scholarly journals Pharmacokinetics and Pharmacogenetics of Apixaban

2020 ◽  
Vol 16 (5) ◽  
pp. 852-860
Author(s):  
A. V. Savinova ◽  
M. M. Petrova ◽  
N. A. Shnayder ◽  
E. N. Bochanova ◽  
R. F. Nasyrova
Keyword(s):  
Candidate Genes ◽  
Factor Xa ◽  
Potential Candidate ◽  
Beta Oxidation ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Vein Thrombosis ◽  
Genes Encoding ◽  
Deep Vein

Apixaban is oral anticoagulant, it is widely used in prevention of stroke in non-valvular atrial fibrillation and treatment of deep vein thrombosis and pulmonary embolism. Its main mechanism of action is through reversible inhibition of factor Xa. It specifically binds and inhibits both free and bound factor Xa which ultimately results in reduction in the levels of thrombin formation. Apixaban is mainly metabolized by CYP3A4 with minor contributions from CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP2J2 isoenzymes. Some of the major metabolic pathways of apixaban include o-demethylation, hydroxylation, and sulfation, with o-demethylapixabansulphate being the major metabolite. The aim of this review is analysis of associated researches of single nucleotide variants (SNV) of CYP3A5 and SULT1A1 genes and search for new candidate genes reflecting effectiveness and safety of apixaban. The search for full-text publications in Russian and English languages containing key words “apixaban”, “pharmacokinetics”, “effectiveness”, “safety” was carried out amongst literature of the past twenty years with the use of eLibrary, PubMed, Web of Science, OMIM data bases. Pharmacokinetics and pharmacogenetics of apixaban are considered in this review. The hypothesis about CYP и SULT1A enzymes influence on apixaban metabolism was examined. To date, numerous SNVs of the CYP3A5 and SULT1A1 genes have been identified, but their potential influence on pharmacokinetics apixaban in clinical practice needs to be further studies. The role of SNVs of other genes encoding beta-oxidation enzymes of apixaban (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2J2) and transporter proteins (ABCB1, ABCG2) in its efficacy and safety are not well understood, and ABCB1 and ABCG2 genes may be potential candidate genes for studies of the drug safety.

The Phenolyzer Suite: Prioritizing the Candidate Genes Involved in Microtia

2019 ◽  
Vol 128 (6) ◽  
pp. 556-562 ◽  
Author(s):  
Huang Xin ◽  
Wang Changchen ◽  
Liu Lei ◽  
Yang Meirong ◽  
Zhang Ye ◽  
...  
Keyword(s):  
Candidate Genes ◽  
High Throughput ◽  
Potential Candidate ◽  
Single Nucleotide Variants ◽  
Gene Score ◽  
Single Nucleotide ◽  
Research Directions ◽  
Score System ◽  
Pathogenic Genes ◽  
First Time

Objective: Microtia is a congenital malformation of the external ear. Great progress about the genetic of microtia has been made in recent years. This article was to prioritize the potential candidate pathogenic genes of microtia based on existing studies and reports, with the purpose of narrowing the range of following study scientifically and quickly. Method: A computational tool called Phenolyzer (phenotype-based gene analyzer) was used to prioritize microtia genes. Microtia, as a query term, was input in the interface of Phenolyzer. After several steps, including disease match, gene query, gene score system, seed gene growth, and gene ranking, the final results about genetic information of microtia were provided. Then we tracked details of the top 10 genes ranked by Phenolyzer on the basis of previous reports. Results: We detected 10 348 genes associated with microtia or related syndromes, and 78 genes of those genes belonged to seed genes. Every gene was given a score, and the gene with higher scores was more likely influence microtia. The top 10 ranked genes included HOXA2, CHD7, CDT1, ORC1, ORC4, ORC6, CDC6, MED12, TWIST1, and GLI3. Otherwise, four gene-gene interactions were displayed. Conclusion: This article prioritized candidate genes of microtia for the first time. High-throughput methods provide tens of thousands of single-nucleotide variants, indels, and structural variants, and only a handful are relevant to microtia or associated syndromes. Combine the ranked potential pathogenic genes list from Phenolyzer with the results of samples provided by high-throughput methods, and more precise research directions are presented.

