outcomes through optimal medication selection and dosing. However, significant differences in the frequency of actionable variants in VIPs may exist within subpopulations of a given ancestral group. Furthermore, these differences can potentially impact drug selection and dosing. Read More

Clin Pharmacol Ther 2020 06 28;107(6):1420-1433. Epub 2020 Jan 28.

Department of Molecular and Clinical Pharmacology, The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.

Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Read More

Ann Lab Med 2020 May;40(3):216-223

Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: Differences in the performance of suggested warfarin dosing algorithms among different ethnicities and genotypes have been reported; this necessitates the development of an algorithm with enhanced performance for specific population groups. Previous warfarin dosing algorithms underestimated warfarin doses in 1173C carriers. We aimed to develop and validate a new warfarin dosing algorithm for Korean patients with 1173C. Read More

Pharmacogenomics J 2020 04 25;20(2):277-284. Epub 2019 Oct 25.

Qatar University, Doha, Qatar.

The objective of this study is to estimate the prevalence of VKORC1, CYP2C9, and CYP4F2 genetic variants and their contribution to warfarin dose variability in Qataris. One hundred and fifty warfarin-treated Qatari patients on a stable dose and with a therapeutic INR for at least three consecutive clinic visits were recruited. Saliva samples were collected using Oragene DNA self-collection kit, followed by DNA purification and genotyping via TaqMan Real-Time-PCR assay. Read More