scholarly journals New anticoagulants for the treatment of venous thromboembolism

2016 ◽  
Vol 42 (2) ◽  
pp. 146-154 ◽  
Author(s):  
Caio Julio Cesar dos Santos Fernandes ◽  
José Leonidas Alves Júnior ◽  
Francisca Gavilanes ◽  
Luis Felipe Prada ◽  
Luciana Kato Morinaga ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Vitamin K Antagonists ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Vein Thrombosis ◽  
New Anticoagulants ◽  
Acute Pulmonary Thromboembolism ◽  
Deep Vein

Worldwide, venous thromboembolism (VTE) is among the leading causes of death from cardiovascular disease, surpassed only by acute myocardial infarction and stroke. The spectrum of VTE presentations ranges, by degree of severity, from deep vein thrombosis to acute pulmonary thromboembolism. Treatment is based on full anticoagulation of the patients. For many decades, it has been known that anticoagulation directly affects the mortality associated with VTE. Until the beginning of this century, anticoagulant therapy was based on the use of unfractionated or low-molecular-weight heparin and vitamin K antagonists, warfarin in particular. Over the past decades, new classes of anticoagulants have been developed, such as factor Xa inhibitors and direct thrombin inhibitors, which significantly changed the therapeutic arsenal against VTE, due to their efficacy and safety when compared with the conventional treatment. The focus of this review was on evaluating the role of these new anticoagulants in this clinical context.

scholarly journals Pharmacokinetics and pharmacogenetics of edoxaban

2020 ◽  
pp. 26-35
Author(s):  
A.V. Savinova ◽  
◽  
M.M. Petrova ◽  
N.A. Shnayder ◽  
E.N. Bochanova ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Coagulation Factor ◽  
Reversible Inhibitor ◽  
Factor X ◽  
Efficacy And Safety ◽  
Vein Thrombosis ◽  
The Past ◽  
Genes Encoding ◽  
New Generation ◽  
Deep Vein

Edoxaban is a new generation of oral anticoagulant; it is selective, direct and reversible inhibitor of activated blood coagulation factor X (F Xa), serine protease responsible for thrombin formation. Edoxaban is used to prevent stroke in non-valvular atrial fibrillation, to treat deep vein thrombosis and pulmonary embolism. The purpose of the review is to analyze the associative studies of OHB of CYP3A4 / 5 and ABCB1 genes, as well as to search for new candidate genes reflecting the efficacy and safety of edoxaban. The search for full-text publications in Russian and English over the past two decades was carried out in eLibrary, PubMed, Web of Science, OMIM databases using the following keywords: edoxaban, pharmacokinetics, pharmacogenetics, efficacy, and safety. The review covers pharmacokinetics of edoxaban, as well as pharmacogenetic features of the drug metabolism in details. Candidate genes influencing concentration of edoxaban are genes encoding key enzymes of its metabolism – CES1, CYP3A4 / 5, ABCB1, and, to a lesser extent, SLCO1B1. By present day, numerous NVS of candidate genes have been identified. They potentially affect pharmacokinetics of edoxaban, but their role in real clinical practice requires further study

Pharmacokinetics and Pharmacogenetics of Dabigatran

2021 ◽  
Vol 17 (1) ◽  
pp. 146-152
Author(s):  
A. V. Savinova ◽  
V. S. Dobrodeeva ◽  
M. M. Petrova ◽  
R. F. Nasyrova ◽  
N. A. Shnayder
Keyword(s):  
Vitamin K Antagonists ◽  
Dabigatran Etexilate ◽  
Potential Candidate ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
The Past ◽  
Potential Candidate Gene ◽  
P Glycoprotein ◽  
Udp Glucuronosyltransferase

Dabigatran etexilate is a prodrug of dabigatran, a oral direct inhibitor of thrombin. Pharmacokinetics of dabigatran etexilate doesn’t have the disadvantages of vitamin K antagonists. However, pharmacokinetics and pharmacogenetics of dabigatran are variable. This can affect both effectiveness and safety of anticoagulant therapy. It is considered that CES1 enzyme and P-glycoprotein (CES1 and ABCB1 genes accordingly) play important role in pharmacokinetics of dabigatran etexilate. UDP-glucuronosyltransferase enzymes UGT2B15, UGT1A9, UGT2B7 (UGT2B15, UGT1A9, UGT2B7 genes accordingly) take part in the metabolism of active dabigatran. Presence of these gene’s single-nucleotide variants (SNV) can affect effectiveness and safety of dabigatran etexilate usage. The goal of this review is analysis of associated researches of SNV genes CES1 and ABCB1 and search for new candidate genes that reveal effectiveness and safety of dabigatran etexilate usage.Materials and methods. The search for full-text publications in Russian and English languages containing key words “dabigatran etexilate”, “dabigatran”, “pharmacokinetics”, “effectiveness”, “safety” was carried out amongst literature of the past twenty years with the use of eLibrary, PubMed, Web of Science, OMIM data bases. Pharmacokinetics and pharmacogenetics of dabigatran etexilate are considered in this review. The hypothesis about UDP-glucuronosyltransferase enzymes influence on dabigatran metabolism was examined. Nowadays more than 2000 SNV CES1 and ABCB1 genes are identified, but their potential influence on pharmacokinetics of dabigatran etexilate and its active metabolite (dabigatran) in clinical practice needs to be further researched. Role of SNV UDP-glucuronosyltransferase genes (UGT2B15, UGT1A9, UGT2B7) in dabigatran’s effectiveness and safety is not explored enough. However, UGT2B15 gene can be a potential candidate gene for research on safety of this drug.

scholarly journals Next-Generation Sequencing and In Vitro Expression Study of ADAMTS13 Single Nucleotide Variants in Deep Vein Thrombosis

PLoS ONE ◽  
2016 ◽  
Vol 11 (11) ◽  
pp. e0165665 ◽  
Author(s):  
Maria Teresa Pagliari ◽  
Luca A. Lotta ◽  
Hugoline G. de Haan ◽  
Carla Valsecchi ◽  
Gloria Casoli ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Next Generation Sequencing ◽  
Single Nucleotide Variants ◽  
Expression Study ◽  
Single Nucleotide ◽  
In Vitro Expression ◽  
Vein Thrombosis ◽  
Deep Vein ◽  
Generation Sequencing

The Possible Role of Platelet Coagulant Activities in the Pathogenesis of Venous Thrombosis

1975 ◽  
Vol 33 (03) ◽  
pp. 435-443 ◽  
Author(s):  
Peter N Walsh
Keyword(s):  
Deep Vein Thrombosis ◽  
Venous Thrombosis ◽  
Intrinsic Factor ◽  
Factor Xa ◽  
Clotting Factors ◽  
Platelet Factor ◽  
Platelet Surface ◽  
Vein Thrombosis ◽  
Deep Vein

SummaryRecent studies of the role of platelets in blood coagulation have shown that platelets can trigger intrinsic coagulation by two alternative pathways, protect platelet-associated active clotting factors from inactivation by plasma inhibitors and catalyze intrinsic coagulation reactions on the platelet surface to form fibrin. These platelet coagulant activities (i.e., contact product forming activity, collagen-induced coagulant activity, intrinsic factor-Xa forming activity and platelet factor 3 activity) were found to be increased in patients with deep vein thrombosis developing after hip surgery, in patients with established retinal vein thrombosis and in patients with established deep vein thrombosis. It is suggested that increases in platelet coagulant activities concerned with triggering and catalyzing intrinsic coagulation reactions may play a role in the pathogenesis of venous thrombosis.

scholarly journals Candidate genes involved in the development of antipsychotic-induced tardive dyskinesia in patients with schizophrenia

2020 ◽  
Vol 10 (3) ◽  
pp. 10-26
Author(s):  
E. E. Vaiman ◽  
N. A. Shnayder ◽  
N. G. Neznanov ◽  
R. F. Nasyrova
Keyword(s):  
Tardive Dyskinesia ◽  
Candidate Genes ◽  
Side Reaction ◽  
Single Nucleotide Variants ◽  
Antipsychotic Therapy ◽  
Drug Induced ◽  
Single Nucleotide ◽  
Genetic Characteristics ◽  
Genes Encoding ◽  
Undesirable Side Reaction

Introduction. Drug-induced dyskinesia is an iatrogenic undesirable side reaction from the extrapyramidal system that occurs during the administration of drugs, most often antipsychotics in patients with schizophrenia. At the end of the 20 th century, studies were conducted on the search for candidate genes and the carriage of single nucleotide variants of antipsychotics-induced tardive dyskinesia. Purpose of the study – to analyze research results reflecting candidate genes and their single nucleotide variants associated with antipsychotic-induced tardive dyskinesia. Materials and methods. We searched for full-text publications in Russian and English in the eLIBRARY, PubMed, Web of Science, Springer databases using keywords (tardive dyskinesia, drug-induced tardive dyskinesia, antipsychotics, antipsychotics, typical antipsychotics, atypical antipsychotics, genes, polymorphisms) and combined searches for words over the past decade. Results. The lecture discusses candidate genes encoding proteins/enzymes involved in the pharmacodynamics and pharmacokinetics of antipsychotics Conclusion. Timely identification of individual genetic characteristics of the patient can contribute to the development of diagnostic test systems and in the future selection of the safest and most effective antipsychotic therapy.

Rare Coding Single Nucleotide Variants of ADAMTS13 Are Associated with Deep Vein Thrombosis in a Next-Generation Sequencing Association Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 107-107
Author(s):  
Luca Andrea Lotta ◽  
Giacomo Tuana ◽  
Jin Yu ◽  
Ida Martinelli ◽  
Mark Wang ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Allele Frequency ◽  
Genomic Dna ◽  
Low Frequency ◽  
Adamts13 Activity ◽  
Single Nucleotide Variants ◽  
Base Pairs ◽  
Single Nucleotide ◽  
Vein Thrombosis ◽  
Deep Vein

Abstract Abstract 107 The considerable genetic predisposition to deep vein thrombosis (DVT) is only partially accounted for by known genetic risk variants. Genome-wide association studies investigating hundreds of thousands of common single nucleotide variants (SNVs) identified a number of associations, but missing heritability remains. Rare (i.e. minor allele frequency below 1%) and low-frequency (i.e. minor allele frequency below 5%) SNVs of the coding area may be responsible for at least part of this missing heritability. In order to investigate this, we sequenced 700,000 base pairs of genomic DNA including the protein coding exons and intron-exon boundaries of 186 hemostatic/pro-inflammatory genes. Indexed genomic DNA libraries were co-captured on NimbleGen HD2 2.1M-probe chips and capture products were sequenced on SOLiD 4 platforms. More than 70 billion base-pairs of raw sequence data were produced to sequence the target area with a median redundancy of 45X in 94 thrombophilia-negative patients with DVT and 98 controls. Most of the 4366 SNVs identified were rare, novel and nonsynonymous indicating pathogenetic potential. We tested the association of coding SNVs in the ADAMTS13 and VWF genes, encoding two interconnected proteins with fundamental roles in hemostasis. Sequencing of the two genes yielded 109 variants, 108 SNVs and a c.8241_8442del frameshift deletion in exon 51 of VWF. Being a carrier of rare coding (prevalence in DVT: 17% [n=16]; prevalence in controls 4% [n=4]; odds ratio [OR]: 4.8; 95% confidence interval [CI]: 1.6–15.0), rare nonsynonymous (prevalence in DVT: 11% [n=10]; prevalence in controls 3% [n=3]; OR: 3.8; 95% CI: 1.0–14.2) or low-frequency coding (prevalence in DVT: 36% [n=34]; prevalence in controls 23% [n=23]; OR: 1.9; 95% CI: 1.0–3.5) SNVs of ADAMTS13 was associated with DVT. Carrying rare or low-frequency SNVs of VWF was not associated with DVT. The 11 different rare missense variants of ADAMTS13 found in DVT patients had never been described in association with congenital thrombotic thrombocytopenic purpura. Patients carrying at least one ADAMTS13 mutation of the categories associated with DVT had lower plasmatic levels of ADAMTS13 activity compared to patients without mutations. The change in ADAMTS13 activity was −7% (95% CI: −24 to 10%) for patients with rare coding ADAMTS13 mutations, −12% (95% CI: −30 to 6%) for patients with rare nonsynonymous mutations and −29% (95% CI: −52 to −6%) for patients with missense mutations predicted to be damaging for protein function by SIFT. Our results uncover for the first time a link between ADAMTS13, an important regulator of hemostasis implicated in microvascular thrombosis, and DVT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258675
Author(s):  
Maria Teresa Pagliari ◽  
Andrea Cairo ◽  
Marco Boscarino ◽  
Ilaria Mancini ◽  
Emanuela Pappalardo ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Low Frequency ◽  
Activity Levels ◽  
Adamts13 Activity ◽  
Common Variants ◽  
Single Nucleotide Variants ◽  
Variable Threshold ◽  
Vein Thrombosis ◽  
Deep Vein

Background We previously described the association between rare ADAMTS13 single nucleotide variants (SNVs) and deep vein thrombosis (DVT). Moreover, DVT patients with at least one rare ADAMTS13 SNV had a lower ADAMTS13 activity than non-carriers. Aims To confirm ADAMTS13 variants association with DVT and reduced plasma ADAMTS13 activity levels in a larger population. To investigate the role of VWF and F8 variants. Methods ADAMTS13, VWF and F8 were sequenced using next-generation sequencing in 594 Italian DVT patients and 571 controls. Genetic association testing was performed using logistic regression and gene-based tests. The association between rare ADAMTS13 variants and the respective plasmatic activity, available for 365 cases and 292 controls, was determined using linear regression. All analyses were age-, sex- adjusted. Results We identified 48 low-frequency/common and 272 rare variants. Nine low-frequency/common variants had a P<0.05, but a false discovery rate between 0.06 and 0.24. Of them, 7 were found in ADAMTS13 (rs28641026, rs28503257, rs685523, rs3124768, rs3118667, rs739469, rs3124767; all protective) and 2 in VWF (rs1800382 [risk], rs7962217 [protective]). Rare ADAMTS13 variants were significantly associated with DVT using the burden, variable threshold (VT) and UNIQ (P<0.05), but not with C-ALPHA, SKAT and SKAT-O tests. Rare VWF and F8 variants were not associated with DVT. Carriers of rare ADAMTS13 variants had lower ADAMTS13 activity than non-carriers (ß -6.2, 95%CI -11,-1.5). This association was stronger for DVT patients than controls (ß -7.5, 95%CI -13.5,-1.5 vs. ß -2.9, 95%CI -10.4,4.5). Conclusions ADAMTS13 and VWF low-frequency/common variants mainly showed a protective effect, although their association with DVT was not confirmed. DVT patients carrying a rare ADAMTS13 variants had slightly reduced ADAMTS13 activity levels, but a higher DVT risk. Rare VWF and FVIII variants were not associated with DVT suggesting that other mechanisms are responsible for the high VWF and FVIII levels measured in DVT patients.

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